4-(2-(dimethylamino)-2-oxoethyl)-3-methyl-5-OXO-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide compounds and uses thereof

Abstract

Disclosed herein are substituted novel 4-(2-(dimethylamino) -2-oxoethyl)-3-methyl-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide compounds of Formula (I), and pharmaceutically acceptable salts thereof. Further disclosed herein are pharmaceutical compositions comprising 4-(2-( di methylamino ) -2-oxoethyl)-3-methyl-5-oxo-2, 3,4, 5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide compounds or pharmaceutically acceptable salts thereof. In some embodiments, the compounds disclosed herein can be used to treat an inflammatory disease or endothelial dysfunction.

Description

[0001] PC073176A

[0002] 4-(2-(D I M ETHYLAM INO)-2-OXOETHYL)-3-M ETHYL-5-OXO-2, 3,4,5- TETRAHYDROBENZOFURO[2,3-f][1,4]OXAZEPINE-3-CARBOXAMIDE COMPOUNDS AND USES THEREOF

[0003] BACKGROUND KLF2 is a transcription factor that plays an essential role in the vascular system as it is required for the atheroprotective effects of laminar shear stress and is reduced in the blood of patients with atherosclerosis. Activation of KLF2 in patients with atherosclerosis may alleviate inflammation, thrombosis, reduce oxidative stress and increase vascular tone therefore providing a potential treatment for vascular indications, for example cardiovascular disease.

[0004] SUMMARY OF THE INVENTION

[0005] The present disclosure provides, in part, a compound of Formula I:

[0006]

[0007] Formula I,

[0008] or a pharmaceutically acceptable salt thereof, wherein:

[0009] =========is a single bond or a double bond;

[0010] X is O or N;

[0011] Y is CR2or O;

[0012] R1and R2is each independently H, C1-6alkyl, or C1-6haloalkyl, wherein at least one of R1and R2is C1-6alkyl or C1-6haloalkyl;

[0013] R3, R4, and R9is each independently C1-6alkyl or C1-6cycloalkyl; or R3and R4together with the nitrogen atom to which R3and R4are bound form a ring; and

[0014] R5, R6, R7, and R8is each independently H or C1-6alkoxy.

[0015] In some embodiments, disclosed herein is a compound that is (3R)-4-[2-(dimethylamino)-2-oxoethyl]-N-[(3-methoxypyridin-2-yl)methyl]-3-methyl-8-(4-methyl-1,3-oxazol-2-yl)-5-oxo-2,3,4,5-tetrahydro[1]benzofuro[2,3-f][1,4]oxazepine-3-carboxamide; (3R)-4-[2-(dimethylamino)-2-oxoethyl]-N-[(3-ethoxypyridin-2-yl)methyl]-3-methyl-5-oxo-8-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-2,3,4,5-tetrahydro[1]benzofuro[2,3-f][1,4]oxazepine-3-carboxamide; or (3R)-4-[2-(Dimethylamino)-2-oxoethyl]-N-[(3-methoxypyridin-2-yl)methyl]-3-methyl-5-oxo-8-[4-(trifluoromethyl)-1,3-oxazol-2-yl]-2,3,4,5-tetrahydro[1]benzofuro[2,3-f][1,4]oxazepine-3-carboxamide, or a pharmaceutically acceptable salt thereof.In some embodiments, disclosed herein is a pharmaceutical composition comprising the compound according to Formula I, la, la’, lb, or lb’, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0016] In one embodiment, disclosed herein is a method of treating a condition comprising administering to a subject in need thereof a therapeutically effective amount of the compound of Formula I, la, la’, lb, or lb’, or a pharmaceutically acceptable salt thereof. In one embodiment, disclosed herein is a compound of Formula I, la, la’, lb, or lb’, or a pharmaceutically acceptable salt thereof, for use as a medicament. In one embodiment, disclosed herein is a compound of Formula I, la, la’, lb, or lb’, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition selected from the group consisting of atherosclerosis, coronary artery disease, stroke, peripheral arterial disease, coronary microvascular disease, angina, systemic hypertension, pulmonary arterial hypertension, heart failure, a diabetic microvascular disease, an inflammatory disease, and an infectious disease. In one embodiment, disclosed herein is a use of a compound of Formula I, la, la’, lb, or lb’, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a condition selected from the group consisting of atherosclerosis, coronary artery disease, stroke, peripheral arterial disease, coronary microvascular disease, angina, systemic hypertension, pulmonary arterial hypertension, heart failure, a diabetic microvascular disease, chronic kidney disease (CKD), diabetic kidney disease (DKD), an inflammatory disease, and an infectious disease.

[0017] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the disclosure, as claimed.

[0018] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 illustrates the assay scheme for the KLF2 Hibit Assay.

[0019] DETAILED DESCRIPTION

[0020] The vascular endothelium is an important regulator of vascular integrity and vascular homeostasis. Dysfunction of the vascular endothelium, including vasoconstriction, impaired vasoreactivity, inflammation, thrombosis, altered barrier permeability and loss of vascular quiescence, is a key driver of many vascular diseases. Kruppel-like Factor 2 (KLF2) is a shear stress-induced transcription factor that may confer anti-inflammatory and / or anti-thrombotic properties to vascular endothelial cells. KLF2 is a key regulator of activation, differentiation, and migration processes in various immune cell types including monocytes, macrophages, neutrophils, T lymphocytes, B lymphocytes and natural killer cells. Accordingly, compounds that induce KLF2 may be useful for maintaining vascular health or for treating vascular or inflammatory conditions. Disclosed herein are compounds that can induce KLF2, and can be used to treat a condition, for example, a condition selected from the group consisting of atherosclerosis, coronary artery disease, stroke, peripheral arterial disease, coronary microvascular disease, angina, systemic hypertension, pulmonary arterial hypertension, heartfailure, a diabetic microvascular disease, chronic kidney disease (CKD), diabetic kidney disease (DKD), an inflammatory disease, and an infectious disease

[0021] The present disclosure may be understood more readily by reference to the following detailed description of the embodiments of the disclosure and the Examples included herein. It is to be understood that this disclosure is not limited to specific synthetic methods of making that may of course vary. It is to be also understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting.

[0022] Definitions

[0023] Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure have the meanings that are commonly understood by those of ordinary skill in the art. The disclosure described herein suitably may be practiced in the absence of any element(s) not specifically disclosed herein.

[0024] “Compounds of the disclosure” include compounds of Formula I, la, la’, lb, or lb’ and the novel intermediates used in the preparation thereof. One of ordinary skill in the art will appreciate that compounds of the disclosure include conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemic, diastereomeric and other mixtures of such isomers, tautomers thereof, where they may exist. One of ordinary skill in the art will also appreciate that compounds of the disclosure include solvates, hydrates, isomorphs, polymorphs, esters, salt forms, prodrugs, and isotopically labelled versions thereof (including deuterium substitutions), where they may be formed.

[0025] As used herein, the singular form "a", "an", and "the" include plural references unless indicated otherwise. For example, "a" substituent includes one or more substituents.

[0026] As used herein, the term “about” when used to modify a numerically defined parameter means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter. For example, a dose of about 5 mg means 5% ± 10%, i.e., it may vary between 4.5 mg and 5.5 mg.

[0027] If substituents are described as being “independently” selected from a group, each substituent is selected independent of the other. Each substituent therefore may be identical to or different from the other substituent(s).

[0028] “Halogen” or “halo” refers to fluoro, chloro, bromo and iodo (F, Cl, Br, I).

[0029] " Alkyl" refers to a saturated, monovalent aliphatic hydrocarbon radical that has a specified number of carbon atoms, including straight chain or branched chain groups. Alkyl groups may contain, but are not limited to, 1 to 12 carbon atoms (“C1-C12 alkyl”), 1 to 8 carbon atoms (“C1-C8 alkyl”), 1 to 6 carbon atoms (“C1-C6 alkyl”), 1 to 5 carbon atoms (“C1-C5 alkyl”), 1 to 4 carbon atoms (“C1-C4 alkyl”), 1 to 3 carbon atoms (“C1-C3 alkyl”), or 1 to 2 carbon atoms (“C1-C2 alkyl”). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, and the like. Alkyl groups may be optionally substituted, unsubstituted or substituted, as furtherdefined herein. In some instances, substituted alkyl groups are specifically named by reference to the substituent group. For example, “haloalkyl” refers to an alkyl group having the specified number of carbon atoms that is substituted by one or more halo substituents, up to the available valence number.

[0030] “Haloalkyl” refers to an alkyl group as defined above containing the specified number of carbon atoms wherein at least one hydrogen atom has been replaced by halogen. Haloalkyl groups man contain, but are not limited to, 1-6 carbon atoms (“C1-C6 haloalkyl”), 1-4 carbon atoms (“C1-C4 haloalkyl”), or 1-2 carbon atoms (“C1-C2 haloalkyl”). More specifically, fluorinated alkyl groups may be specifically referred to as “fluoroalkyl.”

[0031] “Fluoroalkyl” refers to an alkyl group, as defined herein, wherein from one to all of the hydrogen atoms of the alkyl group are replaced by fluoro atoms. Examples include, but are not limited to, fluoromethyl, difluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and tetrafluoroethyl. Examples of fully substituted fluoroalkyl groups (also referred to as perfluoroalkyl groups) include trifluoromethyl (-CF3) and pentafluoroethyl (-C2F5).

[0032] “Alkoxy” refers to an alkyl group, as defined herein, that is single bonded to an oxygen atom. The attachment point of an alkoxy radical to a molecule is through the oxygen atom. An alkoxy radical may be depicted as alkyl-O-. Alkoxy groups may contain, but are not limited to, 1 to 8 carbon atoms (“C1-C8 alkoxy”), 1 to 6 carbon atoms (“C1-C6 alkoxy”), 1 to 4 carbon atoms (“C1-C4 alkoxy”), or 1 to 3 carbon atoms (“C1-C3 alkoxy”). Alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isobutoxy, and the like.

[0033] The term “pharmaceutically acceptable” means the substance (e.g., the compounds described herein) and any salt thereof, or composition containing the substance or salt of the disclosure is suitable for administration to a subject or patient.

[0034] A "pharmaceutical composition" refers to a mixture of one or more of the compounds of the disclosure, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof as an active ingredient, and at least one pharmaceutically acceptable excipient.

[0035] “Deuterium enrichment factor” as used herein means the ratio between the deuterium abundance and the natural abundance of deuterium, each relative to hydrogen abundance. An atomic position designated as having deuterium typically has a deuterium enrichment factor of, in particular embodiments, at least 1000 (15% deuterium incorporation), at least 2000

[0036] (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation)." Excipient" as used herein describes any ingredient other than the compound(s) of the disclosure. The choice of excipient will to a large extent depend on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0037] As used herein, "excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, carriers, diluents and the like that are physiologically compatible. Examples of excipients include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof, and may include isotonic agents, for example, sugar, sodium chloride, or polyalcohol such as mannitol, or sorbitol in the composition. Examples of excipients also include various organic solvents (such as hydrates and solvates). The pharmaceutical compositions may, if desired, contain additional excipients such as flavorings, binders / binding agents, lubricating agents, disintegrants, sweetening or flavoring agents, coloring matters or dyes, and the like. For example, for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Non-limiting examples of excipients, therefore, also include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with additional excipients such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

[0038] Examples of excipients also include pharmaceutically acceptable substances such as wetting agents or minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives, or buffers, which enhance the shelf life or effectiveness of the compound.

[0039] The term "treating", "treat" or "treatment" as used herein embraces both preventative, i.e., prophylactic, and palliative treatment, i.e., relieve, alleviate, or slow the progression of the patient’s disease (or condition) or any tissue damage associated with the disease.

[0040] As used herein, the term, “subject, “individual” or “patient,” used interchangeably, refers to any animal, including mammals. Mammals according to the disclosure include canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, humans and the like, and encompass mammals in utero. In an embodiment, humans are suitable subjects. Human subjects may be of any gender and at any stage of development.As used herein, the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which may include one or more of the following:

[0041] (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease;

[0042] (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting (or slowing) further development of the pathology or symptomatology or both); and

[0043] (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology or symptomatology or both).

[0044] Compounds of the disclosure

[0045] The vascular endothelium is an important regulator of vascular integrity and vascular homeostasis. Dysfunction of the vascular endothelium, including vasoconstriction, impaired vasoreactivity, inflammation, thrombosis, altered barrier permeability and loss of vascular quiescence, is a key driver of many vascular diseases. Kruppel-like Factor 2 (KLF2) is a shear stress- induced transcription factor that may confer anti-inflammatory and / or anti-thrombotic properties to vascular endothelial cells. KLF2 is a key regulator of activation, differentiation, and migration processes in various immune cell types including monocytes, macrophages, neutrophils, T lymphocytes, B lymphocytes and natural killer cells. Accordingly, compounds that induce KLF2 may be useful for maintaining vascular health or for treating vascular or inflammatory conditions.

[0046] In some embodiments, the compound is of Formula I:

[0047]

[0048] Formula I,

[0049] or a pharmaceutically acceptable salt thereof, wherein:

[0050] =======is a single bond or a double bond;

[0051] X is O or N;Y is CR2or O;

[0052] R1and R2is each independently H, C1-6alkyl, or C1-6haloalkyl, wherein at least one of R1and R2is C1-6alkyl or C1-6haloalkyl;

[0053] R3, R4, and R9is each independently C1-6alkyl or C1-6cycloalkyl; or R3and R4together with the nitrogen atom to which R3and R4are bound form a ring; and

[0054] R5, R6, R7, and R8is each independently H or C1-6alkoxy.

[0055] In some embodiments, the compound has the Formula I, or a pharmaceutically acceptable salt thereof, wherein X is O and Y is CR2.

[0056] In some embodiments, the compound has the Formula I, or a pharmaceutically acceptable salt thereof, wherein X is N and Y is O.

[0057] In some embodiments, the compound has the Formula I, or a pharmaceutically acceptable salt thereof, wherein R3, R4, and R9is each independently C1-6alkyl. In some embodiments, the compound has the Formula I, or a pharmaceutically acceptable salt thereof, wherein R9is C1-6cycloalkyl. In some embodiments, the compound has the Formula I, or a pharmaceutically acceptable salt thereof, wherein R3and R4together with the nitrogen atom to which R3and R4are bound form a heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted.

[0058] In some embodiments, the compound has the Formula la:

[0059]

[0060] Formula la,

[0061] or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, the compound has the Formula la’:

[0063]

[0064] Formula la’,

[0065] or a pharmaceutically acceptable salt thereof.

[0066] In some embodiments, the compound has the Formula I, la, or la’, or a pharmaceutically acceptable salt thereof, wherein R1and R2is each independently H, C1-3alkyl, or C1-3haloalkyl. In some embodiments, the compound has the Formula I, la, or la’, or a pharmaceutically acceptable salt thereof, wherein R1and R2is each independently H, methyl, or CF3.

[0067] In some embodiments, the compound has the Formula lb:

[0068]

[0069] Formula lb,

[0070] or a pharmaceutically acceptable salt thereof.

[0071] In some embodiments, the compound has the Formula lb’:

[0072]

[0073] Formula lb’,

[0074] or a pharmaceutically acceptable salt thereof.

[0075] In some embodiments, the compound has the Formula lb or lb’, or a pharmaceutically acceptable salt thereof, wherein R1is H, C1-3alkyl, or C1-3haloalkyl. In some embodiments, the compound has the Formula lb or lb’, or a pharmaceutically acceptable salt thereof, wherein R1is H, methyl, or CF3.

[0076] In some embodiments, the compound is (3R)-4-[2-(dimethylamino)-2-oxoethyl]-N-[(3-methoxypyridin-2-yl)methyl]-3-methyl-8-(4-methyl-1,3-oxazol-2-yl)-5-oxo-2, 3,4,5-tetrahydro[1]benzofuro[2,3-f][1,4]oxazepine-3-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure:H3C-O

[0077]

[0078] In some embodiments, the compound is (3R)-4-[2-(dimethylamino)-2-oxoethyl]-N-[(3-ethoxypyridin-2-yl)methyl]-3-methyl-5-oxo-8-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-2,3,4,5-tetrahydro[1]benzofuro[2,3-f][1,4]oxazepine-3-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure:

[0079]

[0080] In some embodiments, the compound is (3R)-4-[2-(Dimethylamino)-2-oxoethyl]-N-[(3-methoxypyridin-2-yl)methyl]-3-methyl-5-oxo-8-[4-(trifluoromethyl)-1, 3-oxazol-2-yl]-2, 3,4,5-tetrahydro[1]benzofuro[2,3-f][1,4]oxazepine-3-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure:

[0081]

[0082] Pharmaceutically Acceptable Salts

[0083] Salts encompassed within the term “pharmaceutically acceptable salts” refer to the compounds of this disclosure which are generally prepared by reacting the free base or free acid with a suitable organic or inorganic acid, or a suitable organic or inorganic base, respectively, to provide a salt of the compound of the disclosure that is suitable for administration to a subject or patient.

[0084] In addition, the compounds of Formula I, la, la’, lb, or lb’ may also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, which may be useful as intermediates for one or more of the following: 1) preparing compounds of Formula I,la, la’, lb, or lb’; 2) purifying compounds of Formula I, la, la’, lb, or lb’; 3) separating enantiomers of compounds of Formula I, la, la’, lb, or lb’; or 4) separating diastereomers of compounds of Formula I, la, la’, lb, or lb’.

[0085] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include, but are not limited to, acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, 1,5-naphathalenedisulfonic acid and xinofoate salts.

[0086] Suitable base salts are formed from bases which form non-toxic salts. Examples include, but are not limited to aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

[0087] Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts.

[0088] For a review on suitable salts, see PAULEKUHN, G. S., et al., “Trends in Active Pharmaceutical Ingredient Salt Selection Based on Analysis of the Orange Book Database,” Journal of Medicinal Chemistry, 2007, 50(26):6665-6672.

[0089] Pharmaceutically acceptable salts of compounds of the disclosure may be prepared by methods well known to one skilled in the art, including but not limited to the following procedures (i) by reacting a compound of the disclosure with the desired acid or base;

[0090] (ii) by removing an acid- or base-labile protecting group from a suitable precursor of a compound of the disclosure or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or

[0091] (iii) by converting one salt of a compound of the disclosure to another. This may be accomplished by reaction with an appropriate acid or base or by means of a suitable ion exchange procedure.

[0092] These procedures are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.

[0093] Solvates

[0094] The compounds of the disclosure, and pharmaceutically acceptable salts thereof, may exist in unsolvated and solvated forms. The term ‘solvate’ is used herein to describe a molecular complex comprising the compound of the disclosure, or a pharmaceutically acceptable saltthereof, and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term ‘hydrate’ is employed when said solvent is water.

[0095] In addition, the compounds of Formula I, la, la’, lb, or lb’ may also include other solvates of such compounds which are not necessarily pharmaceutically acceptable solvates, which may be useful as intermediates for one or more of the following: 1) preparing compounds of Formula I, la, la', lb, or lb'; 2) purifying compounds of Formula I, la, la’, lb, or lb’; 3) separating enantiomers of compounds of Formula I, la, la’, lb, or lb’; or 4) separating diastereomers of compounds of Formula I, la, la’, lb, or lb’.

[0096] A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see BRITTAIN, H. G. Polymorphism in Pharmaceutical Solids. 2ndEd. CRC Press, 2009. Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion.

[0097] When the solvent or water is tightly bound, the complex may have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water / solvent content may be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

[0098] Complexes

[0099] Also included within the scope of the disclosure are multi-component complexes (other than salts and solvates) wherein the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drughost inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, for example, hydrogen bonded complex (cocrystal) may be formed with either a neutral molecule or with a salt. Co-crystals may be prepared by melt crystallization, by recrystallization from solvents, or by physically grinding the components together - see ALMARSSON, O. and ZAWOROTKO, M. J., “Crystal engineering of the composition of pharmaceutical phases. Do pharmaceutical co-crystals represent a new path to improved medicines?,” Chemical Communications, 2004, 17:1889-1896. For a general review of multicomponent complexes, see HALEBLIAN, J. K., “Characterization of habits and crystalline modification of solids and their pharmaceutical applications,” Journal of Pharmaceutical Sciences, 1975, 64(8): 1269-1288.

[0100] Solid form

[0101] The compounds of the disclosure may exist in a continuum of solid states ranging from amorphous to crystalline. The term ‘amorphous’ refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physicalproperties of a solid or a liquid. Typically, such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order (‘glass transition’). The term ‘crystalline’ refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order (‘melting point’).

[0102] The compounds of the disclosure may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution) and consists of two dimensional order on the molecular level. Mesomorphism arising as the result of a change in temperature is described as ‘thermotropic’ and that resulting from the addition of a second component, such as water or another solvent, is described as ‘lyotropic’. Compounds that have the potential to form lyotropic mesophases are described as ‘amphiphilic’ and consist of molecules which possess an ionic (such as -COONa+, -COOK+, or -SO3-Na+) or non-ionic (such as -N+(CH3)3) polar head group. For more information, see HARTSHORNE, N. H. and STUART, A., Crystals and the Polarizing Microscope. 4thEd. London, Edward Arnold, 1970.

[0103] Stereoisomers

[0104] Compounds of the disclosure may exist as two or more stereoisomers. Stereoisomers of the compounds may include c / s and trans isomers (geometric isomers), optical isomers such as R and S enantiomers, diastereomers, rotational isomers, atropisomers, and conformational isomers. For example, compounds of the disclosure containing one or more asymmetric carbon atoms may exist as two or more stereoisomers. Cis / trans isomers may also exist for saturated rings.

[0105] The pharmaceutically acceptable salts of compounds of the disclosure may also contain a counterion which is optically active (e.g., d-lactate or l-lysine) or racemic (e.g., dl-tartrate or dl-arginine).

[0106] Cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

[0107] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where a compound of the disclosure contains an acidic or basic moiety, a base or acid such as 1 -phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography, fractional crystallization, or by using both of said techniques, and one or both of thediastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person. Chiral compounds of the disclosure (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC Concentration of the eluate affords the enriched mixture. Chiral chromatography using sub-and supercritical fluids may be employed. Methods for chiral chromatography useful in some embodiments of the present disclosure are known in the art (see, for example, SMITH, R. M., Supercritical Fluid Chromatography with Packed Columns. 1stEd. RSC Chromatography Monographs, 1988.

[0108] When any racemate crystallizes, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two crystal forms are produced in equimolar amounts each comprising a single enantiomer. While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, ELIEL, E. L. and WILEN, S. H., Stereochemistry of Organic Compounds. 1stEd. New York, Wiley, 1994.

[0109] Tautomerism

[0110] Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism (‘tautomerism’) may occur. This may take the form of proton tautomerism in compounds of the disclosure containing, for example, an imino / amino, keto / enol, or oxime / nitroso group, lactam / lactim or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.

[0111] It must be emphasized that while, for conciseness, the compounds of the disclosure have been drawn herein in a single tautomeric form, all possible tautomeric forms are included within the scope of the disclosure.

[0112] Isotopes

[0113] The present disclosure includes all pharmaceutically acceptable isotopically-labeled compounds of the disclosure wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.

[0114] Examples of isotopes suitable for inclusion in the compounds of the disclosure may include isotopes of hydrogen, such as2H (D, deuterium) and3H (T, tritium), carbon, such as11C,13C and14C, chlorine, such as36CI, fluorine, such as18F, iodine, such as123l and125l, nitrogen, such as13N and15N, oxygen, such as15O,17O and18O, phosphorus, such as32P, and sulfur, such as35S.

[0115] Certain isotopically-labelled compounds of the disclosure, for example those incorporating a radioactive isotope, are useful in one or both of drug or substrate tissuedistribution studies. The radioactive isotopes, such as, tritium and14C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with positron emitting isotopes, such as,11C,18F,15O and13N, may be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Substitution with deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements, reduced CYP450 inhibition (competitive or time dependent), or an improvement in therapeutic index or tolerability.

[0116] In some embodiments, the disclosure provides deuterium-labeled (or deuterated) compounds and salts, where the formula and variables of such compounds and salts are each and independently as described herein. “Deuterated” means that at least one of the atoms in the compound is deuterium in an abundance that is greater than the natural abundance of deuterium (typically approximately 0.015%). A skilled artisan recognized that in chemical compounds with a hydrogen atom, the hydrogen atom actually represents a mixture of H and D, with about 0.015% being D. The concentration of the deuterium incorporated into the deuterium-labeled compounds and salt of the disclosure may be defined by the deuterium enrichment factor. It is understood that one or more deuterium may exchange with hydrogen under physiological conditions.

[0117] In some embodiments, one or more hydrogen atoms on certain metabolic sites on the compounds of the disclosure are deuterated. Isotopically-labeled compounds of the disclosure may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

[0118] Pharmaceutically acceptable solvates in accordance with the disclosure include those wherein the solvent of crystallization may be isotopically substituted, e.g., D2O, d6-acetone, d6-DMSO.

[0119] Prodrugs

[0120] A compound of the disclosure may be administered in the form of a prodrug. Thus, certain derivatives of a compound of the disclosure which may have little or no pharmacological activity themselves may, when administered into or onto the body, be converted into a compound of the disclosure having the desired activity, for example by hydrolytic cleavage, particularly hydrolytic cleavage promoted by an esterase or peptidase enzyme. Such derivatives are referred to as ‘prodrugs’. Further information on the use of prodrugs may be found in RAUTIO, J., et al., “The expanding role of prodrugs in contemporary drug design and development,” Nature Reviews Drug Discovery, 2018, 17(8):559-587.

[0121] Prodrugs in accordance with the disclosure may, for example, be produced by replacing appropriate functionalities present in compounds of the disclosure with certain moieties known tothose skilled in the art as ‘pro-moieties’ as described, for example, in BUNDGAARD, H., Design of Prodrugs. New York, Elsevier, 1985.

[0122] Thus, a prodrug in accordance with the disclosure may be (a) an ester or amide derivative of a carboxylic acid when present in a compound of the disclosure; (b) an ester, carbonate, carbamate, phosphate or ether derivative of a hydroxyl group when present in a compound of the disclosure; (c) an amide, imine, carbamate or amine derivative of an amino group when present in a compound of the disclosure; (d) a thioester, thiocarbonate, thiocarbamate or sulfide derivatives of a thiol group when present in a compound of the disclosure; or (e) an oxime or imine derivative of a carbonyl group when present in a compound of the disclosure.

[0123] Some specific examples of prodrugs in accordance with the disclosure include:

[0124] (i) when a compound of the disclosure contains a carboxylic acid functionality (-COOH), an ester thereof, such as a compound wherein the hydrogen of the carboxylic acid functionality of the compound is replaced by C1-C8 alkyl (e.g., ethyl) or (C1-C8 alkyl)C(=O)OCH2-(e.g., ‘BuC(=O)OCH2-);

[0125] (ii) when a compound of the disclosure contains an alcohol functionality (-OH), an ester thereof, such as a compound wherein the hydrogen of the alcohol functionality of the compound is replaced by -CO(C1-C8 alkyl) (e.g., methylcarbonyl) or the alcohol is esterified with an amino acid;

[0126] (iii) when a compound of the disclosure contains an alcohol functionality (-OH), an ether thereof, such as a compound wherein the hydrogen of the alcohol functionality of the compound is replaced by (C1-C8 alkyl)C(=O)OCH2- or-CH2OP(=O)(OH)2;

[0127] (iv) when a compound of the disclosure contains an alcohol functionality (-OH), a phosphate thereof, such as a compound wherein the hydrogen of the alcohol functionality of the compound is replaced by -P(=O)(OH)2 or -P(=0)(ONa+)2 or -P(=0)(O)2Ca2+;

[0128] (v) when a compound of the disclosure contains a primary or secondary amino functionality (-NH2or -NHR where R H), an amide thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound is / are replaced by (Ci-Cw)alkanoyl, -COCH2NH2 or the amino group is derivatized with an amino acid;

[0129] (vi) when a compound of the disclosure contains a primary or secondary amino functionality (-NH2or -NHR where R H), an amine thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound is / are replaced by -CH2OP(=O)(OH)2.

[0130] Certain compounds of the disclosure may themselves act as prodrugs of other compounds the disclosure It is also possible for two compounds of the disclosure to be joined together in the form of a prodrug. In certain circumstances, a prodrug of a compound of the disclosure may be created by internally linking two functional groups in a compound of the disclosure, for instance by forming a lactone.

[0131] MetabolitesAlso included within the scope of the disclosure are active metabolites of compounds of the disclosure, that is, compounds formed in vivo upon administration of the drug, often by oxidation or dealkylation. Some examples of metabolites in accordance with the disclosure include, but are not limited to,

[0132] (i) where the compound of the disclosure contains an alkyl group, a hydroxyalkyl derivative thereof (-CH — > -COH):

[0133] (ii) where the compound of the disclosure contains an alkoxy group, a hydroxy derivative thereof (-OR — > -OH);

[0134] (iii) where the compound of the disclosure contains a tertiary amino group, a secondary amino derivative thereof (-NRR’ — > -NHR or -NHR);

[0135] (iv) where the compound of the disclosure contains a secondary amino group, a primary derivative thereof (-NHR — > -NH2);

[0136] (v) where the compound of the disclosure contains a phenyl moiety, a phenol derivative thereof (-Ph — > -PhOH);

[0137] (vi) where the compound of the disclosure contains an amide group, a carboxylic acid derivative thereof (-CONH2 -> COOH); and

[0138] (vii) where the compound contains a hydroxy or carboxylic acid group, the compound may be metabolized by conjugation, for example with glucuronic acid to form a glucuronide. Other routes of conjugative metabolism exist. These pathways are frequently known as Phase 2 metabolism and include, for example, sulfation or acetylation. Other functional groups, such as NH groups, may also be subject to conjugation.

[0139] Protein Degraders

[0140] Disclosed herein are bifunctional compounds comprising a targeting ligand (i.e., compound of the disclosure) linked to an E3 ligase ligand or a ligand known to interact with the ubiquitin proteasome system (UPS) through a linker. The bifunctional compounds of the disclosure have the general structure: [Degron]-[Linker]-[Targeting Ligand], wherein the linker is covalently bound to at least one degron and covalently bound to at least one targeting ligand, wherein the degron is a compound capable of binding to a ubiquitin ligase such as an E3 Ubiquitin Ligase (e.g., cereblon (CRBN), von Hippel-Lindau (VHL), etc.), and the targeting ligand or compound of the disclosure is capable of binding to a targeted protein, for example, KLF2. The bifunctional compounds of the disclosure can be used as therapeutics to treat a condition disclosed herein.

[0141] In one embodiment, a bifunctional compound of the disclosure has the formula:

[0142] [Degron]-[Linker]-[Formula I, la, la’, lb, or lb’].

[0143] Degron: The degron is a compound that is highly effective in recruiting a targeted protein to a ubiquitin ligase for proteosomal degradation. The degron recruits the targeted protein through the linker and the targeting ligand (i.e., compound of the disclosure). In some embodiments, the degron is a compound that can bind to a ubiquitin ligase. In one embodiment,the degron can bind to an E3 ubiquitin ligase, such as cereblon, wherein the degron is thalidomide, lenalidomide, pomalidomide, or iberdomide, or newer IMiDs CRBN ligands, or analogs thereof (e.g., WO2019 / 060693, WO2019 / 140387, WO2019 / 236483). In one embodiment, the degron can bind to an E3 ubiquitin ligase, such as von Hippel-Lindau ligand (e.g., W02020 / 092907; WO2013106643; BUCKLEY, D. L., et al., “Targeting the von Hippel-Lindau E3 Ubiquitin Ligase Using Small Molecules to Disrupt the VHL / HIF-1a Interaction,” Journal of the American Chemical Society, 2012, 134(10):4465-4468; SOARES, P., et al., “Group-Based Optimization of Potent and Cell-Active Inhibitors of the von Hippel-Lindau (VHL) E3 Ubiquitin Ligase: Structure-Activity Relationships Leading to the Chemical Probe (2S,4R)-1-((S)-2-(1-Cyanocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy- / \ / -(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (VH298),” Journal of Medicinal Chemistry, 2018, 61(2): 599-618). In a further embodiment, the degron can bind to an E3 ubiquitin ligase, such as an inhibitor of apoptosis protein ligases (IAP1, IAP2, XIAP) (e.g., ITOH, Y., et al., “Protein knockdown using methyl bestatin-ligand hybrid molecules: design and synthesis of inducers of ubiquitination-mediated degradation of cellular retinoic acid-binding proteins,” Journal of the American Chemical Society, 2010, 132(16):5820-5826; MARES, A., et al., “Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2,” Communications Biology, 2020, 3:1-13; TINWORTH, C., et al., “PROTAC-Mediated Degradation of Bruton’s Tyrosine Kinase Is Inhibited by Covalent Binding,” ACS Chemical Biology, 2019, 14(3):342-347). In a further embodiment, the degron binds a ubiquitin proteasome protein that induces degradation, such as the Hsp70 / 90 chaperone complex (e.g., W02020 / 207395), Usp14 (e.g., WO2019 / 238886), UchL5 (e.g., WO2019238816), and Rpn11 (e.g., WO2019 / 238817). In some embodiments, the degron is an amino acid moiety (e.g., ZHANG, J., et al., “Single amino acid-based PROTACs trigger degradation of the oncogenic kinase BCR-ABL in chronic myeloid leukemia (CML),” Journal of Biological Chemistry, 2023, 299(8): 104994).

[0144] Linker: The Linker (“L”) provides a covalent attachment between the Targeting Ligand and the Degron. The Linker has two terminating groups, wherein one terminating group attaches to the Degron and the other terminating group attaches to the Targeting Ligand. The structure of the Linker may not be critical, provided it does not substantially interfere with the activity of the Targeting Ligand or the Degron. The optimal Linker length and composition may vary by target and may be estimated based upon, for example, 1) X-ray structures of the original Targeting Ligand bound to its target; and / or 2) computational modeling of the protein target and the UPS protein. Linker length and composition can be also modified to modulate metabolic stability and pharmacokinetic (PK) and pharmacodynamics (PD) parameters. In some embodiments, the Linker is designed and optimized based on SAR (structure-activity relationship) and X-ray crystallography of the Targeting Ligand with regard to the location of attachment for the Linker. In some embodiments, a target ligand can bind multiple proteintargets, and selectivity of the bifunctional compounds disclosed herein can be achieved by varying the linker length such that the ligand can target a different binding pocket, e.g., deeper or shallower binding pockets than others.

[0145] In some embodiments, the Linker is a C2-20 alkylene or a polyethylene glycol (PEG) chain. In other embodiments, the Linker may be an alkylene chain, a PEG chain, or a bivalent alkylene chain, each of which may be interrupted by or terminate with at least one of -O-, -S-, — N(RL)—, -C=C-, -C(O)-, -0(0)0- -OC(O)-, -00(0)0-, - C(NORL)-, -C(O)N(RL)-, -C(O)N(RL)C(O)-, -C(O)N(RL)C(O)N(RL)-, -N(RL)C(O)-, -N(RL)C(O)N(RL)-, -N(RL)C(O)O-, -OC(O)N(RL)-, -C(NRL)-,-N(RL)C(NRL)-, — C(NRL)N(RL)—, - N(RL)C(NRL)N(RL)—, -OB(CH3)O--S(0)2-, -0S(0)-, -S(0)0-, -S(0)-, -0S(0)2-, -S(0)20-, - N(RL)S(O)2-, -S(O)2N(RL)-, -N(RL)S(O)-, -S(O)N(RL)-, -N(RL)S(O)2N(RL)-, -N(RL)S(O)N(RL)-, C3-12 carbocyclene, 3- to 12-membered heterocyclene, 5- to 12-membered heteroarylene, or arylene, or any combination thereof, wherein RLis H or Ci-e alkyl. In one embodiment, In some embodiments, the Linker is Ci-io alkylene-NH-, wherein the nitrogen is bound to the degron. In one embodiment, the Linker is Ci-io alkylene or 1-8 PEG units that are interrupted by or terminate in -(CH2)n-C(0)-NH-, where n’ is 0, 1, 2, 3, 4, or 5.

[0146] Nonlimiting examples of a Linker include -(CH2CH2-O)n"-(CH2)n-C(O)-, (CH2)n-C(0)-N(RL)-(CH2CH2-O)n -(CH2)n’-C(O)-, -(CH2CH2-O)n"-(CH2)n’-N(RL)-C(O)-, -(CH2CH2-O)n"-(CH2)n’-C(O)-N(RL)-, -(CH2)n’-phenylene-N(RL)-C(O)-(CH2)n’-, -N(RL)-(CH2)n-O-phenylene-(CH2)n"-N(RL)-(CH2)n-, -(CH2)n’-C(O)-N(RL)-phenylene-C(O)-, -N(RL)-(CH2)n-phenylene-(CH2)n"-heterocyclylene-, -(CH2)n-phenylene-N(RL)-C(O)-(CH2CH2-O)n"-(CH2)n’-,-(CH2)n-phenylene-(CH2)n"-heterocyclylene-(CH2)n" C(O)-N(RL)-(CH2)n’-, -(CH2)n’-phenylene-O-(CH2)n’-heterocyclylene- (CH2)n-, -(CH2)n-phenylene-(CH2)n-heterocyclylene- (CH2)n-0-, -(CH2)n-heterocyclylene-(CH2)n’ wherein RLis H or Ci-e alkyl; n’ is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and n” is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0147] Pharmaceutical Compositions

[0148] In another embodiment, the disclosure comprises pharmaceutical compositions. For pharmaceutical composition purposes, the compound per se or pharmaceutically acceptable salt thereof will simply be referred to as the compounds of the disclosure.

[0149] The compositions of this disclosure may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, capsules, pills, powders, liposomes and suppositories. The form depends on the intended mode of administration and therapeutic application.

[0150] Typical compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with antibodies in general. One mode of administration is parenteral (e.g., intravenous, subcutaneous,intraperitoneal, intramuscular). In another embodiment, the compound is administered by intravenous infusion or injection. In yet another embodiment, the compound is administered by intramuscular or subcutaneous injection.

[0151] Oral administration of a solid dosage form may be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the disclosure, or a pharmaceutically acceptable salt thereof. In another embodiment, the oral administration may be in a powder or granule form. In another embodiment, the oral dosage form is sub-lingual, such as, for example, a lozenge. In such solid dosage forms, the compounds of the disclosure are ordinarily combined with one or more adjuvants. Such capsules or tablets may comprise a controlled release formulation. In the case of capsules, tablets, and pills, the dosage forms also may comprise buffering agents or may be prepared with enteric coatings.

[0152] In another embodiment, oral administration may be in a liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions also may comprise adjuvants, such as one or more of wetting, emulsifying, suspending, flavoring (e.g., sweetening), or perfuming agents.

[0153] In another embodiment, the disclosure comprises a parenteral dosage form. " Parenteral administration" includes, for example, subcutaneous injections, intravenous injections, intraperitoneally, intramuscular injections, intrasternal injections, and infusion. Injectable preparations (i.e., sterile injectable aqueous or oleaginous suspensions) may be formulated according to the known art using one or more of suitable dispersing, wetting agents, or suspending agents.

[0154] In another embodiment, the disclosure comprises a topical dosage form. " Topical administration" includes, for example, dermal and transdermal administration, such as via transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. A topical formulation may include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of this disclosure are administered by a transdermal device, administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical excipients include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, FINNIN, B. C. and MORGAN, T. M., “Transdermal penetrationenhancers: Applications, limitations, and potential,” Journal of Pharmaceutical Sciences, 1999, 88(10):955-958.

[0155] Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of this disclosure is dissolved or suspended in a suitable excipient. A typical formulation suitable for ocular or aural administration may be in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (i.e., absorbable gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

[0156] For intranasal administration, the compounds of the disclosure are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant. Formulations suitable for intranasal administration are typically administered in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

[0157] In another embodiment, the disclosure comprises a rectal dosage form. Such rectal dosage form may be in the form of, for example, a suppository. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

[0158] Other excipients and modes of administration known in the pharmaceutical art may also be used. Pharmaceutical compositions of the disclosure may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures. The above considerations in regard to effective formulations and administration procedures are well known in the art and are described in standard textbooks. Formulation of drugs is discussed in, for example, ALLEN, L. V. and ANSEL, H. C. Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. 10thEd. Philadelphia, Lippincott Williams & Wilkins, 2014; ADEJARE, A. Remington: The Science and Practice of Pharmacy. 23rdEd. Philadelphia, Lippincott Williams & Wilkins, 2000; ROWE, R. C., et al., Handbook of Pharmaceutical Excipients. 5thEd. Chicago, Pharmaceutical Press, 2006; STAHL, P. H. and WERMUTH, C. G.,Pharmaceutical Salts: Properties, Selection, and Use. 2ndRevised Ed. New York, Wiley-VCH, 2011; and BRITTAIN, H. G. Polymorphism in Pharmaceutical Solids. 2ndEd. CRC Press, 2009.

[0159] Acceptable excipients are nontoxic to subjects at the dosages and concentrations employed, and may comprise one or more of the following: 1) buffers such as phosphate, citrate, or other organic acids; 2) salts such as sodium chloride; 3) antioxidants such as ascorbic acid or methionine; 4) preservatives such as octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol; 5) alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, or m-cresol; 6) low molecular weight (less than about 10 residues) polypeptides; 7) proteins such as serum albumin, gelatin, or immunoglobulins; 8) hydrophilic polymers such as polyvinylpyrrolidone; 9) amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; 10) monosaccharides, disaccharides, or other carbohydrates including glucose, mannose, or dextrins; 11) chelating agents such as EDTA; 12) sugars such as sucrose, mannitol, trehalose or sorbitol; 13) salt-forming counter-ions such as sodium, metal complexes (e.g., Zn-protein complexes), or 14) non-ionic surfactants such as polysorbates (e.g., polysorbate 20 or polysorbate 80), poloxamers or polyethylene glycol (PEG).

[0160] For oral administration, the compositions may be provided in the form of tablets or capsules containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250 or 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, or in another embodiment, from about 1 mg to about 100 mg of active ingredient. Dosing regimens may depend on the route of administration, dose scheduling, and use of flat-dose, body surface area or weight-based dosing. For example, for weight-based dosing, intravenously doses may range from about 0.01 to about 10 mg / kg / minute during a constant rate infusion.

[0161] Liposome containing compounds of the disclosure may be prepared by methods known in the art (See, for example, CHANG, H.I. and YEH, M.K., “Clinical development of liposomebased drugs: formulation, characterization, and therapeutic efficacy,” International Journal of Nanomedicine, 2012, 7:49-60). Particularly useful liposomes may be generated by the reverse phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter.

[0162] Compounds of the disclosure may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques aredisclosed in ADEJARE, A. Remington: The Science and Practice of Pharmacy. 23rdEd.

[0163] Philadelphia, Lippincott Williams & Wilkins, 2000.

[0164] Sustained-release preparations may be used. Suitable examples of sustained-release preparations include semi-permeable matrices of solid hydrophobic polymers containing a compound of the disclosure, or a pharmaceutically acceptable salt thereof, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or 'poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and 7 ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as those used in leuprolide acetate for depot suspension (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid.

[0165] The formulations to be used for intravenous administration must be sterile. This is readily accomplished by, for example, filtration through sterile filtration membranes.

[0166] Compounds of the disclosure are generally placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

[0167] Suitable emulsions may be prepared using commercially available fat emulsions, such as a lipid emulsions comprising soybean oil, a fat emulsion for intravenous administration (e.g., comprising safflower oil, soybean oil, egg phosphatides and glycerin in water), emulsions containing soya bean oil and medium-chain triglycerides, and lipid emulsions of cottonseed oil. The active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g., egg phospholipids, soybean phospholipids or soybean lecithin) and water. It will be appreciated that other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%. The fat emulsion may comprise fat droplets between 0.1 and 1.0 pm, particularly 0.1 and 0.5 pm, and have a pH in the range of 5.5 to 8.0.

[0168] For example, the emulsion compositions may be those prepared by mixing a compound of the disclosure, or a pharmaceutically acceptable salt thereof with a lipid emulsions comprising soybean oil or the components thereof (soybean oil, egg phospholipids, glycerol and water).

[0169] 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 set out above. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceuticallyacceptable solvents may be nebulized by use of gases. Nebulized solutions may be breathed 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, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.

[0170] A drug product intermediate (DPI) is a partly processed material that must undergo further processing steps before it becomes bulk drug product. Compounds of the disclosure may be formulated into drug product intermediate DPI containing the active ingredient in a higher free energy form than the crystalline form. One reason to use a DPI is to improve oral absorption characteristics due to low solubility, slow dissolution, improved mass transport through the mucus layer adjacent to the epithelial cells, and in some cases, limitations due to biological barriers such as metabolism and transporters. Other reasons may include improved solid state stability and downstream manufacturability. In one embodiment, the drug product intermediate contains a compound of the disclosure, or a pharmaceutically acceptable salt thereof isolated and stabilized in the amorphous state (for example, amorphous solid dispersions (ASDs)). There are many techniques known in the art to manufacture ASD’s that produce material suitable for integration into a bulk drug product, for example, spray dried dispersions (SDD’s), melt extrudates (often referred to as HME’s), co-precipitates, amorphous drug nanoparticles, and nano-adsorbates. In one embodiment amorphous solid dispersions comprise a compound of the disclosure, or a pharmaceutically acceptable salt thereof and a polymer excipient. Other excipients as well as concentrations of said excipients and the compound of the disclosure, or a pharmaceutically acceptable salt thereof are well known in the art and are described in standard textbooks. See, for example, SHAH, N., et al., Amorphous Solid Dispersions: Theory and Practice. New York, Springer, 2014.

[0171] Administration and Dosing

[0172] Typically, a compound of the disclosure, or a pharmaceutically acceptable salt thereof is administered in an amount effective to treat a condition as described herein. The compounds of the disclosure may be administered as compound per se, or alternatively, as a pharmaceutically acceptable salt. For administration and dosing purposes, the compound per se or pharmaceutically acceptable salt thereof will simply be referred to as the compounds of the disclosure.

[0173] The compounds of the disclosure are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The compounds of the disclosure may be administered orally, rectally, vaginally, parenterally, topically, intranasally, or by inhalation.

[0174] The compounds of the disclosure may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal orsublingual administration may be employed by which the compound enters the bloodstream directly from the mouth.

[0175] In another embodiment, the compounds of the disclosure may also be administered parenterally, for example directly into the bloodstream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.

[0176] In another embodiment, the compounds of the disclosure may also be administered topically to the skin or mucosa, that is, dermally or transdermally. In another embodiment, the compounds of the disclosure may also be administered intranasally or by inhalation. In another embodiment, the compounds of the disclosure may be administered rectally or vaginally. In another embodiment, the compounds of the disclosure may also be administered directly to the eye or ear.

[0177] The dosage regimen for the compounds of the disclosure or compositions containing said compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus, the dosage regimen may vary widely.

[0178] In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof can be administered in an amount of from about 0.01 mg to about 150 mg, from about 150 mg to about 250 mg, from about 250 mg to about 500 mg, from about 500 mg to about 750 mg, from about 750 mg to about 1000 mg, from about 1250 mg to about 1500 mg, from about 1500 mg to about 1750 mg, from about 1750 mg to about 2000 mg, from about 2000 mg to about 2250 mg, from about 2250 mg to about 2500 mg, from about 2500 mg to about 2750 mg, from about 2750 mg to about 3000 mg, from about 3000 mg to about 3250 mg, from about 3250 mg to about 3500 mg, from about 3500 mg to about 3750 mg, from about 3750 mg to about 4000 mg, from about 4000 mg to about 4250 mg, from about 4250 mg to about 4500 mg, from about 4500 mg to about 4750 mg, or from about 4750 mg to about 5000 mg. In one embodiment, a compound of the disclosure, or a pharmaceutically acceptable salt thereof can be administered in an amount of from about 1 mg to about 2500 mg. In one embodiment, a compound of the disclosure, or a pharmaceutically acceptable salt thereof can be administered in an amount of from about 1 mg to about 100 mg. In one embodiment, a compound of the disclosure, or a pharmaceutically acceptable salt thereof can be administered in an amount of from about 1 mg to about 50 mg. In one embodiment, a compound of the disclosure, or a pharmaceutically acceptable salt thereof can be administered in an amount of from about 1 mg to about 25 mg. In one embodiment, a compound of the disclosure, or a pharmaceutically acceptable salt thereof can be administered in an amount of from about 150 mg to about 2500 mg. In one embodiment, a compound of the disclosure, or a pharmaceuticallyacceptable salt thereof can be administered in an amount of from about 150 mg to about 500 mg. In one embodiment, a compound of the disclosure, or a pharmaceutically acceptable salt thereof can be administered in an amount of from about 100 mg to about 1000 mg. In one embodiment, a compound of the disclosure, or a pharmaceutically acceptable salt thereof can be administered in an amount of from about 500 mg to about 1500 mg. In one embodiment, a compound of the disclosure, or a pharmaceutically acceptable salt thereof can be administered in an amount of from about 1500 mg to about 2500 mg. In one embodiment, a compound of the disclosure, or a pharmaceutically acceptable salt thereof can be administered in an amount of from about 2500 mg to about 5000 mg.

[0179] In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof can be administered in an amount of about 0.01 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3200 mg, about 3400 mg, about 3600 mg, about 3800 mg, about 4000 mg, about 4200 mg, about 4400 mg, about 4600 mg, about 4800 mg, or about 5000 mg.

[0180] In one embodiment, a compound of the disclosure, or a pharmaceutically acceptable salt thereof can be administered in an amount of about 5 mg. In one embodiment, a compound of the disclosure, or a pharmaceutically acceptable salt thereof can be administered in an amount of about 10 mg. In one embodiment, a compound of the disclosure, or a pharmaceutically acceptable salt thereof can be administered in an amount of about 15 mg. In one embodiment, a compound of the disclosure, or a pharmaceutically acceptable salt thereof can be administered in an amount of about 25 mg. In one embodiment, a compound of the disclosure, or a pharmaceutically acceptable salt thereof can be administered in an amount of about 50 mg. In one embodiment, a compound of the disclosure, or a pharmaceutically acceptable salt thereof can be administered in an amount of about 75 mg. In one embodiment, a compound of the disclosure, or a pharmaceutically acceptable salt thereof can be administered in an amount of about 100 mg. In one embodiment, a compound of the disclosure, or a pharmaceutically acceptable salt thereof can be administered in an amount of about 250 mg. In one embodiment, a compound of the disclosure, or a pharmaceutically acceptable salt thereof can be administered in an amount of about 500 mg. In one embodiment, a compound ofthe disclosure, or a pharmaceutically acceptable salt thereof can be administered in an amount of about 1000 mg.

[0181] In one embodiment, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, can be administered once a day. In one embodiment, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, can be administered twice a day. In one embodiment, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, can be administered three times a day. In one embodiment, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, can be administered once a week. In one embodiment, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, can be administered twice a week. In one embodiment, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, can be administered three times a week.

[0182] Therapeutic Methods and Uses

[0183] The compounds of the disclosure can induce KLF2 to treat a condition. In some embodiments, disclosed herein is a method of treating an inflammatory disease or endothelial dysfunction comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, la, la’, lb, or lb’ as disclosed herein. In one embodiment, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is used to treat an inflammatory disease. In one embodiment, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is used to treat endothelial dysfunction.

[0184] In some embodiments, the inflammatory disease or endothelial dysfunction is selected from the group consisting of atherosclerosis, coronary artery disease, stroke, peripheral arterial disease, coronary microvascular diseases, angina, systemic hypertension, pulmonary arterial hypertension, heart failure, diabetic microvascular diseases, an autoimmune disease, chronic kidney disease (CKD), diabetic kidney disease (DKD), an inflammatory disease, and an infectious disease. In some embodiments, the diabetic microvascular disease is diabetic nephropathy, diabetic retinopathy or diabetic neuropathy. In some embodiments, the condition is peripheral arterial disease.

[0185] In some embodiments, the compounds of the disclosure can be administered to a subject in need thereof to treat a vascular condition. In some embodiments, the vascular condition is selected from the group consisting of a cardiovascular condition, for example, atherosclerosis, stroke, heart attack, peripheral artery disease, deep vein thrombosis, varicose veins, aneurysm, Raynaud’s disease, renal artery stenosis, renal artery thrombosis, renal vein thrombosis, renal artery aneurysms, and atheroembolic renal disease.

[0186] In some embodiments, the compounds of the disclosure can be used to treat a condition selected from the group consisting of ischemia with non-obstructive coronary arteries (INOCA), pulmonary hypertension (PH), and microvascular and macrovascular disease.

[0187] Co-administrationThe compounds of the disclosure may be used alone, or in combination with one or more other therapeutic agents. The disclosure provides any of the uses, methods or compositions as defined herein wherein the compound of the disclosure, or pharmaceutically acceptable salt thereof, is used in combination with one or more other therapeutic agent discussed herein.

[0188] The administration of two or more compounds “in combination” means that all of the compounds are administered closely enough in time to affect treatment of the subject. The two or more compounds may be administered simultaneously or sequentially, via the same or different routes of administration, on same or different administration schedules and with or without specific time limits depending on the treatment regimen. Additionally, simultaneous administration may be carried out by mixing the compounds prior to administration or by administering the compounds at the same point in time but as separate dosage forms at the same or different site of administration. Examples of “in combination” include, but are not limited to, “concurrent administration,” “co-administration,” “simultaneous administration,” “sequential administration” and “administered simultaneously”.

[0189] A compound of the disclosure and the one or more other therapeutic agents may be administered as a fixed or non-fixed combination of the active ingredients. The term "fixed combination" means a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and the one or more therapeutic agents, are both administered to a subject simultaneously in a single composition or dosage. The term "non-fixed combination" means that a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and the one or more therapeutic agents are formulated as separate compositions or dosages such that they may be administered to a subject in need thereof simultaneously or at different times with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the subject.

[0190] In one embodiment, the compounds of this disclosure are administered in combination with the specifically named agents including the pharmaceutically acceptable salts of the specifically named agents and the pharmaceutically acceptable solvates of said agents and salts.

[0191] In one embodiment, the compounds of the disclosure, or a pharmaceutically acceptable salt thereof, are administered in combination with a statin. In some embodiments, the compounds of the disclosure, or a pharmaceutically acceptable salt thereof, are administered with a statin selected from the group consisting of atorvastatin, simvastatin, rosuvastatin, fluvastatin, lovastatin, pitavastatin, and pravastatin. In some embodiments, the statin administered in combination with a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is atorvastatin. In some embodiments, the statin administered in combination with a compound of the disclosure, or a pharmaceutically acceptable salt thereof,is simvastatin. In some embodiments, the statin administered in combination with a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is rosuvastatin.

[0192] In one embodiment, the compounds of the disclosure, or a pharmaceutically acceptable salt thereof, are administered in combination with a vasodilator. In one embodiment, the compounds of the disclosure, or a pharmaceutically acceptable salt thereof, are administered in combination with a vasodilator that is an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), a calcium channel blocker (CCB), or a nitrate. In some embodiments, the compounds of the disclosure, or a pharmaceutically acceptable salt thereof, are administered in combination with a vasodilator selected from the group consisting of benazepril, lisinopril, losartan, diltiazem, hydralazine, minoxidil, nitroglycerine, cilostazol, sildenafil, tadalafil, vardenafil, and pentoxifylline.

[0193] In one embodiment, the compounds of the disclosure, or a pharmaceutically acceptable salt thereof, are administered in combination with an anticoagulant. In one embodiment, the compounds of the disclosure, or a pharmaceutically acceptable salt thereof, are administered in combination with an anticoagulant selected from the group consisting of clopidogrel, aspirin, rivaroxaban, warfarin, vitamin K, low molecular weight heparin, arixtra, apixaban, heparin, direct thrombin inhibitor, enoxaparin, antiplatelet drug, dabigatrain, edoxaban, lovenox, brilinta, and fragmin. In one embodiment, the compounds of the disclosure, or a pharmaceutically acceptable salt thereof, are administered in combination with warfarin. In one embodiment, the compounds of the disclosure, or a pharmaceutically acceptable salt thereof, are administered in combination with low molecular weight heparin. In one embodiment, the compounds of the disclosure, or a pharmaceutically acceptable salt thereof, are administered in combination with enoxaparin. In one embodiment, the compounds of the disclosure, or a pharmaceutically acceptable salt thereof, are administered in combination with lovenox.

[0194] In one embodiment, the compounds of the disclosure, or a pharmaceutically acceptable salt thereof, are administered to a subject who also receives a medical procedure to treat peripheral artery disease. In one embodiment, the compounds of the disclosure, or a pharmaceutically acceptable salt thereof, are administered to a subject who also receives a medical procedure selected from the group consisting of angioplasty, atherectomy, angioplasty, stent, and a thrombectomy.

[0195] In one embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of Formula I, la, la’, lb, or lb’, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is administered in combination with a pharmaceutical composition comprising a statin, vasodilator, or an anticoagulant described herein simultaneously or at different times.

[0196] These agents and compounds of the disclosure may be combined with pharmaceutically acceptable vehicles such as saline, Ringer’s solution, dextrose solution, and the like. Theparticular dosage regimen, i.e., dose, timing and repetition, will depend on the particular individual and that individual’s medical history.

[0197] Kits

[0198] Another aspect of the disclosure provides kits comprising the compound of the disclosure, or a pharmaceutically acceptable salt thereof or pharmaceutical compositions comprising the compound of the disclosure, or a pharmaceutically acceptable salt thereof. A kit may include, in addition to the compound of the disclosure, or a pharmaceutically acceptable salt thereof or pharmaceutical composition thereof, diagnostic or therapeutic agents. A kit may also include instructions for use in a diagnostic or therapeutic method. In some embodiments, the kit includes the compound or a pharmaceutical composition thereof and a diagnostic agent.

[0199] In yet another embodiment, the disclosure comprises kits that are suitable for use in performing the methods of treatment described herein. In one embodiment, the kit contains a first dosage form comprising one or more of the compounds of the disclosure in quantities sufficient to carry out the methods of the disclosure. In another embodiment, the kit comprises one or more compounds of the disclosure in quantities sufficient to carry out the methods of the disclosure and a container for the dosage and a container for the dosage.

[0200] Synthetic Methods

[0201] Compounds of the present disclosure may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources or may be prepared using methods well known to those skilled in the art. Many of the compounds used herein, are related to, or may be derived from compounds in which one or more of the scientific interest or commercial need has occurred. Accordingly, such compounds may be one or more of 1) commercially available; 2) reported in the literature or 3) prepared from other commonly available substances by one skilled in the art using materials which have been reported in the literature.

[0202] For illustrative purposes, the reaction schemes depicted below provide potential routes for synthesizing the compounds of the present disclosure as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are discussed below, other starting materials and reagents may be substituted to provide one or more of a variety of derivatives or reaction conditions. In addition, many of the compounds prepared by the methods described below may be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0203] The skilled person will appreciate that the experimental conditions set forth in the schemes that follow are illustrative of suitable conditions for effecting the transformations shown, and that it may be necessary or desirable to vary the precise conditions employed forthe preparation of compounds of the disclosure. It will be further appreciated that it may be necessary or desirable to carry out the transformations in a different order from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of the disclosure, or a pharmaceutically acceptable salt thereof.

[0204] In the preparation of compounds of the disclosure it is noted that some of the preparation methods useful for the preparation of the compounds described herein may require protection of remote functionality (e.g., a primary amine, secondary amine, carboxyl, etc. in a precursor of a compound of the disclosure). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. The need for such protection is readily determined by one skilled in the art. The use of such protection / deprotection methods is also within the skill in the art. For a general description of protecting groups and their use, see SMITH, M. B., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure. 8thEd. New Jersey, Wiley, 2019.

[0205] For example, if a compound contains a amine or carboxylic acid functionality, such functionality may interfere with reactions at other sites of the molecule if left unprotected.

[0206] Accordingly, such functionalities may be protected by an appropriate protecting group (PG) which may be removed in a subsequent step. Suitable protecting groups for amine and carboxylic acid protection include those protecting groups commonly used in peptide synthesis (such as / V-t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9-fluorenylmethylenoxycarbonyl (Fmoc) for amines and lower alkyl or benzyl esters for carboxylic acids) which are generally not chemically reactive under the reaction conditions described and may typically be removed without chemically altering other functionality in a compound of the disclosure.

[0207] Abbreviations

[0208] °C is degrees Celsius;

[0209] 5 is chemical shift;

[0210] Boc is terf-butoxycarbonyl;

[0211] br is broad;

[0212] CCl3CO2H is trichloroacetic acid;

[0213] Cs2CO3is cesium carbonate;

[0214] d is doublet;

[0215] dd is doublet of doublets;

[0216] ddd is doublet of doublet of doublets;

[0217] dt is doublet of triplets;

[0218] DMSO is dimethyl sulfoxide;

[0219] DMSO-d6is deuterodimethylsulfoxide;

[0220] ESI is electrospray ionization;Et3N or NEts is triethylamine;

[0221] g is gram;

[0222] H2is hydrogen gas;

[0223] HATU is 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate;

[0224] HCI is hydrogen chloride;

[0225] HPLC is high pressure liquid chromatography;

[0226] hr(s) is hour(s);

[0227] K3F3(CN)6is potassium ferricyanide;

[0228] KOAc is potassium acetate;

[0229] KOH is potassium hydroxide;

[0230] L is liter;

[0231] LCMS is liquid chromatography mass spectrometry;

[0232] LiBH4is lithium borohydride;

[0233] LiOH is lithium hydroxide;

[0234] m is multiplet;

[0235] M is molar;

[0236] MeOH is methanol;

[0237] mg is milligram;

[0238] MHz is mega Hertz;

[0239] min(s) is minute(s);

[0240] mL is milliliter;

[0241] mmol is millimole;

[0242] mol is mole;

[0243] MS (m / z) is mass spectrum peak;

[0244] NaIO4is sodium periodate;

[0245] NaOH is sodium hydroxide;

[0246] NH2OH·HCl is hydroxylamine hydrochloride;

[0247] NMR is nuclear magnetic resonance;

[0248] PdCl2is palladium (II) chloride;

[0249] pH is power of hydrogen;

[0250] ppm is parts per million;

[0251] psi is pounds per square inch;

[0252] q is quartet;

[0253] rt is room temperature;

[0254] RT is retention time;

[0255] RuCI3is ruthenium (III) chloride;Ruphos Pd G3 is (2-dicyclohexylphosphino-2',6'-diisopropoxy-1, T-biphenyl)[2-(2'-amino-1, T-biphenyl)]palladium(ll) methanesulfonate;

[0256] s is singlet;

[0257] SFC is supercritical fluid chromatography;

[0258] t is triplet;

[0259] tBu is tert- butyl;

[0260] tBuXPhos is 2-di-tert-butylphosphino-2’,4’,6’-triisopropylbiphenyl;

[0261] tBuXPhos-Pd G3 is [(2-di-tert-butylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)-2-(2’-amino-1, 1 ’-biphenyl)] palladium^ I) methanesulfonate;

[0262] μL is microliter;

[0263] μmol is micromole; and

[0264] EXAMPLES

[0265] In order that this disclosure may be better understood, the following examples are set forth. These examples are for purposes of illustration only and are not to be construed as limiting the scope of the disclosure in any manner.

[0266] The following illustrate the synthesis of various compounds of the present invention. Additional compounds within the scope of this invention may be prepared using the methods illustrated in these Examples, either alone or in combination with techniques generally known in the art. All starting materials in these Preparations and Examples are either commercially available or can be prepared by methods known in the art or as described herein.

[0267] Reactions were performed in air or, when oxygen- or moisture-sensitive reagents or intermediates were employed, under an inert atmosphere (nitrogen or argon). When appropriate, reaction apparatuses were dried under dynamic vacuum using a heat gun, and anhydrous solvents (Sure-Seal™ products from Sigma-Aldrich or DriSolv™ products from EMD Chemicals, Gibbstown, NJ) were employed. In some cases, commercial solvents were passed through columns packed with 4 molecular sieves, until the following QC standards for water were attained: a) <100 ppm for dichloromethane, toluene, / V, / V-dimethylformamide, and tetra hydrofuran; b) <180 ppm for methanol, ethanol, 1,4-dioxane, and diisopropylamine. For very sensitive reactions, solvents were further treated with metallic sodium, calcium hydride, or molecular sieves, and distilled just prior to use. Other commercial solvents and reagents were used without further purification. For syntheses referencing procedures in other Examples or Methods, reaction conditions (reaction time and temperature) may vary. Products were generally dried under vacuum before being carried on to further reactions or submitted for biological testing.

[0268] When indicated, reactions were heated by microwave irradiation using Biotage Initiator or Personal Chemistry Emrys Optimizer microwave instruments. Reaction progress was monitored using thin-layer chromatography (TLC), liquid chromatography-mass spectrometry(LCMS), high-performance liquid chromatography (HPLC), and / or gas chromatography-mass spectrometry (GCMS) analyses. TLC was performed on pre-coated silica gel plates with a fluorescence indicator (254 nm excitation wavelength) and visualized under UV light and / or with I2, KMnO4, CoCl2, phosphomolybdic acid, or ceric ammonium molybdate stains. LCMS data were acquired on an Agilent 1100 Series instrument with a Leap Technologies autosampler, Gemini C18 columns, acetonitrile / water gradients, and either trifluoroacetic acid, formic acid, or ammonium hydroxide modifiers. The column eluent was analyzed using a Waters ZQ mass spectrometer scanning in both positive and negative ion modes from 100 to 1200 Da. Other similar instruments were also used. HPLC data were generally acquired on an Agilent 1100 Series instrument using Gemini orXBridge C18 columns, acetonitrile / water gradients, and either trifluoroacetic acid or ammonium hydroxide modifiers. GCMS data were acquired using a Hewlett Packard 6890 oven with an HP 6890 injector, HP-1 column (12 m x 0.2 mm x 0.33 pm), and helium carrier gas. Samples were analyzed on an HP 5973 mass selective detector, scanning from 50 to 550 Da using electron ionization. Purifications were generally performed by medium performance liquid chromatography (MPLC) using Isco CombiFlash Companion, AnaLogix IntelliFlash 280, Biotage SP1, or Biotage Isolera One instruments and pre-packed Isco RediSep or Biotage Snap silica cartridges. Chiral purifications were generally performed by chiral supercritical fluid chromatography (SFC) using Berger or Thar instruments; ChiralPAK-AD, -AS, -IC, Chiralcel-OD, or-OJ columns; and CO2 mixtures with methanol, ethanol, propan-2-ol, or acetonitrile, alone or modified using trifluoroacetic acid or propan-2-amine. UV detection was used to trigger fraction collection. For syntheses referencing procedures in other Examples or Methods, purifications may vary: in general, solvents and the solvent ratios used for eluents / gradients were chosen to provide appropriate RfS or retention times.

[0269] Mass spectrometry data are reported from LCMS analyses. Mass spectrometry (MS) was performed via atmospheric pressure chemical ionization (APCI), electrospray ionization (ESI), electron impact ionization (El) or electron scatter (ES) ionization sources. Proton nuclear magnetic spectroscopy (1H NMR) chemical shifts are given in parts per million downfield from tetramethylsilane and were recorded on 300, 400, 500, or 600 MHz Varian, Bruker, or Jeol spectrometers. Chemical shifts are expressed in parts per million (ppm, 8) referenced to the deuterated solvent residual peaks (chloroform, 7.26 ppm; CD2HOD, 3.31 ppm; acetonitrile-^, 1.94 ppm; dimethyl sulfoxide-cfc, 2.50 ppm; DHO, 4.79 ppm). The peak shapes are described as follows: s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet; m, multiplet; br s, broad singlet; app, apparent. Analytical SFC data were acquired on a Berger analytical instrument as described above. Optical rotation data were acquired on a PerkinElmer model 343 polarimeter using a 1 dm cell. Silica gel chromatography was performed primarily using medium-pressure Biotage or ISCO systems using columns pre-packaged by various commercial vendors including Biotage and ISCO. Microanalyses were performed by Quantitative Technologies Inc. and were within 0.4% of the calculated values.Unless otherwise noted, chemical reactions were performed at room temperature (about 23 degrees Celsius).

[0270] Unless noted otherwise, all reactants were obtained commercially without further purifications or were prepared using methods known in the literature.

[0271] The terms “concentrated,” “evaporated,” and “concentrated in vacuo" refer to the removal of solvent at reduced pressure on a rotary evaporator with a bath temperature less than 60 °C. The abbreviation “min” and “h” stand for “minutes” and “hours” respectively. The term “TLC” refers to thin-layer chromatography, “room temperature or ambient temperature” means a temperature between 18 and 25 °C, “GCMS” refers to gas chromatography-mass spectrometry, “LCMS” refers to liquid chromatography-mass spectrometry, “UPLC” refers to ultra-performance liquid chromatography and “HPLC” refers to high-performance liquid chromatography, “SFC” refers to supercritical fluid chromatography.

[0272] Hydrogenation may be performed in a Parr Shaker under pressurized hydrogen gas, or in a Thales-nano H-Cube flow hydrogenation apparatus at full hydrogen and a flow rate between 1 and 2 mL / minute at the specified temperature.

[0273] HPLC, UPLC, LCMS, GCMS, and SFC retention times were measured using the methods noted in the procedures.

[0274] In some examples, chiral separations were carried out to separate enantiomers or diastereomers of certain compounds of the invention (in some examples, the separated enantiomers are designated as ENANT-1 and ENANT-2, according to their order of elution; similarly, separated diastereomers are designated as DIAST-1 and DIAST-2, according to their order of elution). In some examples, the optical rotation of an enantiomer was measured using a polarimeter. According to its observed rotation data (or its specific rotation data), an enantiomer with a clockwise rotation was designated as the (+)-enantiomer and an enantiomer with a counter-clockwise rotation was designated as the (-)-enantiomer. Racemic compounds are indicated either by the absence of drawn or described stereochemistry, or by the presence of (+ / -) adjacent to the structure; in this latter case, the indicated stereochemistry represents just one of the two enantiomers that make up the racemic mixture.

[0275] The compounds and intermediates described below were named using the naming convention provided with ACD / ChemSketch 2020.2.1.1, File Version C25H41, Build 121153 (Advanced Chemistry Development, Inc., Toronto, Ontario, Canada). The naming convention provided with ACD / ChemSketch 2020.2.1.1 is well known by those skilled in the art and it is believed that the naming convention provided with ACD / ChemSketch 2020.2.1.1 generally comports with the IUPAC (International Union for Pure and Applied Chemistry) recommendations on Nomenclature of Organic Chemistry and the CAS Index rules.

[0276] Preparation P1: (3R)-8-Bromo-4-[2-(dimethylamino)-2-oxoethyl]-3-methyl-5-oxo-2, 3,4,5-tetrahydro[1]benzofuro[2,3-f][1,4]oxazepine-3-carboxylic acid (P1)o V-OH KOH / °^7CH3

[0277] N' OCHH

[0278] 33

[0279]

[0280] P1 Step 1. Synthesis of methyl 6-bromo-3-hydroxy-1-benzofuran-2-carboxylate (C1)

[0281] This reaction was carried out in four parallel batches. Methyl bromoacetate (61.5 mL, 650 mmol) was added drop-wise to a mixture of methyl 4-bromo-2-hydroxybenzoate (150 g,649 mmol) and cesium carbonate (634 g, 1.95 mol) in / V, / V-dimethylformamide (1.5 L). After the reaction mixture had stirred at 25 °C for 16 hours, it was filtered. The filtrate was added to water (1.0 L) and extracted with ethyl acetate (700 mL); the organic layer was washed with saturated aqueous sodium chloride solution (700 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The products of the 4 batches were combined at this point, stirred in methyl tert-butyl ether (1.0 L) at 25 °C for 20 minutes, and filtered, providing C1 as a yellow solid. Combined yield: 525 g, 1.94 mol, 75%. LCMS m / z 272.7 (bromine isotope pattern observed) [M+H]+.1H NMR (400 MHz, DMSO-d6) 8 11.03 (br s, 1H), 7.92 (d, J= 1.6 Hz, 1H), 7.84 (d, J= 8.4 Hz, 1H), 7.49 (dd, J= 8.5, 1.6 Hz, 1H), 3.82 (s, 3H).

[0282] Step 2. Synthesis of methyl 6-bromo-3-(2-oxopropoxy)-1-benzofuran-2-carboxylate (C2).

[0283] Triethylamine (92.4 mL, 663 mmol) was added to a solution of C1 (150 g, 553 mmol) in acetonitrile (1.5 L), whereupon the mixture was heated to 65 °C and slowly treated with 1-chloropropan-2-one (72.7 g, 786 mmol). After the reaction mixture had been stirred at 80 °C for 4 hours, it was diluted with water (1.2 L) and extracted with ethyl acetate (3 x 1.2 L). The combined organic layers were washed with saturated aqueous sodium chloride solution (2 x 1.2 L), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford C2 as a yellow solid. Yield: 180 g, 0.550 mmol, 99%. LCMS m / z 326.8 (bromine isotope pattern observed) [M+H]+.1H NMR (400 MHz, DMSO-d6) 88.01 (d, J= 1.6 Hz, 1H), 7.79 (d, J= 8.5 Hz, 1H), 7.52 (dd, J= 8.5, 1.7 Hz, 1H), 5.22 (s, 2H), 3.85 (s, 3H), 2.16 (s, 3H).

[0284] Step 3. Synthesis of 6-bromo-3-(2-oxopropoxy)-1-benzofuran-2-carboxylic acid (C3).

[0285] Trimethoxymethane (361 mL, 3.30 mol) and 4-methylbenzene-1 -sulfonic acid (28.4 g, 165 mmol) were added to a solution of C2 (539 g, 1.65 mol) in methanol (5.39 L). The reaction mixture was stirred at 25 °C for 18 hours, whereupon LCMS analysis indicated conversion to methyl 6-bromo-3-(2,2-dimethoxypropoxy)-1-benzofuran-2-carboxylate: LCMS m / z 394.8 (bromine isotope pattern observed) [M+Na+], A solution of sodium hydroxide (198 g, 4.95 mol) in water (1.0 L) was added, and stirring was continued at 25 °C for 2 hours, providing 6-bromo-3-(2,2-dimethoxypropoxy)-1-benzofuran-2-carboxylic acid, according to LCMS analysis: LCMS m / z 380.8 (bromine isotope pattern observed) [M+Na+], The reaction mixture was then adjusted to pH 2 by addition of hydrochloric acid (1 M; 3.23 L, 3.23 mol) and stirred at 25 °C for 6 hours. The resulting solid was collected via filtration and washed with water (1 L) to afford C3 as a faintly yellow solid. Yield: 430 g, 1.37 mol, 83%. LCMS m / z 334.8 (bromine isotope pattern observed [M+Na+],1H NMR (400 MHz, DMSO-d6) 8 13.49 (br s, 1H), 7.98 (d, J= 1.6 Hz, 1H), 7.77 (d, J= 8.5 Hz, 1H), 7.52 (dd, J= 8.5, 1.6 Hz, 1H), 5.19 (s, 2H), 2.15 (s, 3H).

[0286] Step 4. Synthesis of (3S)-8-bromo-4-[2-(dimethylamino)-2-oxoethyl]-3-methyl-5-oxo- / \ / -[(1S)-1-phenylethyl]-2,3,4,5-tetrahydro[1]benzofuro[2,3-f][1,4]oxazepine-3-carboxamide (C4) and (3R)-8-bromo-4-[2-(dimethylamino)-2-oxoethyl]-3-methyl-5-oxo- / V-[(1S)-1-phenylethyl]-2, 3,4,5-tetrahydro[1]benzofuro[2,3-f][1,4]oxazepine-3-carboxamide (C5).

[0287] This reaction was carried out in two parallel batches. Triethylamine (133 mL, 954 mmol) was added to a solution of / V, / V-dimethylglycinamide, hydrochloride salt (97.4 g, 700 mmol) in 2,2,2-trifluoroethan-1-ol (2 L), whereupon the mixture was stirred at 25 °C for 30 minutes.

[0288] Substrate C3 (200 g, 639 mmol) was then added, and stirring was continued at 25 °C for 20 minutes before addition of [(1S)-1-isocyanoethyl]benzene (101 g, 770 mmol). After the reaction mixture had been stirred at 55 °C for 16 hours, LCMS analysis indicated conversion to diastereomers C4 and C5: LCMS m / z 529.9 (bromine isotope pattern observed) and 529.7 (bromine isotope pattern observed) [M+H]+. The two reaction mixtures were combined and concentrated in vacuo, separation of the diastereomers using silica gel chromatography (Gradient: 2% to 10% dichloromethane in tetrahydrofuran) afforded C4 and C5, both as faintly yellow solids. Elution of C4 occurred while the eluent was held at 6% dichloromethane, and C5 was collected at 8% dichloromethane. The absolute stereochemistries of C4 and C5 were assigned on the basis of synthesis of P1 from C5 (see steps 5 and 6 just below) and the identity of P1 prepared in this way with a sample of P1 derived from methyl / \ / -(tert-butoxycarbonyl)-2-methyl-D-serinate (see Alternate Preparation of P1 below).

[0289] C4: Combined yield: 200 g, 378 mmol, 30%.1H NMR (400 MHz, DMSO-d6) 89.84 (br s, 1 H), 7.99 (d, J = 1.6 Hz, 1 H), 7.65 (d, half of AB quartet, J = 8.4 Hz, 1 H), 7.50 (dd, component of ABX system, J= 8.4, 1.6 Hz, 1H), 7.26-7.10 (m, 5H), 4.91 (brd, J= 12.1 Hz, 1H), 4.69-4.49 (m, 2H), 4.49-4.34 (m, 2H), 3.06 (s, 3H), 2.91 (s, 3H), 1.51 (s, 3H), 1.14- 1.01 (m, 3H).

[0290] C5: Combined yield: 180 g, 341 mmol, 27%.1H NMR (400 MHz, DMSO-d6) 8 10.01 (br s, 1 H), 8.01 (d, J = 1.6 Hz, 1 H), 7.52 (d, half of AB quartet, J = 8.4 Hz, 1 H), 7.44 (dd, component of ABX system, J = 8.4, 1.6 Hz, 1 H), 6.95 - 6.86 (m, 1 H), 6.83 - 6.66 (m, 4H), 4.87 (d, J= 12.0 Hz, 1H), 4.75 -4.56 (m, 2H), 4.37 (brd, J= 17.6 Hz, 1H), 4.32 (d, J= 12.0 Hz, 1H), 3.08 (s, 3H), 2.92 (s, 3H), 1.60 (s, 3H), 1.27 (d, J= 7.0 Hz, 3H).

[0291] Step 5. Synthesis of tert-butyl {(3R)-8-bromo-4-[2-(dimethylamino)-2-oxoethyl]-3-methyl-5-oxo-2,3,4,5-tetrahydro[1]benzofuro[2,3- / ][1,4]oxazepine-3-carbonyl}[(1S)-1-phenylethyl]carbamate (C6).

[0292] This reaction was carried out in two parallel batches. To a solution of C5 (75.0 g, 142 mmol) in 1,4-dioxane (1.62 L) were added triethylamine (1.09 kg, 10.8 mol), di-tert-butyl dicarbonate (1.12 L, 4.98 mol), and 4-(dimethylamino)pyridine (22.5 g, 184 mmol), whereupon the reaction mixture was stirred at 100 °C for 16 hours. It was then concentrated in vacuo, the residue was stirred in methyl tert-butyl ether (500 mL) at 25 °C for 1 hour, and the solid collected via filtration. The solids from the two batches were combined at this point and purified using silica gel chromatography (Gradient: 0% to 45% ethyl acetate in petroleum ether) to provide C6 as a white solid. Combined yield: 102 g, 162 mmol, 57%. LCMS m / z 630.1 (bromineisotope pattern observed) [M+H]+.1H NMR (400 MHz, chloroform-d) 57.64 (d, J= 1.6 Hz, 1H), 7.45 (d, half of AB quartet, J = 8.4 Hz, 1 H), 7.35 (dd, component of ABX system, J = 8.4, 1.6 Hz, 1 H), 7.05 - 6.98 (m, 3H), 6.97 - 6.90 (m, 2H), 5.39 (br q, J = 7 Hz, 1 H), 5.27 (d, J = 17.3 Hz, 1H), 4.95 (s, 2H), 4.03 (d, J= 17.3 Hz, 1H), 3.10 (s, 3H), 2.95 (s, 3H), 1.96 (s, 3H), 1.33 (s, 9H), 1.05 (d, J= 7.1 Hz, 3H).

[0293] Step 6. Synthesis of (3R)-8-bromo-4-[2-(dimethylamino)-2-oxoethyl]-3-methyl-5-oxo-2, 3,4,5-tetrahydro[1]benzofuro[2,3-f][1,4]oxazepine-3-carboxylic acid (P1).

[0294] A mixture of C6 (10.0 g, 15.9 mmol) and potassium hydroxide (8.93 g, 159 mmol) in tetrahydrofuran (79.6 mL) was treated sequentially with ethanol (159 mL) and water (48 mL), whereupon the reaction mixture was heated at 70 °C for 1 hour. After cooling slightly, the reaction mixture was concentrated in vacuo, the resulting aqueous mixture was diluted with water (55 mL) and adjusted to pH 1 by addition of 3 M hydrochloric acid (approximately 100 mL). Solids were collected via filtration, washed with water (3 x 40 mL), and air-dried.

[0295] Subsequent trituration with ethyl acetate (350 mL) provided a filter cake, which was washed with ethyl acetate (2 x 50 mL) to afford P1 as a white solid. Yield: 5.99 g, 14.1 mmol, 89%. LCMS m / z 425.2 (bromine isotope pattern observed) [M+H]+.1H NMR (400 MHz, DMSO-d6) 8 13.69 (brs, 1H), 8.00 (d, J= 1.5 Hz, 1H), 7.66 (d, half of AB quartet, J = 8.4 Hz, 1H), 7.50 (dd, component of ABX system, J= 8.4, 1.6 Hz, 1H), 4.90 (d, J= 12.1 Hz, 1H), 4.81 (brd, J= 17.4 Hz, 1 H), 4.51 (d, J = 12.1 Hz, 1 H), 4.31 (br d, J = 17.5 Hz, 1 H), 3.05 (s, 3H), 2.87 (s, 3H), 1.65 (s, 3H).

[0296] A sample of P1 prepared using the same route was analyzed via supercritical fluid chromatography. Retention time: 4.92 minutes. Analytical conditions: (Column: Chiral Technologies Chiralpak IH, 4.6 x 250 mm, 5 pm; Mobile phase A: carbon dioxide; Mobile phase B: propan-2-ol containing 0.2% propan-2-amine; Gradient: 5% B for 0.50 minutes, then 5% to 60% B over 5.0 minutes, then 60% B for 2.0 minutes; Back pressure: 100 bar; Flow rate: 3.0 mL / minute).

[0297] Compound C7, the enantiomer of P1, was prepared in the same manner, but from diastereomer C4. Retention time, using the same analytical conditions as those described above for P1: 4.64 minutes.

[0298] NEt3^3^|SJ, CH3

[0299] C4

[0300]

[0301] 6

[0302]

[0303] C7

[0304] Alternate Synthesis of Preparation P1: (3R)-8-Bromo-4-[2-(dimethylamino)-2-oxoethyl]-3-methyl-5-oxo-2,3,4,5-tetrahydro[1]benzofuro[2,3- / ][1,4]oxazepine-3-carboxylic acid (P1)

[0305]

[0306] Step 1. Synthesis of 3-tert-butyl 4-methyl (4R)-4-methyl-2,2-dioxo-1,2λ6,3-oxathiazolidine-3,4-dicarboxylate (C8).

[0307] A solution of thionyl chloride (9.12 mL, 125 mmol) in acetonitrile (100 mL) was added to a flask containing acetonitrile that had been cooled to -40 °C (100 mL). 1 / - / -Imidazole (11.0 g, 162 mmol) was then added in one portion, followed by drop-wise addition of a solution of methyl / V-(tert-butoxycarbonyl)-2-methyl-D-serinate (12.2 g, 52.3 mmol) in acetonitrile (100 mL). This addition was carried out at a rate that maintained the internal reaction temperature below -37 °C; after the reaction mixture had been stirred at -40 °C for 10 minutes, triethylamine (12.3 mL, 88.2 mmol) was added. The reaction mixture was allowed to warm to room temperature over 20 minutes, and subsequently stirred at room temperature for 1 hour, whereupon it was diluted with water (150 mL) and extracted with ethyl acetate (3 x 550 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (200 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in acetonitrile (200 mL) and cooled to an internal temperature of 0 °C. To the resulting solution was added ruthenium(lll) chloride trihydrate (102 mg, 0.390 mmol), followed by a chilled solution of sodium periodate (11.7 g, 54.7 mmol) in water (180 mL). After the reaction mixture had been stirred at 0 °C for 1.5 hours, it was inadvertently diluted with water containing 0.1% trifluoroacetic acid (300 mL) (it was intended that the dilution be carried out with water). The mixture was quickly neutralized by addition of saturated aqueous sodium bicarbonate solution, and then extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed sequentially with saturated aqueous ammonium chloride solution, aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and filtered through a small pad of diatomaceous earth. The filtrate was concentrated in vacuo and the residue was purified via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane), affording C8 as a white solid. Yield: 13.0 g, 44.0 mmol, 84%.1H NMR (400 MHz, chloroform-d) 84.62 (d, J= 9.3 Hz, 1H), 4.30 (d, J= 9.3 Hz, 1H), 3.83 (s, 3H), 1.79 (s, 3H), 1.55 (s, 9H).

[0308] Step 2. Synthesis of methyl 6-bromo-3-{(2 / ?)-2-[(tert-butoxycarbonyl)amino]-3-methoxy-2-methyl-3-oxopropoxy}-1-benzofuran-2-carboxylate (C9).

[0309] To a solution of C1 (3.00 g, 11.1 mmol) in acetonitrile (25 mL) was added C8 (3.60 g, 12.2 mmol), followed by a solution of / V, / V, / V', / V'-tetramethylguanidine (4.17 mL, 33.2 mmol) in acetonitrile (5 mL). After the reaction mixture had been stirred overnight at room temperature, most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed sequentially with 5% aqueous citric acid solution, water, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) provided C9 as a colorless oil that solidified uponstanding. Yield: 5.24 g, 10.8 mmol, 97%. LCMS m / z 386.1 (bromine isotope pattern observed) [(M - terf-butoxycarbonyl)+H]+.1H NMR (400 MHz, DMSO-d6) 88.02 (d, J= 1.6 Hz, 1H), 7.80 (d, J= 8.5 Hz, 1H), 7.55 (dd, J= 8.5, 1.6 Hz, 1H), 7.33 (br s, 1H), 4.77 (brd, J= 10.4 Hz, 1H), 4.53 (d, J= 10.3 Hz, 1H), 3.87 (s, 3H), 3.62 (s, 3H), 1.49 (s, 3H), 1.19 (s, 9H).

[0310] Step 3. Synthesis of methyl (3R)-8-bromo-3-methyl-5-oxo-2,3,4,5-tetrahydro[1]benzofuro[2,3-f][1,4]oxazepine-3-carboxylate (C10).

[0311] A mixture of C9 (5.20 g, 10.7 mmol) and trichloroacetic acid (5.24 g, 32.1 mmol) in toluene (100 mL) was heated at 110 °C for 36 hours, whereupon it was concentrated in vacuo. The residue was re-evaporated from ethyl acetate and heptane before being purified via silica gel chromatography (Gradient: 0% to 10% methanol in dichloromethane). The resulting solid was triturated with heptane and ethyl acetate to provide C10 as a white solid. Yield: 2.39 g, 6.75 mmol, 63%. LCMS m / z 354.1 (bromine isotope pattern observed) [M+H]+.1H NMR (400 MHz, DMSO-d6) 88.49 (br s, 1 H), 7.97 (br s, 1 H), 7.64 (d, J = 8.4 Hz, 1 H), 7.48 (br d, J = 8.4 Hz, 1 H), 4.82 (d, J= 12.1 Hz, 1H), 4.28 (d, J= 12.1 Hz, 1H), 3.62 (s, 3H), 1.52 (s, 3H).

[0312] Step 4. Synthesis of methyl (3R)-8-bromo-4-[2-(dimethylamino)-2-oxoethyl]-3-methyl-5-oxo-2,3,4,5-tetrahydro[1]benzofuro[2,3-f][1,4]oxazepine-3-carboxylate (C11).

[0313] A solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (1 M; 1.69 mL, 1.69 mmol) was added slowly via syringe to a solution of C10 (300 mg, 0.847 mmol) in N, N-dimethylformamide (3 mL). After the reaction mixture had been stirred at room temperature for 30 minutes, it was treated with a solution of 2-chloro- / V, / V-dimethylacetamide (206 mg, 1.69 mmol) in / V, / V-dimethylformamide (0.5 mL), and stirring was continued at room temperature for 16 hours. LCMS analysis indicated conversion to C11: LCMS m / z 439.0 (bromine isotope pattern observed) [M+H]+. Aqueous ammonium chloride solution was added, followed by water, and the resulting mixture was extracted three times with ethyl acetate. The combined organic layers were washed sequentially with aqueous sodium bicarbonate solution and aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo purification via chromatography on silica gel (Gradient: 0% to 10% methanol in dichloromethane) afforded C11 as an off-white solid. Yield: 298 mg, 0.678 mmol, 80%.1H NMR (400 MHz, DMSO-d6) 88.00 (d, J = 1.6 Hz, 1 H), 7.66 (d, half of AB quartet, J = 8.4 Hz, 1 H), 7.50 (dd, component of ABX system, J = 8.4, 1.6 Hz, 1 H), 4.93 (d, J = 12.3 Hz, 1 H), 4.91 (d, J = 17.4 Hz, 1H), 4.55 (d, J= 12.3 Hz, 1H), 4.20 (d, J= 17.4 Hz, 1H), 3.59 (s, 3H), 3.03 (s, 3H), 2.84 (s, 3H), 1.67 (br s, 3H).

[0314] Step 5. Synthesis of (3R)-8-bromo-4-[2-(dimethylamino)-2-oxoethyl]-3-methyl-5-oxo-2, 3,4,5-tetrahydro[1]benzofuro[2,3-f][1,4]oxazepine-3-carboxylic acid (P1).A solution of C11 (280 mg, 0.637 mmol) in a mixture of tetrahydrofuran (10 mL) and methanol (1 mL) was combined with an aqueous solution of lithium hydroxide (1 M; 3.19 mL, 3.19 mmol), and the reaction mixture was heated at 50 °C for 16 hours. After cooling to room temperature and removal of most of the solvents via concentration under reduced pressure, the reaction mixture was diluted with water (20 mL) and then adjusted to pH 4 by addition of 3 M hydrochloric acid. The resulting mixture was stirred at room temperature until a filterable precipitate formed; this was collected via filtration to provide P1 as a solid. Yield: 232 mg, 0.546 mmol, 86%. LCMS m / z 425.2 (bromine isotope pattern observed) [M+H]+.1H NMR (400 MHz, DMSO-d6) 8 13.69 (br s, 1 H), 8.00 (d, J = 1.6 Hz, 1 H), 7.66 (d, half of AB quartet, J = 8.4 Hz, 1H), 7.50 (dd, component of ABX system, J= 8.4, 1.6 Hz, 1H), 4.88 (d, J= 12.1 Hz, 1H), 4.81 (d, J= 17.5 Hz, 1H), 4.51 (d, J= 12.1 Hz, 1H), 4.30 (br d, J= 17.5 Hz, 1H), 3.05 (s, 3H), 2.87 (s, 3H), 1.64 (s, 3H).

[0315] Retention time: 4.94 minutes. Analytical conditions: (Column: Chiral Technologies Chiralpak IH, 4.6 x 250 mm, 5 pm; Mobile phase A: carbon dioxide; Mobile phase B: propan-2-ol containing 0.2% propan-2-amine; Gradient: 5% B for 0.50 minutes, then 5% to 60% B over 5.0 minutes, then 60% B for 2.0 minutes; Back pressure: 100 bar; Flow rate: 3.0 mL / minute).

[0316] Preparation P2: (3R)-4-[2-(Dimethylamino)-2-oxoethyl]-3-methyl-8-(1,3-oxazol-2-yl)-5-oxo-2,3,4,5-tetrahydro[1]benzofuro[2,3-f][1,4]oxazepine-3-carboxylic acid (P2)

[0317]

[0318] Step 1. Synthesis of tert-butyl [(3R)-4-[2-(dimethylamino)-2-oxoethyl]-3-methyl-8-(1,3-oxazol-2-yl)-5-oxo-2,3,4,5-tetrahydro[1]benzofuro[2,3- / ][1,4]oxazepine-3-carbonyl][(1S)-1-phenylethyl]carbamate (C12).

[0319] To a mixture of C6 (3.00 g, 4.77 mmol), 1,3-oxazole (659 mg, 9.54 mmol), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1, T-biphenyl)[2-(2'-amino-1, T-biphenyl)]palladium(ll)methanesulfonate (RuPhos Pd G3; 400 mg, 0.478 mmol), and potassium carbonate (1.98 g, 14.3 mmol) in toluene (50 mL) was added 2,2-dimethylpropanoic acid (487 mg, 4.77 mmol), whereupon the reaction mixture was stirred at 110 °C for 16 hours before being concentrated under reduced pressure. Water (100 mL) was added, and the resulting mixture was extracted with dichloromethane (2 x 100 mL); the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by silica gel chromatography (Gradient: 20% to 60% ethyl acetate in dichloromethane), affording C12 as a yellow solid. Yield: 2.10 g, 3.41 mmol, 71%. LCMS m / z 572.3 [M - NMe2]+.1H NMR (400 MHz, chloroform-d) 88.13 (s, 1H), 7.99 (dd, J= 8.3, 1.3 Hz, 1 H), 7.77 (s, 1 H), 7.69 (d, J = 8.3 Hz, 1 H), 7.29 (s, 1 H), 7.08 - 6.90 (m, 5H), 5.47 - 5.36 (m, 1H), 5.31 (d, J= 17.2 Hz, 1H), 4.98 (s, 2H), 4.06 (d, J= 17.2 Hz, 1H), 3.12 (s, 3H), 2.96 (s, 3H), 1.99 (s, 3H), 1.32 (s, 9H), 1.05 - 0.98 (m, 3H).

[0320] Step 2. Synthesis of (3R)-4-[2-(dimethylamino)-2-oxoethyl]-3-methyl-8-(1,3-oxazol-2-yl)-5-oxo-2,3,4,5-tetrahydro[1]benzofuro[2,3-f][1,4]oxazepine-3-carboxylic acid (P2).

[0321] A solution of C12 (2.10 g, 3.41 mmol) in methanol (30 mL) was treated with a solution of sodium hydroxide (1.36 g, 34.0 mmol) in water (3 mL), whereupon the reaction mixture was stirred at 70 °C for 10 hours. Solvent was removed in vacuo the residue was diluted with water (30 mL) and washed with dichloromethane (2 x 40 mL). The aqueous layer was then acidified to pH 3 by addition of 4 M hydrochloric acid. Filtration provided a filter cake, which was washed with water to afford P2 as a white solid. Yield: 1.05 g, 2.54 mmol, 74%. LCMS m / z 414.0 [M+H]+.1H NMR (400 MHz, chloroform-d) 88.11 (s, 1H), 8.00 (dd, J= 8.4, 1.3 Hz, 1H), 7.78 (d, J= 8.4 Hz, 1H), 7.75 (s, 1H), 7.28 (s, 1H), 5.05 (d, J= 17.0 Hz, 1H), 5.04 (d, J= 11.7 Hz, 1H), 4.25 (d, J= 11.9 Hz, 1H), 3.89 (d, J= 16.8 Hz, 1H), 3.22 (s, 3H), 3.11 (s, 3H), 1.76 (s, 3H).

[0322] Example 1: (3R)-4-[2-(dimethylamino)-2-oxoethyl]-N-[(3-ethoxypyridin-2-yl)methyl]-3-methyl-5-oxo-8-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-2,3,4,5-tetrahydro[1]benzofuro[2,3-f][1,4]oxazepine-3-carboxamide (1)

[0323]

[0324]

[0325] Step 1. Synthesis of (3 / ?)-8-bromo-4-[2-(dimethylamino)-2-oxoethyl]- / \ / -[(3-ethoxypyridin-2-yl)methyl]-3-methyl-5-oxo-2,3,4,5-tetrahydro[1]benzofuro[2,3- / ][1,4]oxazepine-3-carboxamide (C13).

[0326] 1-(3-Ethoxypyridin-2-yl)methanamine (2.77 g, 18.2 mmol) was added to a solution of P1 (4.99 g, 11.7 mmol) in dichloromethane (100 mL). 1-Methyl-1 / - / -imidazole (5.12 mL, 64.2 mmol) was then added, followed by chloro(dimethylamino)- / V, / V-dimethylmethaniminium hexafluorophosphate (4.77 g, 17.0 mmol), whereupon the reaction mixture was stirred at room temperature for 7 hours and concentrated in vacuo. The residue was purified using silica gel chromatography (Eluent: 2 column volumes of dichloromethane, followed by a gradient of 0% to 10% methanol in dichloromethane), and the resulting material was triturated with heptane (3 x 100 mL), then with diethyl ether (3 x 50 mL). The remaining gum was dissolved in ethyl acetate (120 mL) and washed with saturated aqueous sodium chloride solution (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. After this material had been subjected to repurification via silica gel chromatography (Eluent: 2 column volumes of dichloromethane, followed by a gradient of 0% to 10% methanol in dichloromethane), it was triturated first with diethyl ether (3 x 70 mL), then with a mixture of diethyl ether and heptane (1:1, 70 mL), affording C13 as an off-white, tacky solid (6.92 g). A portion of this material was progressed to the following step. LCMS m / z 561.3 (bromine isotope pattern observed) [M+H]+.

[0327] 1H NMR (400 MHz, chloroform-d), selected peaks: 87.48 (d, J= 8.4 Hz, 1H), 7.35 (d, J= 8.4Hz, 1 H), 4.60 (br d, J= 16 Hz, 1H), 4.53 - 4.41 (m, 2H), 4.05 - 3.88 (m, 2H), 3.71 (s, 3H), 3.15 (s, 3H), 1.39 (t, J = 6.9 Hz, 3H).

[0328] Step 2. Synthesis of (3R)-8-cyano-4-[2-(dimethylamino)-2-oxoethyl]- / \ / -[(3-ethoxypyridin-2-yl)methyl]-3-methyl-5-oxo-2,3,4,5-tetrahydro[1]benzofuro[2,3- |[1,4]oxazepine-3-carboxamide (C14).

[0329] A vial containing C13 (from the previous step; 1.00 g, <1.69 mmol), potassium hexacyanoferrate(ll) trihydrate (378 mg, 0.895 mmol), [(2-di-terf-butylphosphino-2',4',6'-tri isopropyl- 1, 1 '-biphenyl)-2-(2'-amino-1, 1 -biphenyl)] palladium^ I) methanesulfonate

[0330] (f-BuXPhos Pd G3; 217 mg, 0.273 mmol), and di-tert-butyl[2',4',6'-tri(propan-2-yl)biphenyl-2-yl]phosphane (f-BuXPhos; 113.9 mg, 0.268 mmol) was evacuated and filled with nitrogen. This evacuation-nitrogen cycle was carried out a total of three times, whereupon degassed 1,4-dioxane (3.5 mL) was added. After the resulting mixture had been stirred for 2 minutes, degassed aqueous potassium acetate solution (62 mM; 3.46 mL, 0.214 mmol) was added, and the reaction mixture was heated at 100 °C for 1 hour. It was then allowed to cool to room temperature, combined with two similar reactions carried out using C13 (from the previous step, total 1.50 g, <2.54 mmol), diluted with dichloromethane, and filtered through diatomaceous earth. The filter cake was rinsed with dichloromethane, and the combined filtrates were washed with aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (Eluent: 100% dichloromethane for 1 column volume, followed by a gradient of 0% to 10% methanol in dichloromethane) provided C14 as an off-white solid. Combined yield: 1.70 g, 3.36 mmol, 79% over 2 steps. LCMS m / z 506.4 [M+H]+.

[0331] Step 3. Synthesis of (3R)-4-[2-(dimethylamino)-2-oxoethyl]- / \ / -[(3-ethoxypyridin-2-yl)methyl]-8-( / V-hydroxycarbamimidoyl)-3-methyl-5-oxo-2,3,4,5-tetrahydro[1]benzofuro[2,3- / ][1,4]oxazepine-3-carboxamide (C15).

[0332] A mixture of C14 (1.66 g, 3.28 mmol) and hydroxylamine hydrochloride (342 mg, 4.92 mmol) in methanol (33 mL) was treated with / V, / V-diisopropylethylamine (1.14 mL, 6.54 mmol), whereupon the reaction mixture was allowed to stir overnight at 40 °C. After a second addition of hydroxylamine hydrochloride (57 mg, 0.82 mmol) and / V, / V-diisopropylethylamine (0.18 mL, 1.0 mmol), stirring was continued for 50 minutes at 40 °C. Hydroxylamine hydrochloride (171 mg, 2.46 mmol) and / V, / V-diisopropylethylamine (0.715 mL, 4.10 mmol) were again added; after an additional 2 hours and 40 minutes at 40 °C, the reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The resulting thick gum was dissolved in dichloromethane (150 mL) and washed with saturated aqueous sodium chloride solution (25 mL). The aqueous layer was extracted with dichloromethane (2 x25 mL); the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo toprovide C15 as an off-white solid (2.63 g). By1H NMR analysis, this material was impure; it was progressed to the following step without purification. LCMS m / z 539.3 [M+H]+.

[0333] Step 4. Synthesis of (3R)-4-[2-(dimethylamino)-2-oxoethyl]-N-[(3-ethoxypyridin-2-yl)methyl]-3-methyl-5-oxo-8-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-2,3,4,5-tetrahydro[1]benzofuro[2,3-f][1,4]oxazepine-3-carboxamide (1).

[0334] A mixture of C15 (from the previous step; 2.63 g, <3.28 mmol) and tetrahydrofuran (33 mL) was cooled in an ice bath with stirring. Trifluoroacetic anhydride (0.924 mL, 6.54 mmol) was added; stirring was continued at 0 °C for 5 minutes, whereupon the reaction mixture was allowed to warm slowly to room temperature. After approximately 45 minutes, dichloromethane (100 mL) was added, and the resulting mixture was washed with saturated aqueous sodium bicarbonate solution (30 mL). The aqueous layer was extracted with dichloromethane (2 x 30 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 100% dichloromethane for 1 column volume, then 0% to 5% methanol in dichloromethane) was followed by purification via supercritical fluid chromatography (Column: PrincetonSFC 2-ethylpyridine, 30.0 x 250 mm, 5 pm; Mobile phase: 85:15 carbon dioxide I methanol; Back pressure: 100 bar; Flow rate: 80 mL / minute). The purified material was then taken up in dichloromethane, concentrated in vacuo, dissolved in ethanol (5 mL), and concentrated once more to afford (3R)-4-[2-(dimethylamino)-2-oxoethyl]-N-[(3-ethoxypyridin-2-yl)methyl]-3-methyl-5-oxo-8-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-2,3,4,5-tetrahydro[1]benzofuro[2,3-f][1,4]oxazepine-3-carboxamide (1) as a white solid. Yield: 1.23 g, 1.99 mmol, 61% over 2 steps. LCMS m / z 617.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 89.44 (br s, 1H), 8.20 (s, 1H), 7.96 (dd, component of ABX system, J = 8.2, 1.3 Hz, 1 H), 7.83 (d, half of AB quartet, J = 8.2 Hz, 1 H), 7.49 (br s, 1 H), 7.17 (d, J= 8.3 Hz, 1H), 6.95 (br s, 1H), 4.89 (brd, J= 12.1 Hz, 1H), 4.50 (s, 2H), 4.40 (brd, J = 11.9 Hz, 1 H), [4.33 (d, J = 5.2 Hz) and 4.30 (d, J = 6.2 Hz), total 1 H], 4.21 - 4.05 (m, 1 H), 4.04 - 3.86 (m, 2H), 3.07 (s, 3H), 2.86 (s, 3H), 1.60 (br s, 3H), 1.27 (t, J = 6.9 Hz, 3H).

[0335] Example 2: (3R)-4-[2-(dimethylamino)-2-oxoethyl]-N-[(3-methoxypyridin-2-yl)methyl]-3-methyl- 8-(4-methyl-1,3-oxazol-2-yl)-5-oxo-2,3,4,5-tetrahydro[1]benzofuro[2,3-f][1,4]oxazepine-3-carboxamide (2)

[0336]

[0337] Step 1. Synthesis of methyl 2-[(3R)-4-[2-(dimethylamino)-2-oxoethyl]-3-{[(3-methoxypyridin-2-yl)methyl]carbamoyl}-3-methyl-5-oxo-2,3,4,5-tetrahydro[1]benzofuro[2,3- / ][1,4]oxazepin-8-yl]-1,3-oxazole-4-carboxylate (C17).

[0338] A solution of (3?)-8-(4-cyano-1,3-oxazol-2-yl)-4-[2-(dimethylamino)-2-oxoethyl]- / \ / -[(3-methoxypyridin-2-yl)methyl]-3-methyl-5-oxo-2,3,4,5-tetrahydro[1]benzofuro[2,3-f][1,4]oxazepine-3-carboxamide (C16) (see R. T. Wester and M. Serrano-Wu, WO 2023 / 150374 A1, August 10, 2023; Example 129) (29.7 g, 53.2 mmol) in methanol (665 mL) was treated with an aqueous solution of sodium hydroxide (1 M; 106 mL, 106 mmol), and the reaction mixture was allowed to stir at 40 °C. After 20 minutes, the mixture was adjusted to pH 5 by addition of aqueous sodium bisulfate solution (1 M; 125 mL, 125 mmol). Water (400 mL) and methanol (50 mL) were then added, and heating was continued at 40 °C for 2 hours and 20 minutes, whereupon the reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (250 mL). Filtration of the resulting mixture provided a filter cake, which was washed with water to afford C17 as a solid. Yield: 28.3 g, 47.8 mmol, 90%. LCMS m / z 592.5 [M+H]+.The absolute stereochemistry of starting material C16 was confirmed by the X-ray structure determination carried out below on a sample of Example 2 prepared from C16.

[0339] Step 2. Synthesis of (3R)-4-[2-(dimethylamino)-2-oxoethyl]-8-[4-(hydroxymethyl)-1,3-oxazol-2-yl]- / V-[(3-methoxypyridin-2-yl)methyl]-3-methyl-5-oxo-2,3,4,5-tetrahydro[1]benzofuro[2,3-f|[1,4]oxazepine-3-carboxamide (C18).

[0340] A mixture of C17 (3.30 g, 5.58 mmol), 1,2-dichloroethane (14 mL), and methanol (14 mL) was sonicated for approximately 1 minute. The resulting suspension was cooled in an ice bath, treated with a solution of lithium borohydride in tetrahydrofuran (2 M; 11 mL, 22 mmol), stirred for 5 minutes at room temperature and then heated at 60 °C. After 1 hour, additional lithium borohydride solution (0.5 equivalents) was added; 0.5 equivalents of lithium borohydride solution was again introduced after an additional 30 minutes. The reaction mixture was maintained at 60 °C for another 30 minutes, whereupon it was allowed to cool to room temperature and then acidified by addition of 1 M aqueous sodium bisulfate. After addition of saturated aqueous sodium bicarbonate solution, the resulting mixture was extracted twice with dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo silica gel chromatography (Gradient: 1% methanol in dichloromethane for 2 column volumes, followed by 1% to 15% methanol in dichloromethane) afforded C18 as a white solid. Yield: 2.13 g, 3.78 mmol, 68%. LCMS m / z 564.3 [M+H]+.

[0341] Step 3. Synthesis of (3R)-4-[2-(dimethylamino)-2-oxoethyl]-N-[(3-methoxypyridin-2-yl)methyl]-3-methyl-8-(4-methyl-1,3-oxazol-2-yl)-5-oxo-2,3,4,5-tetrahydro[1]benzofuro[2,3-f][1,4]oxazepine-3-carboxamide (2).

[0342] A solution of C18 (10 g, 18 mmol) in a mixture of methanol (75 mL) and dichloromethane (35 mL) was treated with palladium^ I) chloride (2.0 g, 11 mmol), whereupon it was hydrogenated at 25 to 50 psi overnight at room temperature. The reaction mixture was then filtered; the filter cake was rinsed with methanol, and the combined filtrates were concentrated in vacuo. After the residue had been dissolved in dichloromethane (100 mL), it was washed twice with saturated aqueous sodium bicarbonate solution. The combined aqueous layers were extracted twice with dichloromethane, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. This crude product (8.96 g) was combined with the products of 4 similar hydrogenations carried out on C18 (total of 47.9 g of C18 used in the 5 reactions, 87.5 mmol) and purified via supercritical fluid chromatography {Column: Chiral Technologies Chiralpak AS-H, 30.0x250 mm, 5 pm; Mobile phase: 4:1 carbon dioxide I [methanol containing 0.2% (7 M ammonia in methanol)]; Back pressure: 120 bar; Flow rate: 250 mL / minute}. The resulting material (30.2 g) was stirred in ethanol (180 mL) for 2 days at 600 rpm. Collection of the solids via filtration afforded (3R)-4-[2-(dimethylamino)-2-oxoethyl]-N-[(3-methoxypyridin-2-yl)methyl]-3-methyl-8-(4-methyl-1, 3-oxazol-2-yl)-5-oxo-2, 3,4,5-tetrahydro[1]benzofuro[2,3-f][1,4]oxazepine-3-carboxamide (2) as a solid. Combined yield: 27.7 g, 50.6 mmol, 58%. LCMS m / z 548.4 [M+H]+.1H NMR (600 MHz, DMSO-d6) 89.46 (brs, 1 H), 8.03 (s, 1 H), 7.98 (s, 1 H), 7.87 (d, J = 8.2 Hz, 1 H), 7.73 (br d, J = 8.2 Hz, 1 H), 7.53 (br s, 1 H), 7.26-7.16 (m, 1H), 7.01 (brs, 1H), 4.88 (brs, 1H), 4.48 (brs, 2H), 4.41 -4.34 (m, 1H), 4.31 (dd, J= 15.6, 6.2 Hz, 1H), 4.12 (brs, 1H), 3.68 (s, 3H), 3.06 (s, 3H), 2.85 (s, 3H), 2.20 (s, 3H), 1.59 (brs, 3H).

[0343] The absolute stereochemistry of Example 2 was confirmed via single-crystal X-ray analysis.

[0344] Single-crystal X-ray structural determination of 2

[0345] Data collection was performed on a Bruker D8 Quest diffractometer at 298 K. Data collection consisted of omega and phi scans.

[0346] The structure was solved by intrinsic phasing using SHELX software suite in the monoclinic space group P2i. The structure was subsequently refined by the full-matrix least squares method. All non-hydrogen atoms were found and refined using anisotropic displacement parameters.

[0347] The hydrogen atoms located on nitrogen were found from the Fourier difference map and refined. The remaining hydrogen atoms were placed in calculated positions and were allowed to ride on their carrier atoms. The final refinement included isotropic displacement parameters for all hydrogen atoms.

[0348] The structure contains residual void space of 14.4 A3, which accounts for 1.1% of the unit cell volume.

[0349] Analysis of the absolute structure using likelihood methods (Hooft, 2008) was performed using PLATON (Spek). The results indicate that the absolute structure has been correctly assigned. The method calculates that the probability that the structure is correctly assigned is 1.000. The Hooft parameter is reported as 0.09 with an esd (estimated standard deviation) of 0.05 and the Parson’s parameter is reported as 0.09 with an esd of 0.05.

[0350] The final R-index was 5.51%. A final difference Fourier revealed no missing or misplaced electron density.

[0351] Pertinent crystal, data collection, and refinement information is summarized in Table A. Atomic coordinates, displacement parameters, bond lengths, bond angles, and torsion angles are listed in Tables B - F.

[0352] Software and References

[0353] SHELXTL, Version 5.1, Bruker AXS, 1997.

[0354] PLATON, A. L. Spek, J. Appl. Cryst. 2003, 36, 7–13.

[0355] MERCURY, C. F. Macrae, P. R. Edgington, P. McCabe, E. Pidcock, G. P. Shields, R. Taylor, M.Towler, and J. van de Streek, J. Appl. Cryst. 2006, 39, 453–457.

[0356] OLEX2, O. V. Dolomanov, L. J. Bourhis, R. J. Gildea, J. A. K. Howard, and H. Puschmann, J. Appl. Cryst. 2009, 42, 339–341.

[0357] R. W. W. Hooft, L. H. Straver, and A. L. Spek, J. Appl. Cryst. 2008, 41, 96–103.

[0358] H. D. Flack, Acta Cryst. 1983, A39, 867-881.

[0359] Table A. Crystal data and structure refinement for 2.

[0360] Empirical formula C28H29N5O7

[0361] Formula weight 547.56

[0362] Temperature 298 K

[0363] Crystal system Monoclinic

[0364] Space group P2i

[0365] Unit cell dimensions a = 6.53670(10) A a = 90°

[0366] b = 13.1272(2) A / 3 = 95.0490(10)° c = 15.6628(3) A y = 90° Volume 1338.79(4) A3

[0367] Z 2

[0368] ρcalc1.358 g / cm3

[0369] μ 0.826 mm−1

[0370] F(000) 576.0

[0371] Radiation CuKa (A = 1.54178)

[0372] 2Θ range for data collection 11.342 to 149.452°

[0373] Index ranges −6 ≤ h ≤ 7, −16 ≤ k ≤ 16, −19 ≤ l ≤ 19 Reflections collected 40775

[0374] Independent reflections 5407 [Rint= 0.0471, Rsigma= 0.0262] Data I restraints I parameters 5407 / 1 / 370

[0375] Goodness-of-fit on F21.059

[0376] Final R indices [I ≥ 2σ(I)] R1= 0.0551, wR2= 0.1511

[0377] R indices (all data) R1= 0.0576, wR2= 0.1561

[0378] Largest diff. peak and hole 0.42 and -0.25 e A’3

[0379] Flack parameter 0.07(6)

[0380] Table B. Fractional atomic coordinates (x 104) and equivalent isotropic displacement parameters (A2x 103) for 2. U(eq) is defined as one-third of the trace of the orthogonalized Uijtensor.

[0381] x y z U(eq)01 -2007(4) 5820(2) 3958.8(19) 58.6(6) 02 5025(3) 5418.6(17) 5624.7(15) 43.5(5) 03 8606(4) 6159(2) 6300.5(19) 58.1(7) 04 7041(4) 2891.6(17) 5834.0(16) 47.8(5) 05 6669(6) 2633(3) 7677(2) 76.1(10) 06 9699(7) 3549(4) 9732(3) 98.6(13) 07 9956(5) 5871(3) 8325(2) 81.2(10) N1 -2698(5) 4323(3) 3347(2) 55.5(7) N2 9729(4) 4671(2) 6884.5(16) 39.9(5) N3 12916(6) 6610(3) 8048(3) 74.8(11) N4 7232(5) 4225(3) 8191.2(19) 54.7(7) N5 5840(11) 5349(5) 10067(4) 108.0(18) 01 -6125(7) 4703(5) 2515(3) 76.2(13) 02 -4277(5) 4999(3) 3102(2) 55.3(9) 03 -3860(6) 5899(4) 3469(3) 60.4(9) 04 -1417(5) 4837(3) 3848(2) 45.7(7) 05 521(5) 4514(3) 4298(2) 43.7(7) 06 1772(5) 5219(3) 4754(2) 43.5(7) 07 3575(4) 4847(2) 5163.8(18) 39.8(6) 08 6547(5) 4741(2) 5945.9(19) 39.4(6) 09 8335(5) 5247(2) 6391(2) 41.0(6) 010 9358(5) 3590(2) 7088(2) 42.5(7) 011 9046(5) 2932(3) 6280(2) 49.5(7) 012 6058(4) 3782(2) 5679.0(18) 38.6(6) 013 4144(5) 3826(2) 5159.4(19) 39.3(6) 014 2886(5) 3123(3) 4681(2) 46.0(7) 015 1094(5) 3481(3) 4252(2) 47.3(7) 016 11628(5) 5220(3) 7144(2) 44.4(7) 017 11421(6) 5925(3) 7889(2) 54.2(8) 018 14658(7) 6747(5) 7548(5) 87.2(17) 019 12899(15) 7276(8) 8796(8) 157(5) 020 11234(7) 3143(3) 7619(3) 64.2(11) 021 7571(5) 3462(3) 7673(2) 50.7(8) 022 5990(6) 4101(5) 8913(3) 74.0(14) 023 6866(8) 4638(4) 9711(3) 72.4(12)C24 6510(20) 5778(7) 10798(6) 129(3)

[0382] C25 8450(20) 5480(8) 11203(8) 152(4)

[0383] C26 9628(16) 4794(8) 10840(5) 128(3)

[0384] C27 8857(9) 4320(4) 10093(3) 74.5(13)

[0385] C28 11646(15) 3197(11) 10136(6) 154(5)

[0386] Table C. Anisotropic displacement parameters (A2x 103) for 2. The anisotropic displacement factor exponent takes the form: -2π2[h2a*2U11+ 2hka*b*U12+...].

[0387] >

[0388] U11 U22 U33 U23 U13 U12

[0389] 01 46.8(13) 48.7(14) 76.6(17) -2.4(12) -15.5(11) 5.3(11) 02 41.2(11) 35.9(11) 50.4(11) 0.5(9) -13.6(9) -0.8(8) 03 57.4(14) 41.2(13) 71.7(16) 7.7(11) -16.5(12) -9.2(11) 04 48.4(12) 37.0(11) 54.3(12) -5.7(9) -17.1(10) 6.8(9) 05 86(2) 74(2) 66.3(17) 1.9(15) -1.4(15) -42.2(18) 06 96(3) 118(3) 80(2) -2(2) -6(2) 25(3) 07 79(2) 93(2) 75.3(19) -34.0(17) 26.1(16) -34.0(18) N1 46.2(15) 63.7(19) 53.2(15) -2.7(14) -14.9(12) 3.3(13) N2 30.2(11) 44.2(14) 43.5(12) 2.5(11) -6.5(9) -3.6(10) N3 63(2) 67(2) 95(3) -36(2) 9.3(18) -22.6(18) N4 46.0(15) 73(2) 44.5(14) 1.6(13) 2.4(11) -16.9(14) N5 133(5) 98(4) 97(3) -1(3) 32(4) 10(4) C1 52(2) 99(4) 72(2) -1(3) -25.2(19) 5(2) C2 41.6(16) 74(2) 47.8(17) 6.3(16) -9.4(13) 1.2(16) 03 43.4(17) 64(2) 72(2) 10.2(19) -9.1(16) 8.6(16) 04 41.1(15) 48.4(17) 46.3(16) 1.6(13) -3.7(12) 3.3(13) 05 41.4(16) 46.6(16) 41.5(14) 2.0(13) -5.5(11) 1.6(13) 06 40.1(15) 42.6(15) 46.0(15) 1.4(12) -7.4(12) 3.6(12) 07 37.6(15) 40.3(15) 40.0(14) 0.5(12) -5.2(11) 0.2(12) 08 34.9(14) 40.0(15) 41.7(13) 3.5(12) -5.6(11) 1.7(11) 09 36.9(15) 41.9(15) 43.0(14) 2.0(12) -3.3(11) -4.6(12) C10 38.3(15) 40.8(15) 46.2(15) 4.4(12) -9.2(12) 0.4(12) C11 38.6(16) 46.6(17) 60.8(19) -4.8(15) -9.2(14) 7.2(13) C12 39.3(14) 37.7(14) 37.1(13) -0.1(11) -5.7(11) 4.5(11)C13 39.1(14) 38.5(14) 38.7(13) -1.0(11) -5.2(11) 0.5(12) C14 50.6(18) 40.8(16) 43.6(15) -4.9(12) -12.9(13) 3.3(13) C15 48.3(17) 47.6(17) 43.2(15) -4.7(13) -11.6(13) 1.9(13) C16 32.4(14) 48.3(17) 51.2(16) -2.6(13) -3.1(11) -7.6(12) C17 49.1(18) 56(2) 57.3(19) -9.3(16) 1.8(14) -6.7(15) C18 53(2) 78(3) 132(5) -34(3) 15(3) -24(2) C19 132(6) 148(7) 198(9) -124(8) 47(6) -62(6) C20 54(2) 55(2) 78(3) 8.5(18) -27.2(19) 1.6(16) C21 44.0(17) 61(2) 45.0(16) 6.5(15) -9.6(12) -13.5(14) C22 46(2) 125(4) 50.9(19) -3(2) 4.0(15) -25(2) C23 88(3) 66(2) 67(2) 7(2) 29(2) -1(2) C24 213(11) 84(4) 97(5) -21(4) 49(6) -15(6) C25 202(11) 107(7) 139(8) -44(6) -24(8) 1(7) C26 151(7) 125(6) 97(4) -30(5) -45(5) 4(5) C27 84(3) 84(3) 52(2) 0(2) -18(2) -17(3) C28 109(6) 241(14) 112(6) 38(7) 3(5) 62(7)

[0390] Table D. Bond lengths [A] for 2.

[0391] Atom Atom Length Atom Atom Length

[0392] 01 03 1.380(4) N5 C24 1.317(11)

[0393] 01 04 1.362(5) C1 02 1.503(5)

[0394] 02 07 1.364(4) 02 03 1.331(7)

[0395] 02 08 1.395(4) 04 05 1.457(4)

[0396] 03 09 1.220(4) 05 06 1.391(5)

[0397] 04 011 1.431(4) 05 015 1.410(5)

[0398] 04 012 1.345(4) 06 07 1.380(4)

[0399] 05 021 1.237(5) 07 013 1.391(4)

[0400] 06 027 1.304(7) 08 09 1.466(4)

[0401] 06 028 1.447(9) 08 012 1.357(5)

[0402] 07 017 1.227(5) 010 011 1.530(5)

[0403] N1 02 1.389(5) 010 020 1.536(4)

[0404] N1 04 1.288(5) 010 021 1.556(5)

[0405] N2 09 1.370(4) 012 013 1.433(4)N2 C10 1.479(4) C13 C14 1.407(4)

[0406] N2 C16 1.462(4) C14 C15 1.381(5)

[0407] N3 C17 1.335(5) C16 C17 1.504(5)

[0408] N3 C18 1.448(7) C22 C23 1.503(7)

[0409] N3 C19 1.463(8) C23 C27 1.445(8)

[0410] N4 C21 1.321(5) C24 C25 1.420(15)

[0411] N4 C22 1.458(5) C25 C26 1.343(16)

[0412] N5 C23 1.303(8) C26 C27 1.380(8)

[0413] Table E. Bond angles [°] for 2.

[0414] Atom Atom Atom Angle Atom Atom Atom Angle

[0415] C4 01 C3 104.1(3) N2 C10 C11 112.1(3) C7 02 08 106.3(2) N2 C10 C20 110.2(3) C12 04 C11 117.3(3) N2 C10 C21 112.1(3) C27 06 C28 116.6(6) C11 C10 C20 105.9(3) 04 N1 02 105.1(3) C11 C10 C21 111.9(3) 09 N2 C10 122.5(2) C20 C10 C21 104.2(3) 09 N2 C16 113.0(3) 04 C11 C10 118.3(3) C16 N2 C10 124.4(2) 04 C12 08 130.9(3) C17 N3 C18 125.5(4) 04 012 013 121.2(3) 017 N3 019 119.6(5) 08 012 013 107.9(3) 018 N3 019 114.8(5) 07 013 012 104.9(3) 021 N4 022 121.9(4) 07 013 014 119.4(3) 023 N5 024 122.2(8) 014 013 012 135.7(3) N1 02 01 122.7(4) 015 014 013 117.8(3) 03 02 N1 109.2(3) 014 015 05 121.4(3) 03 02 01 128.1(4) N2 016 017 112.8(3) 02 03 01 108.1(3) 07 017 N3 122.0(4) 01 04 05 117.3(3) 07 017 016 121.6(3) N1 04 01 113.5(3) N3 017 016 116.4(3) N1 04 05 129.3(3) 05 021 N4 123.9(4)06 05 04 120.1(3) 05 021 010 118.8(4) 06 05 015 121.3(3) N4 021 010 117.1(3) 015 05 04 118.7(3) N4 022 023 113.3(3) 07 06 05 116.3(3) N5 023 022 121.2(6) 02 07 06 125.2(3) N5 023 027 120.5(6) 02 07 013 111.0(3) 027 023 022 118.2(4) 06 07 013 123.8(3) N5 024 025 119.2(8) 02 08 09 113.4(3) 026 025 024 121.1(9) C12 08 02 109.8(2) 025 026 027 118.7(9) 012 08 09 136.3(3) 06 027 023 116.3(4) 03 09 N2 120.7(3) 06 027 026 125.4(6) 03 09 08 120.5(3) 026 027 023 118.0(6) N2 09 08 118.8(3)

[0416] Table F. Torsion angles [°] for 2.

[0417] A B C D Angle A B C D Angle

[0418] 01 04 05 06 -5.6(5) 09 N2 010 011 60.0(4) 01 04 05 015 174.9(3) 09 N2 010 020 177.6(3) 02 07 013 012 1.7(3) 09 N2 010 021 -66.9(4) 02 07 013 014 -177.0(3) 09 N2 016 017 79.6(4) 02 08 09 03 -15.7(4) 09 08 012 04 9.4(6) 02 08 09 N2 166.6(3) 09 08 012 013 -171.1(3) 02 08 012 04 -179.2(3) 010 N2 09 03 173.3(3) 02 08 012 013 0.2(3) 010 N2 09 08 -9.0(4) 04 012 013 07 178.4(3) 010 N2 016 017 -103.4(4) 04 012 013 014 -3.3(6) 011 04 012 08 -7.3(5) N1 02 03 01 -0.1(5) 011 04 012 013 173.4(3) N1 04 05 06 174.4(4) 011 010 021 05 30.6(4) N1 04 05 015 -5.1(5) 011 010 021 N4 -155.1(3) N2 010 011 04 -83.8(4) 012 04 011 010 47.1(4) N2 010 021 05 157.5(3) 012 08 09 03 155.4(4) N2 010 021 N4 -28.2(4) 012 08 09 N2 -22.3(5) N2 016 017 07 13.9(6) 012 013 014 015 -179.9(3)N2 C16 017 N3 -166.1(4) 013 014 015 05 -0.8(5) N4 C22 023 N5 119.8(6) 015 05 06 07 -0.7(5)

[0419] N4 C22 023 027 -62.3(6) 016 N2 09 03 -9.7(4)

[0420] N5 C23 027 06 174.7(5) 016 N2 09 08 168.0(3)

[0421] N5 C23 027 026 -0.2(9) 016 N2 010 011 -116.7(3)

[0422] N5 C24 025 026 2.2(17) 016 N2 010 020 0.9(4)

[0423] 01 02 03 01 179.6(4) 016 N2 010 021 116.5(3)

[0424] 02 N1 04 01 -0.3(4) 018 N3 017 07 -177.7(6)

[0425] 02 N1 04 05 179.7(3) 018 N3 017 016 2.2(8)

[0426] 03 01 04 N1 0.3(4) 019 N3 017 07 4.2(10)

[0427] 03 01 04 05 -179.7(3) 019 N3 017 016 -175.9(8)

[0428] 04 01 03 02 -0.1(4) 020 010 011 04 156.0(3)

[0429] 04 N1 02 01 -179.4(4) 020 010 021 05 -83.3(4)

[0430] 04 N1 02 03 0.3(4) 020 010 021 N4 91.0(4)

[0431] 04 05 06 07 179.8(3) 021 N4 022 023 138.7(5)

[0432] 04 05 015 014 -178.4(3) 021 010 011 04 43.2(4)

[0433] 05 06 07 02 178.3(3) 022 N4 021 05 10.1(6)

[0434] 05 06 07 013 -1.9(5) 022 N4 021 010 -163.9(3)

[0435] 06 05 015 014 2.1(5) 022 023 027 06 -3.2(7)

[0436] 06 07 013 012 -178.1(3) 022 023 027 026 -178.1(7)

[0437] 06 07 013 014 3.2(5) 023 N5 024 025 1.8(13)

[0438] 07 02 08 09 174.3(3) 024 N5 023 022 175.1(6)

[0439] 07 02 08 012 0.8(3) 024 N5 023 027 -2.8(9)

[0440] 07 013 014 015 -1.8(5) 024 025 026 027 -5.0(19)

[0441] 08 02 07 06 178.2(3) 025 026 027 06 -170.4(9)

[0442] 08 02 07 013 -1.6(3) 025 026 027 023 3.9(14)

[0443] 08 012 013 07 -1.1(3) 028 06 027 023 -177.1(7)

[0444] 08 012 013 014 177.2(4) 028 06 027 026 -2.7(11)

[0445] Example 3: (3R)-4-[2-(Dimethylamino)-2-oxoethyl]-N-[(3-methoxypyridin-2-yl)methyl]-3-methyl- 5-oxo-8-[4-(trifluoromethyl)-1,3-oxazol-2-yl]-2,3,4,5-tetrahydro[1]benzofuro[2,3-f][1,4]oxazepine-3-carboxamide (3)

[0446]

[0447] Step 1. Synthesis of (3R)-8-bromo-4-[2-(dimethylamino)-2-oxoethyl]- / \ / -[(3-methoxypyridin-2-yl)methyl]-3-methyl-5-oxo-2,3,4,5-tetrahydro[1]benzofuro[2,3- / ][1,4]oxazepine-3-carboxamide (C19).

[0448] To a solution of P1 (1.50 g, 3.53 mmol) in / V, / V-dimethylformamide (20 mL) were added O-(7-azabenzotriazol-1-yl)- / V, / V, / V’, / V -tetramethyl uronium hexafluorophosphate (HATLI; 2.68 g, 7.05 mmol), 1-(3-methoxypyridin-2-yl)methanamine (731 mg, 5.29 mmol), and N, N-diisopropylethylamine (3.07 mL, 17.6 mmol). After the reaction mixture had been stirred at 25 °C for 1 hour, it was diluted with water (40 mL) and extracted with a mixture of dichloromethane and methanol (10:1, 3 x 30 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification using reversed-phase chromatography (Column: C18, 80 g; Mobile phase A: water containing 0.1% formic acid; Mobile phase B: acetonitrile; Gradient: 0% to 30% B) provided C19 as a yellow solid. Yield: 1.20 g, 2.20 mmol, 62%. LCMS m / z 545.0 (bromine isotope pattern observed) [M+H]+.1H NMR (400 MHz, DMSO-d6), characteristic peaks: δ 9.42 (br s, 1 H), 7.92 (d, J = 1.6 Hz, 1 H), 7.56 (d, half of AB quartet, J = 8.5 Hz, 1 H), 7.45 (dd, component of ABX system, J = 8.4, 1.6 Hz, 1 H), 7.23 (d, J = 8.3 Hz, 1 H), 7.11 - 7.00 (m, 1 H), 4.85 (brd, J= 12.0 Hz, 1H), 4.46 (br s, 2H), 4.35 (br d, J= 12 Hz, 1H), 4.29 (dd, J= 15.5, 6.3 Hz, 1H), 4.12 (br s, 1H), 3.69 (s, 3H), 3.05 (s, 3H), 2.85 (s, 3H), 1.57 (br s, 3H).Step 2. Synthesis of (3R)-4-[2-(Dimethylamino)-2-oxoethyl]-N-[(3-methoxypyridin-2-yl)methyl]-3-methyl-5-oxo-8-[4-(trifluoromethyl)-1,3-oxazol-2-yl]-2,3,4,5-tetrahydro[1]benzofuro[2,3-f][1,4]oxazepine-3-carboxamide (3).

[0449] 1,4-Dioxane (8.5 mL) was added to a mixture of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (355 mg, 1.40 mmol), C19 (694 mg, 1.27 mmol), potassium acetate (375 mg, 3.82 mmol), and mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1, T-biphenyl)]palladium(ll) (cataCXium® A Pd G3; 92.7 mg, 0.127 mmol). After the reaction mixture had been heated at 90 °C for 4 hours, it was cooled to room temperature; aqueous potassium carbonate solution (1.5 M; 2.54 mL, 3.81 mmol) was added, followed by 2-bromo-4-(trifluoromethyl)-1,3-oxazole (302 mg, 1.40 mmol). This reaction mixture was stirred for 20 hours at 90 °C, whereupon it was concentrated under reduced pressure and then diluted with a 1: 1 mixture of dichloromethane and water. The aqueous layer was extracted twice with dichloromethane, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 5% methanol in dichloromethane, followed by a slow ramp to 10% methanol in dichloromethane) was followed by slurrying of the purified material in a mixture of ethanol (2.3 mL) and heptane (4.6 mL); filtration and washing of the filter cake with heptane afforded (3R)-4-[2-(Dimethylamino)-2-oxoethyl]-N-[(3-methoxypyridin-2-yl)methyl]-3-methyl-5-oxo-8-[4-(trifluoromethyl)-1,3-oxazol-2-yl]-2,3,4,5-tetrahydro[1]benzofuro[2,3-f][1,4]oxazepine-3-carboxamide (3) as a solid. Yield: 374 mg, 0.622 mmol, 44%. LCMS m / z 602.4 [M+H]+.1H NMR (600 MHz, DMSO-d6) 89.48 (br s, 1H), 9.11 (s, 1H), 8.18 (s, 1H), 7.94 (brd, J= 8 Hz, 1H), 7.84- 7.76 (m, 1H), 7.51 (brs, 1H), 7.22 (br s, 1 H), 7.01 br (s, 1 H), 4.89 (br s, 1 H), 4.50 (br s, 2H), 4.39 (br s, 1 H), 4.35 - 4.27 (m, 1H), 4.11 (brs, 1H), 3.68 (s, 3H), [3.07 (s) and 3.06 (s), total 3H], 2.86 (s, 3H), 1.59 (brs, 3H).

[0450] Table 1. Method of synthesis, structure, and physicochemical data for Examples 4- 7. The examples below were made from analogous processes to the Example(s) identified and from appropriate analogous starting materials.Method of

[0451] 1H NMR (400 MHz, DMSO-d6) 5; Mass synthesis;

[0452] spectrum, observed ion m / z [M+H]+or Example NonStructure HPLC retention time; Mass spectrum Number commerci

[0453] m / z [M+H]+(unless otherwise al starting

[0454] indicated) materials

[0455] 9.84 (br s, 1 H), 8.30 (d, J = 0.8 Hz, 1 H), 8.10 - 8.00 (m, 2H), 7.90 (dd, J= 8.2, 1.3 Hz, 1 H), 7.82 (br s, 1 H), 7.72 (d, J = 8.3 Hz, 1H), 7.46 (d, J= 0.8 Hz, 1H), 6.82 (d, H3C-O

[0456] J = 5.7 Hz, 1 H), 4.90 (d, J = 11.9 Hz, 1 H), 4.48 (AB quartet, downfield doublet is V-NHX- (f TlTN

[0457] 4 P21^ O-^.CH3broad, JAB = 17 Hz, AVAB= 59 Hz, 2H), j U U £.

[0458] 4.35 (d, J= 11.9 Hz, 1H), 4.14 (dd, O y o I

[0459] O ° CH3component of ABX system, J = 15.1, 6.2

[0460] Hz, 1H), 3.97 (dd, component of ABX system, J = 15.0, 5.0 Hz, 1H), 3.72 (s, 3H), 3.07 (s, 3H), 2.90 (s, 3H), 1.58 (br s,

[0461] 3H); 534.3

[0462] H3C-O M

[0463] \=N

[0464] °

[0465] Example 4; V-NH

[0466] 5 ^ O^. CH31.79 minutes2; 534.2

[0467] P2

[0468] MiCH3

[0469] HsCV-O

[0470] \=N

[0471] Example 4; ° v NH —

[0472] 6 ^ O^. CH31.95 minutes2; 548.2

[0473] P2

[0474] MVCH3

[0475] 9.41 (br s, 1 H), 8.30 (s, 1 H), 8.09 (br s, 1H), 7.91 (dd, J= 8.2, 1.3 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1 H), 7.51 (br s, 1 H), 7.45 Example 4;

[0476] 7 (s, 1H), 7.18 (d, J= 8.2 Hz, 1H), 6.97 (br P2

[0477] s, 1H), 4.88 (br d, J= 12.1 Hz, 1H), 4.50 (br s, 2H), 4.38 (br d, J = 11.9 Hz, 1 H), 4.30 (dd, component of ABX system, J =

[0478]

[0479] Method of

[0480] 1H NMR (400 MHz, DMSO-d6) 5; Mass synthesis;

[0481] spectrum, observed ion m / z [M+H]+or Example NonStructure HPLC retention time; Mass spectrum Number commerci

[0482] m / z [M+H]+(unless otherwise al starting

[0483] indicated) materials

[0484] 15.5, 6.1 Hz, 1H), 4.23 -4.07 (m, 1H), 4.03 - 3.87 (m, 2H), 3.06 (s, 3H), 2.85 (s, 3H), 1.59 (br s, 3H), 1.27 (t, J = 6.9 Hz,

[0485] 3H); 548.3

[0486] H3C-O

[0487] Compara O' 'iwCH

[0488] tor A1

[0489] Oven3

[0490] • CF3COOH

[0491]

[0492] 1. Reaction of P2 with 1-(4-methoxypyridin-3-yl)methanamine in the presence of O-(7-azabenzotriazol-1-yl)- / V, / V, / V’, / V-tetramethyluronium hexafluorophosphate and N, N-diisopropylethylamine provided Example 4.

[0493] 2. Analytical conditions. Column: Waters Atlantis C18, 4.6 x 50 mm, 5 pm; Mobile phase A: water containing 0.05% trifluoroacetic acid (v / v); Mobile phase B: acetonitrile containing 0.05% trifluoroacetic acid (v / v); Gradient: 5.0% to 95% B, linear over 4.0 minutes, then 95% B for 1.0 minute; Flow rate: 2 mL / minute.

[0494] EXAMPLE 3: KLF2 Hibit Assay

[0495] The assay conditions described below were designed to assess the induction of KLF2 HiBit-tagged protein by compounds of the disclosure in aortic endothelial immortalized cells (TeloHAECs). HiBit-tagged KLF2 induction in immortalized aortic endothelial cells was measured using the HiBit technology. The HiBiT technology was based on NanoLuc Binary Technology (NanoBiT), in which NanoLuc luciferase is broken down into two complementary components, an 11-amino-acid HiBiT tag and a 17.6 kD polypeptide named LgBiT. In the instant assay, the 11-amino-acid HiBiT peptide tag was introduced into an endogenous copy of KLF2, and the complementary LgBiT protein and furimazine substrate were added at lysis to promote complex formation and generate a bright, luminescent enzyme. The amount of luminescence was proportional to the amount of LKF 2 HiBiT-tagged protein in the cell lysate.

[0496] FIG. 1 illustrates the assay scheme for the KLF2 Hibit Assay.Preparation of compounds: Compounds of the disclosure were resuspended in 100% DMSO. An 11 point ½ log 3 mM top dose dilution scheme was prepared. (R)-4-(2-(dimethylamino)-2-oxoethyl)-N-((3-methoxypyridin-2-yl)methyl)-3-methyl-8-(oxazol-2-yl)-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide was resuspended to 100 μM in 100% DMSO.

[0497] Cell culture and plating: A vial of single use ready-frozen KLF2 Hi Bit Telo HAECs Clone 10 was thawed in growth media, with passage at 80% confluency. On assay day, cells were plated at 5K cells per well in 30 μLs of growth media. The cells were incubated for at least 4 hrs.

[0498] Compound treatment and KLF2 HiBit detection: 35 μLs of controls and / or compounds were plated in a 384 well plate using an ECHO liquid dispenser. 35 μL of starvation media was added to the compound plate. Media was discarded from the cell plate, and 20 μL of diluted compound was transferred to the plate. The compounds were incubated for 4 hours. 20 μL of Nano-Gio® HiBit Lytic reagent was added. The Nano-Gio® HiBit Lytic reagent was prepared by diluting the LgBiT protein 1:100 with an appropriate volume of room temperature Nano-Gio® HiBit Lytic buffer; and diluting the Nano-Gio® HiBit Lytic substrate 1:50 with an appropriate volume of room temperature Nano-Gio® HiBit Lytic buffer in a new tube, which was mixed by inversion. The samples were mixed by placing the plate on an orbital shaker (300 rpm-600 rpm) for 3-10 minutes. The samples were then left for at least 10 minutes to equilibrate LgBiT and Hi BiT in the lysate. Luminescence was measured using the Envision and US Lum settings. Dose data was normalized to zero percent effect (ZPE) using DMSO and hundred percent effect (HPE) using 100 nM of (R)-4-(2-(dimethylamino)-2-oxoethyl)-N-((3-methoxypyridin-2-yl)methyl)-3-methyl-8-(oxazol-2-yl)-5-oxo-2,3,4,5-tetrahydrobenzofuro[2,3-f][1,4]oxazepine-3-carboxamide.

[0499] TABLE 3.

[0500] C9790E: KLF2_E C9790E: KLF2_EC₅₀_HiBit KLF2- C₅₀_HiBit KLF2- Example3 μM Top Dose 3 μM Top Dose IUPAC Name NumberGeometric mean EC₅₀ (nM)EC₅₀ (nM) Replicate count

[0501] (3R)-4-[2-(dimethylamino)-2- oxoethyl]-N-[(3-ethoxypyridin-2- yl)methyl]-3-methyl-5-oxo-8-[5- 1 5.4 4 (trifluoromethyl)-1,2,4-oxadiazol- 3-yl]-2, 3,4,5- tetrahydro

[0001] benzofuro[2,3- f][1,4]oxazepine-3-carboxamide

[0502]

[0503] C9790E: KLF2_E C9790E: KLF2_EC₅₀_HiBit KLF2- C₅₀_HiBit KLF2- Example3 μM Top Dose 3 μM Top Dose IUPAC Name NumberGeometric mean EC₅₀ (nM)EC₅₀ (nM) Replicate count

[0504] (3R)-4-[2-(dimethylamino)-2- oxoethyl]-N-[(3-methoxypyridin-2- yl)methyl]-3-methyl-8-(4-methyl- 2 2.5 17

[0505] 1,3-oxazol-2-yl)-5-oxo-2, 3,4,5- tetrahydro

[0001] benzofuro[2,3- f][1,4]oxazepine-3-carboxamide (3R)-4-[2-(Dimethylamino)-2- oxoethyl]-N-[(3-methoxypyridin-2- yl)methyl]-3-methyl-5-oxo-8-[4- 3 5.9 6 (trifluoromethyl)-1,3-oxazol-2-yl]- 2, 3,4,5- tetrahydro

[0001] benzofuro[2,3- f][1,4]oxazepine-3-carboxamide (3R)-4-[2-(dimethylamino)-2- oxoethyl]- / V-[(4-methoxypyridin-3- yl)methyl]-3-methyl-8-(1,3- 4 13 2

[0506] oxazol-2-yl)-5-oxo-2, 3,4,5- tetrahydro

[0001] benzofuro[2,3- f][1,4]oxazepine-3-carboxamide (3R)-4-[2-(dimethylamino)-2- oxoethyl]- / V-[(2-methoxypyridin-3- yl)methyl]-3-methyl-8-(1,3- 5 1600 1

[0507] oxazol-2-yl)-5-oxo-2, 3,4,5- tetrahydro

[0001] benzofuro[2,3- f][1,4]oxazepine-3-carboxamide (3R)-4-[2-(dimethylamino)-2- oxoethyl]- / V-[(2-ethoxypyridin-3- 6 830 3

[0508] yl)methyl]-3-methyl-8-(1,3- oxazol-2-yl)-5-oxo-2,3,4,5-

[0509]

[0510] C9790E: KLF2_E C9790E: KLF2_EC₅₀_HiBit KLF2- C₅₀_HiBit KLF2- Example3 μM Top Dose 3 μM Top Dose IUPAC Name NumberGeometric mean EC₅₀ (nM)EC₅₀ (nM) Replicate count

[0511] tetrahydro

[0001] benzofuro[2,3- f][1,4]oxazepine-3-carboxamide

[0512] (3R)-4-[2-(dimethylamino)-2- oxoethyl]- / V-[(3-ethoxypyridin-2- yl)methyl]-3-methyl-8-(1,3- 7 29 2

[0513] oxazol-2-yl)-5-oxo-2, 3,4,5- tetrahydro

[0001] benzofuro[2,3- f][1,4]oxazepine-3-carboxamide (3R)-4-[2-(dimethylamino)-2- oxoethyl]- / V-[(3-methoxypyridin-2- yl)methyl]-3-methyl-8-(1,3- Comparat

[0514] 12 108 oxazol-2-yl)-5-oxo-2, 3,4,5- or A1

[0515] tetrahydro

[0001] benzofuro[2,3- f][1,4]oxazepine-3-carboxamide, trifluoroacetate salt

[0516]

[0517] EXAMPLE 4: Deuterated Analogs

[0518] The compounds shown in TABLE 4 are prophetic deuterated analogs (PDA) of Example 1 – Example 7. The PDAs are predicted based on the metabolic profile of each Example.

[0519]

[0520] Ex Number yla- Y1b‘ Y1cY2a. Y2b‘ Y2CY^a. Y3bY^a. Y«bY51-D1 D H H H H 1-D2 H D H H H 1-D3 H H D H H 1-D4 H H H D H 1-D5 H H H H D 1-D6 D D H H H 1-D7 D H D H H 1-D8 D H H D H 1-D9 D H H H D 1-D10 H D D H H 1-D11 H D H D H 1-D12 H D H H D 1-D13 H H D D H 1-D14 H H D H D 1-D15 H H H D D 1-D16 D D D H H 1-D17 D D H D H 1-D18 D D H H D 1-D19 D H D D H 1-D20 D H D H D 1-D21 D H H D D 1-D22 H D D D H 1-D23 H D D H D 1-D24 H D H D D 1-D25 H H D D D 1-D26 D D D D H 1-D27 D D D H D 1-D28 D D H D D 1-D29 D H D D D 1-D30 H D D D D 1-D31 D D D D D

[0521]

[0522]

[0523] TABLE 5. Deuterated Analog of Example 2.

[0524] Ex Number Y1Y2a; Y2b; Y2cY3a; Y3b; Y3cY4a; Y4b; Y4cY5

[0525] 2-D1 D H H H H 2-D2 H D H H H 2-D3 H H D H H 2-D4 H H H D H 2-D5 H H H H D 2-D6 D D H H H 2-D7 D H D H H 2-D8 D H H D H 2-D9 D H H H D 2-D10 H D D H H 2-D11 H D H D H 2-D12 H D H H D 2-D13 H H D D H 2-D14 H H D H D 2-D15 H H H D D 2-D16 D D D H H 2-D17 D D H D H 2-D18 D D H H D 2-D19 D H D D H 2-D20 D H D H D 2-D21 D H H D D 2-D22 H D D D H 2-D23 H D D H D 2-D24 H D H D D 2-D25 H H D D D 2-D26 D D D D H 2-D27 D D D H D

[0526]

[0527] Ex Number Y1Y2a; Y2b; Y2cY3a; Y3b; Y3cY4a; Y4b; Y4cY52-D28 D D H D D 2-D29 D H D D D 2-D30 H D D D D 2-D31 D D D D D

[0528]

[0529]

[0530] TABLE 6. Deuterated Analog of Example 3.

[0531] Ex Number Y1a; Y1b; Y1cY2a; Y2b; Y2cY3a; Y3b; Y3cY4aY5a; Y5b3-D1 D H H H H 3-D2 H D H H H 3-D3 H H D H H 3-D4 H H H D H 3-D5 H H H H D 3-D6 D D H H H 3-D7 D H D H H 3-D8 D H H D H 3-D9 D H H H D 3-D10 H D D H H 3-D11 H D H D H 3-D12 H D H H D 3-D13 H H D D H 3-D14 H H D H D 3-D15 H H H D D 3-D16 D D D H H 3-D17 D D H D H 3-D18 D D H H D 3-D19 D H D D H 3-D20 D H D H D

[0532]

[0533] Ex Number yla- Y1b‘ Y1cY2a. Y2b‘ Y2CY^a. Y3b‘ Y2CY^a Y5a. Y3b3-D21 D H H D D 3-D22 H D D D H 3-D23 H D D H D 3-D24 H D H D D 3-D25 H H D D D 3-D26 D D D D H 3-D27 D D D H D 3-D28 D D H D D 3-D29 D H D D D 3-D30 H D D D D 3-D31 D D D D D

[0534]

[0535] y3a

[0536]

[0537] TABLE 7. Deuterated Analog of Example 4.

[0538] Ex Number Yla. Y1b- Y1cY2a. Y2b- Y2CY3a. Y3b‘ Y3CY<a. Y4bY5

[0539] 4-D1 D H H H H 4-D2 H D H H H 4-D3 H H D H H 4-D4 H H H D H 4-D5 H H H H D 4-D6 D D H H H 4-D7 D H D H H 4-D8 D H H D H 4-D9 D H H H D 4-D10 H D D H H 4-D11 H D H D H 4-D12 H D H H D 4-D13 H H D D H 4-D14 H H D H D

[0540]

[0541] Ex Number yla- Y1b‘ Y1cY2a. Y2b‘ Y2CY^a. Y3b‘ Y2CY^a. Y«bY54-D15 H H H D D 4-D16 D D D H H 4-D17 D D H D H 4-D18 D D H H D 4-D19 D H D D H 4-D20 D H D H D 4-D21 D H H D D 4-D22 H D D D H 4-D23 H D D H D 4-D24 H D H D D 4-D25 H H D D D 4-D26 D D D D H 4-D27 D D D H D 4-D28 D D H D D 4-D29 D H D D D 4-D30 H D D D D 4-D31 D D D D D

[0542]

[0543] y3a

[0544]

[0545] TABLE 8. Deuterated Analog of Example 5.

[0546] Ex Number Yla. Ylb- Y1cY2a. Y2b- Y2CY3a. Y3b‘ Y2CY^a. Y«bY5

[0547] 5-D1 D H H H H 5-D2 H D H H H 5-D3 H H D H H 5-D4 H H H D H 5-D5 H H H H D 5-D6 D D H H H 5-D7 D H D H H 5-D8 D H H D H

[0548]

[0549] Ex Number yla- Y1b‘ Y1cY2a. Y2b‘ Y2CY^a. Y3b‘ Y2CY^a. Y«bY55-D9 D H H H D 5-D10 H D D H H 5-D11 H D H D H 5-D12 H D H H D 5-D13 H H D D H 5-D14 H H D H D 5-D15 H H H D D 5-D16 D D D H H 5-D17 D D H D H 5-D18 D D H H D 5-D19 D H D D H 5-D20 D H D H D 5-D21 D H H D D 5-D22 H D D D H 5-D23 H D D H D 5-D24 H D H D D 5-D25 H H D D D 5-D26 D D D D H 5-D27 D D D H D 5-D28 D D H D D 5-D29 D H D D D 5-D30 H D D D D 5-D31 D D D D D

[0550]

[0551]

[0552] TABLE 9. Deuterated Analog of Example 6.

[0553] Ex Number Y1a; Y1b; Y1cY2a; Y2b; Y2cY3a; Y3bY4a; Y4bY5

[0554] 6-D1 D H H H H 6-D2 H D H H H

[0555]

[0556] Ex Number yla- Y1b‘ Y1cY2a. Y2b‘ Y2CY^a. Y3bY^a. Y«bY56-D3 H H D H H 6-D4 H H H D H 6-D5 H H H H D 6-D6 D D H H H 6-D7 D H D H H 6-D8 D H H D H 6-D9 D H H H D 6-D10 H D D H H 6-D11 H D H D H 6-D12 H D H H D 6-D13 H H D D H 6-D14 H H D H D 6-D15 H H H D D 6-D16 D D D H H 6-D17 D D H D H 6-D18 D D H H D 6-D19 D H D D H 6-D20 D H D H D 6-D21 D H H D D 6-D22 H D D D H 6-D23 H D D H D 6-D24 H D H D D 6-D25 H H D D D 6-D26 D D D D H 6-D27 D D D H D 6-D28 D D H D D 6-D29 D H D D D 6-D30 H D D D D 6-D31 D D D D D

[0557]

[0558]

[0559] TABLE 10. Deuterated Analog of Example 7.

[0560] Ex Number yla- Y1b‘ Y1cY2a. Y2b‘ Y2CY^a. Y3bY^a. Y«bY5

[0561] 7-D1 D H H H H 7-D2 H D H H H 7-D3 H H D H H 7-D4 H H H D H 7-D5 H H H H D 7-D6 D D H H H 7-D7 D H D H H 7-D8 D H H D H 7-D9 D H H H D 7-D10 H D D H H 7-D11 H D H D H 7-D12 H D H H D 7-D13 H H D D H 7-D14 H H D H D 7-D15 H H H D D 7-D16 D D D H H 7-D17 D D H D H 7-D18 D D H H D 7-D19 D H D D H 7-D20 D H D H D 7-D21 D H H D D 7-D22 H D D D H 7-D23 H D D H D 7-D24 H D H D D 7-D25 H H D D D 7-D26 D D D D H 7-D27 D D D H D

[0562]

[0563] Ex Number yla- Y1b‘ Y1cY2a. Y2b‘ Y2CY^a. Y3bY^a. Y«bY57-D28 D D H D D 7-D29 D H D D D 7-D30 H D D D D 7-D31 D D D D D

[0564]

[0565] The metabolite profiles of Example 1-Example 7 were evaluated in liver microsomes and hepatocytes (mouse, rat, rabbit, dog, monkey, and human), recombinant human cytochrome P450 enzymes, recombinant human UGT enzymes, and plasma from animals (mouse, rat, and dog). The metabolite profiles of Example 1-Example 7 are comprised of oxidation and glucuronidation.

[0566] General methods I reviews of obtaining metabolite profile and identifying metabolites of a compound are described in: DAVLIE, D., et al., “Assessment of Three Human in Vitro Systems in the Generation of Major Human Excretory and Circulating Metabolites,” Chemical Research in Toxicology, 2009, 22(2):357-368; KING, R., “Chapter Three - Biotransformations in Drug Metabolism.” Drug Metabolism Handbook: Concepts and Applications in Cancer Research, edited by Ala F. Nassar et al., Wiley, 2022, 17-38; WU, Y., et al., “Metabolite Identification in Preclinical and Clinical Phase of Drug Development,” Current Drug Metabolism, 2021, 22(11):838-857; GODZIEN, J., et al., “Chapter Fifteen - Metabolite Annotation and Identification.” Comprehensive Analytical Chemistry, Elsevier, 2018, 415-445.

[0567] Numerous publicly available and commercially available software tools are available to aid in the predictions of metabolic pathways and metabolites of compounds. Examples of such tools include, BioTransformer 3.0 (BIOTRANSFORMER 3.0, “Metabolism Prediction,” www.biotransformer.ca. Retrieved July 18, 2024, from URL biotransformer.ca / new) which predicts the metabolic biotransformations of small molecules using a database of known metabolic reactions; MetaSite (MOLECULAR DISCOVERY LTD., “MetaSite,” www.moldiscovery.com. Retrieved July 18, 2024, from URL moldiscovery.com / software / metasite / ), which predicts metabolic transformations related to cytochrome P450 and flavin-containing monooxygenase mediated reactions in phase I metabolism; and Lhasa Meteor Nexus (LHASA LIMITED, “Metabolite identification and analysis,” www.lhasalimited.org.

[0568] Retrieved July 18, 2024, from URL lhasalimited.org / products / meteor-nexus.htm) offers prediction of metabolic pathways and metabolite structures using a range of machine learning models, which covers phase I and phase II biotransformations of small molecules.

[0569] deuterated analogs of Example 1-Example 7 in TABLE 4-TABLE 10 may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements, reduced CYP450 inhibition (competitive or time dependent), or an improvement in therapeutic index or tolerability.A person with ordinary skill may make additional deuterated analogs of Example 1-Example 7 with different combinations of Y1-Ym as provided in TABLE 4-TABLE 10. Such additional deuterated analogs may provide similar therapeutic advantages that may be achieved by the deuterated analogs.

[0570] EMBODIMENTS

[0571] The following non-limiting embodiments provide illustrative examples of the disclosure, but do not limit the scope of the disclosure.

[0572] Embodiment 1. A compound of Formula I:

[0573]

[0574] Formula I,

[0575] or a pharmaceutically acceptable salt thereof, wherein:

[0576] ====is a single bond or a double bond;

[0577] X is O or N;

[0578] Y is CR2or O;

[0579] R1and R2is each independently H, C1-6alkyl, or C1-6haloalkyl, wherein at least one of R1and R2is C1-6alkyl or C1-6haloalkyl;

[0580] R3, R4, and R9is each independently C1-6alkyl or C1-6cycloalkyl; or R3and R4together with the nitrogen atom to which R3and R4are bound form a ring; and

[0581] R5, R6, R7, and R8is each independently H or C1-6alkoxy.

[0582] Embodiment 2. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein X is O and Y is CR2.

[0583] Embodiment 3. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein X is N and Y is O.

[0584] Embodiment 4. The compound of embodiment 1, wherein the compound is of Formula la:R5R6

[0585]

[0586] Formula la,

[0587] or a pharmaceutically acceptable salt thereof.

[0588] Embodiments. The compound of embodiment 1, wherein the compound is of Formula la’:

[0589]

[0590] Formula la’,

[0591] or a pharmaceutically acceptable salt thereof.

[0592] Embodiment 6. The compound of embodiment 4 or 5, or a pharmaceutically acceptable salt thereof, wherein R1and R2is each independently H, C1-3alkyl, or C1-3haloalkyl.

[0593] Embodiment 7. The compound of embodiment 6, or a pharmaceutically acceptable salt thereof, wherein R1and R2is each independently H, methyl, or CF3.

[0594] Embodiments. The compound of embodiment 1, wherein the compound is of Formula lb:

[0595]

[0596] Formula lb,

[0597] or a pharmaceutically acceptable salt thereof.

[0598] Embodiment 9. The compound of embodiment 1, wherein the compound is of Formula lb’:

[0599]

[0600] Formula lb’,

[0601] or a pharmaceutically acceptable salt thereof.

[0602] Embodiment 10. The compound of embodiment 8 or 9, or a pharmaceutically acceptable salt thereof, wherein R1is H, C1-3alkyl, or C1-3haloalkyl.

[0603] Embodiment 11. The compound of embodiment 10, or a pharmaceutically acceptable salt thereof, wherein R1is H, methyl, or CF3.

[0604] Embodiment 12. (3R)-4-[2-(dimethylamino)-2-oxoethyl]-N-[(3-methoxypyridin-2-yl)methyl]-3-methyl-8-(4-methyl-1,3-oxazol-2-yl)-5-oxo-2,3,4,5-tetrahydro[1]benzofuro[2,3-f][1,4]oxazepine-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0605] Embodiment 13. A compound of the structure:

[0606]

[0607] Embodiment 14. (3R)-4-[2-(dimethylamino)-2-oxoethyl]-N-[(3-ethoxypyridin-2-yl)methyl]- 3-methyl-5-oxo-8-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-2,3,4,5-tetrahydro[1]benzofuro[2,3-f][1,4]oxazepine-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0608] Embodiment 15. A compound of the structure:

[0609]

[0610] Embodiment 16. (3R)-4-[2-(Dimethylamino)-2-oxoethyl]-N-[(3-methoxypyridin-2-yl)methyl]-3-methyl-5-oxo-8-[4-(trifluoromethyl)-1,3-oxazol-2-yl]-2, 3,4,5-tetrahydro[1]benzofuro[2,3-f][1,4]oxazepine-3-carboxamide, or a pharmaceutically acceptable salt thereof.Embodiment 17. A compound of the structure:

[0611]

[0612] Embodiment 18. A pharmaceutical composition comprising the compound according to any of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0613] Embodiment 19. A method of treating a condition comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of embodiments 1-17, or a pharmaceutically acceptable salt thereof.

[0614] Embodiment 20. The method of embodiment 19, wherein the condition is an inflammatory disease.

[0615] Embodiment 21. The method of embodiment 19, wherein the condition is endothelial dysfunction.

[0616] Embodiment 22. The method of embodiment 19, wherein the condition is selected from the group consisting of atherosclerosis, coronary artery disease, stroke, peripheral arterial disease, coronary microvascular disease, angina, systemic hypertension, pulmonary arterial hypertension, heart failure, a diabetic microvascular disease, chronic kidney disease (CKD), diabetic kidney disease (DKD), an inflammatory disease, and an infectious disease.

[0617] Embodiment 23. The method of embodiment 22, wherein the diabetic microvascular disease is selected from the group consisting of diabetic nephropathy, diabetic retinopathy, and diabetic neuropathy.

[0618] Embodiment 24. The method of embodiment 22, wherein the condition is peripheral arterial disease.

[0619] Embodiment 25. The method of embodiment 22, wherein the administering is oral. Embodiment 26. The method of embodiment 22, wherein the administering is intravenous.

[0620] Embodiment 27. The method of embodiment 22, wherein the subject is human.

[0621] Embodiment 28. The method of embodiment 22, wherein the therapeutically effective amount is from about 1 mg to about 500 mg.

[0622] Embodiment 29. The method of embodiment 22, wherein the therapeutically effective amount is from about 10 mg to about 250 mg.Embodiment 30. A compound according to any one of embodiments 1-17, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0623] Embodiment 31. A compound according to any one of embodiments 1-17, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition selected from the group consisting of atherosclerosis, coronary artery disease, stroke, peripheral arterial disease, coronary microvascular disease, angina, systemic hypertension, pulmonary arterial hypertension, heart failure, a diabetic microvascular disease, an inflammatory disease, and an infectious disease.

[0624] Embodiment 32. Use of a compound according to any one of embodiments 1-17, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a condition selected from the group consisting of atherosclerosis, coronary artery disease, stroke, peripheral arterial disease, coronary microvascular disease, angina, systemic hypertension, pulmonary arterial hypertension, heart failure, a diabetic microvascular disease, chronic kidney disease (CKD), diabetic kidney disease (DKD), an inflammatory disease, and an infectious disease.

[0625] Each of the embodiments described herein may be combined with any other embodiment(s) described herein not inconsistent with the embodiment(s) with which it is combined. In addition, any of the compounds described in the Examples, or pharmaceutically acceptable salts thereof, may be claimed individually or grouped together with one or more other compounds of the Examples, or pharmaceutically acceptable salts thereof, for any of the embodiment(s) described herein. Furthermore, each of the embodiments described herein envisions within its scope pharmaceutically acceptable salts of the compounds described herein.

[0626] It will be apparent to those skilled in the art that various modifications and variations may be made in the present disclosure without departing from the scope or spirit of the disclosure. Other embodiments of the disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the disclosure disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the disclosure being indicated by the following claims.

[0627] All references cited herein, including patents, patent applications, papers, textbooks, and the like, and the references cited therein, to the extent that they are not already, are hereby incorporated by reference in their entireties. In the event that one or more of the incorporated literature and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A compound of Formula I:Formula I,or a pharmaceutically acceptable salt thereof, wherein:=======is a single bond or a double bond;X is O or N;Y is CR2or O;R1and R2is each independently H, C1-6alkyl, or C1-6haloalkyl, wherein at least one of R1and R2is C1-6alkyl or C1-6haloalkyl;R3, R4, and R9is each independently C1-6alkyl or C1-6cycloalkyl; or R3and R4together with the nitrogen atom to which R3and R4are bound form a ring; andR5, R6, R7, and R8is each independently H or C1-6alkoxy.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is O and Y is CR2.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is N and Y is O.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1and R2is each independently H, Ci.salkyl, or C1-3haloalkyl.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1and R2is each independently H, methyl, or CF3.

6. The compound of claim 1, wherein the compound is of Formula lb’:Formula lb’,or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is H, Ci-3alkyl, or C1-3haloalkyl.

8. A compound selected from the group consisting of:(3R)-4-[2-(dimethylamino)-2-oxoethyl]-N-[(3-methoxypyridin-2-yl)methyl]-3-methyl-8-(4- methyl-1,3-oxazol-2-yl)-5-oxo-2,3,4,5-tetrahydro[1]benzofuro[2,3-f][1,4]oxazepine-3- carboxamide;(3R)-4-[2-(dimethylamino)-2-oxoethyl]-N-[(3-ethoxypyridin-2-yl)methyl]-3-methyl-5-oxo- 8-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-2,3,4,5-tetrahydro[1]benzofuro[2,3- f][1,4]oxazepine-3-carboxamide; and(3R)-4-[2-(Dimethylamino)-2-oxoethyl]-N-[(3-methoxypyridin-2-yl)methyl]-3-methyl-5- oxo-8-[4-(trifluoromethyl)-1,3-oxazol-2-yl]-2,3,4,5-tetrahydro[1]benzofuro[2,3- f] [ 1,4]oxazepine-3-carboxamide,or a pharmaceutically acceptable salt thereof.

9. A compound selected from the group consisting of:

10. A pharmaceutical composition comprising the compound according to any of claims 1 to 9, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

11. A method of treating a condition comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof.

12. The method of claim 11, wherein the condition is an inflammatory disease or endothelial dysfunction.

13. The method of claim 11, wherein the condition is selected from the group consisting of atherosclerosis, coronary artery disease, stroke, peripheral arterial disease, coronary microvascular disease, angina, systemic hypertension, pulmonary arterial hypertension, heart failure, a diabetic microvascular disease, chronic kidney disease (CKD), diabetic kidney disease (DKD), an inflammatory disease, and an infectious disease.

14. The method of claim 13, wherein the diabetic microvascular disease is selected from the group consisting of diabetic nephropathy, diabetic retinopathy, and diabetic neuropathy.

15. The method of claim 13, wherein the condition is peripheral arterial disease.

16. The method of any one of claims 11-15, wherein the administering is oral.

17. The method of any one of claims 11-16, wherein the therapeutically effective amount is from about 1 mg to about 500 mg.

18. The method of any one of claims 11-16, wherein the therapeutically effective amount is from about 10 mg to about 250 mg.

19. A compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, for use as a medicament.

20. A compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition selected from the group consisting of atherosclerosis, coronary artery disease, stroke, peripheral arterial disease, coronary microvascular disease, angina, systemic hypertension, pulmonary arterial hypertension, heart failure, a diabetic microvascular disease, chronic kidney disease (CKD), diabetic kidney disease (DKD), an inflammatory disease, and an infectious disease.

21. Use of a compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a condition selected from the group consisting of atherosclerosis, coronary artery disease, stroke, peripheral arterial disease, coronary microvascular disease, angina, systemic hypertension, pulmonary arterial hypertension, heart failure, a diabetic microvascular disease, chronic kidney disease (CKD), diabetic kidney disease (DKD), an inflammatory disease, and an infectious disease.

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