Use of urolithin derivatives in treatment of amyotrophic lateral sclerosis

Abstract

Methods of treating amyotrophic lateral sclerosis (ALS) are disclosed. Also disclosed is a method of treating C9orf72 amyotrophic lateral sclerosis (C9-ALS).

Description

Related applications

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 467,507, filed May 18, 2023. Background Technology

[0002] Urolithin has been shown to be effective in improving many health conditions, and it has been demonstrated to possess high bioactivity both in vitro and in vivo. Urolithin has been proposed as a treatment for various disorders, including those associated with insufficient mitochondrial activity, such as obesity, memory decline, decreased metabolic rate, metabolic syndrome, diabetes, cardiovascular disease, hyperlipidemia, neurodegenerative diseases, cognitive impairment, mood disorders, stress, anxiety disorders, fatty liver disease, and for improving liver function and weight management. In particular, urolithin has been shown to have beneficial effects in enhancing muscle function.

[0003] Amyotrophic lateral sclerosis (ALS) is a progressive and often fatal motor neuron disease. ALS occurs in sporadic (SALS) and familial (FALS) forms. Amplification of the GGGGCC hexanucleotide repeat sequence in the first intron of C9orf72 leads to the most common form of familial ALS. The FDA-approved treatment for ALS is riluzole, a compound that extends survival by approximately 10%. Therefore, additional and improved treatments are needed. Summary of the Invention

[0004] One aspect of the present invention provides a method for treating amyotrophic lateral sclerosis (ALS), such as C9orf72 amyotrophic lateral sclerosis (C9-ALS).

[0005] Therefore, this article provides a method for treating amyotrophic lateral sclerosis (ALS), such as C9orf72 amyotrophic lateral sclerosis (C9-ALS), in a subject in need, the method comprising administering to the subject an effective amount of a compound of formula (Ia), formula (Ic), formula (Id), formula (Ie), formula (If), formula (Ih), formula (IIa), or formula (IIb).

[0006] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although similar or equivalent methods and materials may be used in the practice or testing of this invention, the following description refers to suitable methods and materials. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety. In the event of conflict, this specification (including definitions) shall prevail. Furthermore, materials, methods, and examples are illustrative only and not intended to be limiting.

[0007] Other features, objectives, and advantages of the invention will become apparent from the detailed description and claims. Detailed Implementation

[0008] definition

[0009] For convenience, certain terms used in this specification, embodiments, and appended claims are collected herein before further description of the invention. These definitions should be read in light of the remainder of this disclosure and should be understood as those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0010] To facilitate understanding of the invention, certain terms and phrases are defined below and throughout the specification.

[0011] As used in this article, the article “a / an” refers to the grammatical object of one / a kind or more / a kind (i.e., at least one / a kind). For example, “a / a kind of element” refers to one / a kind of element or more / a kind of element.

[0012] As used herein in the specification and claims, the phrase “and / or” should be understood to mean “any one or both” of the elements so combined (i.e., elements that coexist in some cases and exist separately in others). Multiple elements listed with “and / or” should be understood in the same way, i.e., “one or more” of the elements so combined. In addition to the elements explicitly identified by the “and / or” clause, other elements may optionally be present, whether related to or unrelated to those explicitly identified. Thus, as a non-limiting example, when used in conjunction with open-ended language such as “comprising”, a reference to “A and / or B” may refer to only A (optionally including elements other than B) in one embodiment; only B (optionally including elements other than A) in another embodiment; both A and B (optionally including other elements) in yet another embodiment; and so on.

[0013] As used herein in the specification and claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” should be interpreted as inclusive, that is, including multiple elements or at least one element in a list of elements, but also including more than one element, as well as optional other items not listed. Only terms that clearly indicate the opposite meaning, such as “only one” or “exactly one”, or when used in the claims, “consisting of” will refer to including multiple elements or exactly one element in a list of elements. In general, the term “or” as used herein, when followed by an exclusive term (such as “any,” “one of,” “only one of,” or “exact one of”), should be interpreted only to indicate an exclusive alternative (i.e., “one or the other but not both”). “Substantially consisting of” when used in claims should have its ordinary meaning as used in the field of patent law.

[0014] As used herein in the specification and claims, the phrase “at least one” when referring to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but does not necessarily include at least one of every element specifically listed in the list of elements, nor exclude any combination of elements in the list of elements. This definition also allows for the optional presence of elements other than those expressly identified in the list of elements referred to by the phrase “at least one”, whether related to or unrelated to the expressly identified elements. Thus, as a non-limiting example, “at least one of A and B” (or equivalently, “at least one of A or B”, or equivalently, “at least one of A and / or B”) may refer to at least one A in one embodiment, optionally including more than one A, but without B (and optionally including elements other than B); in another embodiment, refer to at least one B, optionally including more than one B, but without A (and optionally including elements other than A); in yet another embodiment, refer to at least one A, optionally including more than one A, and at least one B, optionally including more than one B (and optionally including other elements); and so on.

[0015] It should also be understood that, unless the context otherwise requires, in any method claimed herein that includes more than one step or action, the order of the steps or actions of the method is not necessarily limited to the order in which the steps or actions of the method are listed herein.

[0016] In the claims and the aforementioned description, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” and “consisting of” should be understood as open-ended, meaning including but not limited to. As explained in Section 2111.03 of the U.S. Patent Examination Procedure Manual, only the transitional phrases “consisting of” and “substantially consisting of” are closed or semi-closed transitional phrases, respectively.

[0017] Some compounds contained in the compositions of the present invention may exist in specific geometric or stereoisomeric forms. Additionally, the polymers of the present invention may also be optically active. The present invention encompasses all such compounds falling within the scope of the present invention, including cis and trans isomers. R -and S - Enantiomers, diastereomers, (d)-isomers, (l)-isomers, racemic mixtures thereof, and other mixtures thereof. Additional asymmetric carbon atoms may be present in substituents (such as alkyl groups). All such isomers and mixtures thereof are intended to be included in this invention.

[0018] "Geometric isomers" refers to isomers that differ in the orientation of the substituent atoms relative to the carbon-carbon double bond, relative to the cycloalkyl ring, or relative to the bridged bicyclic system. Atoms on each side of the carbon-carbon double bond (except H) can be in either an E (substituents on opposite sides of the carbon-carbon double bond) or a Z (substituents on the same side) configuration. "R", "S", "S*", "R*", "E", "Z", "cis", and "trans" indicate the configuration relative to the core molecule. Some of the disclosed compounds may exist as or as "trans-restricted isomers". Trans-restricted isomers are stereoisomers resulting from restricted rotation around a single bond, where the steric strain barrier to rotation is sufficiently high to allow for the separation of conformational isomers. The compounds of this invention can be prepared as individual isomers through isomer-specific synthesis or by separation from mixtures of isomers. Conventional resolution techniques include using optically active acids to form salts of the free base for each isomer of an isomer pair (followed by fractional crystallization and regeneration of the free base); using optically active amines to form salts of the acid form for each isomer of an isomer pair (followed by fractional crystallization and regeneration of the free acid); using optically pure acids, amines, or alcohols to form esters or amides of each isomer of an isomer pair (followed by chromatographic separation and removal of chiral auxiliaries); or using various well-known chromatographic methods to resolve mixtures of isomers of the raw material or final product.

[0019] For example, if a specific enantiomer of the compound of the present invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is isolated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, in the case where the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt can be formed with a suitable optically active acid or base, followed by resolution of the thus formed diastereomeric isomer by fractional crystallization or chromatographic means well known in the art, and then the pure enantiomer is recovered.

[0020] The purity percentage, expressed in molar fractions, is the ratio of the number of moles of the enantiomer (or diastereomer) to the sum of the number of moles of its optical isomers. When the stereochemistry of the disclosed compound is named or described by structure, the purity of the named or described stereoisomer relative to other stereoisomers is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% by molar fraction. When a single enantiomer is named or described by structure, the described or named enantiomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% pure by molar fraction. When a single diastereomer is named or described by structure, the described or named diastereomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% pure by molar fraction.

[0021] When a disclosed compound is named or described by a structure without indicated stereochemistry and has at least one chiral center, it should be understood that the name or structure covers enantiomers of the compound that do not contain the corresponding optical isomers, racemic mixtures of the compound, or mixtures in which one enantiomer is enriched relative to its corresponding optical isomer. When a disclosed compound is named or described by a structure without indicated stereochemistry and has two or more chiral centers, it should be understood that the name or structure covers diastereomers that do not contain other diastereomers, a number of diastereomers that do not contain other diastereomer pairs, mixtures of diastereomers, mixtures of diastereomer pairs, mixtures of diastereomers in which one diastereomer is enriched relative to one or more other diastereomers, or mixtures of diastereomers in which one or more diastereomers are enriched relative to other diastereomers. The present invention covers all of these forms.

[0022] The structures described in this article are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, by replacing hydrogen with deuterium or tritium, or by replacing carbon with... 13 C- or 14Compounds produced by replacing C-enriched carbon are within the scope of this invention.

[0023] As used herein, the term "prodrug" encompasses compounds that are converted to a therapeutically active agent under physiological conditions. A common method for preparing prodrugs involves hydrolysis under physiological conditions to reveal selected moieties of the desired molecule. In other embodiments, the prodrug is converted via the enzymatic activity of the host animal.

[0024] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that participates in the transport or transfer of the subject chemical from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of compatibility with other components of the formulation, harmless to the patient, and substantially pyrogen-free. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered astragalus gum; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution. (19) ethanol; (20) phosphate buffer solution; and (21) other non-toxic and compatible substances used in the pharmaceutical composition. In some embodiments, the pharmaceutical composition of the present invention is pyrogen-free, i.e., it does not cause a significant increase in body temperature when administered to a patient.

[0025] The term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic or organic acid addition salt of a compound. These salts can be prepared in situ during the final separation and purification of the compound, or by reacting the purified free base form of the compound with a suitable organic or inorganic acid and then separating the resulting salt. Representative salts include hydrobromide, hydrochloride, sulfate, hydrogen sulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, methanesulfonate, glucono-p-ethyl, lacturonate, and laurylsulfonate, etc. (See, for example, Berge et al. (1977) "Pharmaceutical Salts") J. Pharm. Sci 66:1-19.

[0026] In other cases, compounds used in the methods of this invention may contain one or more acidic functional groups and are therefore capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these cases, the term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic and organic base addition salt of one or more compounds. These salts can also be prepared in situ during the final separation and purification of one or more of the compounds, or by reacting one or more purified compounds in their free acid form with a suitable base (such as a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation), with ammonia, or with a pharmaceutically acceptable primary, secondary, or tertiary organic amine. Representative alkali metal or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, etc. Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. (see, for example, Berge et al., ibid.).

[0027] The term "pharmaceutically acceptable cocrystal" refers to a solid co-formation that does not form formal ionic interactions with small molecules.

[0028] The "therapeutic effective amount" (or "effective amount") of a compound used in treatment refers to the amount of a compound in a formulation which, when administered as part of the desired dosing regimen (to mammals, preferably humans), is of clinically acceptable standard or cosmetic purpose, such as to relieve symptoms, improve the condition, or slow the onset of the disease, based on a reasonable benefit / risk ratio suitable for any drug treatment.

[0029] The term "preventive or therapeutic" treatment is recognized in the art and includes the administration of one or more subject compositions to a host. Treatment is preventive (i.e., it protects the host from developing the unwanted disease) if it is administered before the clinical manifestation of an unwanted condition (e.g., a disease or other unwanted state in the host animal), and therapeutic (i.e., it is intended to alleviate, improve, or stabilize an existing unwanted condition or its side effects) if it is administered after the manifestation of the unwanted condition.

[0030] The terms "patient" or "subject" refer to a mammal in need of specific treatment. In some embodiments, the patient is a primate, canine, feline, or equine. In some embodiments, the patient is a human.

[0031] Aliphatic chains include the alkyl, alkenyl, and alkynyl categories as defined below. Straight-chain aliphatic chains are limited to the unbranched carbon chain portion. As used herein, the term "aliphatic group" refers to a straight-chain, branched, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups such as alkyl, alkenyl, or alkynyl groups.

[0032] "Alkyl" refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having a specified number of carbon atoms or up to 30 carbon atoms (if not specified). For example, alkyl groups with 1 to 8 carbon atoms refer to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, as well as those that are positional isomers of these moieties. Alkyl groups with 10 to 30 carbon atoms include decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecanyl, octadecyl, nonadecanyl, eicosyl, dodecyl, tridecyl, and tetradecyl. In some embodiments, straight-chain or branched alkyl groups have 30 or fewer carbon atoms in their main chain (e.g., for straight-chain C1-C1 alkyl groups). 30 For C3-C branches 30 ( ), and more preferably 20 or fewer carbon atoms. The alkyl group may be substituted or unsubstituted.

[0033] As used herein, the term "heteroalkyl" refers to an alkyl moiety as defined above that contains one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms.

[0034] As used herein, the term "haloalkyl" refers to an alkyl group as defined above that has been substituted with at least one halogen.

[0035] As used herein, the term "hydroxyalkyl" means an alkyl group as defined herein that is substituted with at least one hydroxyl group.

[0036] As used herein, the term "alkylene" refers to an alkyl group having a specified number of carbon atoms, such as 2 to 12 carbon atoms, containing two connection points on its longest carbon chain to the remainder of the compound. Non-limiting examples of alkylenes include methylene-(CH2)-, ethylene-(CH2CH2)-, n-propylene-(CH2CH2CH2)-, isopropylene-(CH2CH(CH3))-, etc. Alkylenes can be cyclic or acyclic, branched or unbranched carbon chain moieties, and may optionally be substituted with one or more substituents.

[0037] "Cycloalkyl" refers to a saturated carbon ring, whether monocyclic, bicyclic, bridged, spirocyclic, or polycyclic, having 3 to 12 carbon atoms. Preferably, the cycloalkyl group has 3 to 10 carbon atoms in its ring structure, and more preferably 3 to 6 carbon atoms. The cycloalkyl group can be substituted or unsubstituted.

[0038] As used herein, the term "halocycloalkyl" refers to a cycloalkyl group as defined above that has been substituted with at least one halogen.

[0039] "Cycloalkyl" or "heterocyclic alkyl" refers to a cycloalkyl moiety as defined above, containing one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of a carbon atom. Preferably, the cycloalkyl moiety has 4-8 carbon atoms and heteroatoms in its ring structure, and more preferably 4-6 carbon atoms and heteroatoms in its ring structure. The cycloalkyl or heterocyclic alkyl moiety can be substituted or unsubstituted.

[0040] Unless otherwise specified, "lower alkyl" as used herein refers to an alkyl group as defined above, but having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, in its main chain structure, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Similarly, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Throughout the application, preferred alkyl groups are lower alkyl groups. In some embodiments, the substituents designated herein as alkyl groups are lower alkyl groups.

[0041] "Alkenyl" refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain portion having a specified number of carbon atoms, or, if no limit is specified, a maximum of 26 carbon atoms; and having one or more double bonds located within that portion. Examples of alkenyl groups with 6 to 26 carbon atoms are hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosene, dodecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosene, dodecenyl, dodecenyl, tridecenyl, and dodecenyl, wherein one or more unsaturated bonds may be located in any position within that portion and may have (Z) or (E) configurations surrounding one or more double bonds.

[0042] "Alkyne" refers to a hydrocarbon moiety within the alkenyl range, but this hydrocarbon moiety has one or more triple bonds located within it.

[0043] As used herein, the term "aryl" includes 3 to 12-membered substituted or unsubstituted monocyclic aromatic groups, wherein each atom of the ring is a carbon (i.e., carbocyclic aryl) or one or more of the atoms are heteroatoms (i.e., heteroaryl). Preferably, aryl comprises 5 to 12-membered rings, more preferably 6 to 10-membered rings. The term "aryl" also includes polycyclic systems having two or more rings, wherein two or more carbons are common to two adjacent rings, wherein at least one ring is aromatic, for example, the other rings may be cycloalkyl, cycloalkenyl, cycloynyl, aryl, heteroaryl, and / or heterocyclic. Carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, etc. Heteroaryl groups include substituted or unsubstituted aromatic 3 to 12-membered ring structures, more preferably 5 to 12-membered rings, more preferably 5 to 10-membered rings, whose ring structure includes one to four heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Aryl and heteroaryl groups can be monocyclic, bicyclic, or polycyclic.

[0044] As used herein, the terms “halogen,” “halide,” or “halogen” refer to halogens and include, for example, but not limited to, fluorine, chlorine, bromine, iodine, etc., in radioactive and non-radioactive forms. In a preferred embodiment, the halogen is selected from the group consisting of fluorine, chlorine, and bromine.

[0045] The term "heterocyclic group" or "heterocyclic ring" refers to a 3- to 12-membered ring structure, more preferably a 5- to 12-membered ring, and even more preferably a 5- to 10-membered ring, whose ring structure contains 1 to 4 heteroatoms. The heterocycle can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclic groups include, for example, thiophene, thiathracene, furan, pyran, isobenzofuran, chromene, oxanthracene, oxthionthanthracene, pyrrole, imidazole, pyrazole, isothiazol, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indazine, isoindole, indole, indazole, purine, quinazine, isoquinoline, quinoline, phthalazine, naphthidine, quinoxoline, quinazoline, cyclophosphine, pteridine, carbazole, caroline, phenanthridine, acridine, pyrimidine, phenanthrene-rhein, phenazine, phenpyrazine, phenothiazine, furazine, phenothiazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactone, lactam such as azacyclobutanone and pyrrolidone, sulfonamide, sulfonyl lactone, etc. The heterocycle may be substituted at one or more positions with substituents as described above, such as halogens, alkyl groups, arylalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, hydroxyl groups, amino groups, nitro groups, thioalkyl groups, imino groups, amide groups, phosphate groups, phosphonate groups, phosphonite groups, carbonyl groups, carboxyl groups, silyl groups, aminosulfonyl groups, sulfinyl groups, ethers, alkylthio groups, sulfonyl groups, ketones, aldehydes, esters, heterocyclic groups, aromatic or heteroaromatic moieties, -CF3, -CN, etc.

[0046] As used herein, the terms “arylalkyl” and “aralkyl” refer to an alkyl group as defined above that is substituted with at least one aryl group.

[0047] As used herein, the terms “heteroarylalkyl” and “heteroarylalkyl” refer to an alkyl group as defined above that is substituted with at least one heteroaryl group. The term “substituted” refers to a portion having a hydrogen-substituted substituent on one or more carbons of the main chain. It should be understood that “substituted” or “replaced by” includes the implicit condition that the substitution is consistent with the permissible valence of the substituted atom and the substituent, and that the substitution produces a stable compound, for example, a compound that does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is intended to include all permissible substituents of an organic compound. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. Permissible substituents can be one or more substituents and can be the same or different for a suitable organic compound. For the purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of an organic compound that satisfy the valence of the heteroatom as described herein. Substituents may include any substituents described herein, such as halogens, hydroxyl groups, carbonyl groups (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl groups (e.g., thioesters, thioacetates, or thiocarbamates), alkoxy groups, phosphoryl groups, phosphate groups, phosphonate groups, phosphonite groups, amino groups, amide groups, amidine groups, imine groups, cyano groups, nitro groups, azide groups, mercapto groups, alkylthio groups, sulfate groups, sulfonate groups, aminosulfonyl groups, sulfonamide groups, sulfonyl groups, heterocyclic groups, arylalkyl groups, or aromatic or heteroaromatic moieties. In a preferred embodiment, the substituents on the substituted alkyl group are selected from C10. 1-6 Alkyl, C 3-6 Cycloalkyl, halogen, carbonyl, cyano, or hydroxyl groups. In a more preferred embodiment, the substituent on the substituted alkyl group is selected from fluorine, carbonyl, cyano, or hydroxyl. Those skilled in the art will understand that the substituent itself may be substituted where appropriate. Unless specifically stated as “unsubstituted,” references to the chemical portion herein should be understood to include substituted variants. For example, references to “aryl” or a portion implicitly include both substituted and unsubstituted variants.

[0048] As used in this article, the definition of each expression (e.g., alkyl, m, n, etc.) is intended to be independent of its definition elsewhere in the same structure when it appears more than once in any structure.

[0049] As used herein, "small molecule" refers to a small organic or inorganic molecule with a molecular weight of less than about 3,000 Daltons. Generally, the small molecules used in this invention have a molecular weight of less than 3,000 Daltons (Da). Such small molecules can be, for example, at least about 100 Da to about 3,000 Da (e.g., about 100 Da to about 3,000 Da, about 100 Da to about 2,500 Da, about 100 Da to about 2,000 Da, about 100 Da to about 1,750 Da, about 100 Da to about 1,500 Da, about 100 Da to about 1,250 Da, about 100 Da to about 1,000 Da, about 100 Da to about 750 Da, about 100 Da to about 500 Da, about 200 Da to about 1,500 Da, about 500 Da to about 1,000 Da, about 300 Da to about 1,000 Da, or about 100 Da to about 250 Da).

[0050] In some embodiments, "small molecule" refers to organic, inorganic, or organometallic compounds that typically have a molecular weight of less than about 1000. In some embodiments, a small molecule is an organic compound with a size of about 1 nm. In some embodiments, the small molecule pharmaceuticals of the present invention encompass oligopeptides and other biomolecules having a molecular weight of less than about 1000.

[0051] "Effective amount" is an amount sufficient to produce a beneficial or desired result. For example, a therapeutic amount is an amount that achieves the desired therapeutic effect. This amount may be the same as or different from a preventive effective amount, which is the amount necessary to prevent the onset of disease or disease symptoms. An effective amount may be administered, applied, or dosed once or multiple times. The therapeutically effective amount of a composition depends on the composition chosen. The composition may be administered once or multiple times daily to once or multiple times weekly; including every other day. Those skilled in the art will understand that certain factors can influence the dosage and duration required for effective treatment of a subject, including but not limited to, the severity of the disease or condition, prior treatment, the subject's general health and / or age, and any other pre-existing conditions. Furthermore, treatment of a subject with a therapeutically effective amount of the composition described herein may include a single treatment or a series of treatments.

[0052] The terms “decrease,” “reduce,” “reduced,” “reduction,” “decrease,” and “inhibit” are generally used herein to mean a reduction in a statistically significant amount relative to a reference. However, for the avoidance of doubt, “reduce,” “reduction,” “decrease,” or “inhibit” generally mean a reduction of at least 10% compared to a reference level, and may include, for example, a reduction of at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99% compared to a reference level, up to and including, for example, the complete absence of a given entity or parameter, or a reduction between 10% and 99% compared to the absence of a given treatment.

[0053] The terms “increased,” “increase,” “enhance,” or “activate” are generally used throughout this document to mean an increase in a statistically significant amount; to avoid any doubt, the terms “increased,” “increase,” “enhance,” or “activate” mean an increase of at least 10% compared to a reference level, such as at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at most and including 100% increase, or any increase between 10% and 100%, or at least about 2 times, or at least about 3 times, or at least about 4 times, or at least about 5 times, or at least about 10 times, or any increase between 2 times and 10 times or more compared to a reference level.

[0054] As used in this article, the term “regulation” includes both upregulation and downregulation, such as enhancing or inhibiting a response.

[0055] As defined herein, a “radiopharmaceutical” is a pharmaceutical agent containing at least one radioactive isotope that emits radiation. Radiopharmaceuticals are routinely used in nuclear medicine for the diagnosis and / or treatment of various diseases. Radiolabeled pharmaceutical agents, such as radiolabeled antibodies, contain a radioactive isotope (RI) that acts as a radiation source. As contemplated herein, the term “radioactive isotope” includes both metallic and nonmetallic radioactive isotopes. The radioactive isotope is selected based on the medical application of the radiolabeled pharmaceutical agent. When the radioactive isotope is metallic, a chelating agent is typically used to bind the metallic radioactive isotope to the remainder of the molecule. When the radioactive isotope is nonmetallic, it is typically linked to the remainder of the molecule directly or via a linker.

[0056] For the purposes of this invention, chemical elements are identified according to the periodic table, CAS edition, Handbook of Chemistry and Physics, 67th edition, 1986-87, inside cover.

[0057] Treatment

[0058] One aspect of the present invention relates to a method for treating amyotrophic lateral sclerosis (ALS), the method comprising administering an effective amount of a compound of formula (Ia) to a subject in need.

[0059]

[0060] (Ia)

[0061] in

[0062] A is ;

[0063] X1 is selected from O and S;

[0064] Y1 is O;

[0065] R1, R4, R5, and R8 are independently selected from H and halogens;

[0066] R3 and R6 are independently selected from H, CN, OH, CF3, halogens and alkyl groups;

[0067] One of R2 and R7 is H, OH, or OAc, and the other of R2 and R7 is a halogen, CN, CF3, CO2H, NO2, NHAc, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylamino, alkyl-R9, alkenyl-R9, alkynyl-R9, OR 10 NHR 10 NR 11 C(O)R 12 C(O)NR11 R 12 and NR 11 SO2R 12 ;

[0068] Each instance of R9 is independently selected from OH, NH2, O-alkyl, O-alkyl-O-alkyl, alkylamino, NHC(O)-alkyl, N(CH3)C(O)-alkyl, NHSO2-alkyl, N(CH3)SO2-alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclic alkyl;

[0069] R 10 Selected from C2-C 12 Alkyl, C(O)-alkyl, hydroxyalkyl, aminoalkyl, alkyl-O-alkyl, alkyl-O-alkyl-OH, alkyl-O-alkyl-O-alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, alkyl-heterocyclic alkyl, aryl, heteroaryl, cycloalkyl, heterocyclic alkyl, SO3H, SO2-alkyl and SO2-haloalkyl;

[0070] Each occurrence of R 11 Selected from H and alkyl groups; and

[0071] Each occurrence of R 12 Selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, and alkyl-heterocycloalkyl;

[0072] Or its pharmaceutically acceptable salt.

[0073] In some embodiments, the compound is provided that R7 is not OBn if X1 and Y1 are each O, R2 is OH, and R1, R3, R4, R5, R6, and R8 are each H, and R2 is not OCH2C(O)NH2 if X1 and Y1 are each O, R7 is OH, and R1, R3, R4, R5, R6, and R8 are each H.

[0074] In some implementation schemes, A is .

[0075] In some embodiments, R2 is H. In other embodiments, R2 is OH. In still other embodiments, R2 is OAc.

[0076] In some embodiments, the compound, wherein R2 is selected from haloalkyl, substituted cycloalkyl, alkynyl-R9, OR 10 and C(O)NR 11 R 12 R9 is selected from OH, substituted cycloalkyl, and heterocycloalkyl; R 10Selected from alkyl, substituted cycloalkyl, heterocycloalkyl, and alkyl-heterocycloalkyl; and R 11 It is H and R 12 It is an alkyl-heterocyclic alkyl group.

[0077] In some embodiments, R7 is H. In other embodiments, R7 is OH. In still other embodiments, R7 is OAc.

[0078] In some embodiments, the compound, wherein R7 is selected from haloalkyl, substituted cycloalkyl, alkynyl-R9, OR 10 and C(O)NR 11 R 12 R9 is selected from OH, substituted cycloalkyl, and heterocycloalkyl; R 10 Selected from alkyl, substituted cycloalkyl, heterocycloalkyl, and alkyl-heterocycloalkyl; and R 11 It is H and R 12 It is an alkyl-heterocyclic alkyl group.

[0079] In some implementations, each substituted cycloalkyl group is independently replaced by OH, halogen, or hydroxyalkyl.

[0080] In some implementations, R1, R3, R4, R5, R6, and R8 are each H. In other implementations, one of R1, R3, R4, R5, R6, and R8 is not H. In other implementations, two of R1, R3, R4, R5, R6, and R8 are not H.

[0081] In some embodiments, one of R1, R3, R4, R5, R6, and R8 is an alkyl or halogen. In other embodiments, two of R1, R3, R4, R5, R6, and R8 are independently alkyl or halogens.

[0082] In some implementation schemes, A is ;

[0083] R1, R4, R5, and R8 are independently selected from H and halogens;

[0084] R3 and R6 are independently selected from H, CN, OH, CF3, halogens and alkyl groups;

[0085] R2 is OH, and R7 is a haloalkyl, cycloalkyl, alkyl-R9, alkynyl-R9, or OR. 10 and NR 11 SO2R 12 ;

[0086] Each instance of R9 is independently selected from OH, NH2, O-alkyl, O-alkyl-O-alkyl, alkylamino, NHC(O)-alkyl, N(CH3)C(O)-alkyl, NHSO2-alkyl, N(CH3)SO2-alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclic alkyl;

[0087] R 10 Selected from C2-C 12 Alkyl, C(O)-alkyl, hydroxyalkyl, aminoalkyl, alkyl-O-alkyl, alkyl-O-alkyl-OH, alkyl-O-alkyl-O-alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, alkyl-heterocyclic alkyl, aryl, heteroaryl, cycloalkyl, heterocyclic alkyl, SO3H, SO2-alkyl and SO2-haloalkyl;

[0088] R 11 Selected from H and alkyl groups;

[0089] R 12 It is an alkyl group.

[0090] Or its pharmaceutically acceptable salt.

[0091] In some embodiments, R9 is independently selected from OH, NH2, O-alkyl, O-alkyl-O-alkyl, alkylamino, NHC(O)-alkyl, N(CH3)C(O)-alkyl, NHSO2-alkyl, N(CH3)SO2-alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl.

[0092] In some embodiments, R9 is independently selected from OH, NH2, alkylamino and heterocyclic alkyl.

[0093] In some embodiments, R9 is independently selected from OH, O-alkyl, NHC(O)-alkyl, N(CH3)C(O)-alkyl, NHSO2-alkyl, N(CH3)SO2-alkyl, cycloalkyl (OH), and heterocyclic alkyl.

[0094] In some embodiments, the cycloalkyl or heterocycloalkyl group is unsubstituted or substituted with a halogen, alkyl, hydroxy, hydroxyalkyl, alkoxy, or alkoxyalkyl group.

[0095] In some embodiments, the compound of formula (Ia), wherein R 12 It is selected from alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkyl-heterocyclic alkyl and alkyl-alkylamino.

[0096] In some embodiments, R7 is selected from CN, CF3, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylamino, alkyl-R9, alkenyl-R9, alkynyl-R9, OR 10 NHR 10NR 11 C(O)R 12 C(O)NR 11 R 12 and NR 11 SO2R 12 .

[0097] In some embodiments, R7 is selected from haloalkyl, cycloalkyl, alkyl-R9, alkynyl-R9, OR 10 and NR 11 SO2R 12 .

[0098] In some implementations, the condition is that if X1 is 0 and R1, R3, R4, R5, R6, and R8 are each H, then R7 is not -OBn.

[0099] In some embodiments, the compound of formula (Ia) is selected from:

[0100]

[0101] In some embodiments, the compound of formula (Ia) is selected from:

[0102]

[0103]

[0104]

[0105]

[0106]

[0107] In some embodiments, the compound of formula (Ia) is selected from:

[0108]

[0109] In some embodiments, the compound of formula (Ia) is selected from:

[0110]

[0111] In some embodiments, the compound of formula (Ia) is selected from:

[0112]

[0113] In some embodiments, the compound of formula (Ia) is selected from:

[0114]

[0115] Another aspect of the invention relates to a method for treating amyotrophic lateral sclerosis (ALS), the method comprising administering an effective amount of a compound of formula (Ic) to a subject in need.

[0116]

[0117] (Ic)

[0118] in

[0119] A is ;

[0120] n and m One of them is 0; and n and m The other one is 1;

[0121] X1 and Y1 are both 0;

[0122] R1, R2, R3, R6, R7, and R8 are independently selected from H, OH, OCH3, OAc, NH2, halogen, CN, CF3, CO2H, NO2, NHAc, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylamino, alkyl-R9, alkenyl-R9, alkynyl-R9, and OR. 10 NHR 10 NR 11 C(O)R 12 C(O)NR 11 R 12 and NR 11 SO2R 12 ;

[0123] R4 and R5 are independently selected from H, halogens, and alkyl groups;

[0124] Each instance of R9 is independently selected from OH, NH2, O-alkyl, O-alkyl-O-alkyl, alkylamino, NHC(O)-alkyl, N(CH3)C(O)-alkyl, NHSO2-alkyl, N(CH3)SO2-alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclic alkyl;

[0125] R 10 Selected from C2-C 12 Alkyl, hydroxyalkyl, aminoalkyl, alkyl-O-alkyl, alkyl-O-alkyl-OH, alkyl-O-alkyl-O-alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, alkyl-heterocyclicalkyl, aryl, heteroaryl, cycloalkyl, heterocyclicalkyl, SO3H, SO2-alkyl and SO2-haloalkyl;

[0126] Each occurrence of R 11 Selected from H and alkyl groups; and

[0127] Each occurrence of R 12 Selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, and alkyl-heterocycloalkyl;

[0128] Or its pharmaceutically acceptable salt.

[0129] In some implementation schemes, A is selected from and .

[0130] In some embodiments, R2 and R7 are each OH. In other embodiments, R2 and R7 are each O-alkyl. In other embodiments, R2 is OH; and R7 is H or O-alkyl. In other embodiments, R2 is H or O-alkyl; and R7 is OH.

[0131] In some embodiments, R1, R3, R4, R5, R6, and R8 are each H. In other embodiments, one of R1, R3, R4, R5, R6, and R8 is not H. In other embodiments, two of R1, R3, R4, R5, R6, and R8 are not H. In other embodiments, one of R1, R3, R4, R5, R6, and R8 is an alkyl group or a halogen. In other embodiments, two of R1, R3, R4, R5, R6, and R8 are alkyl groups or halogens.

[0132] In some embodiments, the compound of formula (Ic) is selected from:

[0133] , , , , , , , , , , , , , , , , , , , , , , and .

[0134] In some embodiments, the compound of formula (Ic) is selected from:

[0135]

[0136] In some embodiments, the compound of formula (Ic) is selected from:

[0137]

[0138] Another aspect of the invention relates to a method for treating amyotrophic lateral sclerosis (ALS), the method comprising administering an effective amount of a compound of formula (Id) to a subject in need.

[0139]

[0140] (Id)

[0141] in

[0142] A is ;

[0143] Y2 is O;

[0144] Y3 and Y4 are independently selected from H, halogens, and alkyl groups; or they can combine with the carbons they are bonded to to form cycloalkyl or heterocycloalkyl groups.

[0145] R1, R4, R5, and R8 are independently selected from H and halogens;

[0146] R2, R3, R6, and R7 are independently selected from H, OH, OCH3, OAc, NH2, halogen, CN, CF3, CO2H, NO2, NHAc, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylamino, alkyl-R9, alkenyl-R9, alkynyl-R9, OR 10 NHR 10 NR 11 C(O)R 12 C(O)NR 11 R 12 and NR 11 SO2R 12 ;

[0147] Each instance of R9 is independently selected from OH, NH2, O-alkyl, O-alkyl-O-alkyl, alkylamino, NHC(O)-alkyl, N(CH3)C(O)-alkyl, NHSO2-alkyl, N(CH3)SO2-alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclic alkyl;

[0148] R 10 Selected from C2-C 12Alkyl, hydroxyalkyl, aminoalkyl, alkyl-O-alkyl, alkyl-O-alkyl-OH, alkyl-O-alkyl-O-alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, alkyl-heterocyclicalkyl, aryl, heteroaryl, cycloalkyl, heterocyclicalkyl, SO3H, SO2-alkyl and SO2-haloalkyl;

[0149] Each occurrence of R 11 Selected from H and alkyl groups; and

[0150] Each occurrence of R 12 Selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, and alkyl-heterocycloalkyl;

[0151] Or its pharmaceutically acceptable salt.

[0152] In some embodiments, the compound is provided that Y3 and Y4 are not simultaneously halogens when Y2 is O, R2 and R7 are each OH, and R1, R3, R4, R5, R6 and R8 are each H.

[0153] In some implementation schemes, A is selected from , , , , , , , , and .

[0154] In some embodiments, R2 and R7 are each OH. In other embodiments, one of R2 and R7 is OH, and the other of R2 and R7 is an O-alkyl group. In other embodiments, one of R1, R3, R4, R5, R6, and R8 is an alkyl group or a halogen. In other embodiments, two of R1, R3, R4, R5, R6, and R8 are alkyl groups or halogens.

[0155] In some implementations, the compound of formula (Id) is selected from:

[0156] , , , , , , , , , , , , , , , , , , , , , and .

[0157] In some implementations, the compound of formula (Id) is selected from:

[0158]

[0159]

[0160] In some implementations, the compound of formula (Id) is selected from:

[0161] , , , , , , , , , , , , , , , , and .

[0162] In some implementations, the compound of formula (Id) is selected from:

[0163]

[0164] Another aspect of the invention relates to a method for treating amyotrophic lateral sclerosis (ALS), the method comprising administering an effective amount of a compound of formula (Ie) to a subject in need.

[0165]

[0166] (Ie)

[0167] in

[0168] A is ;

[0169] n and m It is 0 at the same time; or n andm One of them is 0, and n and m The other one is 1;

[0170] X1 is O;

[0171] Y1 is selected from NH, N-CH3, N- t -Bu, N-cycloalkyl and N-heterocycloalkyl;

[0172] R1, R2, R3, R6, R7, and R8 are independently selected from H, OH, OCH3, OAc, NH2, halogen, CN, CF3, CO2H, NO2, NHAc, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylamino, alkyl-R9, alkenyl-R9, alkynyl-R9, and OR. 10 NHR 10 NR 11 C(O)R 12 C(O)NR 11 R 12 and NR 11 SO2R 12 ;

[0173] R4 and R5 are independently selected from H, alkyl, and halogen;

[0174] Each instance of R9 is independently selected from OH, NH2, O-alkyl, O-alkyl-O-alkyl, alkylamino, NHC(O)-alkyl, N(CH3)C(O)-alkyl, NHSO2-alkyl, N(CH3)SO2-alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclic alkyl;

[0175] R 10 Selected from C2-C 12 Alkyl, hydroxyalkyl, aminoalkyl, alkyl-O-alkyl, alkyl-O-alkyl-OH, alkyl-O-alkyl-O-alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, alkyl-heterocyclicalkyl, aryl, heteroaryl, cycloalkyl, heterocyclicalkyl, SO3H, SO2-alkyl and SO2-haloalkyl;

[0176] Each occurrence of R 11 Selected from H and alkyl groups; and

[0177] Each occurrence of R 12 Selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, and alkyl-heterocycloalkyl;

[0178] Or its pharmaceutically acceptable salt.

[0179] In some embodiments, R2 and R7 are each -OH, or each is -O-alkyl, or one of R2 and R7 is -OH and the other of R2 and R7 is not -OH.

[0180] In some embodiments, the compound is provided that no more than two of R1, R2, R3, R6, R7, and R8 are OH or OCH3.

[0181] If A is Given that R1, R3, R4, R5, R6, and R8 are each H, then R2 and R7 are either not simultaneously OH, simultaneously OCH3, or simultaneously OR. 10 ,and

[0182] If A is And if R1, R3, R4, R5, R6, and R8 are each H, then R2 and R7 are not simultaneously OR. 10 .

[0183] In some implementation schemes, where n and m It is also 0. In other implementation schemes, n and m One of them is 0, and n and m The other one is 1.

[0184] In some implementation schemes, A is selected from , and In other implementations, A is selected from... , , and .

[0185] In some implementations, R2 and R7 are each OH.

[0186] In some embodiments, one of R2 and R7 is OH, and the other of R2 and R7 is not OH. In other embodiments, R2 and R7 are each O-alkyl. In other embodiments, R2 is OH and R7 is O-alkyl; or R2 is O-alkyl and R7 is OH.

[0187] In some embodiments, R1, R3, R4, R5, R6, and R8 are each H. In other embodiments, one of R1, R3, R4, R5, R6, and R8 is not H. In other embodiments, two of the compounds R1, R3, R4, R5, R6, and R8 are not H. In other embodiments, one of R1, R3, R4, R5, R6, and R8 is an alkyl group or a halogen. In other embodiments, two of R1, R3, R4, R5, R6, and R8 are alkyl groups or halogens.

[0188] In some embodiments, the compound of formula (Ie) is selected from:

[0189] , , , , , , , , , , , , , , , , , , , , , , and .

[0190] In some embodiments, the compound of formula (Ie) is selected from:

[0191] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0192] In some embodiments, the compound of formula (Ie) is selected from:

[0193] , , , , , , , , , and .

[0194] In one embodiment, the compound of formula (Ie) is selected from:

[0195] , , , , , , , , , , , and .

[0196] Another aspect of the invention relates to a method for treating amyotrophic lateral sclerosis (ALS), the method comprising administering an effective amount of a compound of formula (If) to a subject in need.

[0197]

[0198] (If)

[0199] in

[0200] A is selected from , , , , , , , , , and ;

[0201] n and m It is 0 at the same time; or n and m One of them is 0, and n and m The other one is 1;

[0202] o and p It is 0 at the same time; or o and p One of them is 0, and o and p The other one is 1;

[0203] q It is 0 or 1;

[0204] r and s It is 0 at the same time; or r and s One of them is 0, and r and s The other one is 1;

[0205] X1 and X2 are both 0;

[0206] X3 is O or N (alkyl);

[0207] Y1 is S;

[0208] Y2 is selected from O, CH2, NH, N-alkyl, S, S(O) and SO2;

[0209] Y3 and Y4 are independently selected from H, halogens, OH and alkyl groups, or combined with the carbons they are bonded to to form cycloalkyl or cyclohexaalkyl groups;

[0210] Y5 is selected from CH2, NH, N-alkyl, N-arylalkyl, N-cycloalkyl, and N-heterocyclic alkyl;

[0211] Each occurrence of Y6 is independently selected from O, S, S(O), SO2, NH, N-alkyl, N-alkylaryl, and N-cycloalkyl;

[0212] Y7 is selected from O, NH, and N-alkyl groups;

[0213] Y8 is selected from O and S;

[0214] R1, R2, R3, R6, R7, and R8 are independently selected from H, OH, OCH3, OAc, NH2, halogen, CN, CF3, CO2H, NO2, NHAc, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylamino, alkyl-R9, alkenyl-R9, alkynyl-R9, and OR. 10 NHR 10 NR 11 C(O)R 12 C(O)NR 11 R 12 and NR 11 SO2R 12 ,

[0215] R4 and R5 are independently selected from H, alkyl, and halogen;

[0216] Each instance of R9 is independently selected from OH, NH2, O-alkyl, O-alkyl-O-alkyl, alkylamino, NHC(O)-alkyl, N(CH3)C(O)-alkyl, NHSO2-alkyl, N(CH3)SO2-alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclic alkyl;

[0217] R 10 Selected from C2-C 12 Alkyl, hydroxyalkyl, aminoalkyl, alkyl-O-alkyl, alkyl-O-alkyl-OH, alkyl-O-alkyl-O-alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, alkyl-heterocyclicalkyl, aryl, heteroaryl, cycloalkyl, heterocyclicalkyl, SO3H, SO2-alkyl and SO2-haloalkyl;

[0218] Each occurrence of R 11 Selected from H and alkyl groups; and

[0219] Each occurrence of R 12 Selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, and alkyl-heterocycloalkyl;

[0220] Or its pharmaceutically acceptable salt.

[0221] In some embodiments, the compound is defined as follows: if Y2 is CH2, one of Y3 or Y4 is not H, or Y3 or Y4 combines with the carbons they are bonded to to form a cycloalkyl or heterocycloalkyl group, and if Y2 is O, then... r and s One of them is 0, and r and s The other one is 1.

[0222] In some implementation schemes, A is ;and n and m It is also 0. In other implementations, A is... In some implementations, A is... In other implementations, A is selected from... , , , , , and In some implementations, A is... .

[0223] In other implementations, A is selected from , , , , , , , , , , , , , , , , , , , , , and .

[0224] In some implementation schemes, A is selected from , , , , and .

[0225] In other implementations, A is selected from , , , , , , , , , , , , , and .

[0226] In some embodiments, Y2 is selected from CH2, NH, N-alkyl, S, S(O) and SO2.

[0227] In some embodiments, R2 and R7 are each OH. In other embodiments, one of R2 and R7 is OH, and the other of R2 and R7 is not OH. In other embodiments, R2 and R7 are each O-alkyl. In other embodiments, R2 is OH and R7 is O-alkyl; or R2 is O-alkyl and R7 is OH.

[0228] In some embodiments, R1, R3, R4, R5, R6, and R8 are each H. In other embodiments, one of R1, R3, R4, R5, R6, and R8 is not H. In other embodiments, two of R1, R3, R4, R5, R6, and R8 are not H. In other embodiments, one of R1, R3, R4, R5, R6, and R8 is an alkyl or halogen. In other embodiments, two of R1, R3, R4, R5, R6, and R8 are alkyl or halogen.

[0229] In some implementations, the compound of formula (If) is selected from:

[0230] , , , , , , , , , , , , , , , , , , , , , , and .

[0231] In some implementations, the compound of formula (If) is selected from:

[0232] , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , and .

[0233] In some implementations, the compound of formula (If) is selected from:

[0234] , , , , and .

[0235] Another aspect of the invention relates to a method for treating amyotrophic lateral sclerosis (ALS), the method comprising administering an effective amount of a compound of formula (Ih) to a subject in need.

[0236]

[0237] (Ih)

[0238] in

[0239] A is selected from and ;

[0240] n and m It is 0 at the same time; or n and m One of them is 0, and n and m The other one is 1;

[0241] r and s It is 0 at the same time; or r and s One of them is 0, and r and s The other one is 1;

[0242] X1 is O;

[0243] Y1 is selected from O, NH, N-alkyl and N-cycloalkyl;

[0244] Y2 is O;

[0245] Y3 and Y4 are independently selected from H, halogens and alkyl groups, or combined with the carbons they are bonded to to form cycloalkyl or cyclohexaalkyl groups;

[0246] R1, R4, R5, and R8 are independently selected from H and halogens;

[0247] R3 and R6 are independently selected from H, CN, OH, CF3, halogens and alkyl groups;

[0248] One of R2 and R7 is NH2, NHCH3, or N(CH3)2, and the other of R2 and R7 is H, halogen, OCH3, CN, CF3, CO2H, NO2, NHAc, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylamino, alkyl-R9, alkenyl-R9, alkynyl-R9, OR 10 NHR 10 NR 11 C(O)R 12 C(O)NR 11 R 12 and NR 11 SO2R 12 ;

[0249] Each instance of R9 is independently selected from OH, NH2, O-alkyl, O-alkyl-O-alkyl, alkylamino, NHC(O)-alkyl, N(CH3)C(O)-alkyl, NHSO2-alkyl, N(CH3)SO2-alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclic alkyl;

[0250] R 10 Selected from C2-C 12 Alkyl, hydroxyalkyl, aminoalkyl, alkyl-O-alkyl, alkyl-O-alkyl-OH, alkyl-O-alkyl-O-alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, alkyl-heterocyclicalkyl, aryl, heteroaryl, cycloalkyl, heterocyclicalkyl, SO3H, SO2-alkyl and SO2-haloalkyl;

[0251] Each occurrence of R 11 Selected from H and alkyl groups; and

[0252] Each occurrence of R 12 Selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, and alkyl-heterocycloalkyl;

[0253] or its pharmaceutically acceptable salt

[0254] In some embodiments, the compound is provided that if A is If R1, R3, R4, R5, R6, and R8 are each H, and R7 is NH2, then R2 is not OH.

[0255] In some embodiments, Y1 is selected from O, NH and N-alkyl.

[0256] In some implementation schemes, A is ;andn and m It is also 0. In other implementations, A is... In other implementations, A is... or .

[0257] In some implementation schemes, A is ;and n or m One of them is 0, and n or m The other one is 1. In other implementations, A is... and In other implementations, A is selected from... , , and .

[0258] In some implementation schemes, A is ;and r and s It is also 0. In other implementation schemes, A is selected from... , , , , , , , and In other implementations, A is selected from... , and .

[0259] In some implementations, R2 is selected from NH2, NHCH3 and N(CH3)2.

[0260] In some embodiments, R7 is selected from H, OH, halogens, O-alkyl and haloalkyl.

[0261] In some implementations, R7 is selected from alkynyl-R9 and OR. 10 R9 is OH; and R 10 It is an alkyl-heterocyclic alkyl group.

[0262] In some embodiments, R1, R3, R4, R5, R6, and R8 are each H. In other embodiments, one of R1, R3, R4, R5, R6, and R8 is not H. In other embodiments, two of R1, R3, R4, R5, R6, and R8 are not H. In other embodiments, one of R1, R3, R4, R5, R6, and R8 is an alkyl or halogen. In other embodiments, two of R1, R3, R4, R5, R6, and R8 are independently alkyl or halogen.

[0263] In some embodiments, the compound of formula (Ih) is selected from:

[0264]

[0265] In some embodiments, the compound of formula (Ih) is selected from:

[0266]

[0267]

[0268] In some embodiments, the compound of formula (Ih) is selected from:

[0269]

[0270]

[0271] In some embodiments, the compound of formula (Ih) is selected from:

[0272]

[0273]

[0274] In some embodiments, the compound of formula (Ih) is selected from:

[0275]

[0276] Another aspect of the invention relates to a method for treating amyotrophic lateral sclerosis (ALS), the method comprising administering an effective amount of a compound of formula (IIa) to a subject in need.

[0277]

[0278] (IIa)

[0279] in

[0280] Y1 and Y2 are each alkyl groups; or they may combine with the carbon atoms to which they are bonded to form unsubstituted or substituted spirocycloalkyl groups;

[0281] R1, R4, R5, and R8 are independently selected from -H and halogens;

[0282] R2 and R7 are independently selected from -H, -OH, -OAc, -NH2, halogen, -CN, -CF3, -CO2H, -NO2, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylamino, alkyl-R9, alkenyl-R9, alkynyl-R9, -OR 10 -NHR 10 -NR 11 C(O)R 12 -C(O)NR 11 R 12 and -NR 11 SO2R 12 ;

[0283] R3 and R6 are alkyl groups;

[0284] Each instance of R9 is independently selected from OH, NH2, O-alkyl, O-alkyl-O-alkyl, alkylamino, NHC(O)-alkyl, N(CH3)C(O)-alkyl, NHSO2-alkyl, N(CH3)SO2-alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclic alkyl;

[0285] R 10 Selected from alkyl, hydroxyalkyl, aminoalkyl, alkyl-O-alkyl, alkyl-O-alkyl-OH, alkyl-O-alkyl-O-alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, alkyl-heterocyclicalkyl, aryl, heteroaryl, cycloalkyl, heterocyclicalkyl, SO3H, SO2-alkyl, and SO2-haloalkyl;

[0286] Each occurrence of R 11 Selected from H and alkyl groups; and

[0287] Each occurrence of R 12 Selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, and alkyl-heterocycloalkyl;

[0288] The condition is that when R1, R 4、 When R5 and R8 are each -H, R2 and R7 are each -OH, and R3 and R6 are each CH3, then Y1 and Y2 are not each -Me or do not form unsubstituted spirocyclic butyl groups together with the carbons they are bonded to.

[0289] Or its pharmaceutically acceptable salt.

[0290] In some embodiments, Y1 and Y2 are each independently C1-C4 alkyl groups. In some embodiments, Y1 and Y2 are each -CH3.

[0291] In some embodiments, Y1 and Y2, together with the carbon atoms to which they are bonded, form an unsubstituted spirocycloalkyl group. In other embodiments, Y1 and Y2, together with the carbon atoms to which they are bonded, form an unsubstituted spirocyclopropyl, cyclobutyl, or cyclopentyl group.

[0292] In some implementations, R3 and R6 are each independently C1-C4 alkyl groups.

[0293] In some embodiments, R3 and R6 are each independently selected from -CH3 and -CH2CH3. In other embodiments, R3 and R6 are each -CH3. In still other embodiments, R3 and R6 are each -CH2CH3.

[0294] In some implementations, one of R3 and R6 is -CH3, and the other of R3 and R6 is -CH2CH3.

[0295] In some embodiments, the compound has a structure selected from the following:

[0296]

[0297] In some embodiments, R2 and R7 are independently selected from -OH, -NH2, alkylamino, and -OR. 10 .

[0298] In some embodiments, R2 and R7 are each OH. In other embodiments, R2 is -OH and R7 is -CH3. In other embodiments, R7 is -OH and R2 is -OCH3.

[0299] In some embodiments, R2 is selected from -NH2, -NHCH3, and -NH(CH3)2; and R7 is OH. In other embodiments, R7 is selected from -NH2, -NHCH3, and -NH(CH3)2; and R2 is OH.

[0300] In some implementations, R1, R4, R5, and R8 are each -H.

[0301] In some implementation schemes, the compound is selected from:

[0302]

[0303] Or its pharmaceutically acceptable salt.

[0304] Another aspect of the invention relates to a method for treating amyotrophic lateral sclerosis (ALS), the method comprising administering an effective amount of a compound of formula (IIb) to a subject in need.

[0305]

[0306] (IIb)

[0307] in

[0308] X1 and X2 are each alkyl groups; or they may combine with the carbon atoms to which they are bonded to form unsubstituted or substituted spirocycloalkyl groups;

[0309] R1', R4' 、 R5' and R8' are independently selected from -H, -OH, -NH2, alkyl and halogen;

[0310] R2', R3', R6', and R7' are independently selected from -H, -OH, -OAc, -NH2, halogen, -CN, -CF3, -CO2H, -NO2, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylamino, and -OR8'; and

[0311] R8' is selected from alkyl, hydroxyalkyl, aminoalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;

[0312] Or its pharmaceutically acceptable salt.

[0313] In some embodiments, X1 and X2 are each independently C1-C4 alkyl.

[0314] In some implementations, X1 and X2 are each -CH3.

[0315] In some embodiments, X1 and X2, together with the carbon atoms to which they are bonded, form an unsubstituted spirocycloalkyl group. In other embodiments, X1 and X2, together with the carbon atoms to which they are bonded, form an unsubstituted spirocyclopropyl, cyclobutyl, or cyclopentyl group.

[0316] In some embodiments, the compound has a structure selected from the following:

[0317]

[0318] In some embodiments, R2' and R7' are independently selected from -OH, -NH2, alkylamino, and -OR. 10 .

[0319] In some embodiments, R2' and R7' are each OH. In other embodiments, R2' is -OH; and R7' is -OCH3. In other embodiments, R7' is -OH; and R2' is -OCH3.

[0320] In some embodiments, R2' is selected from -NH2, -NHCH3 and -NH(CH3)2; and R7' is OH.

[0321] In some embodiments, R7' is selected from -NH2, -NHCH3 and -NH(CH3)2; and R2' is OH.

[0322] In some embodiments, R3' and R6' are each independently -H or C1-C4 alkyl. In other embodiments, R3' and R6' are each independently -H or -CH3.

[0323] In some embodiments, R1' and R8' are each independently -H or C1-C4 alkyl. In other embodiments, R1' and R8' are each independently -H or -CH3.

[0324] In some implementations, R4' and R5' are each independently -H or -OH.

[0325] In some implementation schemes, the compound is selected from:

[0326]

[0327] Or its pharmaceutically acceptable salt.

[0328] Another aspect of the present invention relates to a method for treating amyotrophic lateral sclerosis (ALS), the method comprising administering to a subject in need an effective amount of a compound having the following structure:

[0329]

[0330] In some embodiments of any of the disclosed methods, the compound is wherein R2 and R7 are each OH. In other embodiments, R2 is OH and R7 is not OH. In other embodiments, R2 is OH and R7 is not OCH3. In other embodiments, R2 is OH and R7 is not H.

[0331] In some embodiments of any of the disclosed compounds, R2 is OH and R7 is OCH3. In other embodiments, R2 is OH and R7 is H. In other embodiments, R2 is OH and R7 is alkynyl-R9. In other embodiments, R2 is OH and R7 is OR. 10 In other embodiments, R2 is OH and R7 is OR. 10 .

[0332] In some embodiments of any of the disclosed methods, the compound, wherein R2 is OH and R7 is

[0333] In some embodiments of any of the disclosed methods, the compounds are selected from Table 1.

[0334] Table 1.

[0335]

[0336]

[0337] In some embodiments of any of the disclosed methods, the compound is a transisomer. Additionally, unless otherwise stated, the structures described herein are also intended to include compounds differing only in the presence of one or more isotopically enriched atoms. For example, by replacing hydrogen with deuterium or tritium, or by replacing carbon with... 13 C- or 14 Compounds resulting from the substitution of C-enriched carbon are within the scope of this invention. Such compounds can be used, for example, as analytical tools, as probes in bioassays, or as therapeutic agents according to the invention. For example, regarding variable R... 1 In this regard, (C1-C4)alkyl or -O-(C1-C4)alkyl may be suitably deuterated (e.g., -CD3, -OCD3).

[0338] Any compound of the present invention can also be radiolabeled for use in the preparation of radiopharmaceuticals.

[0339] In some implementations, amyotrophic lateral sclerosis (ALS) is C9orf72 amyotrophic lateral sclerosis (C9-ALS).

[0340] Pharmaceutical composition, route of administration and administration

[0341] In some embodiments, the present invention relates to a method for treating amyotrophic lateral sclerosis (ALS), the method comprising administering an effective amount of a pharmaceutical composition to a subject in need, the pharmaceutical composition comprising a compound of formula (Ia), formula (Ic), formula (Id), formula (Ie), formula (If), or formula (Ih) and a pharmaceutically acceptable carrier.

[0342] In some implementations, amyotrophic lateral sclerosis (ALS) is C9orf72 amyotrophic lateral sclerosis (C9-ALS).

[0343] In some embodiments, the pharmaceutical composition comprises a variety of compounds of the present invention and pharmaceutically acceptable carriers.

[0344] In some embodiments, the pharmaceutical composition of the present invention further comprises at least one additional pharmaceutically active agent in addition to the compound of the present invention. The at least one additional pharmaceutically active agent may be an agent that can be used to treat ischemia-reperfusion injury.

[0345] The pharmaceutical compositions of the present invention can be prepared by combining one or more compounds of the present invention with a pharmaceutically acceptable carrier and optionally one or more additional pharmaceutical active agents.

[0346] As stated above, “effective amount” means any amount sufficient to achieve the desired biological effect. In conjunction with the teachings provided herein, preventative or therapeutic regimens that do not cause substantial unwanted toxicity but are effective in treating a particular subject can be devised by selecting from various active compounds and trade-offs such as potency, relative bioavailability, patient weight, severity of adverse side effects, and administration mode. The effective amount for any particular application can vary depending on factors such as the disease or ailment being treated, the specific compound of the invention being administered, the size of the subject, or the severity of the disease or ailment. Those skilled in the art can determine the effective amount of a particular compound and / or other therapeutic agent of the invention empirically without excessive experimentation. A maximum dose, i.e., the highest safe dose according to some medical diagnoses, can be used. Multiple daily doses can be considered to achieve appropriate systemic levels of the compound. Appropriate systemic levels can be determined, for example, by measuring the patient’s peak drug levels or sustained plasma levels. “Dosage” and “application amount” are used interchangeably herein.

[0347] The formulations of the present invention can be administered as pharmaceutically acceptable solutions, which may conventionally contain pharmaceutically acceptable concentrations of salts, buffers, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.

[0348] The pharmaceutical compositions of the present invention contain an effective amount of the compounds as described herein and optionally a therapeutic agent contained in a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers, diluents, or encapsulating substances suitable for administration to humans or other vertebrates. The term "carrier" refers to a natural or synthetic organic or inorganic component, with which the active ingredient is combined to facilitate application. The components of the pharmaceutical composition can also be blended with the compounds of the present invention and with each other in such a way that no interactions exist that would substantially impair the desired pharmaceutical efficacy.

[0349] Those skilled in the art will understand that, based on the description of the invention contained herein and given information known to those skilled in the art, other suitable modifications and adaptations to the compositions and methods described herein will be apparent and can be made without departing from the scope of the invention or any embodiments thereof. The invention has now been described in detail, and will be more clearly understood by referring to the following examples, which are included herein for illustrative purposes only and are not intended to limit the invention.

[0350] Example

[0351] The present invention is further described in the following embodiments, which do not limit the scope of the invention as described in the claims.

[0352] Example 1: Synthesis of representative compounds used in the method of the present invention

[0353] Unless otherwise specified, all reactions were carried out using oven-dried glassware and under an inert atmosphere (nitrogen). Unless otherwise specified, all solvents were used as is. Commercial reagents were used as is without further purification. Organic solutions were concentrated under reduced pressure using a Büchi rotary evaporator.

[0354] Thin-layer chromatography was performed using Merck Kieselgel 60 F254 (230-400 mesh) fluorescently treated silica, and visualized under UV light (254 and 366 nm) and / or by staining with an aqueous potassium permanganate solution. ¹H NMR spectra were recorded in deuterated solvents at 400 MHz on a Bruker spectrometer or at 60 MHz on a Nanalysis NMReady-60PRO spectrometer, with the residual proton solvent serving as an internal standard. ¹³C NMR spectra were recorded in deuterated solvents at 100 MHz on a Bruker spectrometer, with the central peak of the deuterated solvent serving as an internal standard. Chemical shifts (δ) are given in parts per million (ppm), and coupling constants (J) are given rounded to the nearest 0.1 Hz in Hertz (Hz). ¹H NMR spectra are reported as δ / ppm (multiplicity, proton number, coupling constant J / Hz) relative to the low field of tetramethylsilane. 13 C10 NMR spectra are reported as δ / ppm. TLC-MS data were obtained on an Advion Expression CMS coupled with a Plate Express TLC reader. Medium-pressure liquid chromatography (MPLC) was performed on a Biotage Isolera Four with a built-in UV detector and a fraction collector with an Interchim silica column.

[0355] 1. Synthesis of a 6-membered urolithin A analogue

[0356] A) Ester "A" group analogues via the Hurtley reaction

[0357] General Procedure 1A (GP1a)

[0358] Using the general procedure of cyclization with NaOH and CuSO4 (GP1a), the synthesis of 3-hydroxy-8-methoxy-6H-benzo[c]chromene-6-one (1) is used as a general example.

[0359]

[0360] A mixture of 2-bromo-5-methoxybenzoic acid (0.500 g, 2.16 mmol, 1.0 equivalent), resorcinol (0.477 g, 4.33 mmol, 2.0 equivalent), and sodium hydroxide (0.2 g, 4.98 mmol, 2.4 equivalent) in water (10 mL) was heated under reflux for 30 minutes. After adding copper sulfate (5% aqueous solution, 2.5 mL), the mixture was refluxed again overnight to form a precipitate. The precipitate was filtered off and washed with 1 M HCl, then dried under vacuum to give 3-hydroxy-8-methoxy-6H-benzo[c]chromene-6-one (300 mg, 1.24 mmol 57%). 1 H NMR (400 MHz, DMSO) δ 8.27 (d, J = 8.9 Hz, 1H), 8.14 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 2.8 Hz, 1H), 7.56 (dd,J = 8.8, 2.9 Hz, 1H), 6.88 (dd, J = 8.7, 2.4 Hz, 1H), 6.80 (d, J = 2.4 Hz, 1H), 3.95 (s, 3H).

[0361] General Procedure 1B (GP1b)

[0362] Using the general procedure of cyclization with Na2CO3 and CuI (GP1b), the synthesis of 3-hydroxy-6-oxo-6H-benzo[c]chromene-8-carboxylic acid (2) is used as a general example.

[0363]

[0364] Resorcinol (8.9 g, 81.6 mmol, 2.0 equivalent) was dissolved in water, and sodium carbonate (8.60 g, 81.6 mmol, 2.0 equivalent) was added. The mixture was heated to 50 °C until all substances dissolved. Then, acid (10.00 g, 40.8 mmol, 1.0 equivalent) was added, and stirring was continued at 50 °C for 1 hour. Subsequently, CuI (0.77 g, 4.08 mmol) was added in one dose, and the reaction mixture was stirred overnight. A precipitate formed, which was filtered and washed twice with 1 M HCl to give 3-hydroxy-6-oxo-6H-benzo[c]chromene-8-carboxylic acid (4.45 g, 17.4 mmol, 43%) as a beige solid. 1H NMR (400 MHz, DMSO) δ 13.31 (s, 1H), 10.52 (s, 1H), 8.65 (s, 1H), 8.35 (d, J = 5.9 Hz, 1H), 8.29 (s, 1H), 8.18 (d, J = 8.7 Hz, 1H), 6.85 (dd, J = 8.7, 2.3 Hz, 1H), 6.75 (d, J = 2.2 Hz, 1H).

[0365] 8-Bromo-3-hydroxy-6H-benzo[c]chromene-6-one (3) Synthesis

[0366]

[0367] The compound was prepared by starting with resorcinol (3.93 g, 35.7 mmol) and 2,5-dibromobenzoic acid (5.00 g, 17.9 mmol) according to GP1a, yielding 8-bromo-3-hydroxy-6H-benzo[c]chromene-6-one (2.14 g, 42%) as a slightly brown solid. 1 H NMR (400 MHz, DMSO) δ 10.44 (s, 1H), 8.21 (d, J = 2.2 Hz, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.12 (d, J = 8.8 Hz, 1H), 8.01 (dd, J = 8.7, 2.2 Hz,1H), 6.84 (dd, J = 8.7, 2.4 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H).

[0368] N-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)acetamide (4) Synthesis

[0369]

[0370] The compound was prepared from resorcinol (1.40, 12.8 mmol) and 5-acetamido-2-bromobenzoic acid (1.00 g, 3.87 mmol) according to GP1b, yielding N-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)acetamide (620 mg, 29%) as a beige solid. 1H NMR (400 MHz, DMSO) δ 10.32 (s, 1H), 10.27 (s, 1H), 8.50 (d, J = 2.2 Hz, 1H), 8.20 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.99 (dd, J = 8.8, 2.3 Hz, 1H), 6.83 (dd, J = 8.7, 2.4 Hz, 1H), 6.74 (d, J =2.3 Hz, 1H), 2.10 (s, 3H).

[0371] 4. Deprotection yields 8-amino-3-hydroxy-6H-benzo[c]chromen-6-one (5)

[0372]

[0373] 8-Fluoro-3-hydroxy-6H-benzo[c]chromene-6-one (6) Synthesis

[0374]

[0375] According to GP1a, the compound was prepared by starting with resorcinol (2.01 g, 18.3 mmol) and 2-bromo-5-fluorobenzoic acid (2.00 g, 9.13 mmol) to obtain 8-fluoro-3-hydroxy-6H-benzo[c]chromene-6-one (1.00 g, 48%) as a slightly brown solid. 1 H NMR (400 MHz, DMSO) δ 10.54 (s, 1H), 8.31 (d, J = 2.2 Hz, 1H), 8.28 (d, J = 8.8 Hz, 1H), 8.32 (d, J = 8.8 Hz, 1H), 8.21 (dd, J = 8.7, 2.2 Hz,1H), 7.04 (dd, J = 8.7, 2.4 Hz, 1H), 6.94 (d, J = 2.4 Hz, 1H).

[0376] B) Amide "A" group analogs

[0377] 3,8-Dihydroxyphenanthridine-6(5H)-one (18) Synthesis

[0378]

[0379] Step 1: Synthesis of 3,8-dimethoxyphenanthridine-6(5H)-one

[0380]

[0381] 2,7-Dimethoxy-9H-fluorene-9-one (1.10 g, 4.57 mmol) was added to cold sulfuric acid (10 mL) at 0 °C, followed by careful addition of sodium azide (387 mg, 5.95 mmol). The reaction mixture was stirred at 0 °C for 3 hours. EtOAc (10 mL) was added, and the mixture was poured into ice water and stirred for 1 hour. The slightly brown precipitate was filtered off, and the aqueous phase was extracted three times with EtOAc. The organic phase was dried over sodium sulfate and evaporated under vacuum. The crude material was purified by MPLC (SiO2, EtOAc / cyclohexane 0% to 80%) to give 3,8-dimethoxyphenanthrene-6(5H)-one (150 mg, 13%) as a brown solid. f =0.4 (EtOAc / 50% hexane). 1 H NMR (400 MHz, DMSO) δ 11.60 (s, 1H), 8.32 (d, J = 8.9Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 7.70 (d, J = 2.8 Hz, 1H), 7.40 (dd, J =8.9, 2.9 Hz, 1H), 6.91 – 6.81 (m, 2H), 3.89 (s, 3H), 3.81 (s, 3H).

[0382] Step 2: Synthesis of 3,8-dihydroxyphenanthridine-6(5H)-one

[0383]

[0384] 18. GP2 was prepared from 3,8-dimethoxyphenanthrene-6(5H)-one (90 mg, 0.35 mmol) and BBr3 (1 mL in THF, 2.10 mL, 2.10 mmol), and after purification by MPLC (SiO2, MeOH / DCM 0% to 10%), 3,8-dihydroxyphenanthrene-6(5H)-one (70 mg, 87%) was obtained as a slightly brown solid. f = 0.2 (MeOH 10% in DCM). 1 HNMR (400 MHz, DMSO) δ 11.91 – 11.20 (m, 1H), 10.34 – 9.57 (m, 2H), 8.08 (d, J= 49.2 Hz, 2H), 7.82 – 7.48 (m, 1H), 7.23 (s, 1H), 6.70 (d, J = 27.5 Hz, 2H).

[0385] 3,8-Dihydroxy-5-methylphenanthidine-6(5H)-one (20) Synthesis

[0386]

[0387] Step 1: Synthesis of 3,8-dimethoxy-5-methylphenanthidine-6(5H)-one (19)

[0388]

[0389] NaH (60% mineral oil dispersion, 59 mg, 1.5 mmol) was added to a solution of 3,8-dimethoxyphenanthrene-6(5H)-one (250 mg, 0.98 mmol) in DMF (10 mL) at 0 °C, and the mixture was stirred at 0 °C for 30 min. Then, MeI (0.122 mL, 1.96 mmol) was added, and stirring was continued at room temperature for 2 h. The reaction mixture was poured into a saturated aqueous NH4Cl solution and extracted three times with EtOAc. The combined organic phases were dried over sodium sulfate and concentrated under vacuum. The crude product was purified by MPLC (SiO2, EtOAc / cyclohexane 0% to 40%) to give 3,8-dimethoxy-5-methylphenanthrene-6(5H)-one (176 mg, 67%). f = 0.3 eluent (EtOAc / hexane 50%). 1 H NMR (400 MHz, CDCl3) δ 8.10(dd, J = 9.2, 8.0 Hz, 2H), 7.93 (d, J = 2.8 Hz, 1H), 7.32 (dd, J = 8.9, 2.9Hz, 1H), 6.93 – 6.86 (m, 2H), 3.95 (s, 3H), 3.93 (s, 3H), 3.80 (s, 3H).

[0390] Step 2: Synthesis of 3,8-dihydroxy-5-methylphenanthidine-6(5H)-one (20)

[0391]

[0392] The preparation of GP2 was initiated from 3,8-dimethoxy-5-methylphenanthrin-6(5H)-one (150 mg, 0.550 mmol), and after purification by MPLC (SiO2, MeOH / DCM 0% to 10%), 3,8-dihydroxy-5-methylphenanthrin-6(5H)-one (120 mg, 89%) was obtained as a beige solid. f = 0.8 (MeOH / DCM 10 / 90).1 H NMR (400 MHz, DMSO) δ9.92 (s, 2H), 8.18 (d, J = 8.9 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.64 (d, J= 2.7 Hz, 1H), 7.22 (dd, J = 8.8, 2.7 Hz, 1H), 6.85 (d, J = 2.3 Hz, 1H), 6.77 (dd, J = 8.7, 2.3 Hz, 1H), 3.63 (s, 3H).

[0393] 5-Cyclopropyl-3,8-Dihydroxyphenanthridine-6(5H)-one (twenty one) Synthesis

[0394]

[0395] Step 1: Synthesis of 5-cyclopropyl-3,8-dimethoxyphenanthridine-6(5H)-one

[0396]

[0397] 3,8-Dimethoxyphenanthrene-6(5H)-one (120 mg, 0.470 mmol, 1.0 equivalent), cyclopropylboronic acid (121 mg, 1.41 mmol, 3.0 equivalent), pyridine (355 mg, 4.23 mmol, 9.0 equivalent), triethylamine (285 mg, 2.82 mmol, 6.0 equivalent), and THF (2.0 mL) were added to a microwave-safe vial, and the resulting mixture was degassed with an N2 balloon for 10 minutes at room temperature. Then, Cu(OAc)2 (171 mg, 0.940 mmol, 2.0 equivalent) was added in a single addition, and the vial was sealed and placed in a preheated 130°C oil bath for 2 hours. After complete consumption of the starting materials, the reaction mixture was cooled to room temperature, subsequently quenched with water, extracted with EtOAc, dried over Na2SO4, and concentrated under vacuum. The crude product was purified by MPLC (SiO2, 25 g, EtOAc in Hex 0%-50%) to give 5-cyclopropyl-3,8-dimethoxyphenanthridine-6(5H)-one (50 mg, 36%) as a brown solid. 1H NMR (400 MHz, CDCl3) δ 8.02 (dd, J = 8.9, 2.1 Hz, 2H), 7.87 (d, J = 2.8Hz, 1H), 7.39 (d, J = 2.5 Hz, 1H), 7.29 (dd, J = 8.9, 2.8 Hz, 1H), 6.87 (dd,J = 8.8, 2.5 Hz, 1H), 3.93 (d,J = 3.2 Hz, 6H), 3.05 – 2.99 (m, 1H), 1.45 –1.36 (m, 2H), 0.97 – 0.90 (m, 2H).

[0398] Step 2: Synthesis of 5-cyclopropyl-3,8-dimethoxyphenanthridine-6(5H)-one

[0399]

[0400] 5-Cyclopropyl-3,8-dimethoxyphenanthrene-6(5H)-one (20 mg, 0.070 mmol, 1.0 equivalent) was dissolved in DCM (1 mL) and cooled to 0°C in an ice bath while stirring for 5 minutes. Then, BBr3 (0.20 mL, 1 M in DCM, 0.020 mmol, 3.0 equivalent) was added dropwise to the reaction mixture. After the addition was complete, the mixture was left in an ice bath and allowed to warm to room temperature over 2 hours. When the starting material could no longer be observed (TLC), the reaction mixture was added dropwise to 0°C cold methanol (10 mL) and stirred for another 10 minutes. The mixture was then concentrated and loaded onto silica for purification by MPLC (SiO2, 12 g, MeOH in DCM 0%–5%) to give 5-cyclopropyl-3,8-dihydroxyphenanthridine-6(5H)-one (13 mg, 0.050 mmol, 71%) as a white solid. MS (ESI+): m / z = 268. 1H NMR (400MHz, DMSO) δ 9.86 (d, J = 9.3 Hz, 2H), 8.12 (d, J = 8.9 Hz, 1H), 8.06 (d, J =8.8 Hz, 1H), 7.57 (d, J = 2.7 Hz, 1H), 7.27 (d, J = 2.3 Hz, 1H), 7.18 (dd, J= 8.7, 2.8 Hz, 1H), 6.73 (dd, J = 8.7, 2.3 Hz, 1H), 2.94 (dt, J = 7.0, 3.1Hz, 1H), 1.35 – 1.18 (m, 2H), 0.74 (p, J = 5.4, ​​5.0 Hz, 2H).

[0401] C) Analogs of the sulfonamide "A" group

[0402] 3,8-Dihydroxy-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (twenty two) Synthesis

[0403]

[0404] Step 1: N Synthesis of -(2-bromo-5-methoxyphenyl)-3-methoxybenzenesulfonamide

[0405]

[0406] 3-Methoxybenzenesulfonyl chloride (2.00 g, 9.68 mmol, 1.3 equivalents) was slowly added to a solution of 2-bromo-5-methoxyaniline (1.79 g, 8.81 mmol, 1.0 equivalents) and pyridine (2.79 g, 35.2 mmol, 4.0 equivalents) in DCM (20 mL) at 0 °C. After heating to room temperature, the starting material was no longer observable by TLC, and the reaction mixture was concentrated under vacuum. The reaction mixture was diluted with EtOAc and washed with 1N HCl aqueous solution. The organic phase was dried over Na2SO4 and concentrated under vacuum to give a brown oily substance. N -(2-bromo-5-methoxyphenyl)-3-methoxybenzenesulfonamide (3.28 g, 99%). 1 H NMR (400 MHz, CDCl3) δ 7.41 – 7.21 (m, 4H), 7.07 (ddd, J = 7.7, 2.5, 1.5Hz, 1H), 6.94 (s, 1H), 6.55 (dd, J= 8.9, 3.0 Hz, 1H), 3.78 (s, 3H), 3.77 (s, 3H).

[0407] Step 2: Synthesis of N-benzyl-N-(2-bromo-5-methoxyphenyl)-3-methoxybenzenesulfonamide

[0408]

[0409] Will N 3-(2-bromo-5-methoxyphenyl)-3-methoxybenzenesulfonamide (5.90 g, 18.9 mmol, 1.0 equivalent) was dissolved in MeCN (53 mL), and K₂CO₃ (6.57 g, 47.6 mmol, 3.0 equivalent) was added in a single addition. Benzyl bromide (2.98 g, 17.4 mmol, 1.1 equivalent) was added dropwise at room temperature, and after the addition was complete, the reaction mixture was heated to 60 °C in an oil bath for 3 hours. After the starting material was completely consumed (as shown by TLC), the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum and loaded onto silica for purification by MPLC (SiO₂, 240 g, EtOAc in Hex 0%–10%) to give a light brown solid. N -Benzyl- N -(2-bromo-5-methoxyphenyl)-3-methoxybenzenesulfonamide (6.83g, 93%). 1 H NMR (400 MHz, CDCl3) δ 7.42 – 7.34 (m, 3H), 7.28 – 7.18 (m, 6H), 7.15 – 7.10 (m, 1H), 6.69 (dd, J = 8.9, 3.0 Hz, 1H), 6.48 (d, J = 3.0 Hz,1H), 4.89 (d, J = 14.4 Hz, 1H), 4.66 (d, J = 14.3 Hz, 1H), 3.79 (s, 3H), 3.59(s, 3H).

[0410] Step 3: Synthesis of 5,5-dioxide of 6-benzyl-3,8-dimethoxy-6H-dibenzo[c,e][1,2]thiazine

[0411]

[0412] Will N -Benzyl- N2-Bromo-5-methoxyphenyl)-3-methoxybenzenesulfonamide (2.00 g, 4.33 mmol, 1.0 equivalent) was dissolved in a mixture of DMA (20 mL) and water (5 mL), and Pd(OAc)₂ (291 mg, 1.30 mmol, 0.3 equivalent) and KOAc (1.69 g, 17.3 mmol, 4.0 equivalent) were added immediately. After the reagents were completely dissolved, the flask was placed in an oil bath at 140 °C and stirred for 48 hours. The reaction mixture was then concentrated to complete dryness using a rotary evaporator at 90 °C. The reaction mixture was loaded onto silica and purified by MPLC (SiO₂, 80 g, EtOAc 0%–15% in Hex) to give 6-benzyl-3,8-dimethoxy-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (560 mg, 34%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 8.00 (t, J = 8.5 Hz, 2H), 7.39 (d, J = 2.7 Hz, 1H), 7.34 (dd, J = 8.8, 2.7 Hz, 1H), 7.25 – 7.09 (m, 5H), 6.95 (d, J =2.5 Hz, 1H), 6.91 (dd, J = 8.8, 2.5 Hz, 1H), 5.16 (s, 2H), 3.91 (s, 3H), 3.75 (s, 3H).

[0413] Step 4: Synthesis of 5,5-dioxide of 6-benzyl-3,8-dihydroxy-6H-dibenzo[c,e][1,2]thiazine

[0414]

[0415] 6-Benzyl-3,8-dimethoxy-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (180 mg, 0.470 mmol, 1.0 equivalent) was dissolved in DCM (2 mL) and cooled to 0°C in an ice bath while stirring for 5 minutes. Then, BBr3 (1.89 mL, 1 M in DCM, 1.88 mmol, 4.0 equivalent) was added dropwise to the reaction mixture. After the addition was complete, the mixture was left in an ice bath and allowed to warm to room temperature over 2 hours. When the starting material could no longer be observed (TLC), the reaction mixture was added dropwise to 0°C cold methanol (20 mL) and stirred for another 10 minutes. The mixture was then concentrated, loaded onto silica, and purified by MPLC (SiO2, 20 g, MeOH in DCM 0%-3%) to give 6-benzyl-3,8-dihydroxy-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (100 mg, 60%) as a pale yellow solid. 1 HNMR (400 MHz, DMSO) δ 10.33 (s, 1H), 9.94 (s, 1H), 7.90 – 7.80 (m, 2H), 7.39– 7.09 (m, 7H), 6.83 – 6.62 (m, 2H), 5.04 (s, 2H).

[0416] Step 5: Synthesis of 5,5-dioxide of 3,8-dihydroxy-6H-dibenzo[c,e][1,2]thiazine

[0417]

[0418] 6-Benzyl-3,8-dihydroxy-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (100 mg, 0.370 mmol, 1.0 equivalent) was dissolved in MeOH (10 mL) and Pd(OH)₂ / C (26 mg) was added in a single batch. The reaction mixture was then evacuated and backfilled three times with N₂, and then placed under a hydrogen atmosphere (balloon). The reaction mixture was stirred for 4 hours and, after the starting material was completely consumed (as indicated by TLC), filtered through silica and concentrated under vacuum. The crude product was loaded onto silica and purified by MPLC (SiO₂, 12 g, EtOAc in Hex 0%–50%) to give 3,8-dihydroxy-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (65 mg, 67%) as a white solid. 1H NMR (400MHz, DMSO) δ 10.24 (s, 1H), 9.87 (s, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.83 (d,J = 8.5 Hz, 1H), 7.17 (d, J = 2.6 Hz, 1H), 7.11 (dd, J = 8.7, 2.6 Hz, 1H), 6.64 (dd, J = 8.7, 2.5 Hz, 1H), 6.55 (d, J = 2.5 Hz, 1H).

[0419] D) Ether "A" group analogues

[0420] 6H-Benzo[c]chromene-3,8-diol (twenty three) Synthesis

[0421]

[0422] Step 1: Synthesis of 3,8-bis((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromene-6-one

[0423]

[0424] Urolithin A (12 g, 53 mmol) was added to a solution of imidazole (9.0 g, 0.13 mol) in 100 mL and stirred for 1 hour. No reaction occurred, so DMF (20 mL) was added and stirring continued overnight. DCM was removed under vacuum. Water was added and the mixture was extracted with Et2O (3*). The organic layer was washed twice with water and then with brine, dried over Na2SO4, filtered through silica, and concentrated. The crude product was purified by MPLC (SiO2, EtOAc / cyclohexane 0% to 20%) to give 3,8-bis((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromene-6-one (20 g, 96%) as a white solid. 1 H NMR(400 MHz, CDCl3) δ 7.89 (d, J = 8.8 Hz, 1H), 7.85 – 7.80 (m, 1H), 7.76 (d, J= 2.6 Hz, 1H), 7.29 (dd, J = 8.7, 2.7 Hz, 1H), 6.86 – 6.80 (m, 2H), 1.02 (s, 9H), 0.98 (s, 9H), 0.26 (s, 6H), 0.24 (s, 6H).

[0425] Step 2: Synthesis of ((6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane)

[0426]

[0427] InBr3 (142 mg, 0.400 mmol) was added to a solution of 3,8-bis((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromene-6-one (1.8 g, 4.0 mmol) in toluene (20 mL), and the reaction mixture was heated at 70 °C for 1 hour. The reaction mixture was cooled to room temperature and filtered. The solvent was evaporated under vacuum and the crude material was purified by MPLC (SiO2, cyclohexane / dichloromethane 0% to 10%) to give ((6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane), 81 mg, 88%, as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.48 (t, J =8.5 Hz, 2H), 6.81 (dd, J = 8.4, 2.5 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H), 6.53(dd, J = 8.4, 2.5 Hz, 1H), 6.47 (d, J = 2.4 Hz, 1H), 5.02 (s, 2H), 1.00 (s,9H), 0.98 (s, 9H), 0.22 (s, 6H), 0.20 (s, 6H).

[0428] Step 3: Synthesis of 6H-benzo[c]chromene-3,8-diol

[0429]

[0430] Acetyl chloride (0.105 mL, 1.40 mmol) was added to a solution of ((6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane) (421 mg, 0.950 mmol) in methanol (10 mL) and stirred overnight. The reaction mixture was concentrated under vacuum and purified by MPLC (EtOAc 0%–100% in SiO2, Hex) to give 6H-benzo[c]chromene-3,8-diol (203 mg, 0.950 mmol, 99%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 9.50 (s, 1H), 9.48 (s, 1H), 7.49 (dd, J= 12.5, 8.4 Hz, 2H), 6.74 (dd, J = 8.4, 2.6 Hz, 1H), 6.60 (d, J = 2.5 Hz, 1H), 6.45 (dd, J = 8.4, 2.4 Hz, 1H), 6.32 (d, J = 2.4 Hz, 1H), 4.96 (s, 2H).

[0431] 6-Methyl-6H-benzo[c]chromene-3,8-diol (twenty four) Synthesis

[0432]

[0433] Step 1: Synthesis of 3,8-bis((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-ol

[0434]

[0435] Under nitrogen atmosphere at -78°C, DIBAL-H (2.10 mL, 2.10 mmol) was slowly added along the side of a flask to a solution of 3,8-bis((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromene-6-one (912 mg, 2.00 mmol) in toluene (20 mL). The reaction was monitored by TLC eluent (cyclohexane / DCM 1:1). The reaction was completed within 1 hour with stirring. After Fieser post-treatment, the product was used in the above step without further purification. 1 H NMR (400 MHz, CDCl3) δ 7.60 (dd, J = 8.9, 6.9 Hz, 2H), 6.93 (dd, J = 8.5, 2.5 Hz, 1H), 6.83 (d, J = 2.6 Hz, 1H), 6.62 – 6.58 (m, 2H), 6.26 (s, 1H), 1.00 (s, 9H), 0.98 (s, 9H), 0.25 – 0.18 (m, 12H).

[0436] Step 2: Synthesis of 4,4'-bis((tert-butyldimethylsilyl)oxy)-2'-(1-hydroxyethyl)-[1,1'-biphenyl]-2-ol

[0437]

[0438] MeMgr (3M in Et2O, 1.0 mL, 3.0 mmol, 3.0 equivalent) was slowly added to a solution of 3,8-bis((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-ol (456 mg, 1.00 mmol, 1.0 equivalent) in anhydrous THF (10 mL) at 0 °C under a nitrogen atmosphere. The reaction was completed within 1 hour. The reaction mixture was diluted with diethyl ether, filtered through a silica pad, washed with diethyl ether, and concentrated to give the title product as a thick, colorless, oily mixture of 60:40 rotational isomers / diastereomers (474 ​​mg, quantified), which was used in the next step without further purification. 1 H NMR (400MHz, CDCl3) δ 7.15 (d, J = 2.6 Hz, 0.4H), 7.12 (d, J = 2.6 Hz, 0.6H), 7.07 (s,0.4H), 7.04 (s, 0.6H), 6.96 (d, J = 8.1 Hz, 0.4H), 6.90 (d, J = 8.5 Hz, 0.6H), 6.86 – 6.78 (m, 1H), 6.52 – 6.43 (m, 2H), 4.79 (q, J = 6.4 Hz, 0.4H), 4.73 (q, J = 6.5 Hz, 0.6H), 1.36 (d, J = 6.4 Hz, 1.2H), 1.30 (d, J = 6.4 Hz, 1.8H), 1.01 (s, 7.2H), 1.00 (s, 10.8H), 0.25 (s, 4.8H), 0.24 (s, 7.2H).

[0439] Step 3: ((6-methyl-6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane)

[0440]

[0441] A solution of 4-methylbenzenesulfonic acid hydrate (19 mg, 0.19 mmol) and 4,4'-bis((tert-butyldimethylsilyl)oxy)-2'-(1-hydroxyethyl)-[1,1'-biphenyl]-2-ol (474 ​​mg, 1.00 mmol) in toluene (10 mL) was heated overnight at 80 °C. TLC (cyclohexane / dichloromethane 9:1) showed no further starting material. The reaction mixture was concentrated under vacuum and purified by column chromatography (SiO2, CyH / DCM) to give ((6-methyl-6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane) (411 mg, 90%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ7.48 (dd, J = 8.5, 4.1 Hz, 2H), 6.80 (dd, J = 8.4, 2.5 Hz, 1H), 6.61 (dd, J =2.4, 0.8 Hz, 1H), 6.52 (dd, J = 8.4, 2.4 Hz, 1H), 6.47 (d, J = 2.4 Hz, 1H), 5.17 (q, J = 6.5 Hz, 1H), 1.00 (s, 9H), 0.98 (s, 9H) 0.92 – 0.84 (m, 3H), 0.21 (s, 6H), 0.20 (s, 6H).

[0442] Step 4: 6-Methyl-6H-benzo[c]chromene-3,8-diol

[0443]

[0444] Acetyl chloride (0.100 mL, 1.40 mmol) was added to a solution of ((6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane) (411 mg, 0.900 mmol) in methanol (10 mL) and stirred overnight. The reaction mixture was concentrated under vacuum and purified by MPLC (EtOAc 0%–100% in SiO2, Hex) to give 6-methyl-6H-benzo[c]chromene-3,8-diol (202 mg, 98%) as a white solid. 1H NMR (400 MHz, DMSO)δ 9.47 (s, 1H), 9.45 (s, 1H), 7.49 (t, J = 8.7 Hz, 2H), 6.73 (dd, J = 8.4,2.5 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H), 6.43 (dd, J = 8.4, 2.4 Hz, 1H), 6.30 (d, J = 2.4 Hz, 1H), 5.14 (q, J = 6.5 Hz, 1H), 1.44 (d, J = 6.5 Hz, 3H).

[0445] 6,6-Dimethyl-6H-benzo[c]chromene-3,8-diol (25) Synthesis

[0446]

[0447] Step 1: Synthesis of 4,4'-bis((tert-butyldimethylsilyl)oxy)-2'-(2-hydroxypropyl-2-yl)-[1,1'-biphenyl]-2-ol

[0448]

[0449] The synthesis of 4,8-bis((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-one (456 mg, 1.00 mmol, 1.0 equivalent) in anhydrous THF (10 mL) was carried out under a nitrogen atmosphere at 0 °C with the slow addition of MeMgBr (3 M in Et2O, 1.00 mL, 3.0 mmol, 3.0 equivalent). The reaction was completed within 1 hour. The reaction mixture was diluted with diethyl ether, filtered through a silica pad, washed with diethyl ether, and concentrated to give the synthesis of 4,4'-bis((tert-butyldimethylsilyl)oxy)-2'-(2-hydroxypropyl-2-yl)-[1,1'-biphenyl]-2-ol (489 mg, quantitative) as a thick, colorless oil, which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 7.13 (d, J = 2.5 Hz, 1H), 6.96 (d, J = 1.0 Hz, 1H), 6.94 (d, J = 1.1 Hz, 1H), 6.76 (dd, J = 8.2, 2.6 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H), 6.45 (dd, J= 8.2, 2.4 Hz, 1H), 1.52 (s, 3H), 1.40 (s,3H), 1.01 (s, 9H), 1.00 (s, 9H), 0.25 (s, 6H), 0.23 (s, 6H).

[0450] Step 2: Synthesis of ((6,6-dimethyl-6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane)

[0451]

[0452] A solution of 4-methylbenzenesulfonic acid hydrate (19 mg, 0.19 mmol) and 4,4'-bis((tert-butyldimethylsilyl)oxy)-2'-(1-hydroxyethyl)-[1,1'-biphenyl]-2-ol (489 mg, 1.00 mmol) in toluene (10 mL) was heated overnight at 80 °C. TLC (cyclohexane / dichloromethane 9:1) showed no further starting material. The reaction mixture was concentrated under vacuum and purified by MPLC (SiO2, CyH / DCM) to give ((6-methyl-6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane) (446 mg, 95%) as a white solid. 1 H NMR (400 MHz, CDCl3)δ 7.49 (dd, J = 8.5, 3.4 Hz, 2H), 6.79 (dd, J = 8.4, 2.4 Hz, 1H), 6.69 (d, J= 2.4 Hz, 1H), 6.50 (dd, J = 8.4, 2.4 Hz, 1H), 6.45 (d, J = 2.4 Hz, 1H), 1.58(s, 6H), 1.00 (s, 9H), 0.99 (s, 9H), 0.22 (s, 6H), 0.21 (s, 6H).

[0453] Step 3: Synthesis of 6,6-dimethyl-6H-benzo[c]chromene-3,8-diol

[0454]

[0455] Acetyl chloride (0.100 mL, 1.40 mmol) was added to a solution of 4,4'-bis((tert-butyldimethylsilyl)oxy)-2'-(2-hydroxypropyl-2-yl)-[1,1'-biphenyl]-2-ol (446 mg, 0.900 mmol) in methanol (10 mL) at room temperature, and the solution was stirred overnight. The reaction mixture was concentrated under vacuum and purified by MPLC (EtOAc 0%–100% in SiO2, Hex) to give 6,6-dimethyl-6H-benzo[c]chromene-3,8-diol (228 mg, 98%) as a white solid. MS (ESI+): m / z = 243. 1 H NMR (400 MHz, DMSO) δ 9.44 (s, 1H), 9.42 (s,1H), 7.49 (dd, J = 8.5, 4.2 Hz, 2H), 6.72 (dd, J = 8.4, 2.5 Hz, 1H), 6.67 (d,J = 2.4 Hz, 1H), 6.40 (dd, J = 8.4, 2.4 Hz, 1H), 6.26 (d, J = 2.4 Hz, 1H), 1.49 (s, 6H).

[0456] E) Ester "A" group analogs with a pyridine ring

[0457] 3,8-Dihydroxy-6H-isocyaneno[4,3-b]pyridin-6-one (27) Synthesis

[0458]

[0459] Step 1: Synthesis of 3,8-dimethoxy-6H-isocyaneno[4,3-b]pyridin-6-one (26)

[0460]

[0461] Sodium nitrite (130 mg, 1.88 mmol) was added to a solution of methyl 2-amino-5-methoxybenzoate (341 mg, 1.88 mmol) in water (1 mL) and HCl (3N, 1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 15 min, and this solution was added dropwise at 0 °C to a solution of 5-methoxypyridin-3-ol (1.18 g, 9.42 mmol) in water (1 mL) and HCl (3N, 1 mL) and TiCl3 (0.25 mL, 1.88 mmol) at room temperature, and stirring was continued overnight at room temperature. A saturated Na2CO3 solution was added. After extraction three times with EtOAc, the combined organic phases were dried over sodium sulfate and concentrated under vacuum. The crude product was purified by MPLC (SiO2, EtOAc / cyclohexane 0% to 30%) to give 3,8-dimethoxy-6H-isocyaneno[4,3-b]pyridin-6-one (85 mg, 18%) as a white solid. f = 0.25 (EtOAc / hexane 20%). 1 H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 8.8 Hz, 1H), 8.33 (d, J = 2.6 Hz, 1H), 7.74 (d, J = 2.7 Hz, 1H), 7.45 (dd, J = 8.8, 2.7 Hz, 1H), 7.14 (d, J = 2.6 Hz,1H), 3.95 (s, 3H), 3.93 (s, 3H).

[0462] Step 2: Synthesis of 3,8-dihydroxy-6H-isocyaneno[4,3-b]pyridin-6-one (27)

[0463]

[0464] According to GP2, preparation was started from 3,8-dimethoxy-6H-isochromeno[4,3-b]pyridin-6-one 26 (120 mg, 0.460 mmol), and after purification by MPLC (SiO2, EtOAc / cyclohexane 5% to 90%), 3,8-dihydroxy-6H-isochromeno[4,3-b]pyridin-6-one (20 mg, 19%) was obtained as a white solid. f = 0.1 (EtOAc / hexane 80%). 1HNMR (400 MHz, DMSO) δ 10.60 (s, 1H), 10.39 (s, 1H), 8.30 (d, J = 8.7 Hz, 1H), 8.19 (d, J = 2.4 Hz, 1H), 7.50 (d, J = 2.6 Hz, 1H), 7.38 (dd, J = 8.7, 2.6Hz, 1H), 7.15 (d, J = 2.4 Hz, 1H).

[0465] 3,8-Dihydroxy-5H-chromeno[4,3-b]pyridin-5-one (28) Synthesis

[0466]

[0467] Step 1: Synthesis of methyl 2-(2-chloro-4-methoxyphenyl)-5-methoxynicotinic acid

[0468]

[0469] Water (1 mL) was added to a mixture of (2-hydroxy-4-methoxyphenyl)boronic acid (144 mg, 0.774 mmol), methyl 2-chloro-5-methoxynicotinic acid (120 mg, 0.595 mmol), cesium carbonate (170 mg, 1.61 mmol), and palladium tetra(triphenylphosphine)palladium (35 mg, 0.029 mmol) in DME (5 mL), and the mixture was refluxed for 3 hours. TLC showed complete conversion of the starting material. Saturated NH4Cl solution was added and the aqueous phase was extracted three times with EtOAc. The combined organic phases were dried over sodium sulfate and concentrated under vacuum. The crude product was purified by MPLC (SiO2, EtOAc / hexane 0% to 60%) to give methyl 2-(2-chloro-4-methoxyphenyl)-5-methoxynicotinic acid (160 mg, 87%) as a colorless oil. f = 0.3 (EtOAc / hexane 50%). 1 HNMR (400 MHz, CDCl3) δ 8.49 (d, J = 3.0 Hz, 1H), 7.77 (d, J = 3.0 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 6.96 (d, J = 2.5 Hz, 1H), 6.90 (dd, J = 8.5, 2.5Hz, 1H), 3.95 (s, 3H), 3.84 (s, 3H), 3.74 (s, 3H).

[0470] Step 2: Synthesis of 3,8-dimethoxy-5H-chromeno[4,3-b]pyridin-5-one

[0471]

[0472] In a microwave-safe container, TMEDA (339 mg, 2.92 mmol, 1.0 equivalent) was added via a microsyringe to a mixture of methyl 2-(2-chloro-4-methoxyphenyl)-5-methoxynicotinate (900 mg, 2.92 mmol, 1.0 equivalent), copper thiophene-2-carboxylate (I) (278 mg, 1.46 mmol, 0.5 equivalent), and Cs₂CO₃ (476 mg, 1.46 mmol, 0.5 equivalent) in deionized water (10 mL). The mixture was stirred at room temperature for 15 minutes and then refluxed overnight at 130 °C. The reaction mixture was cooled to room temperature and extracted with EtOAc and saturated NH₄Cl solution. The organic phase was dried over sodium sulfate and concentrated under vacuum. The crude product was purified by MPLC (SiO2, EtOAc / cyclohexane 0% to 30%) to give 3,8-dimethoxy-5H-chromeno[4,3-b]pyridin-5-one (120 mg, 16%) as a white solid. f = 0.4 (EtOAc / hexane 80%). 1 H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 3.1 Hz, 1H), 8.37 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 3.1Hz, 1H), 6.96 (dd, J = 8.8, 2.5 Hz, 1H), 6.87 (d, J = 2.4 Hz, 1H), 3.96 (s, 3H), 3.89 (s, 3H).

[0473] Step 3: Synthesis of 3,8-dihydroxy-5H-chromeno[4,3-b]pyridin-5-one

[0474]

[0475] According to GP2, preparation was started from 3,8-dimethoxy-5H-chromeno[4,3-b]pyridin-5-one (120 mg, 0.460 mmol), and after purification by MPLC (SiO2, MeOH / DCM 0% to 10%), 3,8-dihydroxy-5H-chromeno[4,3-b]pyridin-5-one (26 mg, 56%) was obtained as a white solid. f = 0.1 (EtOAc / hexane 80%). 1H NMR (400 MHz, DMSO) δ 10.55 (s, 1H), 10.50 (s, 1H), 8.62 (d, J = 2.9 Hz, 1H), 8.19 (dd, J =8.6, 1.5 Hz, 1H), 7.74 (d, J = 2.9 Hz, 1H), 6.86 (dd, J = 8.7, 2.3 Hz, 1H), 6.76 (d, J = 2.3 Hz, 1H).

[0476] F) Preparation of ether-substituted ester "A" ring analogs via phototrail (Mitsunobu reaction)

[0477] The optical extension target is achieved starting with two common intermediates (CI1 and CI2) described below.

[0478] Synthesis of CI1

[0479]

[0480] Step 1: Synthesis of 3-(benzyloxy)-8-bromo-6H-benzo[c]chromen-6-one

[0481]

[0482] K₂CO₃ (522 mg, 3.78 mmol, 2.2 equivalents) was added in a single addition to a suspension of 3 (synthesis above) (500 mg, 1.72 mmol, 1.0 equivalents) in DMF (5 mL). The suspension was then cooled to 0 °C in an ice bath and stirred for 5 min. Benzyl bromide (323 mg, 1.89 mmol, 1.2 equivalents) was added dropwise over a 1-minute interval, and the reaction mixture was stirred at 0 °C for 10 min after the addition was complete, then allowed to warm to room temperature overnight. After the starting material was completely consumed (as indicated by TLC), the reaction mixture was quenched with a semi-saturated aqueous sodium bicarbonate solution. The precipitate was filtered through a Buchner funnel, washed with hexane, and dried to give 3-(benzyloxy)-8-bromo-6H-benzo[c]chromen-6-one (400 mg, 61%) as a light brown solid. 1 HNMR (400 MHz, CDCl3) δ 10.27 (s, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.14 (d, J = 8.9Hz, 1H), 7.53 (d, J= 2.7 Hz, 1H), 7.51 – 7.47 (m, 2H), 7.44 – 7.39 (m, 2H), 7.37 – 7.32 (m, 1H), 7.07 (d, J = 2.5 Hz, 1H), 7.04 (dd, J = 8.7, 2.5 Hz, 1H), 5.21 (s, 2H).

[0483] Step 2: Synthesis of 3-(benzyloxy)-8-hydroxy-6H-benzo[c]chromene-6-one CI1

[0484]

[0485] 3-(benzyloxy)-8-bromo-6H-benzo[c]chromen-6-one (700 mg, 1.84 mmol, 1.0 equivalent) was suspended in 1,4-dioxane (7 mL) in a 20 mL Biotage MW vial. Pd2dba3 (43 mg, 0.18 mmol, 0.1 equivalent) was added to this suspension, followed by... t BuXPhos (175 mg, 0.370 mmol, 0.2 equivalents). The MW vial was then sealed and degassed with nitrogen for 10 min. A solution of KOH (412 mg, 7.34 mmol, 4.4 equivalents) in H2O (3 mL) was then slowly added to the reaction mixture, which was stirred in a preheated oil bath at 90 °C for 3 h. After the starting material was completely consumed (as indicated by TLC), the reaction mixture was cooled to 0 °C and the pH was adjusted to 1 with a 6 M HCl aqueous solution. The mixture was extracted with ethyl acetate (3 x 10 mL), and the combined organic phases were dried over anhydrous Na2SO4 and concentrated under vacuum. The crude material was purified by MPLC (SiO2, 40 g, EtOAc in hexane 0%–30%) to give 3-(benzyloxy)-8-hydroxy-6H-benzo[c]chromen-6-one (390 mg, 67%) as a pale yellow solid. 1 H NMR (400 MHz, DMSO) δ 10.27 (s, 1H),8.18 (d, J = 8.8 Hz, 1H), 8.14 (d, J = 8.9 Hz, 1H), 7.53 (d, J = 2.7 Hz, 1H), 7.51– 7.47 (m, 2H), 7.44 – 7.39 (m, 2H), 7.37 – 7.32 (m, 2H), 7.07 (d, J= 2.5 Hz, 1H), 7.04 (dd, J = 8.7, 2.5 Hz, 1H), 5.21 (s, 2H).

[0486] Synthesis of CI2

[0487]

[0488] Step 1: Synthesis of 8-(benzyloxy)-3-((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-one

[0489]

[0490] 8-(benzyloxy)-3-hydroxy-6H-benzo[c]chromene-6-one (1.46 g, 4.59 mmol) was dissolved in 12 ml of anhydrous THF. Triethylamine (1.92 ml, 13.8 mmol) was added dropwise at room temperature with stirring for 15 min, followed by the addition of tert-butylchlorodimethylsilane (832 mg, 5.51 mmol) and stirring continued at room temperature for 3 h. TLC showed no further starting material. The reaction mixture was extracted twice with EtOAc and HCl (1 M). The organic phase was washed successively with water and brine, and then dried over sodium sulfate to give 8-(benzyloxy)-3-((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromene-6-one (1.83 g, 92%) as a light brown solid. 1 H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.9 Hz, 1H), 7.88 (d, J = 2.8 Hz, 1H), 7.86 – 7.81 (m, 1H), 7.50 – 7.34 (m, 6H), 6.86 –6.80 (m, 2H), 5.18 (s, 2H), 1.00 (s, 9H), 0.25 (s, 6H).

[0491] Step 2: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-hydroxy-6H-benzo[c]chromen-6-one C2

[0492]

[0493] 8-(benzyloxy)-3-((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromene-6-one (1.83 g, 4.23 mmol, 1.0 equivalent) was dissolved in methanol (20 mL) and dichloromethane (10 mL), Pd(OH)₂ / C (368 mg, 0.5 mmol, 0.12 equivalent) was added, and the reaction mixture was hydrogenated at atmospheric pressure. The mixture was filtered through a diatomaceous earth mat, and the solvent was evaporated under vacuum to give 3-((tert-butyldimethylsilyl)oxy)-8-hydroxy-6H-benzo[c]chromene-6-one (1.3 g, 3.8 mmol, 90%) as a beige solid. 1 H NMR (400 MHz, CDCl3) δ 7.95 (d, J =8.8 Hz, 1H), 7.91 (d, J = 2.7 Hz, 1H), 7.89 – 7.83 (m, 1H), 7.39 (dd, J =8.7, 2.8 Hz, 1H), 6.92 – 6.83 (m, 2H), 6.21 (s, 1H), 1.03 (s, 9H), 0.28 (s, 6H).

[0494] 3-Hydroxy-8-(oxecyclobutane-3-ylmethoxy)-6H-benzo[c]chromene-6-one Synthesis of (29)

[0495]

[0496] Step 1: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-(oxecyclobutane-3-ylmethoxy)-6H-benzo[c]chromen-6-one

[0497]

[0498] In a sealed tube, DIAD (0.187 mL, 0.960 mmol) was added to a solution of 3-((tert-butyldimethylsilyl)oxy)-8-hydroxy-6H-benzo[c]chromen-6-one (150 mg, 0.430 mmol) and oxetane-3-ylmethanol (58 mg, 0.65 mmol) in THF (2 mL) at 0 °C, and stirring was continued overnight at room temperature. TLC indicated complete conversion of the starting material. The reaction mixture was loaded onto silica gel and purified by MPLC (SiO2, EtOAc / cyclohexane 0% to 30%) to give 280 mg of a mixture of 3-((tert-butyldimethylsilyl)oxy)-8-(oxetane-3-ylmethoxy)-6H-benzo[c]chromen-6-one and reduced DIAD. f= 0.3 (EtOAc / hexane 20 / 80). A significant amount of reduced DIAD was present in the NMR after purification, and therefore will not be described further as it was used as crude in the next step.

[0499] Step 2: Synthesis of 3-hydroxy-8-(oxetane-3-ylmethoxy)-6H-benzo[c]chromen-6-one

[0500]

[0501] KHF2 (108 mg, 1.38 mmol) was added in a single addition to a solution of 3-((tert-butyldimethylsilyl)oxy)-8-(oxetane-3-ylmethoxy)-6H-benzo[c]chromen-6-one (285 mg, 0.690 mmol) (a crude mixture of PPh3O and reduced DIAD) in MeOH (5 ml) at room temperature and stirred for 4 hours. The resulting white precipitate was filtered and dried under vacuum to give 3-hydroxy-8-(oxetane-3-ylmethoxy)-6H-benzo[c]chromen-6-one (65 mg, 32%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 10.27 (s, 1H), 8.26 – 8.06 (m,2H), 7.64 – 7.52 (m, 1H), 7.52 – 7.27 (m, 1H), 7.08 – 6.96 (m, 1H), 6.85 –6.71 (m, 1H), 4.73 (ddd, J = 7.6, 6.0, 1.4 Hz, 2H), 4.46 (dt, J = 11.9, 6.1Hz, 2H), 4.33 (dd, J = 18.2, 6.7 Hz, 2H), 3.43 (tt, J = 6.8, 6.8 Hz, 1H).

[0502] 3-Hydroxy-8-(2-(4-methylpiperazin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one (30) Synthesis

[0503]

[0504] Step 1: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-(2-(4-methylpiperazin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one

[0505]

[0506] 3-((tert-butyldimethylsilyl)oxy)-8-(2-(4-methylpiperazin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one was prepared from 3-((tert-butyldimethylsilyl)oxy)-8-hydroxy-6H-benzo[c]chromen-6-one (80 mg, 0.23 mmol) and 2-(4-methylpiperazin-1-yl)-ethanol (34 mg, 0.23 mmol) (according to the synthesis in 29), and after MPLC purification (SiO2, MeOH / DCM 0% to 20%), 3-((tert-butyldimethylsilyl)oxy)-8-(2-(4-methylpiperazin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one (60 mg, 55%) was obtained as a pale yellow oil. NMR still showed significant amounts of reduced DIAD, but the impure / crude substance continued to the next step. R f = 0.4 (20% MeOH / DCM).

[0507] Step 2: Synthesis of 3-hydroxy-8-(2-(4-methylpiperazin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one

[0508]

[0509] Acetyl chloride (0.046 ml, 0.64 mmol, 5.0 equivalent) was added to a solution of 3-((tert-butyldimethylsilyl)oxy)-8-(2-(4-methylpiperazin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one (60 mg, 0.13 mmol, 1.0 equivalent) in MeOH (2 ml) at room temperature, and the reaction mixture was stirred overnight. Methanol was evaporated under vacuum, and the crude product was diluted with EtOAc and washed with saturated sodium carbonate solution. The aqueous layer was extracted with EtOAc, and the combined organic phases were dried over sodium sulfate. The crude product was purified by MPLC (SiO2, MeOH / DCM 0% to 30%) to give 3-hydroxy-8-(2-(4-methylpiperazin-1-yl)ethoxy)-6H-benzo[c]chromen-6-one (17 mg, 0.048 mmol, 37%). 1H NMR (400 MHz, DMSO) δ 10.23 (br, 1H), 8.25 – 8.06 (m, 2H), 7.53 (d, J = 2.7 Hz, 1H), 7.50 (dd, J = 8.8, 2.9 Hz, 1H), 7.02 – 6.94 (m, 1H), 6.86 – 6.71 (m, 1H), 4.18 (dt, J = 18.4, 5.7 Hz, 3H), 2.76 – 2.65 (m, 6H), 2.34-2.32 (m, 3H), 2.14 (s, 3H).

[0510] (S)-3-hydroxy-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one (31) Synthesis

[0511]

[0512] Step 1: ( S Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one

[0513]

[0514] ( S )-3-((tert-butyldimethylsilyl)oxy)-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one (according to the synthesis of 29) was prepared by starting with C2 (80 mg, 0.23 mmol) and (R)-tetrahydrofuran-3-ol (31 mg, 0.35 mmol), yielding a pale yellow oil. S )-3-((tert-butyldimethylsilyl)oxy)-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromene-6-one (45 mg, 47%). R f = 0.6 (EtOAc / hexane 1 / 1). 1H NMR (400 MHz, CDCl3) δ 8.00 – 7.80 (m, 2H), 7.74 (dd, J = 23.0, 2.7 Hz, 1H), 7.33 (ddd, J = 26.5, 8.8, 2.7 Hz, 1H), 6.90 – 6.80 (m, 2H), 5.09 – 4.95(m, 1H), 4.13 – 3.88 (m, 4H), 2.43 – 2.07 (m, 2H), 1.02 (s, J = 3.8 Hz, 9H), 0.27 (s, 3H), 0.25 (s, 3H).

[0515] Step 2: Synthesis of (S)-3-hydroxy-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one

[0516]

[0517] 31. Based on the synthesis of 29, ( S The preparation was initiated with 3-((tert-butyldimethylsilyl)oxy)-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one (40 mg, 0.097 mmol) and KHF2 (27 mg, 0.34 mmol), yielding a white solid. S )-3-hydroxy-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromene-6-one (22 mg, 76%). 1 H NMR (400 MHz, CDCl3) δ 7.92 – 7.76 (m, 2H), 7.69 (s, 1H), 7.29 (ddd, J = 11.3, 8.8, 2.8 Hz, 1H), 6.88 – 6.70 (m, 2H), 5.41-5.35 (m, 1H), 4.01 – 3.82 (m, 4H), 2.36 – 2.04 (m, 2H).

[0518] 3-Hydroxy-8-(2-(2-methoxyethoxy)ethoxy)-6H-benzo[c]chromene-6-one (32) Synthesis

[0519]

[0520] Step 1: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-(2-(2-methoxyethoxy)ethoxy)-6H-benzo[c]chromen-6-one

[0521]

[0522] 3-((tert-butyldimethylsilyl)oxy)-8-(2-(2-methoxyethoxy)ethoxy)-6H-benzo[c]chromene-6-one (synthesis according to 29) was prepared starting from C2 (100 mg, 0.29 mmol) and 2-(2-methoxyethoxy)ethanol-1-ol (42 mg, 0.35 mmol) to give 3-((tert-butyldimethylsilyl)oxy)-8-(2-(2-methoxyethoxy)ethoxy)-6H-benzo[c]chromene-6-one (125 mg, 47%), a pale yellow oil contaminated with reduced DIAD. R f = 0.5 (EtOAc / hexane 1 / 1). 1 H NMR (400 MHz, CDCl3) δ 7.91 - 7.66 (m,3H), 7.32-7.24 (m, 1H), 6.88 - 6.74 (m, 2H), 4.22 - 4.11 (m, 2H), 3.87 - 3.81(m, 2H), 3.74 - 3.63 (m, 2H), 3.59 - 3.49 (m, 2H), 3.33 (s, 3H), 0.95-0.93 (m, 9H), 0.20 (s, 3H).

[0523] Step 2: Synthesis of 3-hydroxy-8-(2-(2-methoxyethoxy)ethoxy)-6H-benzo[c]chromen-6-one

[0524]

[0525] 32 was prepared according to the synthesis of 29 starting with (100 mg, 0.220 mmol) and KHF2 (70 mg, 0.90 mmol), and after purification by MPLC (SiO2, EtAOc / hexane 0% to 30%), 3-hydroxy-8-(2-(2-methoxyethoxy)ethoxy)-6H-benzo[c]chromen-6-one (24 mg, 32%) was obtained as a white solid in the form of a mixture of the two compounds. 1H NMR(400 MHz, CDCl3) δ 7.75 – 7.56 (m, 2H), 7.34 (dd, J = 42.4, 2.8 Hz, 1H), 7.21– 6.48 (m, 3H), 4.05 (dt, J = 14.8, 4.4 Hz, 2H), 3.92 – 3.85 (m, 2H), 3.80 (dt, J = 6.1, 2.5 Hz, 2H), 3.70 (ddd, J = 4.4, 3.5, 1.5 Hz, 2H), 3.46 (d, J =1.4 Hz, 3H).

[0526] 3-Hydroxy-8-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one (33) Synthesis

[0527]

[0528] Step 1: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one

[0529]

[0530] According to the synthesis of 29, the compound was prepared starting from C2 (100 mg, 0.29 mmol) and tetrahydro-2H-pyran-4-ol (36 mg, 0.35 mmol), yielding a pale yellow oily substance, 3-((tert-butyldimethylsilyl)oxy)-8-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one (64 mg, 51%). f = 0.67 (EtOAc / hexane 4 / 6). 1H NMR (400 MHz, CDCl3) δ 7.98 – 7.81 (m, 2H), 7.77 (dd, J = 7.3, 2.7 Hz,1H), 7.42 – 7.27 (m, 1H), 6.96 – 6.80 (m, 2H), 4.61 (dtt, J = 44.2, 7.8, 3.9Hz, 1H), 4.01 (ddd, J = 10.4, 5.9, 3.9 Hz, 2H), 3.62 (ddt, J = 11.9, 7.8, 3.7Hz, 2H), 2.06 (d, J = 12.6 Hz, 2H), 1.83 (dtd, J = 12.5, 8.2, 3.9 Hz, 2H), 1.01 (d, J = 3.7 Hz, 9H), 0.32 – 0.20 (m, 6H).

[0531] Step 2: Synthesis of 3-hydroxy-8-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one

[0532]

[0533] 33 was prepared by starting with 3-((tert-butyldimethylsilyl)oxy)-8-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one (60 mg, 0.14 mmol) and KHF2 (38 mg, 0.49 mmol) to give 3-hydroxy-8-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one (29 mg, 66%) as a white solid. MS (ESI+): m / z = 313. 1 H NMR (400 MHz, DMSO) δ 10.30 – 10.11 (m, 1H), 8.23 ​​– 7.98 (m, 2H), 7.66 – 7.28 (m, 2H), 7.09 – 6.68 (m, 2H), 4.74 (dtt, J = 25.7, 8.6,4.0 Hz, 1H), 3.86 (dt, J = 10.3, 4.2 Hz, 2H), 3.52 (tdd, J = 11.6, 8.9, 2.7Hz, 2H), 2.01 (dd, J = 13.2, 3.5 Hz, 2H), 1.62 (dtt, J = 14.1, 9.1, 4.6 Hz, 2H).

[0534] 3-Hydroxy-8-((tetrahydro-2H-pyran-3-yl)oxy)-6H-benzo[c]chromen-6-one (34) Synthesis

[0535]

[0536] Step 1: Synthesis of 3-(benzyloxy)-8-((tetrahydro-2H-pyran-3-yl)oxy)-6H-benzo[c]chromen-6-one

[0537]

[0538] 3-(benzyloxy)-8-hydroxy-6H-benzo[c]chromene-6-one (64 mg, 0.20 mmol, 1.0 equivalent) was dissolved in 0.7 mL of THF in a 10 mL Biotage MW vial. PPh3 (79 mg, 0.30 mmol, 1.5 equivalent) and tetrahydro-2H-pyran-3-ol (31 mg, 0.30 mmol, 1.5 equivalent) were then added, and the reaction mixture was cooled to 0°C in an ice bath and stirred for 5 minutes. A solution of di-tert-butyl-diazepine-1,2-dicarboxylate (69 mg, 0.30 mmol, 1.5 equivalent) (DTAD) in 0.1 mL of THF was then added dropwise to the reaction mixture. After the addition was complete, the reaction mixture turned deep yellow and was stirred overnight at room temperature. After overnight stirring, the starting material was still present, so a solution of PPh3 (79 mg, 0.30 mmol, 1.5 equivalents), tetrahydro-2H-pyran-3-ol (31 mg, 0.30 mmol, 1.5 equivalents), and di-tert-butyl-diazepine-1,2-dicarboxylate (DTAD) in THF (0.1 mL) was added to the reaction mixture to complete the reaction. After stirring for another 2 hours at room temperature, the reaction mixture was concentrated under vacuum and loaded onto silica for purification by MPLC (SiO2, 12 g, EtOAc in Hex 0%–35%) to give 3-(benzyloxy)-8-((tetrahydro-2H-pyran-3-yl)oxy)-6H-benzo[c]chromen-6-one (50 mg, 62%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.9 Hz, 1H), 7.86 (d, J = 8.9 Hz, 1H), 7.77 (d, J = 2.8 Hz,1H), 7.46 – 7.31 (m, 5H), 6.97 (dd, J = 8.8, 2.6 Hz, 1H), 6.92 (d,J = 2.5 Hz,1H), 5.12 (s, 2H), 4.47 (tt, J = 6.8, 3.5 Hz, 1H), 3.95 (ddd, J = 11.6, 3.2, 1.2Hz, 1H), 3.75 (ddd, J = 10.6, 6.2, 3.9 Hz, 1H), 3.70 – 3.60 (m, 2H), 2.12 (tt, J = 11.8, 6.0 Hz, 1H), 1.89 (dddt, J = 31.0, 17.3, 8.0, 3.9 Hz, 3H), 1.70 – 1.59(m, 1H).

[0539] Step 2: Synthesis of 3-hydroxy-8-((tetrahydro-2H-pyran-3-yl)oxy)-6H-benzo[c]chromen-6-one

[0540]

[0541] 3-(benzyloxy)-8-((tetrahydro-2H-pyran-3-yl)oxy)-6H-benzo[c]chromen-6-one (50 mg, 0.12 mmol, 1.0 equivalent) was dissolved in MeOH / DCM (5 mL, 10 / 1), and Pd(OH)2 / C (20 mg) was added in a single batch. The reaction mixture was then evacuated and backfilled three times with N2, and then placed under a hydrogen atmosphere (balloon). The reaction mixture was stirred for 2 hours and, after the starting material was completely consumed (as indicated by TLC), filtered through silica and concentrated under vacuum to give a crude product. The crude product was loaded onto silica and purified by MPLC (SiO2, 12 g, EtOAc 0%-50% in Hex) to give 3-hydroxy-8-((tetrahydro-2H-pyran-3-yl)oxy)-6H-benzo[c]chromen-6-one (33 mg, 0.11 mmol, 89%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 10.21 (s, 1H), 8.20 (d, J = 9.0 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 2.8 Hz, 1H), 7.53 (dd, J =8.9, 2.8 Hz, 1H), 6.82 (dd,J = 8.7, 2.4 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 4.57(dt, J = 6.2, 3.2 Hz, 1H), 3.84 (dd, J = 11.6, 2.1 Hz, 1H), 3.64 (ddd, J = 10.8,6.5, 3.7 Hz, 1H), 3.56 (dd, J = 11.7, 5.6 Hz, 2H), 2.05 (dd, J = 8.9, 4.9 Hz,1H), 1.87 – 1.68 (m, 2H), 1.63 – 1.48 (m, 1H).

[0542] 3-Hydroxy-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromene-6-one (35) Synthesis

[0543]

[0544] Step 1: Synthesis of 3-(benzyloxy)-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one

[0545]

[0546] 3-(benzyloxy)-8-hydroxy-6H-benzo[c]chromene-6-one (100 mg, 0.31 mmol, 1.0 equivalent) was dissolved in THF (1.1 mL). Then, PPh3 (124 mg, 0.470 mmol, 1.5 equivalent) and tetrahydrofuran-3-ol (42 mg, 0.47 mmol, 1.5 equivalent) were added, and the reaction mixture was cooled to 0°C in an ice bath and stirred for 5 minutes. A solution of di-tert-butyl-diazepine-1,2-dicarboxylate (109 mg, 0.470 mmol, 1.5 equivalent) (DTAD) in THF (0.2 mL) was then added dropwise to the reaction mixture. After the addition was complete, the reaction mixture turned deep yellow and was stirred overnight at room temperature. After overnight stirring, the starting material was still present, so a solution of PPh3 (124 mg, 0.470 mmol, 1.5 equivalents), tetrahydrofuran-3-ol (42 mg, 0.47 mmol, 1.5 equivalents), and di-tert-butyl-diazepine-1,2-dicarboxylate (109 mg, 0.470 mmol, 1.5 equivalents) (DTAD) in THF (0.2 mL) was added to the reaction mixture to complete the reaction. After stirring for another 2 hours at room temperature, the reaction mixture was concentrated under vacuum and loaded onto silica for purification by MPLC (SiO2, 12 g, EtOAc in Hex 0%–35%) to give 3-(benzyloxy)-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromene-6-one (100 mg, 82%) as a pale yellow solid. The purified NMR still showed a significant amount of reduced DTAD, but the reaction proceeded to the next step of the crude material, so the NMR was not reported here.

[0547] Step 2: Synthesis of 3-hydroxy-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one

[0548]

[0549] 3-(benzyloxy)-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one (100 mg, 0.260 mmol, 1.0 equivalent) was dissolved in MeOH / DCM (7 mL, 10 / 1) and Pd(OH)2 / C (60 mg) was added in a single batch. The reaction mixture was then evacuated and backfilled three times with N2, and then placed under a hydrogen atmosphere using a balloon. The reaction mixture was stirred for 2 hours and filtered through silica after the starting material was completely consumed (as indicated by TLC), and concentrated under reduced pressure to give a crude product. The crude product was loaded onto silica and purified by rapid column chromatography (SiO2, 12 g, EtOAc in Hex 0%-50%) to give 3-hydroxy-8-((tetrahydrofuran-3-yl)oxy)-6H-benzo[c]chromen-6-one (65 mg, 72%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 10.21 (s, 1H), 8.22 (d, J = 8.8 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 2.7 Hz, 1H), 7.49 (dd, J = 8.9, 2.8 Hz, 1H), 6.83 (dd, J = 8.7, 2.4 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 5.25 – 5.19 (m,1H), 3.92 (dd, J = 10.2, 4.4 Hz, 1H), 3.88 – 3.83 (m, 2H), 3.78 (td, J = 8.4, 4.6Hz, 1H), 2.36 – 2.20 (m, 1H), 2.02 (dd, J = 14.2, 7.5 Hz, 1H).

[0550] 3-Hydroxy-8-(oxecyclobutane-3-yloxy)-6H-benzo[c]chromen-6-one (36) Synthesis

[0551]

[0552] Step 1: Synthesis of 3-(benzyloxy)-8-(oxetane-3-yloxy)-6H-benzo[c]chromen-6-one

[0553]

[0554] A solution of cyanomethylenetributylphosphine (150 mg, 0.630 mmol, 2.5 equivalents) was added in a single addition to a solution of 3-(benzyloxy)-8-hydroxy-6H-benzo[c]chromene-6-one (80 mg, 0.25 mmol, 1.0 equivalents) and oxetane-3-ol (56 mg, 0.75 mmol, 3.0 equivalents) in toluene (1.3 mL) at room temperature, and the reaction mixture was heated to 120 °C for 2 hours in a sealed vial. After complete conversion of the starting materials, the reaction mixture was cooled to room temperature, concentrated, and loaded onto silica for purification by MPLC (SiO2, 12 g, EtOAc in Hex 0%–30%) to obtain a pale yellow foamy 3-(benzyloxy)-8-(oxetane-3-yloxy)-6H-benzo[c]chromene-6-one (74 mg, 79%). 1 H NMR (400MHz, CDCl 3 ) δ 7.96 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 8.9 Hz, 1H), 7.48 – 7.34(m, 7H), 6.99 (dd, J = 8.8, 2.6 Hz, 1H), 6.94 (d, J = 2.5 Hz, 1H), 5.39 –5.29 (m, 1H), 5.14 (s, 2H), 5.07 (ddd,J = 7.1, 6.0, 0.9 Hz, 2H), 4.79 (ddd,J = 7.4, 5.0, 1.0 Hz, 2H).

[0555] Step 2: Synthesis of 3-hydroxy-8-(oxetane-3-yloxy)-6H-benzo[c]chromen-6-one

[0556]

[0557] 3-(benzyloxy)-8-(oxetane-3-yloxy)-6H-benzo[c]chromen-6-one (70 mg, 0.19 mmol, 1.0 equivalent) was dissolved in MeOH / DCM (5 mL, 10 / 1), and Pd(OH)2 / C (15 mg) was added in a single batch. The reaction mixture was then evacuated and backfilled three times with N2, and then placed under a hydrogen atmosphere using a balloon. The reaction mixture was stirred for 4 hours and filtered through silica after the starting material was completely consumed (as indicated by TLC), and concentrated under reduced pressure to give a crude product. The crude product was loaded onto silica and purified by rapid column chromatography (SiO2, 12 g, EtOAc in Hex 0%–50%) to give 3-hydroxy-8-(oxetane-3-yloxy)-6H-benzo[c]chromen-6-one (25 mg, 0.09 mmol, 47%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 10.24 (s, 1H), 8.24 (d,J = 8.9 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.45 (dd, J = 8.8, 2.8 Hz, 1H), 7.35 (d, J = 2.8 Hz, 1H), 6.83 (dd, J = 8.7, 2.4 Hz, 1H), 6.75 (d, J = 2.4Hz, 1H), 5.47 (q, J = 5.4, 4.8 Hz, 1H), 4.98 (t, J = 7.0 Hz, 2H), 4.59 (dd, J= 7.7, 5.1 Hz, 2H).

[0558] 8-((2-oxaspiro[3.3]hept-6-yl)oxy)-3-hydroxy-6H-benzo[c]chromen-6-one (37) Synthesis

[0559]

[0560] Step 1: Synthesis of 8-((2-oxaspiro[3.3]hept-6-yl)oxy)-3-(benzyloxy)-6H-benzo[c]chromen-6-one

[0561]

[0562] A solution of cyanomethylenetributylphosphine (95 mg, 0.39 mmol, 2.5 equivalents) was added in one step to a solution of 3-(benzyloxy)-8-hydroxy-6H-benzo[c]chromene-6-one (50 mg, 0.16 mmol, 1.0 equivalents) and 2-oxaspiro[3.3]hepta-6-ol (39 mg, 0.35 mmol, 2.2 equivalents) in toluene (3.0 mL) at room temperature, and the reaction mixture was heated to 120 °C for 2 hours in a sealed vial. After the starting material was completely converted, the reaction mixture was cooled to room temperature, concentrated and loaded onto silica for purification by rapid column chromatography (SiO2, 12 g, EtOAc in Hex 0%-30%) to give 8-((2-oxaspiro[3.3]hept-6-yl)oxy)-3-(benzyloxy)-6H-benzo[c]chromen-6-one (40 mg, 0.10 mmol, 61%) as a pale yellow solid. 1 H NMR (400 MHz, DMSO) δ 8.26 (d, J = 8.9 Hz, 1H), 8.20 (d, J= 8.9 Hz, 1H), 7.54 – 7.32 (m, 7H), 7.09 (d, J = 2.5 Hz, 1H), 7.06 (dd, J =8.7, 2.6 Hz, 1H), 5.22 (s, 2H), 4.77 (p, J = 6.8 Hz, 1H), 4.66 (s, 2H), 4.55(s, 2H), 2.88 – 2.78 (m, 2H), 2.33 – 2.24 (m, 2H).

[0563] Step 2: Synthesis of 8-((2-oxaspiro[3.3]hept-6-yl)oxy)-3-hydroxy-6H-benzo[c]chromen-6-one

[0564]

[0565] 8-((2-oxaspiro[3.3]hept-6-yl)oxy)-3-(benzyloxy)-6H-benzo[c]chromen-6-one (40 mg, 0.10 mmol, 1.0 equivalent) was dissolved in MeOH / DCM (5 mL, 10 / 1) and Pd(OH)2 / C (14 mg) was added in one go. The reaction mixture was then evacuated and backfilled three times with N2, and then placed under a hydrogen atmosphere using a balloon. The reaction mixture was stirred for 4 hours and, after complete consumption of the starting material (as indicated by TLC), filtered through silica and concentrated under vacuum to obtain a crude product. This crude product was loaded onto silica and purified by rapid column chromatography (SiO2, 12 g, EtOAc in Hex 0%–50%) to give 8-((2-oxaspiro[3.3]hept-6-yl)oxy)-3-hydroxy-6H-benzo[c]chromen-6-one (26 mg, 0.08 mmol, 83%) as a white solid. MS (ESI+): m / z = 325. 1 H NMR (400 MHz, DMSO) δ 10.23 (s, 1H), 8.19 (d, J = 8.9 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 2.8 Hz, 1H), 7.41 (dd, J = 8.8, 2.8 Hz, 1H), 6.82 (dd, J = 8.7,2.4 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 4.76 (q, J = 6.8 Hz, 1H), 4.66 (s,2H), 4.55 (s, 2H), 2.87 – 2.76 (m, 2H), 2.32 – 2.18 (m, 2H).

[0566] Similarly, 9-substituted analogue 38 was prepared according to the following scheme:

[0567] 3-Hydroxy-9-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one (38) Synthesis

[0568]

[0569] Step 1: Synthesis of 9-bromo-3-hydroxy-6H-benzo[c]chromen-6-one

[0570]

[0571] A mixture of 2,4-dibromobenzoic acid (5.00 g, 17.9 mmol, 1.0 equivalent), resorcinol (3.93 g, 35.7 mmol, 2.0 equivalent), and sodium hydroxide (1.71 g, 42.9 mmol, 2.4 equivalent) in water (15 mL) was heated under reflux for 60 minutes. After adding copper sulfate (5% aqueous solution, 10 mL), the mixture was refluxed again overnight, and a precipitate formed. The precipitate was filtered off and washed with HCl (1 M), then dried under vacuum to give 2.91 g, 56%, of 9-bromo-3-hydroxy-6H-benzo[c]chromen-6-one as an ochre solid. 1 H NMR (400 MHz, DMSO) δ 10.44 (s, 1H), 8.47 (s, 1H), 8.19 (d, J = 8.7 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 8.4Hz, 1H), 6.86 – 6.78 (m, 1H), 6.73 (s, 1H).

[0572] Step 2: Synthesis of 3-(benzyloxy)-9-bromo-6H-benzo[c]chromen-6-one

[0573]

[0574] K₂CO₃ (2.09 g, 15.1 mmol, 2.2 equivalents) was added in a single addition to a suspension of 9-bromo-3-hydroxy-6H-benzo[c]chromene-6-one (2.00 mg, 6.87 mmol, 1.0 equivalent) in DMF (35 mL). The suspension was cooled to 0 °C and stirred for 5 min. Benzyl bromide (1.41 g, 8.24 mmol, 1.2 equivalents) was added dropwise over 5 min intervals, and after the addition was complete, the reaction mixture was stirred at 0 °C for 10 min, then allowed to warm to room temperature over 2 h. After the starting material was completely consumed (as indicated by TLC), the reaction mixture was quenched with a semi-saturated aqueous sodium bicarbonate solution. The precipitate was filtered through a Buchner funnel, washed with hexane, and dried to give 3-(benzyloxy)-9-bromo-6H-benzo[c]chromene-6-one (1.49 g, 61%) as a light brown solid. 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.7 Hz, 1H), 7.78 (d, J = 8.9 Hz, 1H), 7.41 – 7.28 (m, 6H), 6.91 – 6.88 (m, 2H), 6.85 (d, J = 2.5 Hz, 1H), 5.07 (s,2H).

[0575] Step 3: Synthesis of 3-(benzyloxy)-9-hydroxy-6H-benzo[c]chromene-6-one

[0576]

[0577] 3-(benzyloxy)-9-bromo-6H-benzo[c]chromen-6-one (800 mg, 2.10 mmol, 1.0 equivalent) was suspended in 1,4-dioxane (7 mL) in a 20 mL Biotage MW vial. Pd2dba3 (49 mg, 0.21 mmol, 0.1 equivalent) was added to this suspension, followed by tBuXPhos (200 mg, 0.42 mmol, 0.2 equivalent). The MW vial was then sealed and degassed with nitrogen for 10 min. A solution of KOH (471 mg, 8.39 mmol, 4.4 equivalent) in H2O (3 mL) was then slowly added to the reaction mixture, and the mixture was incubated in a preheated oil bath at 90 °C for 3 h. After the starting material was completely consumed (as indicated by TLC), the reaction mixture was cooled to 0 °C and the pH was adjusted to 1 with 6 M HCl aqueous solution. The mixture was extracted with ethyl acetate (3 x 10 mL), and the combined organic phases were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crude material was purified by MPLC (SiO₂, 40 g, EtOAc in hexane 0%–30%) to give 3-(benzyloxy)-9-hydroxy-6H-benzo[c]chromen-6-one (225 mg, 37%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.7 Hz,1H), 7.78 (d, J = 8.9 Hz, 1H), 7.41 – 7.28 (m, 6H), 6.91 – 6.88 (m, 2H), 6.85(d, J = 2.5 Hz, 1H), 5.07 (s, 2H).

[0578] Step 4: Synthesis of 3-(benzyloxy)-9-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one

[0579]

[0580] A solution of cyanomethylenetributylphosphine (227 mg, 0.940 mmol, 2.5 equivalents) was added in one step to a solution of 3-(benzyloxy)-9-hydroxy-6H-benzo[c]chromene-6-one (120 mg, 0.380 mmol, 1.0 equivalents) and tetrahydro-2H-pyran-4-ol (77 mg, 0.71 mmol, 2.0 equivalents) in toluene (3.8 mL) at room temperature, and the reaction mixture was heated to 120 °C for 2 hours in a sealed vial. After the starting material was completely converted, the reaction mixture was cooled to room temperature, concentrated and loaded onto silica for purification by MPLC (SiO2, 12 g, EtOAc in Hex 0%-30%) to give 3-(benzyloxy)-9-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one (135 mg, 89%) as a pale yellow foam. 1 HNMR (400 MHz, CDCl3) δ 8.28 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 8.9 Hz, 1H), 7.51 – 7.32 (m, 6H), 7.03 (dd, J = 8.9, 2.4 Hz, 1H), 6.97 (dd, J = 8.8, 2.6Hz, 1H), 6.91 (d, J = 2.5 Hz, 1H), 5.13 (s, 2H), 4.73 (tt, J = 7.7, 3.8 Hz, 1H), 4.02 (ddd, J = 11.8, 6.3, 3.8 Hz, 2H), 3.65 (ddd, J = 11.5, 8.1, 3.3 Hz,2H), 2.17 – 2.05 (m, 2H), 1.94 – 1.82 (m, 2H).

[0581] Step 5: Synthesis of 3-hydroxy-9-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one

[0582]

[0583] 3-(benzyloxy)-9-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one (135 mg, 0.340 mmol, 1.0 equivalent) was dissolved in MeOH / DCM (10 mL, 10 / 1) and Pd(OH)2 / C (70 mg) was added in a single batch. The reaction mixture was then evacuated and backfilled three times with N2 and placed under a hydrogen atmosphere (balloon). The reaction mixture was stirred for 4 hours and filtered through silica after the starting material was completely consumed (as indicated by TLC), and concentrated under vacuum to give a crude product. The crude product was loaded onto silica and purified by MPLC (SiO2, 12 g, EtOAc 0%-50% in Hex) to give 3-hydroxy-9-((tetrahydro-2H-pyran-4-yl)oxy)-6H-benzo[c]chromen-6-one (40 mg, 34%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 10.33 (s, 1H), 8.25 (d, J = 8.9Hz, 1H), 8.11 (d, J = 8.9 Hz, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.17 (dd, J =8.9, 2.4 Hz, 1H), 6.83 (dd, J = 8.7, 2.4 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 4.97 (tt, J = 8.6, 4.1 Hz, 1H), 3.90 (dt, J = 11.7, 4.3 Hz, 2H), 3.56 (ddd, J= 11.8, 9.6, 2.7 Hz, 2H), 2.07 (dd, J = 11.3, 7.7 Hz, 2H), 1.66 (ddt, J =13.7, 9.1, 4.6 Hz, 2H).

[0584] G) Alkyne-substituted ester "A" ring analogs prepared by the Sonogashira reaction.

[0585] 3-Hydroxy-8-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (39) Synthesis

[0586]

[0587] Step 1: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one

[0588]

[0589] Subsequently, propargyl alcohol (501 mg, 8.94 mmol, 2.5 equivalence), Pd(PPh3)2Cl2 (251 mg, 0.360 mmol, 0.1 equivalence), and CuI (68 mg, 0.36 mmol, 0.1 equivalence) were added to a solution of S8-bromo-3-((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-one (1.45 g, 3.58 mmol, 1.0 equivalence) in THF (50 mL) in a 250 mL flask, and the reaction mixture was degassed with N2 for 10 min at room temperature. Triethylamine (724 mg, 7.15 mmol, 2.0 equivalence) was added in a single addition, and the reaction mixture was placed in a preheated oil bath at 90 °C. After complete conversion of the starting material (as indicated by TLC), the reaction mixture was cooled to room temperature and quenched with water, and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by MPLC (SiO2, 80 g, EtOAc in Hex 0%-40%) to give 3-((tert-butyldimethylsilyl)oxy)-8-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (490 mg, 36%) as a light brown solid. 1 H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 1.8 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.79 (dd, J = 8.3,1.8 Hz, 1H), 6.94 – 6.80 (m, 2H), 4.54 (d, J = 6.1 Hz, 2H), 1.00 (s, 9H), 0.26 (s, 6H).

[0590] Step 2: Synthesis of 3-hydroxy-8-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one

[0591]

[0592] 3-((tert-butyldimethylsilyl)oxy)-8-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (160 mg, 0.420 mmol, 1.0 equivalence) was dissolved in MeOH (2 mL) and cooled to room temperature in an ice bath. The resulting yellow solution was stirred for 10 minutes. KHF2 (66 mg, 0.82 mmol, 2.0 equivalence) was then added in a single batch, and the reaction mixture was stirred overnight at room temperature. After the starting material was completely consumed (as indicated by TLC), the reaction mixture was filtered through a glass frit (Por. 4), and the residue was washed with MeOH and dried under vacuum to give 3-hydroxy-8-(3-methoxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (112 mg, 0.420 mmol, 99%) as a light brown solid. 1 H NMR (400 MHz, DMSO) δ 10.45 (s, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 8.12 (d, J = 1.8 Hz, 1H), 7.87 (dd, J = 8.4, 1.9 Hz, 1H), 6.85 (dd, J = 8.7,2.4 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 5.41 (s, 1H), 4.35 (s, 2H).

[0593] In addition, the hydrogenation of the above compounds is carried out as follows:

[0594] Step 3: Synthesis of 3-hydroxy-8-(3-hydroxypropyl)-6H-benzo[c]chromen-6-one (40)

[0595]

[0596] 3-hydroxy-8-(3-methoxypropyl-1-yn-1-yl)-6H-benzo[c]chromen-6-one (86 mg, 0.32 mmol, 1.0 equivalent) and Pd(OH)₂ / C (9 mg, 0.07 mmol, 0.2 equivalent) in MeOH (5 ml) were hydrogenated overnight at atmospheric pressure. The reaction mixture was filtered through a diatomaceous earth mat, and the solvent was concentrated by evaporation under vacuum to give 3-hydroxy-8-(3-hydroxypropyl)-6H-benzo[c]chromen-6-one (70 mg, 80%) as a white solid. MS (ESI+): m / z = 271. 1H NMR (400 MHz, DMSO) δ 8.13 (d, J = 8.3 Hz, 1H), 8.04 (dd, J = 8.8, 2.2 Hz, 1H), 7.97 (d, J = 1.9 Hz, 1H), 7.70 (dd, J = 8.3, 2.0 Hz, 1H), 6.76 (dd, J = 8.7,2.4 Hz, 1H), 6.64 (d, J = 2.5 Hz, 1H), 4.52 (s, 1H), 3.43 (t, J = 6.4 Hz,2H), 2.81 – 2.71 (m, 2H), 1.86 – 1.73 (m, 2H).

[0597] 3-Hydroxy-8-(3-methoxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one ( 41) Synthesis

[0598]

[0599] Step 1: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-(3-methoxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one

[0600]

[0601] Subsequently, 3-methoxyprop-1-yne (224 mg, 3.19 mmol, 3.5 equivalents), Pd(PPh3)2Cl2 (64 mg, 0.09 mmol, 0.1 equivalents), and CuI (17 mg, 0.09 mmol, 0.1 equivalents) were added to a solution of 8-bromo-3-((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-one (370 mg, 0.910 mmol, 1.0 equivalents) in THF (3.04 mL) in a 20 mL Biotage MW vial, and the reactants were degassed with N2 for 10 min at room temperature. Triethylamine (277 mg, 2.74 mmol, 3.0 equivalents) was added in a single addition, and the reaction mixture was placed in a preheated oil bath at 90 °C. After complete conversion of the starting material (as indicated by TLC), the reaction mixture was cooled to room temperature and quenched with water, and extracted with EtOAc (2 x 25 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by MPLC (SiO2, 40 g, EtOAc in Hex 0%–40%) to give 3-((tert-butyldimethylsilyl)oxy)-8-(3-methoxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (160 mg 44%) as a light brown solid.1 H NMR (400 MHz, CDCl3)δ 8.42 (d, J = 1.8 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.4 Hz,1H), 7.80 (dd, J = 8.4, 1.8 Hz, 1H), 6.86 – 6.81 (m, 2H), 4.35 (s, 2H), 3.48 (s, 3H), 1.00 (s, 9H), 0.26 (s, 6H).

[0602] Step 2: Synthesis of 3-hydroxy-8-(3-methoxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one

[0603]

[0604] 3-((tert-butyldimethylsilyl)oxy)-8-(3-methoxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (160 mg, 0.410 mmol, 1.0 equivalent) was dissolved in MeOH (2 mL) and cooled to room temperature in an ice bath. The resulting yellow solution was stirred for 10 minutes. KHF2 (63 mg, 0.81 mmol, 2.0 equivalent) was then added in a single batch, and the reaction mixture was stirred overnight. After the starting material was completely consumed (as indicated by TLC), the reaction mixture was filtered through a glass frit (Por. 4), and the residue was washed with MeOH and dried under vacuum to give 3-hydroxy-8-(3-methoxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (85 mg, 75%) as a light brown solid. 1 H NMR (400 MHz, DMSO) δ 10.45 (s,1H), 8.28 (d, J = 8.5 Hz, 1H), 8.20 – 8.13 (m, 2H), 7.91 (dd, J = 8.4, 1.9Hz, 1H), 6.86 (dd, J = 8.7, 2.4 Hz, 1H), 6.76 (d, J = 2.4 Hz, 1H), 4.38 (s, 2H), 3.36 (s, 3H).

[0605] Synthesis of 3-hydroxy-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-6H-benzo[c]chromen-6-one (42)

[0606]

[0607] Step 1: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-6H-benzo[c]chromen-6-one

[0608]

[0609] Subsequently, 2-methylbut-3-yn-2-ol (269 mg, 3.19 mmol, 3.5 equivalents), Pd(PPh3)2Cl2 (64 mg, 0.090 mmol, 0.1 equivalents), and CuI (17 mg, 0.090 mmol, 0.1 equivalents) were added to a solution of 8-bromo-3-((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-one (370 mg, 0.910 mmol, 1.0 equivalents) in THF (3.0 mL) in a 20 mL Biotage MW vial, and the reactants were degassed with N2 for 10 min at room temperature. Triethylamine (277 mg, 2.74 mmol, 3.0 equivalents) was added in a single addition, and the reaction mixture was placed in a preheated oil bath at 90 °C. After complete conversion of the starting material (as indicated by TLC), the reaction mixture was cooled to room temperature and quenched with water, and extracted with EtOAc (2 x 25 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by MPLC (SiO2, 40 g, EtOAc in Hex 0%–40%) to give 3-((tert-butyldimethylsilyl)oxy)-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-6H-benzo[c]chromen-6-one (233 mg, 0.570 mmol, 63%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 1.8 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.78 (dd, J = 8.4, 1.9 Hz, 1H), 6.88 – 6.82 (m, 2H), 1.65 (s, 6H), 1.00 (s, 9H), 0.26 (s, 6H).

[0610] Step 2: Synthesis of 3-hydroxy-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-6H-benzo[c]chromen-6-one

[0611]

[0612] 3-((tert-butyldimethylsilyl)oxy)-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-6H-benzo[c]chromen-6-one (233 mg, 0.570 mmol, 1.0 equivalent) was dissolved in MeOH (3 mL) and cooled to room temperature in an ice bath. The resulting yellow solution was stirred for 10 minutes. KHF2 (89 mg, 1.1 mmol, 2.0 equivalent) was then added in a single batch, and the reaction mixture was stirred overnight. After the starting material was completely consumed (as indicated by TLC), the reaction mixture was filtered through a glass frit (Por. 4), and the residue was washed with MeOH and dried under vacuum to give 3-hydroxy-8-(3-hydroxy-3-methylbut-1-yn-1-yl)-6H-benzo[c]chromen-6-one (120 mg, 0.410 mmol, 72%) as a light brown solid. 1 H NMR (400MHz, DMSO) δ 10.44 (s, 1H), 8.25 (d, J = 8.5 Hz, 1H), 8.16 (d, J = 8.9 Hz,1H), 8.10 (d, J = 1.8 Hz, 1H), 7.83 (dd, J = 8.4, 1.9 Hz, 1H), 6.86 (dd, J =8.8, 2.4 Hz, 1H), 6.76 (d, J = 2.4 Hz, 1H), 5.54 (s, 1H), 3.32 (s, 6H).

[0613] Synthesis of 3-hydroxy-8-((1-hydroxycyclobutyl)ethynyl)-6H-benzo[c]chromen-6-one (43)

[0614]

[0615] Step 1: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-8-((1-hydroxycyclobutyl)ethynyl)-6H-benzo[c]chromen-6-one

[0616]

[0617] Subsequently, 1-ethynylcyclobutanol (208 mg, 2.16 mmol, 3.5 equivalents), Pd(PPh3)2Cl2 (43 mg, 0.060 mmol, 0.1 equivalents), and CuI (12 mg, 0.060 mmol, 0.1 equivalents) were added to a solution of 8-bromo-3-((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-one (250 mg, 0.620 mmol, 1.0 equivalents) in THF (2.06 mL) in a 20 mL Biotage MW vial. The reactants were then degassed with N2 for 10 min at room temperature. Triethylamine (187 mg, 1.85 mmol, 3.00 equivalents) was added in a single addition, and the reaction mixture was placed in a preheated oil bath at 90 °C. After complete conversion of the starting material (as indicated by TLC), the reaction mixture was cooled to room temperature and quenched with water, and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by MPLC (SiO2, 40 g, EtOAc in Hex 0%–40%) to give 3-((tert-butyldimethylsilyl)oxy)-8-((1-hydroxycyclobutyl)ethynyl)-6H-benzo[c]chromen-6-one (195 mg, 75%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3)δ 8.38 (d, J = 1.8 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.6 Hz,1H), 7.76 (dd, J = 8.4, 1.9 Hz, 1H), 6.86 – 6.78 (m, 2H), 2.61 – 2.52 (m,2H), 2.36 (td, J = 9.3, 2.8 Hz, 2H), 2.06 – 1.79 (m, 2H), 1.00 (s, 9H), 0.25(s, 6H).

[0618] Step 2: Synthesis of 3-hydroxy-8-((1-hydroxycyclobutyl)ethynyl)-6H-benzo[c]chromen-6-one

[0619]

[0620] 3-((tert-butyldimethylsilyl)oxy)-8-((1-hydroxycyclobutyl)ethynyl)-6H-benzo[c]chromen-6-one (195 mg, 0.460 mmol, 1.0 equivalent) was dissolved in MeOH (2 mL) and cooled to room temperature in an ice bath. The resulting yellow solution was stirred for 10 minutes. KHF2 (72 mg, 0.93 mmol, 2.0 equivalent) was then added in a single batch, and the reaction mixture was stirred overnight. After the starting material was completely consumed (as indicated by TLC), the reaction mixture was filtered through a glass frit (Por. 4), and the residue was washed with MeOH and dried under vacuum to give 3-hydroxy-8-((1-hydroxycyclobutyl)ethynyl)-6H-benzo[c]chromen-6-one (100 mg, 70%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 10.44 (s,1H), 8.26 (d, J = 8.4 Hz, 1H), 8.17 (d, J = 8.9 Hz, 1H), 8.13 (d, J = 1.8 Hz,1H), 7.87 (dd, J = 8.4, 1.9 Hz, 1H), 6.86 (dd, J = 8.7, 2.4 Hz, 1H), 6.76 (d,J = 2.4 Hz, 1H), 5.95 (s, 1H), 2.41 (ddd, J = 9.2, 7.6, 4.4 Hz, 2H), 2.25(td, J = 9.3, 2.7 Hz, 2H), 1.84 – 1.76 (m, 2H).

[0621] Synthesis of 3-hydroxy-9-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (44)

[0622]

[0623] Step 1: Synthesis of 9-bromo-3-((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-one

[0624]

[0625] 9-Bromo-3-hydroxy-6H-benzo[c]chromene-6-one (610 mg, 2.10 mmol, 1.0 equivalent) was suspended in DMF (10 mL), and triethylamine (636 mg, 6.29 mmol, 3.0 equivalent) was added in a single addition. The reaction mixture was cooled to 0 °C in an ice bath and stirred at this temperature for 10 min. Subsequently, TBSCl (411 mg, 2.72 mmol, 1.3 equivalent) was added in a single addition, and the reaction mixture was warmed to room temperature and stirred for another 2 h. After complete conversion of the starting material (as indicated by TLC), the reaction mixture was quenched with a semi-saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous Na₂SO₄. The crude product was purified by MPLC (SiO2, 80 g, EtOAc in Hex 0%-15%) to give 9-bromo-3-((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-one (566 mg, 67%) as a light brown solid. 1 HNMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 1.8 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.52 (dd, J = 8.5, 1.8 Hz, 1H), 6.84 – 6.67 (m,2H), 0.90 (s, 9H), 0.17 (s, 6H).

[0626] Step 2: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-9-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one

[0627]

[0628] Subsequently, propargyl alcohol (208 mg, 2.16 mmol, 3.5 equivalents) and Pd(PPh3) were added to a solution of 9-bromo-3-((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromene-6-one (250 mg, 0.620 mmol, 1.0 equivalent) in THF (2.0 mL) in a 20 mL Biotage MW vial. 2.0Cl2 (43 mg, 0.060 mmol, 0.1 equivalent) and CuI (12 mg, 0.060 mmol, 0.1 equivalent) were added, and the reaction mixture was bubbled with N2 for 10 min at room temperature. Triethylamine (187 mg, 1.85 mmol, 3.0 equivalent) was added in a single addition, and the reaction mixture was placed in a preheated oil bath at 90 °C. After complete conversion of the starting material (as indicated by TLC), the reaction mixture was cooled to room temperature and quenched with water, and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by MPLC (SiO2, 40 g, EtOAc 0%–40% in Hex) to give 3-((tert-butyldimethylsilyl)oxy)-9-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (176 mg, 75%) as a pale yellow solid. 1 H NMR (500 MHz, DMSO) δ 11.36(s, 1H), 8.28 (s, 1H), 8.19 (dd, J = 8.8, 1.6 Hz, 1H), 8.13 (d, J = 8.2 Hz,1H), 7.51 (d, J = 8.2 Hz, 1H), 6.80 (dd, J = 8.8, 2.4 Hz, 1H), 6.71 (d, J =2.4 Hz, 1H), 5.63 (d, J = 124.9 Hz, 1H), 4.39 (s, 2H), 0.90 (s, 9H), 0.17 (s,6H).

[0629] Step 2: Synthesis of 3-hydroxy-9-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one

[0630]

[0631] 3-((tert-butyldimethylsilyl)oxy)-9-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (176 mg, 0.460 mmol, 1.0 equivalent) was dissolved in MeOH (2 mL), and the resulting yellow solution was stirred for 10 min. KHF2 (72 mg, 0.93 mmol, 2.0 equivalent) was then added in a single batch, and the reaction mixture was stirred overnight. After the starting material was completely consumed (as indicated by TLC), the reaction mixture was filtered through a glass frit (Por. 4), and the residue was washed with MeOH and dried under vacuum to give 3-hydroxy-8-((1-hydroxycyclobutyl)ethynyl)-6H-benzo[c]chromen-6-one (90 mg, 0.34 mmol, 73%) as a white solid. MS (ESI+): m / z = 267. 1 H NMR (500 MHz, DMSO) δ11.36 (s, 1H), 8.28 (s, 1H), 8.19 (dd, J = 8.8, 1.6 Hz, 1H), 8.13 (d, J = 8.2Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H), 6.80 (dd, J = 8.8, 2.4 Hz, 1H), 6.71 (d, J= 2.4 Hz, 1H), 5.63 (d, J = 124.9 Hz, 1H), 4.39 (s, 2H).

[0632] 3-((tert-butyldimethylsilyl)oxy)-8-(3-(4-methylpiperazin-1-yl)prop-1-yn-1-yl)- Synthesis of 6H-benzo[c]chromen-6-one

[0633]

[0634] Methanesulfonyl chloride (0.037 mL, 0.47 mmol) was added to a solution of 3-((tert-butyldimethylsilyl)oxy)-8-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromene-6-one (140 mg, 0.360 mmol) and NEt3 (0.150 mL, 1.10 mmol) in THF (5 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 1 hour. TLC showed complete conversion of the starting materials. N1,1-methylpiperazine (111 mg, 1.10 mmol) was added, and the mixture was heated overnight at 60 °C. A saturated ammonium chloride solution was added, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The crude product was purified by MPLC (SiO2, MeOH / DCM 0% to 20%) to give 3-((tert-butyldimethylsilyl)oxy)-8-(3-(4-methylpiperazin-1-yl)prop-1-yn-1-yl)-6H-benzo[c]chromen-6-one, which was used in the next step without further purification.

[0635] 3-((tert-butyldimethylsilyl)oxy)-8-(3-(4-methylpiperazin-1-yl)propyl)-6H-benzo[c] Synthesis of chromone-6-one

[0636]

[0637] A suspension of 10 (67 mg, 0.14 mmol) of 3-((tert-butyldimethylsilyl)oxy)-8-(3-(4-methylpiperazin-1-yl)propyl-1-yn-1-yl)-6H-benzo[c]chromen-6-one and Pd(OH)2 / C (20 mg, 0.030 mmol) in MeOH (5 ml) was hydrogenated overnight at atmospheric pressure. The reaction mixture was filtered through a diatomaceous earth mat, and the solvent was evaporated and concentrated under vacuum to give 64 mg, 95%, of 3-((tert-butyldimethylsilyl)oxy)-8-(3-(4-methylpiperazin-1-yl)propyl)-6H-benzo[c]chromen-6-one as a pale yellow oil, which was used in the next step without further purification.

[0638] Synthesis of 3-hydroxy-8-(3-(4-methylpiperazin-1-yl)propyl)-6H-benzo[c]chromen-6-one (45)

[0639]

[0640] 45 was prepared by starting with 3-((tert-butyldimethylsilyl)oxy)-8-(3-(4-methylpiperazin-1-yl)propyl)-6H-benzo[c]chromen-6-one (65 mg, 0.14 mmol) and KHF2 (22 mg, 0.28 mmol), and was purified by MPLC (SiO2, MeOH / DCM 5% to 30%) to give 3-hydroxy-8-(3-(4-methylpiperazin-1-yl)propyl)-6H-benzo[c]chromen-6-one (36 mg, 73%) as a pale yellow solid. f = 0.4 (MeOH / DCM 30 / 70). 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 6.5 Hz, 1H), 6.61 (d, J = 9.1 Hz, 1H), 6.53 (s, 1H), 2.86 – 2.48 (m, 12H), 2.39 (s, 3H), 1.99 (s, 2H).

[0641] 3-((tert-butyldimethylsilyl)oxy)-8-(3-morpholinopropyl-1-yn-1-yl)-6H-benzo[c]color Synthesis of en-6-one

[0642]

[0643] Methanesulfonyl chloride (0.04 mL, 0.51 mmol) was added to a solution of 3-((tert-butyldimethylsilyl)oxy)-8-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromene-6-one (150 mg, 0.39 mmol) and NEt3 (0.160 mL, 1.18 mmol) in THF (5 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 1 hour. TLC showed complete conversion of the starting material. Morpholine (0.100 mL, 1.18 mmol) was added, and the mixture was heated at 60 °C overnight. A saturated ammonium chloride solution was added, and the reaction mixture was extracted three times with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The crude product was purified by MPLC (SiO2, MeOH / DCM 0% to 20%) to give 3-((tert-butyldimethylsilyl)oxy)-8-(3-morpholinoprop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (101 mg, 57%), which was used in the next step without further purification.

[0644] 3-((tert-butyldimethylsilyl)oxy)-8-(3-morpholinopropyl)-6H-benzo[c]chromen-6-one synthesis

[0645]

[0646] 3-(3-((tert-butyldimethylsilyl)oxy)-6-oxo-6H-benzo[c]chromene-8-yl)propyl-2-yn-1-yl ester OTBS-morpholine (100 mg, 0.220 mmol) and Pd(OH)2 / C (31 mg, 0.22 mmol) in MeOH (5 ml) were hydrogenated overnight at atmospheric pressure. The reaction mixture was filtered through a diatomaceous earth mat, and the solvent was concentrated under vacuum to give 3-((tert-butyldimethylsilyl)oxy)-8-(3-morpholinopropyl)-6H-benzo[c]chromene-6-one (70 mg, 69%) as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 1.9 Hz, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.87 (d, J = 9.4 Hz, 1H), 7.61 (dd, J = 8.2, 2.0Hz, 1H), 6.82 (h, J = 2.4 Hz, 2H), 3.71 (t, J = 4.7 Hz, 4H), 2.76 (d, J = 7.8Hz, 2H), 2.43 (t, J = 4.6 Hz, 4H), 2.36 (dd, J = 8.4, 6.4 Hz, 2H), 1.87 (h, J= 7.4, 6.8 Hz, 2H), 0.99 (s, 9H), 0.24 (s, 6H).

[0647] Synthesis of 3-hydroxy-8-(3-morpholinopropyl)-6H-benzo[c]chromen-6-one (46)

[0648]

[0649] 46 was prepared by starting with 3-((tert-butyldimethylsilyl)oxy)-8-(3-morpholinopropyl)-6H-benzo[c]chromen-6-one (70 mg, 0.15 mmol) and KHF2 (24 mg, 0.31 mmol), and was purified by MPLC (SiO2, MeOH / DCM 5% to 30%) to give 3-hydroxy-8-(3-morpholinopropyl)-6H-benzo[c]chromen-6-one (70 mg, 69%) as a pale yellow solid. f = 0.4 (MeOH / DCM 30 / 70). 1H NMR (400 MHz, DMSO) δ 10.31 (s, 1H), 8.18 (d, J = 8.3 Hz, 1H), 8.13 (d, J = 8.9 Hz, 1H), 8.01 (d, J = 1.9 Hz, 1H), 7.75 (dd, J = 8.3, 2.0 Hz, 1H), 6.83 (dd, J = 8.7, 2.4 Hz, 1H), 6.74 (d, J =2.4 Hz, 1H), 3.57 (t, J = 4.7 Hz, 4H), 2.74 (t, J = 7.6 Hz, 2H), 2.35 – 2.31(m, 4H), 2.28 (t, J = 7.2 Hz, 2H), 1.78 (p, J = 7.4 Hz, 2H).

[0650] 3-((tert-butyldimethylsilyl)oxy)-8-(3-(piperidin-1-yl)prop-1-yn-1-yl)-6H-benzo[] [c] Synthesis of chromone-6-one

[0651]

[0652] Methanesulfonyl chloride (0.0980 ml, 1.26 mmol) was added to a solution of 3-((tert-butyldimethylsilyl)oxy)-8-(3-hydroxyprop-1-yn-1-yl)-6H-benzo[c]chromene-6-one (240 mg, 0.630 mmol) and NEt3 (0.260 ml, 1.89 mmol) in THF (10 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 1 hour. TLC showed complete conversion of the starting material. Piperidine (0.081 ml, 0.82 mmol) was added, and the mixture was heated at 60 °C overnight. A saturated ammonium chloride solution was added, and the reaction mixture was extracted three times with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The crude product was purified by MPLC (SiO2, MeOH / DCM 0% to 20%) to give 3-((tert-butyldimethylsilyl)oxy)-8-(3-(piperidin-1-yl)prop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (66 mg, 23%). 1HNMR (400 MHz, CDCl3) δ 8.41 (d, J = 1.8 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.79 (dd, J = 8.3, 1.8 Hz, 1H), 6.85 (d, J = 8.2Hz, 2H), 3.53 (s, 2H), 2.61 (s, 4H), 1.70 – 1.45 (m, 6H), 1.00 (s, 9H), 0.26 (s, 6H).

[0653] Synthesis of 3-hydroxy-8-(3-(piperidin-1-yl)prop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (47)

[0654]

[0655] 47 was prepared by starting with 3-((tert-butyldimethylsilyl)oxy)-8-(3-(piperidin-1-yl)prop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (60 mg, 0.13 mmol) and KHF2 (21 mg, 0.27 mmol), and was purified by MPLC (SiO2, EtOAc / cyclohexane 0% to 80%) to give 3-hydroxy-8-(3-(piperidin-1-yl)prop-1-yn-1-yl)-6H-benzo[c]chromen-6-one (37 mg, 83%) as a pale yellow solid. f = 0.4 (EtOAc / hexane 40%). 1 H NMR(400 MHz, CDCl3) δ 7.70 – 7.62 (m, 2H), 7.59 (d, J = 1.7 Hz, 1H), 7.54 (dd, J= 8.4, 1.8 Hz, 1H), 6.82 (dd, J = 8.7, 2.4 Hz, 1H), 6.55 (d, J = 2.4 Hz, 1H), 3.36 (s, 2H), 2.77 (s, 4H), 1.80 (q, J = 5.7 Hz, 4H), 1.58 (b, 2H).

[0656]

[0657] (3-(3-((tert-butyldimethylsilyl)oxy)-6-oxo-6H-benzo[c]chromen-8-yl)propyl-2- Synthesis of tert-butyl 1-yl)carbamate

[0658] NEt3 (0.330 mL, 2.38 mmol, 4.0 equivalent) was added to a well-degassed solution of Pd(PPh3)2Cl2 (41.8 mg, 0.059 mmol, 0.1 equivalent) and CuI (11.3 mg, 0.059 mmol, 0.1 equivalent) and 8-bromo-3-((dimethyl(tert-butyl)silyl)oxy)-6H-benzo[c]chromene-6-one (250 mg, 0.590 mmol) and prop-2-ynyl-carbamate tert-butyl ester (277 mg, 1.79 mmol, 3.0 equivalent) in THF (10 mL), and the mixture was heated at 70 °C overnight. The reaction mixture was diluted with saturated NH4Cl solution and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated under vacuum. The crude product was purified by MPLC (SiO2, EtOAc / hexane 0% to 20%) to give tert-butyl (3-(3-((tert-butyldimethylsilyl)oxy)-6-oxo-6H-benzo[c]chromen-8-yl)prop-2-yn-1-yl)carbamate (190 mg, 0.39 mmol, 66%), which was a slightly yellow foam. f = 0.4 (EtOAc / hexane 20%). 1 H NMR (400 MHz, CDCl3) δ8.39 (d, J = 1.7 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.87 (dd, J = 8.5, 0.8Hz, 1H), 7.77 (dd, J = 8.3, 1.8 Hz, 1H), 6.89 – 6.81 (m, 2H), 4.79 (s, 1H), 4.19 (d, J = 5.6 Hz, 2H), 1.48 (s, 9H), 1.00 (s, 9H), 0.26 (s, 6H).

[0659] (3-(3-((tert-butyldimethylsilyl)oxy)-6-oxo-6H-benzo[c]chromen-8-yl)propyl)amino Synthesis of tert-butyl carbamate

[0660] A suspension of (3-(3-((tert-butyldimethylsilyl)oxy)-6-oxo-6H-benzo[c]chromen-8-yl)prop-2-yn-1-yl)carbamate (190 mg, 0.390 mmol) and Pd(OH)2 / C 20% (56 mg, 0.79 mmol) was hydrogenated in methanol at atmospheric pressure and stirred overnight. The reaction mixture was filtered through a diatomaceous earth mat, and the solvent was evaporated under vacuum. The crude product was purified by MPLC (SiO2, EtOAc / cyclohexane 0% to 20%) to give (3-(3-(((tert-butyldimethylsilyl)oxy)-6-oxo-6H-benzo[c]chromen-8-yl)prop-1-yl)carbamate (175 mg, 91%) as a pale, slightly oily substance. f = 0.4 (EtOAc / hexane 20%). 1 H NMR (400 MHz, CDCl3) δ 8.17 (d, J= 1.9 Hz, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.88 (d, J = 9.3 Hz, 1H), 7.62 (dd,J = 8.2, 2.0 Hz, 1H), 6.84 (dq, J = 4.5, 2.4 Hz, 2H), 4.57 (s, 1H), 3.18 (d,J = 7.0 Hz, 2H), 2.89 – 2.71 (m, 2H), 1.88 (p, J = 7.3 Hz, 2H), 1.45 (s, 9H),1.00 (s, 9H), 0.26 (s, 6H).

[0661] Synthesis of tert-butyl (3-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)propyl)carbamate (48)

[0662]

[0663] 48 was prepared by starting with (3-(3-((tert-butyldimethylsilyl)oxy)-6-oxo-6H-benzo[c]chromen-8-yl)propyl)carbamate tert-butyl ester (170 mg, 0.350 mmol) and KHF2 (55 mg, 0.70 mmol), and after purification by MPLC (SiO2, EtOAc / cyclohexane 0% to 20%), yielded (3-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)propyl)carbamate tert-butyl ester (108 mg, 0.290 mmol, 83%) as a white solid. f = 0.4 (EtOAc / hexane 20 / 100). 1H NMR (400 MHz, DMSO) δ 10.27 (s, 1H), 8.15 (dd, J = 21.4, 8.5 Hz, 2H), 8.00 (d, J = 1.9 Hz, 1H), 7.73 (dd, J = 8.3, 2.0 Hz, 1H), 6.87 (t, J =5.4 Hz, 1H), 6.82 (dd, J = 8.7, 2.4 Hz, 1H), 6.73 (d, J = 2.3 Hz, 1H), 2.94(q, J = 6.6 Hz, 2H), 2.70 (t, J = 7.6 Hz, 2H), 1.72 (p, J = 7.3 Hz, 2H), 1.36(s, 9H).

[0664] Synthesis of 8-(3-aminopropyl)-3-hydroxy-6H-benzo[c]chromene-6-one hydrochloride (49)

[0665]

[0666] HCl (4 M in dioxane, 1.35 mL, 5.4 mmol) was added to a solution of (3-(3-hydroxy-6-oxo-6H-benzo[c]chromene-8-yl)propyl)carbamate tert-butyl (100 mg, 0.270 mmol) in dioxane (0.5 mL) at room temperature, and the reaction mixture was stirred overnight at room temperature, resulting in the formation of a precipitate. The solvent was concentrated under vacuum, and the crude product was milled in Et2O, filtered, and dried to give (3-aminopropyl)-3-hydroxy-6H-benzo[c]chromene-6-one hydrochloride (70 mg, 86%) as a white solid. MS (ESI+): m / z = 270. 1 H NMR (400 MHz, DMSO) δ 10.36(s, 1H), 8.22 (d, J = 8.3 Hz, 1H), 8.14 (d, J = 8.8 Hz, 1H), 8.05 (d, J = 1.9Hz, 1H), 7.83 (s, 3H), 7.76 (dd, J = 8.3, 2.0 Hz, 1H), 6.85 (dd, J = 8.7, 2.4Hz, 1H), 6.76 (dd, J = 2.4, 1.2 Hz, 1H), 2.81 (q, J = 7.7, 6.4 Hz, 4H), 1.98– 1.85 (m, 2H).

[0667] H) Spirocyclic (oxobutane and azircyclic butane) "A" ring analogues

[0668] Synthesis of spiro[benzo[c]chromene-6,3'-oxetane]-3,8-diol (50)

[0669]

[0670] Step 1: Synthesis of 2-bromo-4'-chloro-2'-fluoro-4-methoxy-1,1'-biphenyl

[0671]

[0672] 2-Bromo-1-iodo-4-methoxybenzene (4.00 g, 12.8 mmol) and (4-chloro-2-fluorophenyl)boronic acid (1.01 g, 23.0 mmol) were dissolved in dioxane (80 mL). Tetra(triphenylphosphine)palladium(0) (738 mg, 0.640 mmol) was added, followed by a solution of Na₂CO₃ (2.70 g, 25.6 mmol), and the reaction mixture was heated overnight at 80 °C. The reaction mixture was diluted with saturated sodium carbonate solution and extracted twice with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The crude product was purified by MPLC (SiO₂, 0% to 8% DCM / cyclohexane) to give 2-bromo-4'-chloro-2'-fluoro-4-methoxy-1,1'-biphenyl (1.80 g, 45%) as a colorless oil. f = 0.2 (DCM / cyclohexane 3%). 1 H NMR (400MHz, CDCl3) δ 7.24 – 7.14 (m, 5H), 6.92 (dd, J = 8.5, 2.6 Hz, 1H), 3.84 (s,3H).

[0673] Step 2: Synthesis of 2-bromo-4'-chloro-2'-fluoro-[1,1'-biphenyl]-4-ol

[0674]

[0675] BBr3 (1 M in DCM, 6.97 mL, 6.97 mmol) was added to a solution of 2-bromo-4'-chloro-2'-fluoro-4-methoxy-1,1'-biphenyl (1.10 g, 3.48 mmol) in DCM (5 mL) at 0 °C, and the reaction mixture was allowed to warm to room temperature overnight. Methanol (10 mL) was added at 0 °C, and the solvent was evaporated under vacuum. The crude product was diluted with saturated sodium bicarbonate solution and extracted with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under vacuum to give 2-bromo-4'-chloro-2'-fluoro-[1,1'-biphenyl]-4-ol (1.10 g), which was used in the next step without further purification. 1H NMR (400MHz, CDCl3) δ 7.23 – 7.01 (m, 5H), 6.79 (dd, J = 8.4, 2.6 Hz, 1H).

[0676] Step 3: Synthesis of 4-(benzyloxy)-2-bromo-4'-chloro-2'-fluoro-1,1'-biphenyl

[0677]

[0678] Benzyl bromide (0.470 mL, 3.98 mmol) was added to a solution of 2-bromo-4'-chloro-2'-fluoro-[1,1'-biphenyl]-4-ol (1.00 g, 3.31 mmol) and potassium carbonate (0.916 g, 6.63 mmol) in ACN (10 mL), and the mixture was heated overnight at 60 °C. The crude product was cooled to room temperature and extracted from a bicarbonate-saturated solution with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The crude product was purified by MPLC (25 g silica column, EtOAc / cyclohexane 0% to 10%) to give 4-(benzyloxy)-2-bromo-4'-chloro-2'-fluoro-1,1'-biphenyl (1.10 g, 85%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.48 – 7.35 (m, 5H), 7.32 (d, J = 2.6Hz, 1H), 7.23 – 7.15 (m, 4H), 6.99 (dd, J = 8.5, 2.6 Hz, 1H), 5.09 (s, 2H).

[0679] Step 4: Synthesis of 3-(4-(benzyloxy)-4'-chloro-2'-fluoro-[1,1'-biphenyl]-2-yl)oxetane-3-ol

[0680]

[0681] At -78℃ nBuLi (1.6M in hexane, 2.58 ml, 4.13 mmol) was added dropwise to a solution of 4-(benzyloxy)-2-bromo-4'-chloro-2'-fluoro-1,1'-biphenyl (900 mg, 2.29 mmol) in anhydrous THF (8 ml). The pale pink solution was stirred at -78°C for 45 minutes, followed by the dropwise addition of a solution of oxetane-3-one (662 mg, 9.19 mmol), and the reaction mixture was allowed to cool to room temperature over 5 hours. The reaction mixture was quenched with saturated NH4Cl solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The crude product was purified by MPLC (25 g silica column, EtOAc / cyclohexane 0% to 50%) to give 3-(4-(benzyloxy)-4'-chloro-2'-fluoro-[1,1'-biphenyl]-2-yl)oxetane-3-ol (383 mg, 85%) as a colorless oil. f = 0.3 (EtOAc / hexane 50 / 50). 1 H NMR (400 MHz, CDCl3) δ 7.55 –7.28 (m, 6H), 7.19 – 7.14 (m, 3H), 7.00 (dd, J = 8.5, 2.6 Hz, 1H), 6.85 (d, J= 2.6 Hz, 1H), 5.11 (s, 2H), 4.82 (s, 2H), 4.36 (s, 2H), 2.77 (s, 1H).

[0682] Step 5: Synthesis of 8-(benzyloxy)-3-chlorospiro[benzo[c]chromene-6,3'-oxetane

[0683]

[0684] NaH (70.5 mg, 1.76 mmol, 60% dispersion in mineral oil) was added to a solution of 3-(4-(benzyloxy)-4'-chloro-2'-fluoro-[1,1'-biphenyl]-2-yl)oxetane-3-ol (377 mg, 0.980 mmol) in 4 mL of DMF at 0 °C, and the reaction mixture was allowed to warm to room temperature overnight. The crude product was extracted with a half-saturated solution of bicarbonate and ethyl acetate. The organic phase was dried over sodium sulfate and evaporated under vacuum. The crude product was purified by MPLC (25 g silica column, EtOAc / cyclohexane 0% to 5%) to give 8-(benzyloxy)-3-chlorospiro[benzo[c]chromene-6,3'-oxetane] (290 mg, 81%) as a yellow solid. f = 0.3 (EtOAc / hexane 10%). 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J= 8.7 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.49 – 7.35 (m, 5H), 7.32 (d, J =2.5 Hz, 1H), 7.08 (d, J = 2.1 Hz, 1H), 7.04 (dd, J = 8.7, 2.6 Hz, 1H), 7.01 (dd, J = 8.3, 2.1 Hz, 1H), 5.17 (s, 2H), 5.08 – 5.01 (m, 2H), 4.90 – 4.78 (m,2H).

[0685] Step 6: Synthesis of 8-(benzyloxy)spiro[benzo[c]chromene-6,3'-oxetane]-3-ol

[0686]

[0687] t-BuXPhos (9 mg, 0.020 mmol) was added to a suspension of Pd2dba3 (2.3 mg, 0.099 mmol) in dioxane (1 ml), degassed, and stirred for 5 minutes. 8-(benzyloxy)-3-chlorospiro[benzo[c]chromene-6,3'-oxetane] (45 mg, 0.12 mmol) was added at room temperature, followed by a solution of KOH (15 mg, 0.27 mmol) in water (0.3 ml), and the mixture was heated overnight at 90 °C. Water was added, and the mixture was extracted three times with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and evaporated under vacuum. The crude product was purified by MPLC (25 g silica column, EtOAc / cyclohexane 0% to 30%) to give 8-(benzyloxy)spiro[benzo[c]chromen-6,3'-oxetane]-3-ol (30 mg, 0.87 mmol, 70%) as a white solid. f = 0.3 (EtOAc / hexane 20%). MS (ESI+): m / z = 347. 1 H NMR (400MHz, DMSO) δ 9.72 (s, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.53 – 7.36 (m, 6H), 7.09 (dd, J = 8.6, 2.6 Hz, 1H), 6.56 – 6.43 (m,2H), 5.21 (s, 2H), 4.86 – 4.80 (m, 4H).

[0688] Step 7: Synthesis of spiro[benzo[c]chromene-6,3'-oxetane]-3,8-diol

[0689]

[0690] A suspension of 8-(benzyloxy)spiro[benzo[c]chromene-6,3'-oxetane]-3-ol (40 mg, 0.12 mmol) and Pd(OH)₂ / C (16 mg, 0.23 mmol) in methanol (4 ml) was hydrogenated overnight at atmospheric pressure. The reaction mixture was filtered through a diatomaceous earth mat, the solvent was evaporated, and the product was further purified by filtration through a silica mat using 10% DCM / methanol to give spiro[benzo[c]chromene-6,3'-oxetane]-3,8-diol (23 mg, 0.09 mmol, 78%) as a pale yellow solid. MS (ESI+): m / z = 257. 1 H NMR (400 MHz, DMSO) δ 9.66 (d, J = 19.6 Hz,2H), 7.57 (d, J = 8.5 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 2.4 Hz,1H), 6.84 (dd, J = 8.4, 2.4 Hz, 1H), 6.51 – 6.44 (m, 2H), 4.83 (d, J = 7.3Hz, 2H), 4.74 (d, J = 7.2 Hz, 2H).

[0691] Synthesis of spiro[azacyclobutane-3,6'-benzo[c]chromene]-3',8'-diol (51)

[0692]

[0693] Step 1: Synthesis of tert-butyl 3-(4'-chloro-2'-fluoro-4-methoxy-[1,1'-biphenyl]-2-yl)-3-hydroxyazacyclobutane-1-carboxylate

[0694]

[0695] At -78℃ nBuLi (1.6M in hexane, 2.69 ml, 4.31 mmol) was added dropwise to a solution of 4-(benzyloxy)-2-bromo-4'-chloro-2'-fluoro-1,1'-biphenyl (900 mg, 2.29 mmol) in anhydrous THF (8 ml). The pale pink solution was stirred at -78°C for 45 minutes, followed by the dropwise addition of tert-butyl 3-oxazolidinyl-1-carboxylate (1.84 g, 10.8 mmol) in anhydrous THF (5 ml), and the reaction mixture was allowed to cool to room temperature for 5 hours. The reaction mixture was quenched with saturated NH4Cl solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate. The crude product was purified by MPLC (80 g silica column, EtOAc / cyclohexane 0% to 50%) to give tert-butyl 3-(4'-chloro-2'-fluoro-4-methoxy-[1,1'-biphenyl]-2-yl)-3-hydroxyazacyclobutane-1-carboxylate (400 mg, 36%) as a colorless oil, which is a mixture of the two compounds. f = 0.3 (EtOAc / hexane 50 / 50). 1 H NMR (400 MHz, CDCl3) δ 7.32 (t, J =8.2 Hz, 1H), 7.21 – 7.12 (m, 3H), 6.93 (dd, J = 8.5, 2.7 Hz, 1H), 6.86 (d, J= 2.6 Hz, 1H), 4.18 – 3.97 (m, 1H), 3.95 – 3.87 (m, 1H), 3.86 (s, 3H), 3.73(s, 2H), 2.70 (d, J = 14.5 Hz, 1H), 1.39 (s, 9H).

[0696] Step 2: Synthesis of tert-butyl 3'-chloro-8'-methoxyspiro[azacyclobutane-3,6'-benzo[c]chromene]-1-carboxylate

[0697]

[0698] NaH (12 mg, 0.30 mmol) was added to a solution of 3-(4'-chloro-2'-fluoro-4-methoxy-[1,1'-biphenyl]-2-yl)-3-hydroxyaziridine-1-carboxylic acid tert-butyl ester (67 mg, 0.16 mmol) in 3 ml of DMF at 0 °C, and the reaction mixture was stirred for 3 hours. A saturated solution of NH4Cl was added, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by MPLC (EtOAc / cyclohexane 0% to 8%) to give 3'-chloro-8'-methoxyspiro[aziridine-3,6'-benzo[c]chromene]-1-carboxylic acid tert-butyl ester (30 mg, 47%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.5 Hz, 1H), 7.55 (d, J =8.3 Hz, 1H), 7.09 – 6.93 (m, 4H), 4.31 (d, J = 9.5 Hz, 2H), 4.19 (s, 2H), 3.88 (s, 3H), 1.47 (s, 9H).

[0699] Step 3: Synthesis of tert-butyl 3'-hydroxy-8'-methoxyspiro[azacyclobutane-3,6'-benzo[c]chromene]-1-carboxylate

[0700]

[0701] 3'-Chloro-8'-methoxyspiro[azacyclobutane-3,6'-benzo[c]chromene]-1-carboxylate (155 mg, 0.400 mmol, 1.0 equivalent) was dissolved in 1,4-dioxane (1.5 mL), and Pd2dba3 (9 mg, 0.04 mmol, 0.1 equivalent) and tBuXPhos (38 mg, 0.080 mmol, 0.2 equivalent) were added to the solution. The mixture was then degassed using an N2 balloon for 10 minutes. Subsequently, a solution of KOH (67 mg, 1.2 mmol, 3.0 equivalent) in water (0.3 mL) was added in a single addition, and the reaction mixture was placed in a preheated oil bath at 90 °C. Stirring continued overnight, and the reaction mixture was then cooled to room temperature, quenched with water, and the aqueous phase was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude substance was purified by rapid column chromatography (SiO2, 20 g, EtOAc in Hex 0%-30%) to obtain tert-butyl 3'-hydroxy-8'-methoxyspiro[azacyclobutane-3,6'-benzo[c]chromene]-1-carboxylate (120 mg, 0.330 mmol, 81%) as a light yellow solid. f = 0.3 (EtOAc / hexane 20%), a pale yellow solid. 1 H NMR (400 MHz, DMSO) δ 9.70 (s,1H), 7.68 (d, J = 8.6 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.05 (d, J = 2.6 Hz,1H), 7.00 (dd, J = 8.6, 2.6 Hz, 1H), 6.51 (dd, J = 8.5, 2.4 Hz, 1H), 6.45 (d,J = 2.4 Hz, 1H), 4.19 (d, J = 9.6 Hz, 2H), 4.10 (d, J = 9.7 Hz, 2H), 3.83 (s,3H), 1.41 (s, 9H).

[0702] Step 4: Synthesis of spiro[azacyclobutane-3,6'-benzo[c]chromene]-3',8'-diol hydrobromide

[0703]

[0704] BBr3 (0.54 mL, 0.54 mmol, 2.0 equivalent) was added to a solution of tert-butyl 3'-hydroxy-8'-methoxyspiro[azacyclobutane-3,6'-benzo[c]chromene]-1-carboxylate (100 mg, 0.270 mmol, 1.0 equivalent) in DCM (5 mL) at 0 °C, and the mixture was allowed to warm to room temperature overnight. Methanol was added to the mixture at 0 °C, the mixture was concentrated under vacuum and loaded onto silica, and then purified by FC elution with MeOH / DCM 0% to 8% to give spiro[azacyclobutane-3,6'-benzo[c]chromene]-3',8'-diol hydrobromide (40 mg, 44%) as a white solid. MS (ESI+): m / z = 256. 1 HNMR (400 MHz, DMSO) δ 9.76 (d, J = 22.3 Hz, 2H), 9.42 (s, 1H), 8.91 (s, 1H), 7.59 (t, J = 8.7 Hz, 2H), 7.06 (d, J = 2.4 Hz, 1H), 6.95 – 6.83 (m, 1H), 6.54 (dd, J = 8.4, 2.4 Hz, 1H), 6.49 (d, J = 2.3 Hz, 1H), 4.38 (dt, J = 12.6, 6.8Hz, 2H), 4.24 (ddd, J = 12.2, 7.4, 4.0 Hz, 2H).

[0705] I) Peptide-substituted ester "A" ring analogs

[0706] 3-Acetoxy-6-oxo-6, a common intermediate H -benzo[ c Synthesis of chromone-8-carboxylic acid

[0707]

[0708] Acetyl chloride (0.36 ml, 5.2 mmol) was added to a suspension of 3-hydroxy-6-oxo-6H-benzo[c]chromene-8-carboxylic acid (2 (600 mg, 2.34 mmol)) in THF (8 mL) at 0 °C, and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture remained a suspension (no substance dissolved). 1 M HCl was added to the suspension and stirred at room temperature for 30 minutes. The white suspension was filtered off, and the solid was washed with cold water and dried under vacuum to give (17) (400 mg, 57%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.72 (d, J = 1.8 Hz, 1H), 8.53 (d, J = 8.5Hz, 1H), 8.47 (d, J = 8.8 Hz, 1H), 8.39 (dd, J = 8.4, 1.9 Hz, 1H), 7.34 (d, J = 2.2 Hz, 1H), 7.26 (dd, J = 8.7, 2.3 Hz, 1H), 2.33 (s, 3H).

[0709] General procedures for peptide conjugation using FDPP and deprotection using potassium carbonate

[0710] Synthesis of 8-((2-morpholinoethyl)carbamoyl)-6-oxo-6H-benzo[c]chromene-3-yl ester (52)

[0711]

[0712] Step 1: Synthesis of 8-((2-morpholinoethyl)carbamoyl)-6-oxo-6H-benzo[c]chromene-3-yl ester of acetate

[0713]

[0714] DIPEA (0.15 mL, 0.86 mmol) was added to a solution of 3-acetoxy-6-oxo-6H-benzo[c]chromene-8-carboxylic acid (80 mg, 0.21 mmol) in DMF (2 mL), followed by the addition of pentafluorophenyl diphenylphosphonite (91 mg, 0.24 mmol). The mixture was stirred for 15 min, and then 2-morpholinoethyl-1-amine (28 mg, 0.21 mmol) was added dropwise while stirring continued for 1 h. The reaction mixture was extracted three times with a saturated solution of EtOAc and bicarbonate. The combined organic phases were dried over sodium sulfate and concentrated under vacuum. The crude product was purified by MPLC (SiO2, MeOH / DCM 0% to 10%) to give 8-((2-morpholinoethyl)carbamoyl)-6-oxo-6H-benzo[c]chromene-3-yl ester (45 mg, 51%).

[0715] R f = 0.3 (10% MeOH / DCM). 1H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 1.9 Hz, 1H), 8.39 (dd, J = 8.4, 2.0 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 8.10 (d, J =8.7 Hz, 1H), 7.20 (d, J = 2.2 Hz, 1H), 7.17 (dd, J = 8.6, 2.3 Hz, 1H), 7.00(s, 1H), 3.78 (t, J = 4.6 Hz, 4H), 3.63 (q, J = 5.6 Hz, 2H), 2.68 (d, J = 4.6Hz, 2H), 2.57 (s, 4H), 2.36 (s, 3H).

[0716] Step 2: Synthesis of 3-hydroxy-N-(2-morpholinoethyl)-6-oxo-6H-benzo[c]chromene-8-carboxamide

[0717]

[0718] Potassium carbonate (36 mg, 0.26 mmol) was added to a solution of 8-((2-morpholinoethyl)carbamoyl)-6-oxo-6H-benzo[c]chromene-3-yl ester (36 mg, 0.088 mmol) in MeOH at room temperature, and the reaction mixture was stirred at room temperature for 10 min. The mixture was loaded onto silica gel and purified by MPLC (SiO2, MeOH / dichloromethane 0% to 10%) to give 3-hydroxy- N -(2-morpholinoethyl)-6-oxo-6H-benzo[c]chromene-8-carboxamide UA0350 (23mg, 71%). R f = 0.2 (10% MeOH / DCM). 1¹H NMR (400 MHz, DMSO) δ 10.48 (s, 1H), 8.76 (t, J = 5.6 Hz, 1H), 8.68 (d, J = 1.9 Hz, 1H), 8.36 (d, J = 8.6 Hz, 1H), 8.29 (dd, J = 8.5, 1.9 Hz, 1H), 8.24 – 8.19 (m, 1H), 6.90 – 6.84 (m, 1H), 6.78 (d, J = 2.4 Hz, 1H), 3.58 (t, J = 4.6 Hz, 4H), 3.43 (q, J = 6.5 Hz, 2H), 2.43 (s, 4H) (Two missing protons were masked by the solvent).

[0719] Synthesis of 3-hydroxy-6-oxo-N-(2-(piperidin-1-yl)ethyl)-6H-benzo[c]chromene-8-carboxamide (53)

[0720]

[0721] Step 1: Synthesis of 6-oxo-8-((2-(piperidin-1-yl)ethyl)carbamoyl)-6H-benzo[c]chromene-3-yl ester of acetate

[0722]

[0723] The compound was prepared according to a general procedure starting with 3-acetoxy-6-oxo-6H-benzo[c]chromene-8-carboxylic acid (120 mg, 0.320 mmol), pentafluorophenyl-diphenylphosphonite (136 mg, 0.35 mmol), 2-(piperidin-1-yl)ethyl-1-amine (41 mg, 0.32 mmol), and DIPEA (0.224 ml, 1.29 mmol). After purification by MPLC (SiO2, MeOH / DCM 0% to 10%), a white solid 6-oxo-8-((2-(piperidin-1-yl)ethyl)carbamoyl)-6H-benzo[c]chromene-3-yl ester 19 (65 mg, 49%) was obtained. f = 0.3 (MeOH / DCM 10%). 1H NMR (400 MHz, CDCl3) δ 8.74 (d, J = 1.9 Hz, 1H), 8.40 (dd, J = 8.4, 1.9 Hz, 1H), 8.16 (d, J= 8.5 Hz, 1H), 8.09 (d, J = 8.7 Hz, 1H), 7.54 – 7.36 (m, 1H), 7.22 – 7.13 (m,2H), 3.63 (q, J = 5.5 Hz, 2H), 2.68 (t, J = 5.8 Hz, 2H), 2.56 (s, 4H), 2.36(s, 3H), 1.75 – 1.60 (m, 4H), 1.51 (s, 2H).

[0724] Step 2: Synthesis of 3-hydroxy-6-oxo-N-(2-(piperidin-1-yl)ethyl)-6H-benzo[c]chromene-8-carboxamide

[0725]

[0726] 3-hydroxy-6-oxo-N-(2-(piperidin-1-yl)ethyl)-6H-benzo[c]chromene-8-carboxamide was prepared from 6-oxo-8-((2-(piperidin-1-yl)ethyl)carbamoyl)-6H-benzo[c]chromene-8-carboxamide 19 (49 mg, 0.12 mmol) and potassium carbonate (50 mg, 0.36 mmol) according to GP5. After purification by MPLC (SiO2, MeOH / DCM 5% to 35%), 3-hydroxy-6-oxo-N-(2-(piperidin-1-yl)ethyl)-6H-benzo[c]chromene-8-carboxamide 53 (15 mg, 34%) was obtained as a white solid. f = 0.3 (MeOH / DCM 20%). 1 H NMR (400 MHz, DMSO) δ 10.52 (s, 1H), 8.83 (s, 1H), 8.68 (d, J = 1.9 Hz, 1H), 8.36 (d, J = 8.6 Hz, 1H), 8.29 (dd, J= 8.5, 1.9 Hz, 1H), 8.22 (d, J = 8.8 Hz, 1H), 6.87 (dd, J = 8.7, 2.4 Hz, 1H), 6.78 (d, J = 2.4 Hz, 1H), 3.47 (d, J = 21.5 Hz, 5H), 1.65 – 1.19 (m, 9H).

[0727] -Hydroxy-N-(2-(4-methylpiperazin-1-yl)ethyl)-6-oxo-6H-benzo[c]chromene-8-carboxamide (54) Synthesis

[0728]

[0729] Step 1: Synthesis of 8-((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)-6-oxo-6H-benzo[c]chromene-3-yl ester of acetate

[0730]

[0731] The compound was prepared from GP4 by 3-acetoxy-6-oxo-6H-benzo[c]chromene-8-carboxylic acid (120 mg, 0.260 mmol), pentafluorophenyl diphenylphosphonite (113 mg, 0.290 mmol), and DIPEA (0.187 ml, 1.070 mmol). After purification by MPLC (SiO2, MeOH / DCM 0% to 10%), 20 (73 mg, 59%) of 8-((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)-6-oxo-6H-benzo[c]chromene-3-yl ester was obtained as a white solid. f = 0.3 eluent (MeOH / DCM 10%). 1 NMR (400 MHz, CDCl3) δ 8.68 (d, J = 1.9 Hz, 1H), 8.39 (dd, J= 8.4, 2.0 Hz, 1H), 8.16 (d, J = 8.5 Hz, 1H), 8.09 (d, J = 8.7 Hz, 1H), 7.19(d, J = 2.2 Hz, 1H), 7.16 (dd, J = 8.6, 2.3 Hz, 1H), 7.11 (s, 1H), 3.62 (q, J= 5.6 Hz, 2H), 2.73 – 2.58 (m, 10H), 2.37 (d, J = 5.2 Hz, 6H).

[0732] Step 2: Synthesis of -hydroxy-N-(2-(4-methylpiperazin-1-yl)ethyl)-6-oxo-6H-benzo[c]chromene-8-carboxamide

[0733]

[0734] 3-hydroxy-N-(2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)-6-oxo-6H-benzo[c]chromene-3-yl ester 20 (60 mg, 0.14 mmol) and potassium carbonate (39 mg, 0.28 mmol) were prepared according to GP5. The 3-hydroxy-N-(2-(4-methylpiperazin-1-yl)ethyl)-6-oxo-6H-benzo[c]chromene-8-carboxamide was obtained after purification by MPLC (RP-C18, MeOH / water 0% to 95%).

[0735] R f = 0.1 eluent (MeOH / DCM 30%). 1 H NMR (400 MHz, DMSO) δ 8.75 (t, J = 5.6Hz, 1H), 8.68 (d, J = 1.8 Hz, 1H), 8.36 (d, J = 8.6 Hz, 1H), 8.29 (dd, J =8.5, 1.9 Hz, 1H), 8.22 (d, J = 8.9 Hz, 1H), 8.18 (s, 1H), 6.88 (dd, J = 8.7,2.4 Hz, 1H), 6.78 (d, J = 2.4 Hz, 1H), 3.47 – 3.40 (m, 2H), 2.48 – 2.30 (m,10H), 2.20 (s, 3H).

[0736] J) Ester "A" group analogs with reverse amide substitution

[0737] The synthesis of reverse amides is based on common intermediates described below.

[0738] Synthesis of N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-chloroacetamide

[0739]

[0740] Step 1: Synthesis of 8-amino-3-(benzyloxy)-6H-benzo[c]chromene-6-one

[0741]

[0742] 15 mg (864 mg, 3.80 mmol) of 8-amino-3-hydroxy-6H-benzo[c]chromen-6-one was dissolved in DMF (13 mL) and cooled to 0 °C. NaH (152 mg, 3.80 mmol) was then added in a single addition. After stirring for 15 minutes, benzyl chloride (0.44 mL, 3.80 mmol) was added dropwise, and the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was then quenched with a semi-saturated NaHCO3 solution and extracted with ethyl acetate (3 x 25 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by MPLC (SiO2, ethyl acetate / Hex 0%–50%) to give 738 mg (61%) of 8-amino-3-(benzyloxy)-6H-benzo[c]chromen-6-one as an ochre solid. 1 H NMR (400 MHz, DMSO) δ 8.02(dd, J = 17.2, 8.7 Hz, 2H), 7.51 – 7.34 (m, 6H), 7.14 (dd, J = 8.7, 2.6 Hz,1H), 7.06 – 6.95 (m, 2H), 5.79 (s, 2H), 5.19 (s, 2H).

[0743] Step 2: Synthesis of N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-chloroacetamide

[0744]

[0745] 8-Amino-3-(benzyloxy)-6H-benzo[c]chromene-6-one (738 mg, 2.33 mmol) was added to a solution of DMF (16 ml) containing TEA (0.324 ml, 2.56 mmol). The mixture was stirred at room temperature for 10 minutes. Chloroacetyl chloride (0.205 ml, 2.33 mmol) was added to the mixture, and the temperature was maintained between 0°C and 5°C. The resulting solution was then stirred at room temperature for 4–6 hours. The completion of the reaction was monitored by TLC. The solution was then added to crushed ice, and the separated precipitate was filtered and dried under vacuum. The product was recrystallized from methanol to give N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromene-8-yl)-2-chloroacetamide (833 mg, 91%) as a pale yellow solid. 1H NMR (400 MHz, DMSO) δ10.72 (s, 1H), 8.52 (d, J = 2.4 Hz, 1H), 8.31 (d, J = 8.8 Hz, 1H), 8.19 (d, J= 8.8 Hz, 1H), 8.03 (dd, J = 8.8, 2.4 Hz, 1H), 7.48 – 7.35 (m, 5H), 7.10 –7.06 (m, 2H), 5.22 (s, 2H), 4.32 (s, 2H).

[0746] Synthesis of N-(3-(hydroxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-morpholinoacetamide (55)

[0747]

[0748] Step 1: Synthesis of N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-morpholinoacetamide

[0749]

[0750] N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-chloroacetamide (60 mg, 0.15 mmol) was suspended in THF (5 ml), and potassium carbonate (42 mg, 0.30 mmol) was added in a single addition. A minimum amount of DMF (2–3 ml) was added dropwise to dissolve the suspension. Morpholine (0.014 mL, 0.17 mmol) was then added via syringe, and the reaction mixture was heated to 80 °C for 2 hours. After the starting material was completely consumed (as indicated by TLC), the reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The crude product was purified by MPLC (SiO2, MeOH in DCM 0%–10%) to give N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-morpholinoacetamide (46 mg, 0.10 mmol, 68%) as a white solid. 1H NMR (400 MHz, DMSO) δ 10.17 (s, 1H), 8.60 (d, J = 2.3 Hz,1H), 8.29 (d, J = 8.9 Hz, 1H), 8.21 (d, J = 8.7 Hz, 1H), 8.13 (dd, J = 8.8,2.4 Hz, 1H), 7.50 – 7.35 (m, 5H), 7.11 – 7.06 (m, 2H), 5.23 (s, 2H), 3.66 (t,J = 4.7 Hz, 4H), 3.19 (s, 2H), 2.55 – 2.52 (m, 4H).

[0751] Step 2: Synthesis of N-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)-2-morpholinoacetamide

[0752]

[0753] A solution of N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-morpholinoacetamide (40 mg, 0.090 mmol) and Pd(OH)₂ / C (7 mg, 0.009 mmol) in MeOH (2 ml) and DCM (2 ml) was stirred overnight under hydrogen atmosphere at atmospheric pressure. The reaction mixture was filtered through a diatomaceous earth mat and the solvent was evaporated under vacuum to give N-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)-2-morpholinoacetamide (25 mg, 78%) as a grayish-white solid. 1 ¹H NMR (400 MHz, DMSO) δ 10.26 (s, 1H), 10.14 (s, 1H), 8.57 (d, J = 2.3 Hz, 1H), 8.23 ​​(d, J = 9.0 Hz, 1H), 8.10 (d, J = 8.8 Hz, 2H), 6.83 (dd, J = 8.7, 2.5 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 3.65 (t, J = 4.8 Hz, 4H), 3.18 (s, 2H). (Clean, but four aliphatic protons are masked by the solvent)

[0754] Synthesis of N-(3-(hydroxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-(piperidin-1-yl)acetamide (56)

[0755]

[0756] Step 1: Synthesis of N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-(piperidin-1-yl)acetamide

[0757]

[0758] N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-chloroacetamide (200 mg, 0.510 mmol) was suspended in THF (5 ml), and potassium carbonate (140 mg, 1.02 mmol) was added in a single addition. A minimum amount of DMF (5–6 ml) was added to dissolve the suspension. Piperidine (0.055 mL, 0.56 mmol) was then added dropwise via syringe, and the reaction mixture was heated to 80 °C for 2 hours. After the starting material was completely consumed (as indicated by TLC), the reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The crude product was purified by rapid column chromatography (MeOH 0%–10% in DCM) to give N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-(piperidin-1-yl)acetamide (154 mg, 0.51 mmol, 69%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 10.10 (s, 1H), 8.61 (d, J =2.3 Hz, 1H), 8.28 (d, J = 8.9 Hz, 1H), 8.20 (d, J = 8.8 Hz, 1H), 8.12 (dd, J= 8.8, 2.4 Hz, 1H), 7.53 – 7.37 (m, 5H), 7.13 – 7.05 (m, 2H), 5.23 (s, 2H), 3.13 (s, 2H), 2.47 (d, J = 5.0 Hz, 4H), 1.58 (p, J = 5.6 Hz, 4H), 1.41 (q, J= 6.0 Hz, 2H).

[0759] Step 2: Synthesis of N-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)-2-(piperidin-1-yl)acetamide

[0760]

[0761] A solution of N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-(piperidin-1-yl)acetamide (154 mg, 0.350 mmol) and Pd(OH)₂ / C (34 mg, 0.035 mmol) in MeOH (3 ml) and DCM (3 ml) was stirred overnight under hydrogen atmosphere at atmospheric pressure. The reaction mixture was filtered through a diatomaceous earth mat and the solvent was evaporated under vacuum to give N-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)-2-(piperidin-1-yl)acetamide (95 mg, 77%) as a deep yellow solid. 1 H NMR (400 MHz, DMSO) δ 10.07 (s, 1H), 8.58 (d, J = 2.3 Hz, 1H), 8.21 (d, J = 8.9 Hz, 1H), 8.09 (dd, J = 8.8, 2.8 Hz, 2H), 6.83 (dd, J = 8.7,2.4 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 3.12 (s, 2H), 2.47 (d, J = 5.6 Hz, 4H), 1.59 (q, J = 5.6 Hz, 4H), 1.41 (q, J = 6.2 Hz, 2H).

[0762] MS (ESI+): m / z = 353

[0763] N-(3-(hydroxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-(4-methylpiperazin-1-yl)acetamide (57) Synthesis

[0764]

[0765] Step 1: Synthesis of N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-(piperidin-1-yl)acetamide

[0766]

[0767] N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-chloroacetamide (200 mg, 0.51 mmol) was suspended in THF (5 ml), and potassium carbonate (140 mg, 1.02 mmol) was added in a single addition. A minimum amount of DMF (5–6 ml) was added to dissolve the suspension. Then, 1-methylpiperazine (0.062 mL, 0.56 mmol) was added dropwise via syringe, and the reaction mixture was heated to 80 °C for 2 hours. After the starting material was completely consumed (as indicated by TLC), the reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The crude product was purified by rapid column chromatography (MeOH 0%–20% in DCM) to give N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-(piperidin-1-yl)acetamide (148 mg, 64%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 10.21 (s, 1H), 8.59 (d, J =2.3 Hz, 1H), 8.29 (d, J = 8.9 Hz, 1H), 8.20 (d, J = 8.8 Hz, 1H), 8.11 (dd, J= 8.8, 2.3 Hz, 1H), 7.55 – 7.30 (m, 5H), 7.14 – 7.03 (m, 2H), 5.23 (s, 2H), 3.17 (s, 2H), 2.68 – 2.66 (m, 8H), 2.39 (s, 3H).

[0768] Step 2: Synthesis of N-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)-2-(4-methylpiperazin-1-yl)acetamide

[0769]

[0770] A solution of N-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)-2-(piperidin-1-yl)acetamide (148 mg, 0.320 mmol), Pd(OH)₂ / C (40 mg, 0.032 mmol) in MeOH (3 ml) and DCM (3 ml) was stirred overnight under hydrogen atmosphere at atmospheric pressure. The reaction mixture was filtered through a diatomaceous earth mat, and the solvent was evaporated under vacuum to give N-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)-2-(4-methylpiperazin-1-yl)acetamide (69 mg, 58%) as a pale yellow solid.

[0771] MS (ESI+): m / z = 368.

[0772] K) Thiocarbonyl ester "A" group analogues

[0773] Synthesis of 3,8-dimethoxy-6H-benzo[c]chromene-6-thionone (58)

[0774]

[0775] A mixture of 3,8-dimethoxy-6H-benzo[c]chromene-6-one (as previously described) (140 mg, 0.154 mmol) and Lawesson's reagent (552 mg, 1.34 mmol) was refluxed overnight in toluene. TLC monitoring showed incomplete reaction; therefore, Lawesson's reagent (884 mg, 2.19 mmol) was added and reflux continued overnight. The reaction mixture was filtered off and the solvent was evaporated under vacuum. The crude product was purified by MPLC (SiO2, EtOAc / cyclohexane 0% to 25%) to give 3,8-dimethoxy-6H-benzo[c]chromene-6-thione (110 mg, 74%) as a yellow solid. f =0.4 (EtOAc / hexane 20%), yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 2.8 Hz,1H), 7.92 (dd, J = 8.9, 6.7 Hz, 2H), 7.39 (dd, J = 8.9, 2.8 Hz, 1H), 7.03 (d,J = 2.6 Hz, 1H), 6.99 – 6.95 (dd, 1H), 3.96 (s, 3H), 3.88 (s, 3H).

[0776] Synthesis of 3,8-dihydroxy-6H-benzo[c]thiochromene-6-one (59)

[0777]

[0778] 58 was prepared from 17 in four steps, following the procedure described in Org. Lett., Vol. 7, No. 3, 2005, 411-414. A product as a white solid was obtained. The analytical data were in perfect agreement with those previously reported in the literature.

[0779] Step 5: Synthesis of 3,8-dihydroxy-6H-benzo[c]thiochromene-6-one

[0780]

[0781] In a sealed tube, a mixture of lithium chloride (65 mg, 1.5 mmol) and 3,8-dimethoxy-6H-benzo[c]thiochromene-6-one (70 mg, 0.26 mmol) in DMF (1 mL) was heated at 130 °C for 2 days. The solvent was evaporated under vacuum, and the crude material was loaded onto silica gel and purified by MPLC (SiO2, methanol / dichloromethane 0% to 10%) to give 3,8-dihydroxy-6H-benzo[c]thiochromene-6-one (28 mg, 45%) as a yellow solid. 1 H NMR (400 MHz, DMSO)δ 10.19 (s, 2H), 8.32 (dd, J = 15.6, 9.1 Hz, 2H), 7.53 (d, J = 2.8 Hz, 1H), 7.31 (dd, J = 8.9, 2.9 Hz, 1H), 6.92 (dd, J = 8.9, 2.6 Hz, 1H), 6.87 (d, J =2.5 Hz, 1H).

[0782] Synthesis of 3,8-dihydroxy-6H-benzo[c]thiochromene 5,5-dioxide (62)

[0783]

[0784] Step 1: Synthesis of 3,8-dimethoxy-6H-benzo[c]thiochromene (60)

[0785]

[0786] LAH (35 mg, 0.91 mmol) was added to a solution of 3,8-dimethoxy-6H-benzo[c]thiochromene-6-one (250 mg, 0.910 mmol) in DCM (10 mL) at 0 °C, and the mixture was stirred overnight at room temperature. Post-treatment: 10 mL of Et₂O was added, followed by 0.05 mL of MeOH, 0.025 mL of NaOH 1N, and then 3 drops of water, and stirring was continued for 15 min. Na₂SO₄ was added, the reaction mixture was filtered off and concentrated under vacuum. The crude material was dissolved in DCM (5 mL) and cooled to -78 °C, TFA (0.354 mL, 4.59 mmol) was added dropwise and stirred at -78 °C for 60 min, then EtSi₃H (0.290 mL, 1.84 mmol) was added, and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was washed with a saturated solution of Na2CO3, and the organic layer was dried with sodium sulfate and concentrated under vacuum to obtain 230 mg of crude material. The crude material was ground in Et2O to obtain 160 mg, 67% white solid 3,8-dimethoxy-6H-benzo[c]thiochromene. 1 H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.7 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 2.7 Hz, 1H), 6.89 (dd, J = 8.6, 2.7 Hz, 1H), 6.81 (dd, J = 8.7, 2.7Hz, 1H), 6.77 (d, J = 2.7 Hz, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.81 (s, 2H).

[0787] Step 2: Synthesis of 3,8-dimethoxy-6H-benzo[c]thiochromene 5,5-dioxide (61)

[0788]

[0789] At 0℃ m-CPBA (150 mg, 0.62 mmol) was added to a solution of 3,8-dimethoxy-6H-benzo[c]thiochromene (80 mg, 0.31 mmol) in dichloromethane (4 ml), and the mixture was allowed to cool to room temperature for 2 hours. A 1 M Na₂S₂O₃ solution was added to the reaction mixture. The aqueous phase was extracted with EtOAc, and the organic phase was washed twice with a saturated solution of bicarbonate. The organic phase was dried over sodium sulfate. The organic phase was concentrated under vacuum, filtered through a diatomaceous earth mat using EtOAc, and then concentrated to give 3,8-dimethoxy-6H-benzo[c]thiochromene 5,5-dioxide (66 mg, 73%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.71 (dd, J = 8.7, 4.4 Hz, 2H), 7.52 (d, J =2.8 Hz, 1H), 7.20 (dd, J = 8.8, 2.7 Hz, 1H), 7.01 (dd, J = 8.7, 2.7 Hz, 1H), 6.83 (d, J = 2.7 Hz, 1H), 4.36 (s, 2H), 3.91 (s, 3H), 3.86 (s, 3H).

[0790] Step 3: Synthesis of 3,8-dihydroxy-6H-benzo[c]thiochromene 5,5-dioxide (62)

[0791]

[0792] BBr3 (0.76 ml, 0.76 mmol) was added to a solution of 3,8-dimethoxy-6H-benzo[c]thiochromene 5,5-dioxide (55 mg, 0.19 mmol) in 2 ml of DCM at -70 °C, and the mixture was allowed to warm to room temperature overnight. TLC showed two spots. Methanol was added to the mixture at 0 °C, the mixture was concentrated under vacuum and loaded onto silica, and then purified by MPLC (SiO2, MeOH / DCM 0% to 8%) to give 3,8-dihydroxy-6H-benzo[c]thiochromene 5,5-dioxide (23 mg, 46%) as a pale yellow solid. 1H NMR (400 MHz, DMSO) δ 10.29 (s, 1H), 9.87 (s,1H), 7.79 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.24 (d, J = 2.6 Hz,1H), 7.11 (dd, J = 8.6, 2.7 Hz, 1H), 6.86 (dd, J = 8.5, 2.6 Hz, 1H), 6.82 (d,J = 2.6 Hz, 1H), 4.65 (s, 2H).

[0793] Synthesis of 3,8-dihydroxy-6H-benzo[c]thiochromene 5-oxide (64)

[0794]

[0795] Step 1: Synthesis of 6H-benzo[c]thiochromene-3,8-diol (63)

[0796]

[0797] BBr3 (0.81 ml, 0.81 mmol) was added to a solution of 3,8-dimethoxy-6H-benzo[c]thiochromene (70 mg, 0.27 mmol) in 4 ml of DCM at 0 °C, and allowed to warm to room temperature overnight. The reaction mixture was poured into methanol at 0 °C and stirred for 10 minutes, then the solvent was evaporated under vacuum. The crude mixture was filtered through a diatomaceous earth mat to give 6H-benzo[c]thiochromene-3,8-diol (40 mg, 64%) as a gray solid. f = 0.75 (EtOAc / hexane 50 / 50). 1 H NMR(400 MHz, DMSO) δ 9.56 (s, 1H), 9.50 (s, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.44(d, J = 8.5 Hz, 1H), 6.75 – 6.64 (m, 4H), 5.76 (s, 1H), 3.78 (s, 2H).

[0798] Step 2: 3,8-Dihydroxy-6H-benzo[c]thiochromene 5-oxide (64) Synthesis

[0799]

[0800] A solution of NaIO4 (26 mg 0.12 mmol) in 0.3 mL of water was added to a solution of 6H-benzo[c]thiochromene-3,8-diol (28 mg, 0.12 mmol) in 1.5 mL of MeOH at room temperature, and the mixture was stirred overnight. A precipitate formed. TLC showed that the starting material was still present. Therefore, 0.2 equivalents of NaIO4 dissolved in 0.2 mL of water were added and stirring was continued; the reaction was incomplete but stopped. DCM was added to dissolve the precipitate, and the crude material was loaded onto silica and purified by MPLC (SiO2, MeOH / DCM 0% to 8%) to give 3,8-dihydroxy-6H-benzo[c]thiochromene 5-oxide (16 mg, 53%) as a gray solid. f = 0.3 (MeOH / DCM 5%). 1 H NMR (400 MHz, DMSO) δ 10.05 (s, 1H),9.72 (s, 1H), 7.64 (dd, J = 32.7, 8.5 Hz, 2H), 7.11 (d, J = 2.6 Hz, 1H), 7.00(dd, J = 8.5, 2.6 Hz, 1H), 6.83 (d, J = 6.7 Hz, 2H), 4.21 (dd, J = 90.8, 14.2Hz, 2H).

[0801] l) Ester "A" group with bicyclopentane substitution

[0802] Synthesis of 3-hydroxy-8-(3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl)-6H-benzo[c]chromen-6-one (65)

[0803]

[0804] Step 1: Synthesis of 3-(benzyloxy)-8-(3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)bicyclo[1.1.1]pent-1-yl)-6H-benzo[c]chromen-6-one

[0805]

[0806] Carefully add dropwise tert-butyllithium (1.7 M in pentane, 0.95 mL, 1.63 mmol) dropwise to a 2.7 mL anhydrous solution of 2-(3-bromobicyclo[1.1.1]pent-1-yl)-4,4-dimethyl-4,5-dihydrooxazole (192 mg, 0.788 mmol) cooled to -78 °C. Stir the reaction mixture at -78 °C for 60 minutes. Add dropwise a solution of ZnCl2 [0.5 M in THF] (1.78 mL, 0.89 mmol). Allow the reaction mixture to reach room temperature for 60 minutes. The resulting zincate solution was slowly added dropwise at room temperature under a nitrogen atmosphere to a mixture of 3-(benzyloxy)-8-bromo-6H-benzo[c]chromen-6-one (200 mg, 0.525 mmol), RuPhos (49 mg, 0.105 mmol), and tris(dibenzylacetone)dipalladium (48 mg, 0.052 mmol). The reaction vessel was sealed and heated at 60 °C for 12 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was adsorbed onto SiO2. The residue was purified by MPLC (SiO2, EtOAc / cyclohexane 0% to 20%) to give 3-(benzyloxy)-8-(3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)bicyclo[1.1.1]pent-1-yl)-6H-benzo[c]chromen-6-one (90 mg, 0.19 mmol, 37%). 1 H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 1.9 Hz, 1H), 7.94 (t, J= 8.4 Hz, 2H), 7.64 (dd, J = 8.2, 1.9 Hz, 1H), 7.45 – 7.35 (m, 5H), 6.99 (dd,J = 8.8, 2.6 Hz, 1H), 6.93 (d, J = 2.6 Hz, 1H), 5.14 (s, 2H), 3.97 (s, 2H), 2.40 (s, 6H), 1.31 (s, 6H).

[0807] Step 2: Synthesis of 3-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)bicyclo[1.1.1]pentane-1-carboxylic acid

[0808]

[0809] A suspension of 3-(benzyloxy)-8-(3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)bicyclo[1.1.1]pentan-1-yl)-6H-benzo[c]chromen-6-one (110 mg, 0.236 mmol) in 6 M HCl was heated overnight at 100 °C in a sealed tube. The reaction mixture was cooled to room temperature, filtered, washed with water, and dried under high vacuum. The crude material was purified by elution with FC eluent MeOH / DCM 0% to 8% to give 3-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromen-8-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (70 mg, 72%) as a beige solid. LCMS: massless TLC / MS 413. f = 0.5 (10%MeOH / DCM). 1 H NMR (400 MHz, DMSO) δ 12.45 (s, 1H), 8.29 (dd, J = 13.3, 8.6 Hz, 2H), 8.00 (d, J = 1.9 Hz, 1H), 7.81 (dd, J = 8.3, 1.9 Hz, 1H), 7.53 – 7.32 (m, 5H), 7.13 – 7.06 (m, 2H), 5.24 (s, 2H), 2.33 (s, 6H).

[0810] Step 3: Synthesis of 3-(benzyloxy)-8-(3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl)-6H-benzo[c]chromen-6-one

[0811]

[0812] A solution of borane dimethyl sulfide complex (0.22 ml, 0.44 mmol, 2 M in THF, 3.0 equivalent) was added to a solution of (3-(3-(benzyloxy)-6-oxo-6H-benzo[c]chromene-8-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (60 mg, 0.15 mmol, 1.0 equivalent) in 2 ml of THF at 0 °C, and stirred for 2 hours from 0 °C to room temperature. MeOH was added, and the crude material was loaded onto silica and purified by FC elution with MeOH / DCM 0% to 5% to give a beige solid of 3-(benzyloxy)-8-(3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl)-6H-benzo[c]chromene-6-one (47 mg, 0.12 mmol, 81%). f = 0.6 (MeOH / DCM 5%). 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 1.9 Hz, 1H), 7.94 (dd, J = 8.6, 3.3 Hz, 2H), 7.65 (dd, J = 8.3, 1.9 Hz, 1H), 7.42(dtdd, J = 14.5, 8.7, 6.9, 1.8 Hz, 5H), 6.99 (dd, J = 8.8, 2.6 Hz, 1H), 6.94 (d, J = 2.5 Hz, 1H), 5.30 (s, 1H), 5.14 (s, 2H), 3.74 (s, 2H), 2.07 (s, 6H).

[0813] Step 4: Synthesis of 3-hydroxy-8-(3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl)-6H-benzo[c]chromen-6-one

[0814]

[0815] 3-(benzyloxy)-8-(3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl)-6H-benzo[c]chromen-6-one (45 mg, 0.11 mmol) was dissolved in 3 ml MeOH and 1 ml DCM. PtO2 (6.4 mg, 0.023 mmol) was added and the mixture was hydrogenated at atmospheric pressure for 5 hours. The reaction mixture was filtered through a diatomaceous earth pad and concentrated under vacuum. The crude material was purified by 0% to 10% FC MeOH / DCM to give 3-hydroxy-8-(3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl)-6H-benzo[c]chromen-6-one (1.5 mg, 0.069 mmol, 62%) as a white solid. f = 0.3 (EtOAc / hexane 50%); R f = 0.5 (MeOH / DCM 10%). 1H NMR (400 MHz, DMSO) δ 10.31 (s, 1H), 8.21 (d, J = 8.3 Hz,1H), 8.14 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 1.9 Hz, 1H), 7.74 (dd, J = 8.2,1.9 Hz, 1H), 6.84 (dd, J = 8.7, 2.4 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 4.58(t, J = 5.5 Hz, 1H), 3.48 (d, J = 5.6 Hz, 2H), 1.96 (s, 6H).

[0816] 2. Synthesis of 7-membered urolithin A analogues

[0817] A) Lactone and ether "A" group analogs

[0818] Synthesis of 3,9-dihydroxydibenzo[c,e]oxacon-5(7H)-one (66)

[0819]

[0820] Step 1: Synthesis of 2-bromo-5-methoxybenzoate

[0821]

[0822] 2-Bromo-5-methoxybenzoic acid (11.6 g, 50.0 mmol, 1.00 equivalent) was dissolved in MeOH (250 mL), and the resulting solution was cooled to 0 °C in an ice bath. Stirring was continued at 0 °C for 10 min, and then SOCl2 (17.8 g, 150 mmol, 3.00 equivalent) was added dropwise through a dropping funnel. The reaction mixture was heated to room temperature, and once no starting material was observed (stirring overnight), all volatiles were evaporated, and the crude residue was dissolved in diethyl ether and filtered through silica. The filtrate was concentrated under vacuum to give methyl 2-bromo-5-methoxybenzoate (12.3 g, 49.9 mmol, 99%), which solidified as a colorless oil upon storage. NMR matched previous literature.

[0823] Step 2: Synthesis of dimethyl 4,4'-dimethoxy-[1,1'-biphenyl]-2,2'-dicarboxylate

[0824]

[0825] 2-Bromo-5-methoxybenzoate (12.3 g, 50 mmol, 1.00 equivalent) was dissolved in DMF (60 mL), and copper powder (12.7 g, 200 mmol, 4.00 equivalent) was added to the solution in one step. The reaction mixture was then heated to 150 °C overnight with stirring. After overnight stirring, the reaction mixture was cooled to room temperature and diluted with a large amount of water, then extracted with diethyl ether (3 x 100 mL). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered through silica, and concentrated under vacuum. The crude product was purified by rapid column chromatography (SiO2, 330 g, EtOAc in Hex 0%–30%) to give dimethyl 4,4'-dimethoxy-[1,1'-biphenyl]-2,2'-dicarboxylate (7.5 g, 23 mmol, 91%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ 7.49 (d, J = 2.7 Hz, 2H), 7.11 (d, J = 8.3 Hz, 2H), 7.06 (dd, J= 8.4, 2.7 Hz, 2H), 3.88 (s, 6H), 3.63 (s, 6H).

[0826] Step 3: Synthesis of 4,4'-dimethoxy-[1,1'-biphenyl]-2,2'-dicarboxylic acid

[0827]

[0828] Dimethyl 4,4'-dimethoxy-[1,1'-biphenyl]-2,2'-dicarboxylic acid (7.5 g, 23 mmol, 1.0 equivalent) was dissolved in MeOH (90 mL), and 2M NaOH aqueous solution (57 mL, 110 mmol, 5.0 equivalent) was added dropwise via a feeding funnel. The reaction mixture was refluxed over the weekend, then cooled to room temperature, and the reaction mixture was concentrated under vacuum. The remaining organic layer was slightly diluted with water and washed with DCM to remove all organic impurities. The layers were separated, and the aqueous layer was transferred to an Erlenmeyer flask and acidified to pH 1 with 2M KHSO4 under stirring. Stirring was continued for 30 min, and the precipitate formed was filtered, washed with water, and dried under high vacuum to give 4,4'-dimethoxy-[1,1'-biphenyl]-2,2'-dicarboxylic acid (6.64 g, 22.0 mmol, 97%) as a free-flowing white solid. 1 H NMR (400 MHz, DMSO) δ 12.43(s, 2H), 7.33 (d, J = 2.6 Hz, 2H), 7.14 – 7.01 (m, 4H), 3.82 (s, 6H).

[0829] Step 4: Synthesis of 3,9-dimethoxydibenzo[c,e]oxaphen-5,7-dione

[0830]

[0831] 4,4'-Dimethoxy-[1,1'-biphenyl]-2,2'-dicarboxylic acid (2.60 g, 10.1 mmol, 1.0 equivalent) was suspended in Ac₂O (50 mL) and the suspension was stirred overnight. The reaction was monitored by LCMS, and after stirring overnight, the starting material completely disappeared. The reaction mixture was then filtered and washed with diethyl ether to promote drying. The filter cake was dried under high vacuum to give 3,9-dimethoxydibenzo[c,e]oxaphen-5,7-dione (2.87 g, 10.1 mmol, 99%). The NMR was consistent with that reported in the literature.

[0832] Step 5: Synthesis of 3,9-dimethoxydibenzo[c,e]oxacon-5(7H)-one

[0833]

[0834] 3,9-Dimethoxydibenzo[c,e]oxaphen-5,7-dione (150 mg, 0.530 mmol, 1.0 equivalent) was suspended in DMF (5 mL) and cooled to 0 °C, followed by the slow addition of sodium borohydride (20 mg, 0.53 mmol, 1.0 equivalent). After 2 hours, the reaction mixture was poured into an aqueous HCl solution (6 M, 5 mL), diluted with water (10 mL), and stirred overnight. The product was precipitated overnight and filtered, then dissolved in DCM (25 mL) and washed with water (3 x 10 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, concentrated under vacuum, filtered through alkaline alumina with DCM, and dried to give 3,9-dimethoxydibenzo[c,e]oxaphen-5(7H)-one (85 mg, 0.31 mmol, 60%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.6 Hz, 1H), 7.50 – 7.44 (m, 2H), 7.19 (dd, J = 8.7,2.8 Hz, 1H), 7.05 (dd, J = 8.6, 2.7 Hz, 1H), 6.97 (d, J = 2.7 Hz, 1H), 4.98 (d, J = 28.5 Hz, 2H), 3.90 (s, 3H), 3.87 (s, 3H).

[0835] Step 5: Synthesis of 3,9-dihydroxydibenzo[c,e]oxacon-5(7H)-one

[0836]

[0837] 3,9-Dimethoxydibenzo[c,e]oxacon-5(7H)-one (75 mg, 0.28 mmol, 1.0 equivalent) was dissolved in DCM (6 mL) and cooled to 0°C in an ice bath while stirring for 5 minutes. Then, BBr3 (0.83 mL, 1 M in DCM, 0.83 mmol, 3.00 equivalent) was added dropwise to the reaction mixture. After the addition was complete, the mixture was left in an ice bath and allowed to warm to room temperature over 2 hours. When the starting material was no longer observable, the reaction mixture was added dropwise to 0°C cold methanol (10 mL) and stirred for another 10 minutes. The mixture was then concentrated and loaded onto silica for purification by rapid column chromatography (SiO2, 12 g, MeOH in DCM 0%-5%) to give 3,9-dihydroxydibenzo[c,e]oxazo-5(7H)-one (19 mg, 0.8 mmol, 28%) as a white solid. 1 H NMR (400 MHz, MeOD) δ 7.49(dd, J = 8.5, 7.3 Hz, 2H), 7.28 (d, J = 2.7 Hz, 1H), 7.14 (dd, J = 8.6, 2.7Hz, 1H), 6.97 (dd, J = 8.4, 2.6 Hz, 1H), 6.93 (d, J = 2.6 Hz, 1H), 4.96 (d, J = 19.5 Hz, 2H).

[0838] Synthesis of 5,7-dihydrodibenzo[c,e]oxazo-3,9-diol (67)

[0839]

[0840] Step 1: Synthesis of 3,9-bis((tert-butyldimethylsilyl)oxy)dibenzo[c,e]oxazo-5(7H)-one

[0841]

[0842] TBSCl (174 mg, 1.15 mmol, 2.2 equivalents) was dissolved in DCM (9 mL), and the resulting solution was cooled to 0 °C in an ice bath and stirred for 5 min. Imidazole (89 mg, 1.3 mmol, 2.5 equivalents) was then slowly added in portions, with stirring continued for 15 min after the addition was complete. Subsequently, 3,9-dihydroxydibenzo[c,e]oxazo-5(7H)-one (127 mg, 0.520 mmol, 1.0 equivalents) was added to the reaction mixture, which became heterogeneous after substrate addition. Therefore, DMF (1 mL) was added to homogenize the mixture. Stirring continued overnight at room temperature, followed by removal of DCM in a rotary evaporator, quenching of the remaining DMF solution with copious amounts of water, and extraction with diethyl ether (3 x 10 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to obtain a crude product. The crude product was further purified by MPLC (SiO2, 40 g, EtOAc in Hex 0%-20%) to obtain 3,9-bis((tert-butyldimethylsilyl)oxy)dibenzo[c,e]oxazo-5(7H)-one (199 mg, 0.42 mmol 82%) as a white solid. 1 H NMR (400 MHz, CDCl3)δ 7.47 – 7.38 (m, 3H), 7.10 (dd, J = 8.6, 2.6 Hz, 1H), 6.97 (dd, J = 8.4, 2.6Hz, 1H), 6.90 (d, J = 2.6 Hz, 1H), 4.88 (d, 2H), 1.01 (d, J = 1.9 Hz, 18H), 0.25 (d, J = 8.8 Hz, 12H).

[0843] Step 2: Synthesis of 3,9-bis((tert-butyldimethylsilyl)oxy)-5,7-dihydrodibenzo[c,e]oxacon

[0844]

[0845] 3,9-bis((tert-butyldimethylsilyl)oxy)dibenzo[c,e]oxazo-5(7H)-one (200 mg, 0.430 mmol, 1.0 equivalent) was dissolved in toluene (5 mL), and Et3SiH (0.27 mL, 1.7 mmol, 4.0 equivalent) was added in a single batch. The reaction mixture was heated to 70 °C in a preheated oil bath. After stirring at 70 °C for 5 min, InBr3 (15 mg, 0.04 mmol, 0.10 equivalent) was added in a single batch. A rapid color change to orange and gas emission were observed, and stirring was continued for 1 h. TLC showed no additional starting material. The reaction mixture was cooled, filtered, and the precipitate was washed with DCM. The filtrate was loaded onto silica and the crude substance was purified by rapid column chromatography (SiO2, 25 g, DCM in Hex 0%-10%) to obtain 3,9-bis((tert-butyldimethylsilyl)oxy)-5,7-dihydrodibenzo[c,e]oxazolidinium (194 mg, 0.430 mmol, 99%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 7.36 (d, J = 8.3 Hz, 2H), 6.94 (dd, J = 8.3, 2.5 Hz, 2H), 6.90 (d, J = 2.5 Hz, 2H), 4.31 (s, 4H), 1.01 (s, 18H), 0.24 (s, 12H).

[0846] Step 3: Synthesis of 5,7-dihydrodibenzo[c,e]oxazo-3,9-diol

[0847]

[0848] 3,9-bis((tert-butyldimethylsilyl)oxy)-5,7-dihydrodibenzo[c,e]oxazopyrrol (194 mg, 0.430 mmol, 1.0 equivalence) was dissolved in MeOH (12 mL), and the reaction mixture was cooled to 0 °C. AcCl (167 mg, 2.12 mmol, 5.0 equivalence) was added dropwise via syringe. After the addition was complete, the reaction mixture was allowed to reach room temperature and stirred over the weekend. The reaction mixture was quenched with water and extracted into diethyl ether (3 x 15 mL). The combined organic layers were washed with NaHCO3 and brine, dried over Na2SO4, filtered through silica, washed with diethyl ether, and concentrated to give pure 5,7-dihydrodibenzo[c,e]oxazopyrrol-3,9-diol (71 mg, 0.31 mmol, 73%) as a white solid. 1H NMR (400 MHz, DMSO) δ 9.55 (s, 2H), 7.30 (d, J = 8.2 Hz, 2H), 6.87 (dd, J = 8.2,2.6 Hz, 2H), 6.84 (d, J = 2.5 Hz, 2H), 4.13 (s, 4H).

[0849] B) Amine "A" group analogues

[0850] Synthesis of 6-methyl-6,7-dihydro-5H-dibenzo[c,e]azapyro-3,9-diol (68)

[0851]

[0852] Step 1: Synthesis of 4,4'-dimethoxy-2'-(methylcarbamoyl)-[1,1'-biphenyl]-2-carboxylic acid

[0853]

[0854] 3,9-Dimethoxydibenzo[c,e]oxazo-5,7-dione (569 mg, 2.00 mmol, 1.0 equivalent) was dissolved in CHCl3 (20 mL), and 2M MeNH2 solution (1.20 mL, 2.40 mmol, 1.2 equivalent) was added to the resulting solution in a single addition. Upon addition of MeNH2, a precipitate formed, and the complete disappearance of the starting material was observed by LCMS. The precipitate was filtered through a glass frit (Por. 4), and the residue was dried under vacuum to give pure 4,4'-dimethoxy-2'-(methylcarbamoyl)-[1,1'-biphenyl]-2-carboxylic acid (631 mg, 2.00 mmol, 99%) as a light brown solid. LCMS showed a clean product, which was further used in the next step.

[0855] Step 2: Synthesis of 3,9-dimethoxy-6-methyl-5H-dibenzo[c,e]azapyro-5,7(6H)-dione

[0856]

[0857] 4,4'-Dimethoxy-2'-(methylcarbamoyl)-[1,1'-biphenyl]-2-carboxylic acid (631 mg, 2.00 mmol, 1.00 equivalent) was suspended in Ac2O (20 mL), and KOAc (393 mg, 4.00 mmol, 2.00 equivalent) was added in a single batch. The reaction mixture was stirred overnight, and LCMS showed complete conversion of the starting material. Therefore, the suspension was filtered, and the residue was dried under high vacuum to give 3,9-dimethoxy-6-methyl-5H-dibenzo[c,e]azapyro-5,7(6H)-dione (595 mg, 2.00 mmol, 99%). 1 H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 8.7 Hz, 2H), 7.38 (d, J= 2.8 Hz, 2H), 7.16 (dd, J = 8.7, 2.8 Hz, 2H), 3.90 (s, 6H), 3.54 (s, 3H).

[0858] Step 3: Synthesis of 3,9-dimethoxy-6-methyl-6,7-dihydro-5H-dibenzo[c,e]azapyrrolidone

[0859]

[0860] 3,9-Dimethoxy-6-methyl-5H-dibenzo[c,e]azapyrrolidone (541 mg, 1.82 mmol, 1.0 equivalence) was suspended in THF (15 mL), and BH3*THF (7.28 mL, 7.28 mmol, 1 M, 4.0 equivalence) was added dropwise over 5 minutes at room temperature. After the addition was complete, the reaction mixture was heated to reflux and stirred overnight. The reaction mixture was then quenched with MeOH (200 mL) and stirred for another 30 minutes at 50 °C. The evaporation was then evaporated and the crude substance was purified by MPLC (SiO2, 40 g, MeOH in EtOAc 0%-50%) to give 3,9-dimethoxy-6-methyl-6,7-dihydro-5H-dibenzo[c,e]azapyrrolidone (485 mg, 1.80 mmol, 99%) as an orange-brown solid. 1 H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.4 Hz, 2H), 6.97 (dd, J = 8.4, 2.7 Hz, 2H), 6.91 (d, J= 2.7 Hz, 2H), 3.86 (s, 6H), 3.37 (s, 4H), 2.48 (s, 3H).

[0861] Step 4: Synthesis of 6-methyl-6,7-dihydro-5H-dibenzo[c,e]azapyro-3,9-diol

[0862]

[0863] 3,9-Dimethoxy-6-methyl-6,7-dihydro-5H-dibenzo[c,e]azapyridine (376 mg, 1.40 mmol, 1.0 equivalent) was dissolved in DCM (10 mL) and cooled to 0°C in an ice bath while stirring for 5 minutes. Then, BBr3 (6.28 mL, 1 M in DCM, 6.28 mmol, 4.5 equivalent) was added dropwise to the reaction mixture. After the addition was complete, the mixture was left in an ice bath and allowed to warm to room temperature over 2 hours. When the starting material was no longer observable, the reaction mixture was added dropwise to 0°C cold methanol (10 mL) and stirred for another 10 minutes. The mixture was then concentrated and loaded onto silica for purification by rapid column chromatography (SiO2, 40 g, MeOH in DCM 0%-5%) to give 6-methyl-6,7-dihydro-5H-dibenzo[c,e]azapyro-3,9-diol (190 mg, 0.790 mmol, 56%) as a pale orange solid. 1 H NMR(400 MHz, DMSO) δ 10.92 – 10.62 (m, 2H), 7.37 (d, J = 8.2 Hz, 2H), 7.10 –6.93 (m, 4H), 3.16 (s, 4H), 2.83 (d, J = 4.6 Hz, 3H).

[0864] Synthesis of 2,2'-bis(bromomethyl)-4,4'-dimethoxy-1,1'-biphenyl as a common intermediate

[0865] Step 1: Synthesis of (4,4'-dimethoxy-[1,1'-biphenyl]-2,2'-diyl)diethanol

[0866]

[0867] LiAlH4 (251 mg, 6.61 mmol) was carefully added to a solution of 4,4'-dimethoxy-[1,1'-biphenyl]-2,2'-dicarboxylic acid (described above) (1.00 g, 3.30 mmol) in THF (8 ml) at 0 °C, and then refluxed for 4 h (the reaction was monitored by TLC). After Fieser post-treatment, 850 mg of (4,4'-dimethoxy-[1,1'-biphenyl]-2,2'-diyl)diethanol (810 mg, 2.90 mmol, 89%) was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.08 – 7.03 (m, 4H), 6.87 (dd, J = 8.3, 2.8 Hz, 2H), 4.40 – 4.28 (m,4H), 3.86 (s, 6H), 2.20 (s, 2H).

[0868] Step 2: Synthesis of 2,2'-bis(bromomethyl)-4,4'-dimethoxy-1,1'-biphenyl

[0869]

[0870] A solution of PPh3 (3.06 g, 11.7 mmol) in CH2Cl2 (20 mL) was added fractionally to a solution of (4,4'-dimethoxy-[1,1'-biphenyl]-2,2'-diyl)diethanol (0.800 g, 2.92 mmol) and CBr4 (4.84 g, 14.6 mmol) in CH2Cl2 (40 mL) cooled to 0 °C under an argon atmosphere. The reaction mixture was stirred at room temperature for 48 hours, then concentrated and purified by MPLC (EtOAc / hexane: 0% to 10%) on silica gel to give a colorless oil of 2,2'-bis(bromomethyl)-4,4'-dimethoxy-1,1'-biphenyl (0.88 g, 2.20 mmol, 75%). f = 0.5 (EtOAc / cyclohexane 10%). 1 H NMR (400 MHz, CDCl3) δ 7.17 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 2.7Hz, 2H), 6.91 (dd, J = 8.4, 2.7 Hz, 2H), 4.31 (d, J = 10.0 Hz, 2H), 4.17 (d,J = 10.0 Hz, 2H), 3.87 (s, 6H).

[0871] Synthesis of 6-cyclobutyl-6,7-dihydro-5H-dibenzo[c,e]azapyro-3,9-diol (69)

[0872]

[0873] Step 1: Synthesis of 6-cyclobutyl-3,9-dimethoxy-6,7-dihydro-5H-dibenzo[c,e]azapyrrolidone

[0874]

[0875] Cyclobutylamine (28 mg, 0.39 mmol) was added to a suspension of 2,2'-bis(bromomethyl)-4,4'-dimethoxy-1,1'-biphenyl (130 mg, 0.325 mmol) and sodium carbonate (138 mg, 130 mmol) in 2 mL of THF, and the mixture was refluxed in THF for 3 hours. The reaction mixture was filtered off and the solvent was removed under vacuum to give a colorless oily substance, 6-cyclobutyl-3,9-dimethoxy-6,7-dihydro-5H-dibenzo[c,e]azapyrrolidone (100 mg, 0.323 mmol, 99%). f =0.3 (EtOAc). 1 H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.4 Hz, 2H), 6.95 (dd, J =8.4, 2.7 Hz, 2H), 6.87 (d, J = 2.7 Hz, 2H), 3.86 (s, 6H), 3.28 (s, 4H), 3.12(p, J = 8.0 Hz, 1H), 2.21 – 2.12 (m, 2H), 2.05 (d, J = 9.6 Hz, 2H), 1.82 –1.65 (m, 2H).

[0876] Step 2: Synthesis of 6-cyclobutyl-6,7-dihydro-5H-dibenzo[c,e]azapyro-3,9-diol

[0877]

[0878] BBr3 (0.87 ml, 0.87 mmol, 1.0 M in DCM) was added to a solution of 6-cyclobutyl-3,9-dimethoxy-6,7-dihydro-5H-dibenzo[c,e]azapyridine (90 mg, 0.29 mmol) in 3 ml of anhydrous DCM at 0 °C, and stirring was continued overnight. 2 ml of methanol was added at 0 °C, and the mixture was evaporated under vacuum. The crude product was purified by rapid chromatography on silica gel (methanol / DCM: 0% to 10%) to give 6-cyclobutyl-6,7-dihydro-5H-dibenzo[c,e]azapyridine-3,9-diol hydrobromide (35 mg, 0.97 mmol, 33%) as a beige solid. f = 0.3 (MeOH / DCM 8%). MS (ESI+): m / z= 282. 1H NMR (400 MHz, DMSO) δ 10.72 (s, 1H), 9.85 (s, 2H), 7.37 (d, J = 9.0Hz, 2H), 6.99 (dd, J = 5.9, 2.8 Hz, 4H), 3.89 (s, 2H), 3.74 (d, J = 8.7 Hz,1H), 3.51 (s, 2H), 2.37 – 2.21 (m, 4H), 1.75 (dt, J = 28.5, 10.0 Hz, 2H).

[0879] Synthesis of 6-isopropyl-6,7-dihydro-5H-dibenzo[c,e]azapyro-3,9-diol (70)

[0880]

[0881] Step 1: Synthesis of 6-isopropyl-3,9-dimethoxy-6,7-dihydro-5H-dibenzo[c,e]azapyrrolidone

[0882]

[0883] Isopropylamine (27 mg, 0.45 mmol) was added to a suspension of 2,2'-bis(bromomethyl)-4,4'-dimethoxy-1,1'-biphenyl (150 mg, 0.375 mmol) and sodium carbonate (159 mg, 1.50 mmol) in THF (2 mL), and the mixture was refluxed in THF for 3 hours. The reaction mixture was filtered off and the solvent was removed under vacuum to give 6-isopropyl-3,9-dimethoxy-6,7-dihydro-5H-dibenzo[c,e]azapyrrolidone (110 mg, 0.323 mmol, 99%) as a colorless oil. 1 HNMR (400 MHz, CDCl3) δ 7.44 – 7.33 (m, 2H), 6.99 (d, J = 7.3 Hz, 4H), 3.87(s, 6H), 3.65 (s, 4H), 3.14 – 3.00 (m, 1H), 1.38 (d, J = 6.4 Hz, 6H).

[0884] Step 2: Synthesis of 6-isopropyl-6,7-dihydro-5H-dibenzo[c,e]azapyro-3,9-diol

[0885]

[0886] BBr3 (1.87 ml, 1.87 mmol, 1.0 M in DCM) was added to a solution of 6-isopropyl-3,9-dimethoxy-6,7-dihydro-5H-dibenzo[c,e]azapyrrol (111 mg, 0.370 mmol) in 3 ml of anhydrous DCM at 0 °C, and stirring was continued overnight. 2 ml of methanol was added at 0 °C, and the mixture was evaporated under vacuum. The crude product was purified by rapid chromatography on silica gel (methanol / DCM: 0% to 10%) to give 6,6-isopropyl-6,7-dihydro-5H-dibenzo[c,e]azapyrrol-3,9-diol (35 mg, 0.97 mmol, 35%) as a beige solid. f = 0.3 (MeOH / DCM 8%). 1 H NMR (400 MHz, DMSO) δ 10.19 (s, 1H), 9.84 (s, 2H), 7.37 (d, J = 8.3 Hz, 2H), 7.05 (d, J =2.6 Hz, 2H), 6.99 (dd, J = 8.4, 2.5 Hz, 2H), 3.92 (s, J = 4.3 Hz, 4H), 3.63 –3.51 (m, 1H), 1.40 (d, J = 6.5 Hz, 6H).

[0887] C) Imidamine "A" group analogs

[0888] Synthesis of 3,9-dihydroxy-5H-dibenzo[c,e]azapyro-5,7(6H)-dione (71)

[0889]

[0890] Step 1: Synthesis of 2'-carbamoyl-4,4'-dimethoxy-[1,1'-biphenyl]-2-carboxylic acid

[0891]

[0892] 3,9-Dimethoxydibenzo[c,e]oxaphen-5,7-dione (100 mg, 0.350 mmol, 1.0 equivalent) was suspended in 25% NH3 aqueous solution (0.70 mL, 0.42 mmol, 1.2 equivalent) for 30 minutes until the starting material was confirmed to have completely disappeared by LCMS (too polar to be monitored by TLC). The reaction mixture was filtered through a glass frit (Por. 4) and the residue was dried under vacuum to give pure 2'-carbamoyl-4,4'-dimethoxy-[1,1'-biphenyl]-2-carboxylic acid (106 mg, 0.350 mmol, 99%) as a white solid. LCMS showed a clean product after filtration, and this product was used in the next step without further purification.

[0893] Step 2: Synthesis of 3,9-dimethoxy-5H-dibenzo[c,e]azapyro-5,7(6H)-dione

[0894]

[0895] 2'-Carbamoyl-4,4'-dimethoxy-[1,1'-biphenyl]-2-carboxylic acid (106 mg, 0.350 mmol, 1.0 equivalent) was suspended in Ac2O (4 mL), and KOAc (69 mg, 0.70 mmol, 2.0 equivalent) was added in a single batch. The reaction mixture was stirred overnight at room temperature and then filtered through a small glass frit (Por. 4). The precipitate was dried under vacuum to give 3,9-dimethoxy-5H-dibenzo[c,e]azapyro-5,7(6H)-dione (65 mg, 0.23 mmol, 65%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 11.69 (s, 1H), 7.71 (dd, J = 8.7, 1.5 Hz, 2H), 7.40 – 7.36 (m, 2H), 7.31 (dt, J = 8.8, 2.4 Hz, 2H), 3.86 (s, 6H).

[0896] Step 3: Synthesis of 3,9-dihydroxy-5H-dibenzo[c,e]azapyro-5,7(6H)-dione

[0897]

[0898] 3,9-Dimethoxy-5H-dibenzo[c,e]azapyro-5,7(6H)-dione (100 mg, 0.350 mmol, 1.0 equivalent) was dissolved in DCM (2 mL) and cooled to 0°C in an ice bath while stirring for 5 minutes. Then, BBr3 (1.41 mL, 1 M in DCM, 1.41 mmol, 4.0 equivalent) was added dropwise to the reaction mixture. After the addition was complete, the mixture was left in an ice bath and allowed to warm to room temperature over 2 hours. When the starting material was no longer observable, the reaction mixture was added dropwise to 0°C cold methanol (10 mL) and stirred for another 10 minutes. The mixture was then concentrated and loaded onto silica for purification by rapid column chromatography (SiO2, 12 g, MeOH in DCM 0%-5%) to give 3,9-dihydroxy-5H-dibenzo[c,e]azapyro-5,7(6H)-dione (56 mg, 0.22 mmol, 62%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 9.66 (s, 2H), 7.13 (d, J = 2.6 Hz, 1H), 7.03 (s, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.93 (s, 1H), 6.90 (dd, J = 8.3, 2.6 Hz, 1H), 6.87 –6.84 (m, 2H), 6.77 (dd, J = 8.2, 2.6 Hz, 1H).

[0899] D) Analogs of thioethers and sulfones with "A" groups

[0900] Synthesis of 5,7-dihydrodibenzo[c,e]thiazo-3,9-diol (72)

[0901] Step 1: Synthesis of 3,9-dimethoxy-5,7-dihydrodibenzo[c,e]thiazolide

[0902]

[0903] A mixture of 2,2'-bis(bromomethyl)-4,4'-dimethoxy-1,1'-biphenyl (as described above) (220 mg, 0.55 mmol) and sodium sulfide hydrate (69 mg, 0.71 mmol) in DMF (3 mL) was heated at 100 °C for 20 min. After cooling, the mixture was poured into water (10 mL), and the precipitate was filtered and washed with water (2 x 3 mL). The precipitate was dissolved in CHCl3 (15 mL), and the solution was dried over Na2SO4 and the solvent was evaporated under vacuum to give 3,9-dimethoxy-5,7-dihydrodibenzo[c,e]thiopyroxene (140 mg, 0.510 mmol, 93%) as a pale yellow solid.

[0904] 1 H NMR (400 MHz, CDCl3) δ 7.19 (d, J = 8.4 Hz, 2H), 6.91 (dd, J = 8.3,2.7 Hz, 2H), 6.87 (d, J = 2.6 Hz, 2H), 3.86 (s, 6H), 3.56 (d, J = 12.7 Hz, 2H), 3.27 (s, 2H).

[0905] Step 2: Synthesis of 5,7-dihydrodibenzo[c,e]thiazo-3,9-diol

[0906]

[0907] A BBr3 solution (0.59 ml, 0.59 mmol, 1 M in DCM) was added to a solution of 3,9-dimethoxy-5,7-dihydrodibenzo[c,e]thiazopyrrolizidine (54 mg, 0.20 mmol) in 2 ml of DCM at -78 °C, and the mixture was stirred overnight at room temperature. Methanol (5 ml) was added at 0 °C, and the solvent was removed under vacuum. The crude product was purified by MPLC (SiO2, MeOH / DCM 0% to 8%) to give 5,7-dihydrodibenzo[c,e]thiazopyrrolizidine-3,9-diol (18 mg, 0.074 mmol, 37%) as a beige solid. f = 0.3 (MeOH / DCM 5%). 1 H NMR (400 MHz, DMSO) δ 9.46 (s, 2H), 7.09 – 6.91 (m, 2H), 6.78 – 6.67 (m, 4H), 3.28 (s, 4H).

[0908] Synthesis of 3,9-dihydroxy-5,7-dihydrodibenzo[c,e]thiazolinone 6,6-dioxide (73)

[0909]

[0910] Step 1: Synthesis of 3,9-dimethoxy-5,7-dihydrodibenzo[c,e]thiazolinone 6,6-dioxide

[0911]

[0912] 3,9-Dimethoxy-5,7-dihydrodibenzo[c,e]thiazophene (90 mg, 0.33 mmol) was added to DCM (2 ml) at 0 °C, and the reaction mixture was stirred overnight at room temperature. 1M Na₂S₂O₃ solution was added, and the mixture was stirred for 10 min. A saturated NaHCO₃ solution was then added, and the mixture was extracted twice with the NaHCO₃ solution. The organic phase was dried over sodium sulfate, filtered, and evaporated under vacuum. The crude product was purified by MPLC (SiO₂, EtOAc / cyclohexane 0% to 30%) to give 3,9-dimethoxy-5,7-dihydrodibenzo[c,e]thiazophene 6,6-dioxide (90 mg, 0.30 mmol, 89%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.4Hz, 2H), 7.03 (dd, J = 8.4, 2.6 Hz, 2H), 6.99 (d, J = 2.6 Hz, 2H), 4.07 –3.93 (q, 4H), 3.88 (s, 6H).

[0913] Step 2: Synthesis of 3,9-dihydroxy-5,7-dihydrodibenzo[c,e]thiazolinone 6,6-dioxide

[0914]

[0915] A solution of BBr3 (1.0 mL, 1.0 mmol, 1 M in DCM, 3.5 equivalences) was added to a solution of 3,9-dimethoxy-5,7-dihydrodibenzo[c,e]thiazophene 6,6-dioxide (90 mg, 0.30 mmol, 1.0 equivalences) in DCM (2 mL) at 0 °C, and stirring was continued overnight at room temperature. Methanol (5 mL) was added at 0 °C, and the solvent was removed under vacuum. The crude material was purified by MPLC (EtOAc / Hex 0% to 70%) to give 3,9-dihydroxy-5,7-dihydrodibenzo[c,e]thiazophene 6,6-dioxide (46 mg, 0.17 mmol, 56%) as a beige solid. f= 0.3 (MeOH / DCM 5%). 1 H NMR (400MHz, DMSO) δ 9.76 (s, 2H), 7.26 (d, J = 8.1 Hz, 2H), 6.94 – 6.83 (m, 4H), 4.29 (d, J = 13.7 Hz, 2H), 3.73 (d, J = 13.7 Hz, 2H)

[0916] E) Amide "A" group analogs

[0917] Synthesis of 3,9-dihydroxy-6,7-dihydro-5H-dibenzo[c,e]azapyro-5-one (74)

[0918]

[0919] Step 1: Synthesis of 2-(azidomethyl)-1-bromo-4-methoxybenzene

[0920]

[0921] 1-Bromo-2-(bromomethyl)-4-methoxybenzene (5.00 g, 17.9 mmol, 1.0 equivalent) was dissolved in DMF (60 mL), and NaN3 (5.81 g, 89.3 mmol, 5.0 equivalent) was added in a single batch. The reaction mixture was then heated to 90 °C and stirred overnight. After stirring overnight, the reaction mixture was cooled to room temperature, quenched with water (300 mL), and extracted with cyclohexane (3 x 75 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum to give pure 2-(azidomethyl)-1-bromo-4-methoxybenzene (4.32 g, 17.8 mmol, 99%) as a colorless oil. 1 H NMR (400 MHz, CDCl3)δ 7.47 (d, J = 8.8 Hz, 1H), 6.95 (d, J = 3.0 Hz, 1H), 6.76 (dd, J = 8.8, 3.0 Hz, 1H), 4.45 (s, 2H), 3.81 (s, 3H).

[0922] Step 2: Synthesis of 5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane-2-yl)benzoate

[0923]

[0924] Methyl 2-bromo-5-methoxybenzoate (10.0, 40.8 mmol, 1.0 equivalent) was dissolved in 1,4-dioxane (140 mL). B2pin2 (11.4 g, 44.9 mmol, 1.1 equivalent), Pd(dppf)Cl2 (1.49 g, 2.04 mmol, 0.1 equivalent), and KOAc (12.0 g, 122 mmol, 3.0 equivalent) were added to this solution, and the reaction mixture was repeatedly degassed using an N2 balloon for 10 minutes. The reaction mixture was then placed in an oil bath preheated to 85 °C and stirred overnight. After complete consumption of the starting materials, the reaction mixture was cooled to room temperature and then quenched with water. The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by MPLC (SiO2, 240 g, EtOAc in Hex 0%-15%) to obtain methyl 5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzoate (9.51 g, 32.6 mmol, 78%), which was a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.27(d, J = 6.1 Hz, 1H), 7.09 (s, 1H), 6.88 (dd, J = 8.1, 2.6 Hz, 1H), 3.73 (s, 3H), 3.67 (s, 3H), 1.23 (s, 12H).

[0925] Step 3: Synthesis of (4-methoxy-2-(methoxycarbonyl)phenyl)boronic acid

[0926]

[0927] 5-Methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane-2-yl)benzoate (1.33 g, 4.55 mmol, 1.0 equivalent) was dissolved in a mixture of acetone (23 mL) and water (23 mL), and NH4OAc (1.05 g, 13.7 mmol, 3.0 equivalent) and NaIO4 (2.92 g, 13.7 mmol, 3.0 equivalent) were added in a single batch. After the addition was complete, the mixture was slightly warmed and stirred overnight. After one hour of initial material reaction (as indicated by TLC), the reaction mixture was filtered and the white precipitate was washed with acetone. The mother liquor was concentrated to give pure (4-methoxy-2-(methoxycarbonyl)phenyl)boronic acid (590 mg, 2.81 mmol, 62%) as a white solid. Analytical data matched those in the literature.

[0928] Step 4: Synthesis of 2'-(azidomethyl)-4,4'-dimethoxy-[1,1'-biphenyl]-2-carboxylate

[0929]

[0930] To a 20 mL Biotage MW vial, add (4-methoxy-2-(methoxycarbonyl)phenyl)boronic acid (563 mg, 2.68 mmol, 1.10 equivalence), 2-(azidomethyl)-1-bromo-4-methoxybenzene (590 mg, 2.44 mmol, 1.0 equivalence), Pd(OAc)₂ (27 mg, 0.12 mmol, 0.05 equivalence), and XPhos (116 mg, 0.24 mmol, 0.1 equivalence), and dissolve all reagents in THF (15 mL). Degas the reaction mixture for 10 minutes using an N₂ balloon, and then add dropwise a solution of Na₂CO₃ (775 mg, 7.31 mmol, 3.0 equivalence) in water (5 mL) at room temperature. After the addition is complete, heat the reaction mixture in an oil bath to 80 °C and continue stirring overnight. After stirring overnight, the reaction mixture was cooled to room temperature and quenched with water. The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crude product was purified by MPLC (SiO₂, 25 g, EtOAc in Hex 0%–20%) to give methyl 2'-(azidomethyl)-4,4'-dimethoxy-[1,1'-biphenyl]-2-carboxylate (367 mg, 1.12 mmol, 46%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 2.7 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.08 (dd, J = 8.4, 2.8 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 2.6 Hz, 1H), 6.87 (dd, J = 8.4, 2.7 Hz, 1H), 4.09 (d, J = 3.1 Hz, 2H), 3.89 (s, 3H), 3.86 (s, 3H), 3.63 (s, 3H).

[0931] Step 5: Synthesis of 3,9-dimethoxy-6,7-dihydro-5H-dibenzo[c,e]azapyro-5-one

[0932]

[0933] 2'-(azidomethyl)-4,4'-dimethoxy-[1,1'-biphenyl]-2-carboxylate (50 mg, 0.15 mmol, 1.0 equivalent) was dissolved in MeOH (8 mL), and Pd(OH)₂ / C (16 mg, 0.02 mmol, 0.15 equivalent) and NaOMe (33 mg, 0.15 mmol, 1.0 equivalent) were added to the solution. The solution was degassed three times with N₂, followed by three hydrogen exchange atmospheres. The reaction mixture was stirred overnight at room temperature, filtered through a diatomaceous earth pad, and purified by MPLC (SiO₂, EtOAc in Hex 0%–30%) to give 3,9-dimethoxy-6,7-dihydro-5H-dibenzo[c,e]azapyro-5-one (22 mg, 0.08 mmol, 53%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 8.53 (s, 1H), 7.45(t, J = 8.4 Hz, 2H), 7.28 (d, J = 2.8 Hz, 1H), 7.11 (dd, J = 8.6, 2.7 Hz, 1H), 6.94(dd, J = 12.2, 3.8 Hz, 2H), 3.84 (dd, J = 9.5, 3.6 Hz, 1H), 3.82 (s, 3H), 3.78(s, 3H), 3.18 (d, J = 14.8 Hz, 1H).

[0934] Step 6: Synthesis of 3,9-dihydroxy-6,7-dihydro-5H-dibenzo[c,e]azapyro-5-one

[0935]

[0936] 3,9-Dimethoxy-6,7-dihydro-5H-dibenzo[c,e]azapyro-5-one (64 mg, 0.24 mmol, 1.0 equivalent) was dissolved in DCM (2 mL) and cooled to 0°C in an ice bath while stirring for 5 minutes. Then, BBr3 (0.95 mL, 1 M in DCM, 0.95 mmol, 4.0 equivalent) was added dropwise to the reaction mixture. After the addition was complete, the mixture was left in an ice bath and allowed to warm to room temperature over 2 hours. When the starting material was no longer observable, the reaction mixture was added dropwise to 0°C cold methanol (10 mL) and stirred for another 10 minutes. The mixture was then concentrated and loaded onto silica for purification by rapid column chromatography (SiO2, 12 g, MeOH 0%-5% in DCM) to give 3,9-dihydroxy-6,7-dihydro-5H-dibenzo[c,e]azapyro-5-one (25 mg, 0.10 mmol, 44%) as an orange solid. 1 H NMR (400 MHz, DMSO) δ 8.39 (t, J = 6.1 Hz, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 2.6 Hz, 1H), 6.97 (dd, J = 8.6, 2.6 Hz, 1H), 6.80 (dd, J = 8.4, 2.3 Hz, 1H), 6.71 (d, J =2.3 Hz, 1H), 3.80 (ddd, J = 35.6, 14.6, 6.1 Hz, 2H).

[0937] Synthesis of 3,9-dihydroxy-6-methyl-6,7-dihydro-5H-dibenzo[c,e]azapyro-5-one (75)

[0938]

[0939] Step 1: Synthesis of 3,9-dimethoxy-6-methyl-6,7-dihydro-5H-dibenzo[c,e]azapyro-5-one

[0940]

[0941] 3,9-Dimethoxy-6,7-dihydro-5H-dibenzo[c,e]azapyro-5-one (80 mg, 0.30 mmol, 1.0 equivalent) was dissolved in DMF (3.0 mL), and the solution was cooled to 0°C in an ice bath and stirred for 10 minutes. Then, 60% NaH (14 mg, 0.36 mmol, 1.2 equivalent) from petroleum was added in a single batch. The reaction mixture was stirred until hydrogen escaping completely stopped, at which point MeI (0.13 g, 0.89 mmol, 3.0 equivalent) was added dropwise. The reaction mixture was then heated to room temperature and stirred for 3 hours until the starting material disappeared (as indicated by TLC). The reactants were quenched with ice water (10 mL), and the aqueous solution was extracted with diethyl ether (3 x 10 mL). The organic layer was washed with water and brine, dried over Na2SO4, and concentrated to give 3,9-dimethoxy-6-methyl-6,7-dihydro-5H-dibenzo[c,e]azapyro-5-one (84 g, 0.30 mmol, 99%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.35 (dd, J = 16.3, 8.4 Hz, 2H), 7.14 (d, J = 2.7Hz, 1H), 6.96 (dd, J = 8.5, 2.7 Hz, 1H), 6.90 – 6.81 (m, 2H), 4.10 – 3.75 (m,2H), 3.10 (s, 3H), 3.00 (s, 3H), 2.90 (s, 3H).

[0942] Step 2: Synthesis of 3,9-dihydroxy-6-methyl-6,7-dihydro-5H-dibenzo[c,e]azapyrrolidone

[0943]

[0944] 3,9-Dimethoxy-6-methyl-6,7-dihydro-5H-dibenzo[c,e]azapyro-5-one (84 mg, 0.84 mmol, 1.0 equivalent) was dissolved in DCM (1 mL) and cooled to 0°C in an ice bath while stirring for 5 minutes. Then, BBr3 (1.20 mL, 1 M in DCM, 1.20 mmol, 4.0 equivalent) was added dropwise to the reaction mixture. After the addition was complete, the mixture was left in an ice bath and allowed to warm to room temperature over 2 hours. When the starting material was no longer observable, the reaction mixture was added dropwise to 0°C cold methanol (10 mL) and stirred for another 10 minutes. The mixture was then concentrated and loaded onto silica for purification by rapid column chromatography (SiO2, 12 g, MeOH in DCM 0%-5%) to give 3,9-dihydroxy-6-methyl-6,7-dihydro-5H-dibenzo[c,e]azapyro-5-one (40 mg, 0.16 mmol, 52%) as a light orange solid. 1 H NMR (400 MHz, DMSO) δ 9.65 (s, 2H), 7.35 (dd, J = 16.3, 8.4 Hz, 2H), 7.14 (d, J = 2.7 Hz, 1H), 6.96 (dd, J = 8.5, 2.7 Hz, 1H), 6.90 – 6.81 (m,2H), 4.20 – 3.85 (m,2H), 3.02 (s, 3H).

[0945] Synthesis of 3,9-dihydroxy-5,7-dihydro-6H-dibenzo[b,d]azapyro-6-one (76)

[0946]

[0947] Step 1: Synthesis of 2-(2-bromo-5-methoxyphenyl)acetic acid

[0948]

[0949] Bromine (1.92 g, 12.0 mmol, 1.0 equivalent) was added dropwise to a solution of 2-(3-methoxyphenyl)acetic acid (2.00 g, 12.0 mmol, 1.0 equivalent) in DCM (40 mL) at 0 °C. After the bromine addition was complete, the reaction mixture was heated to room temperature and stirred overnight, protected from light by aluminum foil. The dark red solution was stained with sodium thiosulfate solution (1 M), washed with water (50 mL), and separated. The aqueous layer was extracted into DCM (2 x 25 mL), and the combined organic layers were dried over Na2SO4, filtered, and evaporated to dryness to give 2-(2-bromo-5-methoxyphenyl)acetic acid (2.80 g, 11.0 mmol, 95%) as a pale red solid.

[0950] 1 H NMR (400 MHz, CDCl3) δ 10.07 (s, 1H), 7.45 (d, J = 8.8 Hz, 1H), 6.85(d, J = 3.0 Hz, 1H), 6.72 (dd, J = 8.8, 3.0 Hz, 1H), 3.79 (s, 2H), 3.78 (s, 3H).

[0951] Step 2: Synthesis of 2-(2-bromo-5-methoxyphenyl)acetic acid ester

[0952]

[0953] 2-(2-bromo-5-methoxyphenyl)acetic acid (6.63 g, 27.1 mmol, 1.0 equivalent) was dissolved in MeOH (90 mL), and a catalytic amount of concentrated sulfuric acid (0.2 mL) was added to the mixture. The mixture was then refluxed for 4 hours, cooled to room temperature, quenched with water, and extracted into ethyl acetate (3 x 100 mL). The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over Na₂SO₄, and concentrated under vacuum. The crude product was purified by MPLC (SiO₂, 240 g, EtOAc in Hex 0%–20%) to give methyl 2-(2-bromo-5-methoxyphenyl)acetic acid (6.44 g, 24.9 mmol, 92%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 3.0 Hz, 1H), 6.74 (dd, J = 8.8, 3.0 Hz, 1H), 3.81 (s, 3H), 3.78 (s, 2H), 3.75 (s, 3H).

[0954] Step 3: Synthesis of 2-(5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)acetate

[0955]

[0956] Methyl 2-(2-bromo-5-methoxyphenyl)acetate (2.00 g, 7.72 mmol, 1.0 equivalent) was dissolved in 1,4-dioxane (150 mL), and B2pin2 (3.53 g, 13.9 mmol, 1.8 equivalent), Pd(PPh3)2Cl2 (542 mg, 0.770 mmol, 0.1 equivalent), and KOAc (3.03 g, 30.9 mmol, 4.0 equivalent) were added. The resulting reaction mixture was degassed using an N2 balloon for 10 minutes and then placed in a preheated oil bath at 100 °C overnight. After stirring overnight, the mixture was cooled to room temperature and quenched with a saturated aqueous solution of NH4Cl, and extracted into ethyl acetate (3 x 75 mL). The combined organic layers were dried over anhydrous Na2SO4, concentrated under vacuum, and the crude material was purified by MPLC (SiO2, 120 g, EtOAc in Hex 0%-20%) to obtain methyl 2-(5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)acetate (1.32 g, 4.31 mmol, 56%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.3 Hz, 1H), 6.80 (dd, J = 8.3, 2.5 Hz, 1H), 6.74 (d, J = 2.5 Hz, 1H), 3.96 (s, 2H), 3.81 (s, 3H), 3.66 (s, 3H), 1.30 (s, 12H).

[0957] Step 4: Synthesis of 2-(4,4'-dimethoxy-2'-nitro-[1,1'-biphenyl]-2-yl)acetic acid ester

[0958]

[0959] Methyl 2-(5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)acetate (670 mg, 2.19 mmol, 1.0 equivalent) and 1-iodo-4-methoxy-2-nitrobenzene (733 mg, 2.63 mmol, 1.2 equivalent) were dissolved in THF (2 mL), and Pd2dba3 (100 mg, 0.110 mmol, 0.05 equivalent) and tBuXPhos (93 mg, 0.22 mmol, 0.1 equivalent) were added to this solution. The resulting mixture was degassed using an N2 balloon for 10 minutes, after which a solution of Na2CO3 (696 mg, 6.56 mmol, 3.0 equivalent) in water (4 mL) was added dropwise. The reaction mixture was then heated to 60°C overnight (until the starting material completely disappeared on TLC), cooled to room temperature, quenched with a saturated aqueous NH4Cl solution, extracted with ethyl acetate (3 x 50 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified by MPLC (SiO2, 40 g, EtOAc in Hex 0%–35%) to give methyl 2-(4,4'-dimethoxy-2'-nitro-[1,1'-biphenyl]-2-yl)acetate (490 mg, 1.48 mmol, 68%) as a green oil. 1 H NMR (400 MHz, CDCl3) δ7.48 (d, J = 2.7 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 7.14 (dd, J = 8.5, 2.7Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 2.6 Hz, 1H), 6.83 (dd, J =8.4, 2.7 Hz, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 3.59 (s, 3H), 3.48 – 3.33 (m,2H).

[0960] Step 5: Synthesis of 3,9-dimethoxy-5,7-dihydro-6H-dibenzo[b,d]azapyro-6-one

[0961]

[0962] 2-(4,4'-dimethoxy-2'-nitro-[1,1'-biphenyl]-2-yl)methyl acetate (485 mg, 1.46 mmol, 1.0 equivalent) was dissolved in H₂O (3 mL), AcOH (2 mL), and EtOH (3 mL), and powdered Fe (818 mg, 14.6 mmol, 10.0 equivalent) was added to the mixture. The mixture was stirred for 2 hours until TLC showed no further starting material. The reaction mixture was then filtered through a diatomaceous earth pad and concentrated under reduced pressure (AcOH was removed by azeotropic distillation with cyclohexane) and purified by MPLC (SiO₂, 40 g, EtOAc in Hex 0%–85%) to give 3,9-dimethoxy-5,7-dihydro-6H-dibenzo[b,d]azapyro-6-one (150 mg, 0.560 mmol, 38%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 9.93 (s, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.44 (d, J = 9.0 Hz, 1H), 7.00 –6.94 (m, 2H), 6.85 (dd, J = 8.7, 2.6 Hz, 1H), 6.72 (d, J = 2.6 Hz, 1H), 3.80 (s, 3H), 3.78 (s, 3H).

[0963] Step 6: Synthesis of 3,9-dihydroxy-5,7-dihydro-6H-dibenzo[b,d]azapyro-6-one

[0964]

[0965] 3,9-Dimethoxy-5,7-dihydro-6H-dibenzo[b,d]azapine-6-one (70 mg, 0.26 mmol, 1.0 equivalent) was dissolved in DCM (2 mL) and cooled to 0°C in an ice bath while stirring for 5 minutes. Then, BBr3 (1.30 mL, 1 M in DCM, 1.30 mmol, 5.0 equivalent) was added dropwise to the reaction mixture. After the addition was complete, the mixture was left in an ice bath and allowed to warm to room temperature over 2 hours. When the starting material was no longer observable, the reaction mixture was added dropwise to 0°C cold methanol (10 mL) and stirred for another 10 minutes. The mixture was then concentrated and loaded onto silica for purification by rapid column chromatography (SiO2, 12 g, MeOH in DCM 0%-5%) to give 3,9-dihydroxy-5,7-dihydro-6H-dibenzo[b,d]azapyro-6-one (35 mg, 0.15 mmol, 56%) as a pale yellow solid. 1 H NMR (400MHz, DMSO) δ 9.82 (s, 1H), 9.56 (s, 2H), 7.33 (d, J = 8.5 Hz, 1H), 7.27 (d, J =8.4 Hz, 1H), 6.77 (dd, J = 8.4, 2.5 Hz, 1H), 6.69 (d, J = 2.5 Hz, 1H), 6.63 (dd, J = 8.5, 2.5 Hz, 1H), 6.55 (d, J = 2.5 Hz, 1H), 3.20 (s, 2H).

[0966] Synthesis of 3,9-dihydroxy-5-methyl-5,7-dihydro-6H-dibenzo[b,d]azapyro-6-one (77)

[0967]

[0968] Step 1: Synthesis of 3,9-dimethoxy-5-methyl-5,7-dihydro-6H-dibenzo[b,d]azapyro-6-one

[0969]

[0970] 3,9-Dimethoxy-5,7-dihydro-6H-dibenzo[b,d]azapyro-6-one (85 mg, 0.32 mmol, 1.0 equivalent) was dissolved in DMF (3.2 mL), and the solution was cooled to 0°C in an ice bath and stirred for 10 minutes. Then, 60% NaH (14 mg, 0.36 mmol, 1.2 equivalent) in petroleum was added in a single batch. The reaction mixture was stirred until hydrogen escaping completely stopped, at which point MeI (0.060 g, 0.38 mmol, 1.2 equivalent) was added dropwise. The reaction mixture was then heated to room temperature and stirred for 3 hours until the starting material disappeared (as indicated by TLC). The reactants were quenched with ice water (10 mL), and the aqueous solution was extracted with diethyl ether (3 x 10 mL). The organic layer was washed with water and brine, dried over Na2SO4, and concentrated to give 3,9-dimethoxy-5-methyl-5,7-dihydro-6H-dibenzo[b,d]azapyro-6-one (60 mg, 0.21 mmol, 67%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.46 (dd, J = 8.4, 5.6 Hz, 2H), 6.98 – 6.85 (m,4H), 3.89 (s, 3H), 3.86 (s, 3H), 3.56 – 3.39 (dd, 2H), 3.33 (s, 3H).

[0971] Step 1: Synthesis of 3,9-dihydroxy-5-methyl-5,7-dihydro-6H-dibenzo[b,d]azapyro-6-one

[0972]

[0973] 3,9-Dimethoxy-5,7-dihydro-6H-dibenzo[b,d]azapyro-6-one (58 mg, 0.20 mmol, 1.0 equivalent) was dissolved in DCM (2 mL) and cooled to 0°C in an ice bath while stirring for 5 minutes. Then, BBr3 (0.82 mL, 1 M in DCM, 0.82 mmol, 4.0 equivalent) was added dropwise to the reaction mixture. After the addition was complete, the mixture was left in an ice bath and allowed to warm to room temperature over 2 hours. When the starting material was no longer observable, the reaction mixture was added dropwise to 10 mL of cold methanol at 0°C and stirred for another 10 minutes. The mixture was then concentrated and loaded onto silica for purification by rapid column chromatography (SiO2, 12 g, MeOH in DCM 0%-5%) to give 3,9-dihydroxy-5-methyl-5,7-dihydro-6H-dibenzo[b,d]azapyro-6-one (30 mg, 0.12 mmol, 57%) as a light orange solid. 1 HNMR (400 MHz, DMSO) δ 9.74 (s, 1H), 9.57 (s, 1H), 7.31 (dd, J = 8.4, 2.3 Hz, 2H), 6.82 – 6.71 (m, 4H), 3.31 – 3.20 (m, 2H), 3.15 (s, 3H).

[0974] Compound 77A is prepared by employing a suitable methyl-substituted iodophenyl intermediate in the Pd coupling step of the above-described synthesis of 76, providing a methyl-substituted analog of 76. The remaining steps are similar to those used to provide compound 77, namely, amide methylation followed by deprotection.

[0975] (77A).

[0976] Example 2: Synthesis of additional representative compounds

[0977] Unless otherwise specified, the reaction shall not be carried out under an inert atmosphere, and all solvents and commercially available reagents shall be used as is.

[0978] Purification by chromatography refers to purification using a COMBIFLASH® Companion purification system or a Biotage SP1 purification system. When purifying products using an Isolute® SPE Si II column, the "Isolute SPE Si column" refers to a pre-packed polypropylene column containing unbonded active silica with irregular particles having an average size of 50 µm and a nominal porosity of 60 Å. Fractions containing the desired product (identified by TLC and / or LCMS analysis) are combined, and the organic fraction is recovered by evaporation to obtain the final product. When using thin-layer chromatography (TLC), this refers to a silica gel TLC plate, typically a 3 × 6 cm silica gel plate (e.g., Fluka 60778) on an aluminum foil plate with a fluorescent indicator (254 nm). Microwave experiments are performed using the Biotage Initiator 60™, which employs a single-mode resonator and dynamic field tuning. Temperatures from 40°C to 250°C and pressures up to 30 bar can be achieved.

[0979] NMR spectra were obtained on a Bruker Avance 400 MHz, 5 mm QNP probe H, C, F, P, single Z gradient, dual-channel instrument running TopSpin 2.1 or on a Bruker Avance III 400 MHz, 5 mm BBFO Plus probe, single Z gradient, dual-channel instrument running TopSpin 3.0.

[0980] Analytical LC-MS conditions

[0981] Method 1: Experiments were performed on a Waters Acquity SQD2 mass spectrometer connected to a Waters Acquity UPLC binary pump / PDA detector. The mass spectrometer features an electrospray source operating in both positive and negative ion modes. Additional detection was performed using an Acquity UPLC HSS C18 1.7 µm, 100 x 2.1 mm column maintained at 40 °C and a flow rate of 0.4 mL / min. The initial solvent system used for the first 0.4 min was 95% water containing 0.1% formic acid (solvent A) and 5% MeCN containing 0.1% formic acid (solvent B), followed by gradients up to 5% solvent A and 95%.

[0982] Method 2: Experiments were performed on a Waters Acquity SQD2 mass spectrometer connected to a Waters Acquity UPLC binary pump / PDA detector. The spectrometer features an electrospray source operating in both positive and negative ion modes. Additional detection was performed using an Acquity UPLC BEH Shield RP18 1.7 µm 100 x 2.1 mm column. The column was maintained at 40 °C and a flow rate of 0.4 mL / min. The initial solvent system used for the first 0.4 min was 95% water containing 0.03% ammonia (solvent A) and 5% MeCN containing 0.03% ammonia (solvent B), followed by a gradient of 5% solvent A and 95% solvent B over the next 5.4 min. The final solvent system was then kept constant for another 0.8 min.

[0983] Method 3: Experiments were performed on a Waters Acquity ZQ mass spectrometer connected to a Waters Acquity UPLC binary pump / PDA detector. The mass spectrometer features an electrospray source operating in both positive and negative ion modes. Additional detection was performed using an Acquity UPLC BEH C18 1.7 µm, 100 x 2.1 mm column maintained at 40 °C and a flow rate of 0.4 mL / min. The initial solvent system used for the first 0.4 min was 95% water containing 0.1% formic acid (solvent A) and 5% MeCN containing 0.1% formic acid (solvent B), followed by a gradient of 5% solvent A and 95% solvent B over the next 5.6 min. The final solvent system was then kept constant for another 0.8 min.

[0984] Method 4: Experiments were performed on a Waters Acquity ZQ mass spectrometer connected to a Waters Acquity UPLC binary pump / PDA detector. The mass spectrometer features an electrospray source operating in both positive and negative ion modes. Additional detection was performed using an Acquity UPLC BEH C18 1.7 µm, 100 x 2.1 mm column maintained at 40 °C and a flow rate of 0.4 mL / min. The initial solvent system used for the first 0.4 min was 95% water containing 0.03% ammonia (solvent A) and 5% MeCN containing 0.03% ammonia (solvent B), followed by a gradient of 5% solvent A and 95% solvent B over the next 4 min. The final solvent system was then kept constant for another 0.8 min.

[0985] Method 5: Experiments were performed on a WatersAcquity ZQ mass spectrometer connected to a Waters Acquity H-class UPLC with a DAD detector and QDa. The mass spectrometer has an electrospray source operating in both positive and negative ion modes. Additional detection was performed using an Acquity UPLC CSH 1.7 µm, 50 x 2.1 mm column maintained at 40 °C and a flow rate of 1.0 mL / min. The initial solvent system used for the first 0.4 min was 97% water containing 0.1% formic acid (solvent A) and 3% MeCN containing 0.1% formic acid (solvent B), followed by a gradient of 1% solvent A and 99% solvent B over the next 1.4 min. The final solvent system was then kept constant for another 0.5 min.

[0986] Method 6: Experiments were performed on a WatersAcquity ZQ mass spectrometer connected to a WatersAcquity H-class UPLC with a DAD detector and QDa. The mass spectrometer has an electrospray source operating in both positive and negative ion modes. Additional detection was performed using an Acquity BEH UPLC 1.7 µm, 50 x 2.1 mm column maintained at 40 °C and a flow rate of 0.8 mL / min. The initial solvent system used for the first 0.4 min was 97% ammonia in water (solvent A) and 3% ammonia in MeCN (solvent B), followed by a gradient of 3% solvent A and 97% solvent B over the next 1.6 min. The final solvent system was then kept constant for another 0.5 min.

[0987] A) Ester "A" group analogues

[0988] General Procedure B

[0989] N- (8-methoxy-6-oxo-6) H -benzo[ c [Creno-3-yl)methanesulfonamide (79)

[0990]

[0991] GP B1

[0992] 2-Bromo-5-methoxybenzoic acid 3-(methylsulfonamide)phenyl ester (intermediate 1)

[0993] To a suspension of 2-bromo-5-methoxybenzoic acid (642 mg, 2.78 mmol) in DCM (10 mL), oxalyl chloride (0.27 mL, 3.06 mmol) and 1 drop of DMF were added dropwise. The solution was stirred at room temperature for 1 hour and the solvent was removed under vacuum. The resulting mixture was redissolved in DCM (5 mL) and then... N A suspension of 3-(hydroxyphenyl)methanesulfonamide (520 mg, 2.78 mmol) in DCM (5 mL) was subsequently added, followed by the addition of TEA (0.58 mL, 4.17 mmol). The resulting mixture was stirred for 4 hours, then diluted with DCM and washed with saturated NH4Cl aqueous solution. The organic extract was filtered through PTFE and concentrated under vacuum, and the crude product was purified by chromatography on silica (ISCO 12 g) using 0%–50% EtOAc in cyclohexane as the eluent to give the product 2-bromo-5-methoxybenzoic acid 3-(methylsulfonamide)phenyl ester (1 g, 90%) as a colorless oil. LCMS (Method 5): R t 1.43 min; m / z 398.0 / 400.0 [MH] - . 1 H NMR (400 MHz, CDCl3)δ 7.61 (1H, d, J=8.9 Hz), 7.52 (1H, d, J=3.1 Hz), 7.41 (1H, t, J=8.1 Hz),7.19-7.08 (3H, m), 6.98 (1H, dd, J=8.9, 3.1 Hz), 6.77 (1H, s), 3.87 (3H, s), 3.07 (6H, s).

[0994] GP B2

[0995] N- (8-methoxy-6-oxo-6) H -benzo[ c [Creno-3-yl)methanesulfonamide (79)

[0996] A mixture of 3-(methylsulfonamido)phenyl ester of 2-bromo-5-methoxybenzoic acid (intermediate 1) (900 mg, 2.26 mmol), SPhos (92 mg, 0.225 mmol), palladium(II) acetate (50 mg, 0.225 mmol), and sodium acetate (369 mg, 4.5 mmol) in DMA (45 mL) was placed in a sealed tube, degassed, and purged with argon (x3). The mixture was heated to 130 °C for 3 hours, then cooled and diluted with water (400 mL), and extracted into DCM (3 x 50 mL). The combined organic extracts were washed with brine and evaporated under vacuum at 80 °C to remove residual DMA. The crude mixture was recrystallized from MeCN to give a product as a creamy solid. N -(8-methoxy-6-oxo-6) H -benzo[ c [Creno-3-yl]methanesulfonamide (200 mg, 27%). LCMS (Method 3): R t =3.85 min; m / z=320.0 [M+H] + . 1 H NMR (400 MHz: DMSO- d 6) δ 10.22 (1H, s), 8.30 (1H, d, J=8.6 Hz), 8.25 (1H, d, J=9.2 Hz), 7.65 (1H, d, J=2.8 Hz), 7.54 (1H, dd, J=8.9, 2.8 Hz), 7.22-7.19 (2H, m), 3.92(3H, s), 3.11 (3H, s).

[0997] 3-Chloro-8-hydroxy-6 H -benzo[ c ]Crone-6-one (80)

[0998]

[0999] GP C1

[1000] 3-Chloro-8-methoxy-6 H -benzo[ c Chromene-6-one (intermediate 2)

[1001] A solution of 4-chloro-2-hydroxyphenylboronic acid (253 mg, 1.47 mmol) in DME (8.0 mL) and water (2.0 mL) was added with methyl 2-bromo-5-methoxybenzoate (300 mg) and cesium carbonate (1.60 g, 4.90 mmol), followed by tetrakis(triphenylphosphine)palladium(O) (141 mg, 0.122 mmol). The reaction mixture was heated in a microwave at 120 °C for 30 min. The mixture was diluted with EtOAc (100 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was passed through a phase separator and concentrated under vacuum. The residue was purified by chromatography on silica using elution with 5%–15% EtOAc in cyclohexane, followed by grinding in MeOH and drying in a vacuum oven to give the title compound (112 mg, 35%) as a white solid. LCMS (Method 1). t =5.51 min; m / z=261.0, 263.1 [M+H] + . 1 H NMR (400 MHz: CDCl3) δ7.99 (1H, d, J=8.8 Hz), 7.91 (1H, d, J=8.3 Hz), 7.81 (1H, d, J=2.8 Hz), 7.44-7.36 (2H, m), 7.31 (1H, dd, J=8.6, 2.0 Hz), 3.95 (3H, s);

[1002] GP C2

[1003] 3-Chloro-8-hydroxy-6 H -benzo[ c ]Crone-6-one (80)

[1004] Under nitrogen atmosphere, 3-chloro-8-methoxy-6 H -benzo[ cA solution of chromone-6-one (intermediate 2) (70 mg, 0.268 mmol) in anhydrous DCM (10 mL) was added dropwise to a solution of boron tribromide in DCM (1.0 M, 5.4 mL, 5.36 mmol). The reaction mixture was stirred at room temperature for 3 days. Water (20 mL) was added and the mixture was diluted with DCM (10 mL). The mixture was stirred at room temperature for 10 minutes. The resulting precipitate was filtered off, and the aqueous layer was extracted with DCM (2 x 50 mL). The combined organic layers were passed through a phase separation column and concentrated under reduced pressure. The precipitate was dissolved in MeOH / DCM and concentrated under vacuum. The combined residues were purified by chromatography on silica gel by elution with 2%–4% MeOH in DCM to give the title compound (28 mg, 42%) as a white solid. LCMS (Method 1): R t =4.55 min; m / z=247.1, 249.0 [M+H] + . 1 H NMR (400 MHz: DMSO- d 6) δ 10.54 (1H, s), 8.35-8.31 (2H, m), 7.63-7.61 (2H, m), 7.51-7.42 (2H, m).

[1005] General Procedure D

[1006] 2-(dimethylamino)- N -(6-oxo-6) H -benzo[ c [Creno-3-yl)acetamide (81)

[1007]

[1008] GP D1

[1009] Trifluoromethanesulfonic acid 6-oxo-6 H -benzo[ c Chromene-3-yl ester (intermediate 3)

[1010] 6-hydroxy-6 H -benzo[ c Chromone-6-one (2.50 g, 11.78 mmol), NA mixture of phenyl-bis(trifluoromethanesulfonylimide) (5.05 g, 14.1 mmol) and DIPEA (4.1 mL, 23.6 mmol) in DCM (50 mL) was stirred at room temperature under nitrogen. A catalytic amount of DMAP was added and the mixture was stirred for 48 hours. The resulting red solution was washed with 1 M HCl (50 mL), and the DCM layer (PTFE glass frit) was dried and evaporated. The crude residue was recrystallized from DCM / cyclohexane to give a product as a creamy solid. The mother liquor was purified by chromatography on silica using 20%–100% DCM in cyclohexane as the eluent. This yielded an additional 1.22 g of product (total yield 2.86 g, 71%). LCMS (Method 5): R t =1.60 min (no m / z detected – poor ionization). 1 H NMR (CDCl3) δ 8.43 (1H, dd, J=1.3, 8.0 Hz), 8.16 (1H, d, J=8.9 Hz), 8.11 (1H, d, J=8.0 Hz), 7.92-7.87 (1H, m), 7.69-7.64 (1H,m), 7.34 (1H, d, J=2.3 Hz), 7.30 (1H, dd, J=2.5, 8.9 Hz).

[1011] GP D2

[1012] 2-(dimethylamino)- N -(6-oxo-6) H -benzo[ c [Creno-3-yl)acetamide (81)

[1013] Trifluoromethanesulfonic acid 6-oxo-6 H -benzo[ cA mixture of chromene-3-yl ester (intermediate 3) (344 mg, 1.0 mmol), 2-(dimethylamino)acetamide (153 mg, 1.5 mmol), tBuXPhos-Pd-G3 (24 mg, 0.03 mmol), and tripotassium phosphate (318 mg, 1.5 mmol) in a septum-sealed vial was degassed (vacuumed and purged with argon for 3 cycles). Warm, degassed (argon-purged) tert-butanol (8.5 mL) was added via syringe, and the mixture was then heated at 95 °C for 2 hours. The cooled mixture was diluted with water (15 mL), filtered, and dried under vacuum to give a gray solid. This solid was dissolved in DCM (15 mL) and filtered through a 2 g fast Si(II) column, which was then further eluted with 2% MeOH in DCM to give the title compound (125 mg, 42%) as a white solid. LCMS (Method 3): R t =2.72 min; m / z = 296.9 [M+H] + .

[1014] 1 H NMR (400 MHz, DMSO- d 6) δ 10.14 (1H, s), 8.37 (1H, d, J=8.1 Hz), 8.29 (1H, d, J=8.8 Hz), 8.23 ​​(1H, dd, J=1.1, 7.9 Hz), 7.96-7.90 (1H, m), 7.88(1H, d, J=2.1 Hz), 7.68 (1H, dd, J=2.1, 8.7 Hz), 7.66-7.60 (1H, m), 3.13 (2H,s), 2.30 (6H, s).

[1015] General Procedure E

[1016] (6-oxo-6) H -benzo[ c ]Creno-3-yl)methyl carbamate (82)

[1017]

[1018] Trifluoromethanesulfonic acid 6-oxo-6 H -benzo[ cA mixture of chromene-3-yl ester (intermediate 3) (250 mg, 0.73 mmol), methyl carbamate (82 mg, 1.09 mmol), allyl palladium(II) chloride dimer (2.7 mg, 0.007 mmol), Jackie Phos (29 mg, 0.036 mmol), and K₂CO₃ (301 mg, 2.18 mmol) in toluene (6.0 mL) was purged with argon for 5 minutes. The reaction vessel was then sealed, and the mixture was heated at 110 °C for 1 hour. The cooled reaction mixture was diluted with DCM (20 mL) and water (20 mL) to obtain a suspension in the aqueous phase. The organic phase was separated, and the aqueous phase was washed with DCM (20 mL). The aqueous phase was filtered, and the recovered black solid was dissolved in 6% MeOH in DCM. The solution was filtered through a 5 g fast Si(II) column, and then the column was further eluted with 6% MeOH in DCM to give a white solid (129 mg, 65%). LCMS (Method 3): R t =4.05 min; m / z=269.9 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 10.12 (1H, s), 8.32 (1H, d, J=8.1 Hz), 8.28 (1H, d, J=8.8 Hz), 8.22 (1H, dd, J=1.1, 7.9 Hz), 7.95-7.89 (1H, m), 7.65-7.58 (2H, m), 7.45 (1H,dd, J=2.1, 8.7 Hz), 3.72 (3H, s).

[1019] General Procedure F

[1020] 3-Bromo-8-methoxy-6 H -benzo[ c ]Crone-6-one (84)

[1021]

[1022] GP F1

[1023] Trifluoromethanesulfonic acid 8-methoxy-6-oxo-6 H -benzo[ c ]Crotene-3-yl ester (83) (Intermediate 4)

[1024] 3-hydroxy-8-methoxy-6 H -benzo[ cChromene-6-one (1 g, 4.13 mmol) was dissolved in pyridine (10 mL), and the mixture was cooled in ice water. Trifluoromethanesulfonic anhydride (1 mL, 6.19 mmol) was added dropwise, and the resulting brown mixture was stirred at 0 °C until room temperature was reached for 2 hours. The mixture was concentrated under vacuum, and the residue was dissolved in DCM and washed with 1 M HCl and brine, dried (PTFE glass frit), and concentrated under vacuum. The resulting residue was passed through a silica pad (12 g), and the product was eluted with 50%–100% DCM in cyclohexane to give a white crystalline compound (1.2 g, 80%). 1 H NMR (400 MHz, CDCl3) δ 8.56 (1H, d, J=9.1 Hz), 8.48 (1H, d, J=8.8 Hz), 7.80 (1H, d, J=2.5 Hz), 7.75 (1H, d, J=2.8 Hz), 7.65 (1H, dd, J=2.8, 8.8 Hz), 7.59 (1H, dd, J=2.7, 9.0 Hz), 4.00 (3H, s); LCMS (Method 1): R t =5.64 min; m / z=375.0[M+H] + .

[1025] GP F2

[1026] 8-Methoxy-3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-6 H -benzo[ c Chromene-6-one (intermediate 5)

[1027] 8-methoxy-6-oxo-6-trifluoromethanesulfonic acid H -benzo[ cA mixture of chromene-3-yl ester (intermediate 4) (1.0 g, 2.67 mmol), potassium acetate (393 mg, 4.0 mmol), the complex of [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with DCM (65 mg, 0.08 mmol), 1,1-bis(diphenylphosphino)ferrocene (44 mg, 0.08 mmol), and dioxane (20 mL) was purged with argon. Bis(pinacolyl)diboron (746 mg, 2.94 mmol) was added, and after a period of re-degassing, the mixture was heated at 90 °C under argon for 19 hours. The cooled mixture was partitioned between ether (25 mL) and water (25 mL), and the phases were separated. The aqueous phase was extracted with ether (2 x 25 mL). The combined organic extracts were washed with saturated brine, dried (Na₂SO₄), and concentrated under vacuum. The residue was purified by rapid chromatography on a 20 g Si-(II) column eluted with DCM, followed by 10% EtOAc in DCM. The resulting product was ground with cyclohexane (10 mL) and then dried under vacuum to give the title compound (0.76 g, 81%) as a grayish-white solid. LCMS (Method 5): R t =1.65 min; m / z=353.1[M+H] + and R t =1.11 min; m / z=271.1 [M-Pin+H] + .

[1028] GP F3

[1029] 3-Bromo-8-methoxy-6 H -benzo[ c ]Crone-6-one (84)

[1030] 8-Methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-6 H -benzo[ cA suspension of chromone-6-one (intermediate 5) (352 mg, 1.0 mmol) in MeOH (10 mL) was treated with a solution of copper(II) bromide (670 mg, 3.0 mmol) in water (10 mL). The resulting mixture was heated under reflux for 16 hours and then cooled. The cold mixture was extracted with ether (2 x 25 mL) and then with DCM (2 x 25 mL). The combined organic phases were filtered through a hydrophobic glass frit and then concentrated under vacuum. The residue was purified by rapid chromatography on a 5 g Si-(II) column and eluted with [1:1]DCM / cyclohexane followed by DCM to give the title compound (240 mg, 78%) as a white solid. ¹H NMR(400 MHz, CDCl3) δ 8.00 (1H, d, J=8.9 Hz), 7.84 (1H, d, J=8.7 Hz), 7.80 (1H,d, J=3.0 Hz), 7.53 (1H, d, J=1.9 Hz), 7.46-7.39 (2H, m), 3.95 (3H, s);

[1031] LCMS (Method 5), R t =1.53 min; m / z=304.8, 306.8 [M+H] + .

[1032] Program G

[1033] 8-(difluoromethyl)-3-(methoxymethoxy)-6 H -benzo[ c Chromene-6-one (85)

[1034]

[1035] GP G1

[1036] 8-Bromo-3-(methoxymethoxy)-6 H -benzo[ c Chromene-6-one (intermediate 6)

[1037] 8-bromo-3-hydroxy-6 H -benzo[ cChromene-6-one (1.0 g, 3.44 mmol), K₂CO₃ (1.42 g, 10.31 mmol), and chloromethyl methyl ether (0.39 mL, 5.15 mmol) were suspended in acetone (10 mL), and the mixture was stirred for 3 hours. An additional aliquot of chloromethyl methyl ether (0.39 mL, 5.15 mmol) was added, and the mixture was stirred for 2 hours. The mixture was concentrated under vacuum and dispersed between DCM and water. The DCM layer was washed with brine, dried (PTFE glass frit), and evaporated to give a product as a white solid (1 g, 86%). 1 H NMR (400 MHz, CDCl3) δ 8.50 (1H, s), 7.9 -7.88 (3H,m), 7.07-7.02 (2H, m), 5.25-5.24 (2H, m), 3.51 (3H, s).

[1038] GP G2

[1039] 3-(methoxymethoxy)-8-vinyl-6 H -benzo[ c Chromene-6-one (intermediate 7)

[1040] 8-bromo-3-(methoxymethoxy)-6 H -benzo[ c A mixture of xanthine-6-one (intermediate 6) (1 g, 2.98 mmol), potassium vinyltrifluoroborate (520 mg, 3.88 mmol), TEA (1.2 mL, 8.95 mmol), and a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with DCM (122 mg, 0.15 mmol) in isopropanol (20 mL) and water (10 mL) was placed in a sealed tube, evacuated, and purged with argon (x3). The mixture was heated at 90 °C under argon for 2 hours. The cooled mixture was concentrated under vacuum, and the residue was dispersed between EtOAc and water. The EtOAc layer was washed with brine, dried (PTFE glass frit), and concentrated under vacuum. The residue was purified by chromatography on silica using 0%–50% DCM in cyclohexane as the eluent to give a product as a white solid (705 mg, 71%). 1H NMR (400 MHz, CDCl3) δ 8.37 (1H, d, J=1.9 Hz), 7.98 (1H, d, J=8.5 Hz), 7.94 (1H, d, J=8.7Hz), 7.84 (1H, dd, J=2.0, 8.4 Hz), 7.07-7.02 (2H, m), 6.81 (1H, dd, J=10.9,17.6 Hz), 5.91 (1H, d, J=17.6 Hz), 5.40 (1H, d, J=11.0 Hz), 5.25 (2H, s), 3.51 (3H, s).

[1041] GP G3

[1042] 3-(methoxymethoxy)-6-oxo-6 H -benzo[ c Xanthine-8-carboxaldehyde (intermediate 8)

[1043] To 3-(methoxymethoxy)-8-vinyl-6 H -benzo[ c A solution of chromone-6-one (intermediate 7) (700 mg, 2.48 mmol) in THF (40 mL) was mixed with osmium tetroxide (0.25 mL, 0.025 mmol), followed by sodium periodate (1.59 g, 7.44 mmol). The resulting solution was stirred for 18 hours to obtain a white suspension. The mixture was concentrated under vacuum, and the residue was partitioned between DCM and water. The DCM layer was washed with an aqueous solution of sodium sulfite and brine, and then dried (PTFE glass frit) to obtain a white solid (700 mg, quantitative). 1 ¹H NMR (400 MHz, CDCl₃) δ 10.11 (¹H, s), 8.83 (¹H, d, J=1.8 Hz), 8.30 (¹H, dd, J=1.8, 8.4 Hz), 8.16 (¹H, d, J=8.4 Hz), 8.04–8.00 (¹H, m), 7.10–7.07 (2H, m), 5.27 (2H, s), 3.52 (3H, s); LCMS (Method 6): R t =1.41 min; m / z=284.2 [M+1] + .

[1044] GP G4

[1045] 8-(difluoromethyl)-3-(methoxymethoxy)-6 H -benzo[c Chromene-6-one (intermediate 9)

[1046] 3-(methoxymethoxy)-6-oxo-6 H -benzo[ c A suspension of chromene-8-carboxaldehyde (intermediate 8) (190 mg, 0.67 mmol) in DCM (3 mL) was placed under argon atmosphere. DAST (0.26 mL, 2.01 mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 18 hours. The resulting solution was neutralized with a saturated aqueous NaHCO3 solution, and the DCM layer was washed with brine, dried (PTFE glass frit), and concentrated under vacuum. The residue was purified by chromatography on silica using 0%–70% DCM in cyclohexane as the eluent to give a product as a pale yellow solid (175 mg, 85%). 1 ¹H NMR (400 MHz, CDCl₃, 258114) δ 8.49 (¹H, d, J=1.1 Hz), 8.12 (¹H, d, J=8.4 Hz), 7.98 (¹H, d, J=8.5 Hz), 7.96–7.92 (¹H, m), 7.09–7.05 (2H, m), 6.76 (¹H, t, J=56.1 Hz), 5.26 (2H, s), 3.51 (3H, s); LCMS (Method 6): R t =1.55 min (no m / z detected – poor ionization).

[1047] GP G5

[1048] 8-(difluoromethyl)-3-hydroxy-6 H -benzo[ c Chromene-6-one (85)

[1049] 8-(difluoromethyl)-3-(methoxymethoxy)-6 under argon atmosphere H -benzo[ cA solution of chromone-6-one (intermediate 9) (65 mg, 0.21 mmol) and 2,2'-bipyridine in MeCN was placed in a sealed tube and cooled in ice water. Trifluoromethyl trifluoromethanesulfonate (0.08 mL, 0.42 mmol) was added and the solution was stirred for 18 hours. The resulting mixture was stirred with water (0.5 mL) for 30 minutes, then concentrated under vacuum, and the residue was partitioned between EtOAc and water. The EtOAc layer was washed with brine, dried (PTFE glass frit), and concentrated under vacuum. The crude residue was purified by chromatography on silica using 0%–5% MeOH in DCM as the eluent to give a product as a pale yellow solid. The product was further purified by chromatography on silica using 0%–50% EtOAc in cyclohexane as the eluent to give the title compound as a white solid (25 mg, 45% yield). 1 H NMR (400 MHz, DMSO- d 6) δ 10.50 (1H, s), 8.41 (1H, d, J=8.5 Hz), 8.35 (1H, d, J=1.1 Hz), 8.21 (1H, d, J=8.9 Hz), 8.04 (1H, d, J=8.4 Hz), 7.21(1H, t, J=55.6 Hz), 6.88 (1H, dd, J=2.4, 8.7 Hz), 6.78 (1H, d, J=2.4 Hz). LCMS (Method 3): R t =4.03 min; m / z=260.9 [MH] - .

[1050] Program H

[1051] 3-Amino-8-methoxy-6H-benzo[c]chromene-6-one (86)

[1052]

[1053] GP H1

[1054] 3-((diphenylmethylene)amino)-8-methoxy-6 H -benzo[ c Chromene-6-one (Intermediate 10)

[1055] A mixture of 8-methoxy-6-oxo-6H-benzo[c]chromene-3-yl ester trifluoromethanesulfonate (intermediate 4) (300 mg, 0.802 mmol), benzophenone imine (0.20 mL, 1.20 mmol), cesium carbonate (392 mg, 1.20 mmol), and XPhos-Pd-G3 (76 mg, 0.080 mmol) in THF (4.0 mL) was placed in a glass vial. The reaction mixture was evacuated and purged with nitrogen (x 3) and heated at 80 °C for 2 hours. The cooled mixture was partitioned between EtOAc (x 2) and water, and the combined organic extracts were washed with brine, dried (MgSO4), and concentrated under vacuum. The residue was purified by chromatography on silica using 5%–95% EtOAc in cyclohexane as the eluent to give a product as a white solid (250 mg, 77%). 1 H NMR (400 MHz, DMSO- d 6) δ 8.23 ​​(1H, d, J=9.0 Hz), 8.05 (1H,d, J=8.5 Hz), 7.61 (1H, d, J=2.8 Hz), 7.72-7.66 (2H, m), 7.53-7.46 (4H, m),7.36-7.31 (2H, m), 7.33 (1H, ob. s), 7.27-7.21 (2H, m), 6.79 (1H, d, J=2.0Hz), 6.73 (1H, dd, J=2.0, 8.4 Hz), 3.89 (3H, s). LCMS (Method 5): R t =1.94 min; m / z=406.3 [M+H] + .

[1056] GP H1

[1057] 3-Amino-8-methoxy-6H-benzo[c]chromene-6-one (86)

[1058] A solution of 3-((diphenylmethylene)amino)-8-methoxy-6H-benzo[c]chromen-6-one (intermediate 10) (250 mg, 0.617 mmol) in THF (3.0 mL) was treated with 2 M HCl (3.1 mL) and stirred at room temperature for 10 min. The precipitate was collected by filtration, dissolved in MeOH, and applied to a MeOH-equilibrated SCX-2 column; after washing with MeOH / DCM, the title compound was eluted with 7 M NH3 in MeOH to give the product as a beige solid (50 mg, 34%).1 H NMR (400 MHz, DMSO- d 6) δ 8.15 (1H, d, J=8.8 Hz), 7.94 (1H, d, J=8.6 Hz), 7.61 (1H, d, J=2.8 Hz), 7.49 (1H, dd, J=2.8, 8.8 Hz), 6.67 (1H, dd,J=2.3, 8.6 Hz), 6.54 (1H, d, J=2.3 Hz), 5.82 (2H, s), 3.92 (3H, s ); LCMS (Method 1): R t =3.91 min; m / z=242.3[M+H] + .

[1059] The following examples in Table A are prepared using a method similar to that described above by utilizing the general procedure (GP) shown.

[1060] Table A.

[1061]

[1062]

[1063]

[1064] *=The salt was prepared by treatment with 1.1 equivalents of HCl aqueous solution followed by lyophilization. Unless otherwise specified, the NMR spectrum is in... d 6 Obtained from -DMSO.

[1065] B) Ether and amide "A" group analogs

[1066] Program I

[1067] 2-Chloro-3,8-dihydroxy-6H-benzo[c]chromene-6-one (114) and

[1068] 2-Chloro-6H-benzo[c]chromene-3,8-diol (115)

[1069]

[1070] 2-Chloro-3,8-dihydroxy-6H-benzo[c]chromene-6-one (114)

[1071] 2-Chloro-3,8-dihydroxy-6H-benzo[c]chromene-6-one was prepared from 113 using the general procedure C2. 1 H NMR (400 MHz, DMSO-) d6) δ 10.25 (1H, br s), 8.24 (1H, s), 8.19 (1H, d J=8.8 Hz), 7.51 (1H, d J=2.6 Hz), 7.31 (1H, dd J=2.7, 8.7 Hz), 6.91 (1H, s);

[1072] LCMS (Method 3): R t =3.52 min; m / z=260.9 [MH] - .

[1073] GP I1

[1074] 3,8-Bis((tert-butyldimethylsilyl)oxy)-2-chloro-6H-benzo[c]chromen-6-one (Intermediate 11)

[1075] A suspension of 2-chloro-3,8-dihydroxy-6H-benzo[c]chromen-6-one (114) (2.37 g, 9.04 mmol) in DMF (15 mL) was treated with imidazole (2.46 g, 36.14 mmol), followed by treatment with TBDMSCl, and the resulting mixture was stirred at room temperature for 18 hours. The reactants were partitioned between EtOAc (x 3) and water, and the combined organic extracts were washed with brine, dried (PTFE glass frit), and concentrated under vacuum. The residue was purified by chromatography on silica using 0%–25% DCM in cyclohexane as the eluent to give a product as a white solid (2.0 g, 45%). 1 H NMR (400MHz, CDCl3) δ 7.94 (1H, s), 7.85 (1H, d J=8.7 Hz), 7.76 (1H, d J=2.6 Hz), 7.31 (1H, dd J=2.7, 8.7 Hz), 6.89 (1H, s), 1.05 (9H, s), 1.01 (9H, s), 0.28 (6H, s), 0.26 (6H, s).

[1076] GP I2

[1077] 4,4'-Bis((tert-butyldimethylsilyl)oxy)-5-chloro-2'-(hydroxymethyl)-[1,1'-biphenyl]-2-ol (Intermediate 12)

[1078] DIBAL-H (1.0 M in THF; 1.60 mL, 1.60 mmol) was added dropwise to a solution of 3,8-bis((tert-butyldimethylsilyl)oxy)-2-chloro-6H-benzo[c]chromen-6-one (intermediate 11) (385 mg, 0.784 mmol) in 2-Me THF (10 mL), and the resulting solution was stirred at room temperature for 1 hour. The mixture was cooled in an ice bath and then quenched by adding 15% NaOH aqueous solution (0.1 mL), followed by adding water (0.16 mL). After stirring for 30 minutes, Na2SO4 was added, and the resulting mixture was stirred at room temperature for 18 hours. The mixture was filtered through a Celite® filter and washed with a DCM pad, and the combined organic layers were concentrated under vacuum to give a yellow solid (388 mg, quantified). 1 H NMR (400 MHz, CDCl3) δ 7.24 (1H, s), 7.04 (1H, d J=8.3 Hz), 6.98 (1H, s), 6.88 (1H, s), 6.79 (1H, d J=7.7 Hz), 6.42 (1H, s), 4.27 (2H, m), 1.23 (1H, m), 1.02 (9H, s), 0.98 (9H, s), 0.20 (6H, s), 0.19 (6H, s).

[1079] GP I3

[1080] ((2-chloro-6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane) (Intermediate 13)

[1081] DEAD (0.18 mL) was added dropwise to a solution of 4,4'-bis((tert-butyldimethylsilyl)oxy)-5-chloro-2'-(hydroxymethyl)-[1,1'-biphenyl]-2-ol (intermediate 12) (388 mg, 0.783 mmol) and triphenylphosphine (308 mg, 1.17 mmol) in 2-Me THF (5.0 mL), and the mixture was stirred at room temperature for 30 min. The resulting solution was concentrated under vacuum and purified by chromatography on silica using 0%–50% EtOAc in cyclohexane as the eluent to give a semi-pure product. LCMS analysis revealed the desired product after adding approximately 70% of the completely deprotected diol. The crude reaction mixture was used for the next stage without purification.

[1082] GP I4

[1083] 2-Chloro-6H-benzo[c]chromene-3,8-diol (115)

[1084] A solution of crude ((2-chloro-6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane) (intermediate 13) (0.783 mmol) in MeOH (5.0 mL) was treated with 4 M HCl in dioxane (1.96 mL, 7.83 mmol), and the reaction mixture was stirred at room temperature for 18 hours. The resulting mixture was concentrated under vacuum, and the residue was partitioned between DCM (x 2) and water. The combined organic extracts were washed with brine, dried (Na2SO4), concentrated under vacuum, and the crude residue was purified by chromatography on silica using 0%–50% EtOAc in cyclohexane as the eluent to give the title compound (60 mg, 31% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO- d 6) δ 10.22 (1H,br s), 9.60 (1H, br s), 7.66 (1H, s), 7.54 (1H, d J=8.3 Hz), 6.74 (1H, d J=7.5 Hz), 6.62 (1H, s), 6.53 (1H, s), 4.99 (2H, s); LCMS (Method 3): R t =3.57 min; m / z=246.9 [MH] - .

[1085] Program J

[1086] 3,8-Dihydroxy-2-methyl-6H-benzo[c]chromen-6-one (116) and

[1087] 2,6,6-Trimethyl-6H-benzo[c]chromene-3,8-diol (117)

[1088]

[1089] 3,8-Dihydroxy-2-methyl-6H-benzo[c]chromen-6-one (116)

[1090] 3,8-Dihydroxy-2-methyl-6H-benzo[c]chromene-6-one was prepared using standard procedures A and C2. 1 H NMR (400 MHz, DMSO-) d6) δ 10.15 (2H, br s), 8.11 (1H, d J=8.9 Hz), 7.92 (1H, s), 7.50 (1H, d J=2.7 Hz), 7.31 (1H, dd J=2.7, 8.7 Hz), 6.74 (1H, s), 2.21 (3H,s); LCMS (Method 3): R t =3.45 min; m / z=242.9 [M+1] + .

[1091] GP J1

[1092] 3,8-Bis((tert-butyldimethylsilyl)oxy)-2-methyl-6H-benzo[c]chromen-6-one (Intermediate 14)

[1093] 3,8-bis((tert-butyldimethylsilyl)oxy)-2-methyl-6H-benzo[c]chromene-6-one was prepared from 3,8-dihydroxy-2-methyl-6H-benzo[c]chromene-6-one (120) using general procedure I1. 1 H NMR (400 MHz, CDCl3) δ 7.89 (1H, d J=8.7 Hz), 7.76 (1H, d J=2.7 Hz), 7.71 (1H, s), 7.28 (1H, dd J=2.6, 8.8 Hz), 6.78 (1H, s), 2.29 (3H, s), 1.03 (9H, s), 1.01 (9H, s), 0.27 (6H, s), 0.26 (6H, s).

[1094] GP J2

[1095] 4,4'-Bis((tert-butyldimethylsilyl)oxy)-2'-(2-hydroxypropyl-2-yl)-5-methyl-[1,1'-biphenyl]-2-ol (Intermediate 15)

[1096] MeMgCl (3.0 M in THF; 0.64 mL, 1.92 mmol) was added to a solution of 3,8-bis((tert-butyldimethylsilyl)oxy)-2-methyl-6H-benzo[c]chromen-6-one (intermediate 14) (300 mg, 0.637 mmol) in 2-Me THF (6.0 mL), and the resulting solution was stirred at room temperature for 18 hours. The reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc (x 2), then dried (Na2SO4) and concentrated under vacuum to give the title compound (320 mg, quantified) as a colorless oil.1 H NMR (400 MHz, CDCl3) δ 7.10 (1H, d J=2.5 Hz), 6.94 (1H, d J=8.2 Hz), 6.86 (1H, s), 6.75 (1H, dd J=2.5, 8.2 Hz), 6.43 (1H, s), 5.08 (1H, s), 2.13 (3H, s), 2.04 (1H, s), 1.53 (3H, s), 1.42 (3H, s), 1.03(9H, s), 1.01 (9H, s), 0.26 (3H, s), 0.25 (3H, s), 0.24 (6H, s).

[1097] GP J3

[1098] ((2,6,6-trimethyl-6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane)(Intermediate 16)

[1099] A solution of 4,4'-bis((tert-butyldimethylsilyl)oxy)-2'-(2-hydroxypropyl-2-yl)-5-methyl-[1,1'-biphenyl]-2-ol (intermediate 15) (320 mg, 0.637 mmol) in toluene (5.0 mL) was treated with PTSA·H₂O, and the resulting mixture was heated at 50 °C for 1 hour. The resulting solution was directly purified by chromatography on silica using DCM as the eluent to give a product (280 mg, 90%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.48(1H, d J=8.4 Hz), 6.38 (1H, s), 6.77 (1H, dd J=2.4, 8.4 Hz), 6.68 (1H, d J=2.4 Hz), 6.39 (1H, s), 2.19 (3H, s), 1.57 (6H, s), 1.02 (9H, s), 0.99 (9H, s), 0.23 (6H, s), 0.21 (6H, s). LCMS (Method 3): R t =3.57 min; m / z=246.9 [MH] - .

[1100] GP J4

[1101] 2,6,6-Trimethyl-6H-benzo[c]chromene-3,8-diol (117)

[1102] A suspension of ((2,6,6-trimethyl-6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane) (intermediate 16) (270 mg, 0.557 mmol) in MeOH (5.0 mL) was treated with solid KF (97 mg, 1.67 mmol), and the resulting suspension was stirred at room temperature for 18 hours. The resulting mixture was adsorbed onto HMN and purified by chromatography on silica using 0%–30% EtOAc in cyclohexane as the eluent to give a semi-pure product (121 mg) as a pale yellow oil. Further purification was achieved by grinding from a mixture of DCM and n-pentane to give the title compound (91 mg, 64%) as a white solid. 1 H NMR (400 MHz, DMSO- d 6) δ 9.40 (1H, s), 9.32 (1H,s), 7.47 (1H, d J=8.4 Hz), 7.38 (1H, s), 6.71 (1H, dd J=2.3, 8.4 Hz), 6.66(1H, d J=2.3 Hz), 6.31 (1H, s), 2.09 (3H, s), 1.50 (6H, s); LCMS (Method 3): R t =3.80 min; m / z=257.1 [M+H] + .

[1103] Program K

[1104] 1-Fluoro-3,8-Dihydroxyphenanthridine-6(5H)-one(118)

[1105]

[1106] GP K1

[1107] 2-Bromo-N-(3-fluoro-5-methoxyphenyl)-5-methoxybenzamide (Intermediate 17)

[1108] Triethylamine (0.58 mL, 4.17 mmol) was added to a solution of 2-bromo-5-methoxybenzoyl chloride (694 mg, 2.78 mmol) in THF (15 mL), followed by the addition of 5-methoxyaniline (393 mg, 2.78 mmol). The resulting solution was stirred at room temperature for 18 hours, then partitioned between water and DCM (x 2), and the combined organic extracts were dried and concentrated under vacuum. The residue was purified by chromatography on silica using 0%–100% DCM in cyclohexane as the eluent to give the title compound (700 mg, 71% yield) as a pale yellow solid. LCMS (Method 6): R t =1.53 min; m / z=354.2 / 356.2 [M+H] + .

[1109] GP K2

[1110] 2-Bromo-N-(3-Fluoro-5-methoxyphenyl)-5-methoxy-N-((2-(trimethylsilyl)ethoxy)methyl)benzamide (Intermediate 18)

[1111] A solution of 2-bromo-N-(3-fluoro-5-methoxyphenyl)-5-methoxybenzamide (intermediate 17) (300 mg, 1.09 mmol) in anhydrous DMF (3.0 mL) was treated with NaH (60 wt%; 87 mg, 2.18 mmol) and stirred at room temperature for 30 min until gas escaping stopped. SEM-Cl (0.72 mL, 3.27 mmol) was added to the reaction mixture and stirring was continued at room temperature for 18 h. The resulting solution was diluted with water (100 mL), extracted with EtOAc (x 3), and the combined organic extracts were washed with brine, dried, and concentrated under vacuum. The residue was purified by chromatography on silica using 0%–30% EtOAc in cyclohexane as the eluent to give the title compound (430 mg, 97% yield) as a pale yellow solid. LCMS (Method 6): R t =1.89 min; m / z=482.3 / 484.3 [M+H] + .

[1112] GP K3

[1113] 1-Fluoro-3,8-dimethoxy-5-((2-(trimethylsilyl)ethoxy)methyl)phenanthridine-6(5H)-one (Intermediate 19)

[1114] A solution of 2-bromo-N-(3-fluoro-5-methoxyphenyl)-5-methoxy-N-((2-(trimethylsilyl)ethoxy)methyl)benzamide (intermediate 18) (830 mg, 1.71 mmol) in anhydrous DMF (8.0 mL) was added to a microwave-safe vial. AgCO3 (945 mg, 3.43 mmol), Pd(OAc)2 (58 mg, 0.257 mmol), and tris(o-tolyl)phosphine (156 mg, 0.514 mmol) were added, and the resulting mixture was degassed under argon and then heated at 130 °C for 18 hours. The cooled reaction mixture was filtered through Celite®, then partitioned between water and EtOAc (x 3), and the combined organic extracts were washed with brine, dried, and concentrated under vacuum. The residue was purified by chromatography on silica using 0%–50% EtOAc in cyclohexane as the eluent to give a semi-pure product (270 mg). Further purification by grinding from a mixture of DCM and n-pentane yielded a purer substance, but additional purification by chromatography on silica using 0%–20% EtOAc in cyclohexane as the eluent was required to give the pure title compound as a white solid (186 mg, 27%). 1 HNMR (400 MHz, CDCl3) δ 8.52 (1H, dd J=2.5, 9.1 Hz), 7.98 (1H, d J=3.0 Hz), 7.33 (1H, m), 7.04 (1H, m), 6.66 (1H, dd J=2.5, 14.9 Hz), 5.83 (2H, s), 3.95(3H, s), 3.90 (3H, s), 3.76 (2H, t J=7.9 Hz), 0.97 (2H, t, J=8.1 Hz), -0.02(9H, s).

[1115] GP K4

[1116] 1-Fluoro-3,8-Dihydroxyphenanthridine-6(5H)-one(118)

[1117] A solution of 1-fluoro-3,8-dimethoxy-5-((2-(trimethylsilyl)ethoxy)methyl)phenanthridine-6(5H)-one (intermediate 19) (86 mg, 0.213 mmol) in DCM (2.0 mL) was treated dropwise with BBr3, and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was carefully quenched with water and then azeotropically reacted with MeOH (x 4) to give a yellow solid intermediate hydroxymethylamide, which was partially deprotected from the SEM protecting group. LCMS (Method 6): Rt =1.09 min; m / z=276.0 [M+1] + .

[1118] The intermediate hydroxymethylamide (3.0 mL) was treated with concentrated ammonia, and the resulting turbid solution was stirred at room temperature for 3 hours. It was then azeotropically reacted with MeOH (x 4) to give a crude product as a gray solid. Further purification was achieved by reversed-phase chromatography on C18 silica using 3%–97% MeCN in water (+0.1% formic acid) to give the pure title compound (52 mg, 84%) as a grayish-white solid after lyophilization. 1 H NMR (400 MHz, DMSO- d 6) δ 11.60 (1H, br s), 10.05 (2H, brs), 8.28 (1H, d J=9.2 Hz), 7.66 (1H, d J=2.3 Hz), 7.25 (1H, m), 6.64 (1H, s),6.49 (1H, d J=15.3 Hz); LCMS (Method 3): R t =2.98 min; m / z=246.0 [M+1] + .

[1119] Program L

[1120] 6-Methyl-6H-benzo[c]chromene-3,8-diol (119)

[1121]

[1122] GP L1

[1123] 3,8-Bis((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromene-6-one (Intermediate 20)

[1124] 3,8-bis((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-one was prepared using standard procedure I1. 1 H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.8 Hz, 1H), 7.85 – 7.80 (m, 1H), 7.76 (d, J = 2.6 Hz, 1H), 7.29 (dd, J = 8.7, 2.7 Hz, 1H), 6.86 – 6.80 (m,2H), 1.02 (s, 9H), 0.98 (s, 9H), 0.26 (s, 6H), 0.24 (s, 6H).

[1125] GP L2

[1126] 3,8-Bis((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromene-6-ol (Intermediate 21)

[1127] DIBAL-H (1M in toluene, 2.10 mL, 2.10 mmol) was added very slowly to a solution of 3,8-bis((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-one (intermediate 20) (912 mg, 2.0 mmol) in toluene (20 mL) under an inert atmosphere and at -78 °C. Stirring was continued at -78 °C for 1 hour. The reaction mixture was quenched at -78 °C by adding water, following Fieser post-treatment and subsequent standard Fieser post-treatment. The solvent was removed by filtration through silica and under vacuum to give the desired mesoacetal as a white solid, which was used in the next step without further purification (921 mg, quantified). 1 H NMR (400 MHz, CDCl3) δ 7.60 (dd, J = 8.9, 6.9 Hz, 2H), 6.93 (dd, J = 8.5, 2.5 Hz, 1H), 6.83 (d, J = 2.6 Hz, 1H), 6.62 – 6.58 (m, 2H), 6.26 (s, 1H), 1.00 (s, 9H), 0.98 (s, 9H), 0.25 – 0.18 (m, 12H).

[1128] GP L3

[1129] 4,4'-Bis((tert-butyldimethylsilyl)oxy)-2'-(1-hydroxyethyl)-[1,1'-biphenyl]-2-ol (Intermediate 22)

[1130] MeMgBr (3M in Et2O, 1.0 mL) was added to a solution of 3,8-bis((tert-butyldimethylsilyl)oxy)-6H-benzo[c]chromen-6-ol (intermediate 21) (458 mg, 1 mmol) in anhydrous THF (10 mL) under an inert atmosphere and at 0 °C. Stirring was continued at 0 °C for 1 hour. The reaction mixture was quenched with water (100 mL) and extracted with Et2O; the ether extract was dried over Na2SO4, filtered through silica, washed with Et2O, and then concentrated under vacuum. The crude residue was used in the next step without further purification (475 mg, quantified).

[1131] 1H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 2.6 Hz, 0.4H), 7.12 (d, J = 2.6 Hz,0.6H), 7.07 (s, 0.4H), 7.04 (s, 0.6H), 6.96 (d, J = 8.1 Hz, 0.4H), 6.90 (d, J =8.5 Hz, 0.6H), 6.86 – 6.78 (m, 1H), 6.52 – 6.43 (m, 2H), 4.79 (q, J = 6.4 Hz, 0.4H), 4.73 (q, J = 6.5 Hz, 0.6H), 1.36 (d, J = 6.4 Hz, 1.2H), 1.30 (d, J = 6.4 Hz, 1.8H), 1.01 (s, 7.2H), 1.00 (s, 10.8H), 0.25 (s, 4.8H), 0.24 (s, 7.2H).

[1132] GP L4

[1133] ((6-methyl-6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane) (Intermediate 23)

[1134] PTSA monohydrate (19.0 mg, 0.19 mmol) was added to a solution of 4,4'-bis((tert-butyldimethylsilyl)oxy)-2'-(1-hydroxyethyl)-[1,1'-biphenyl]-2-ol (intermediate 22) (470 mg, 0.98 mmol) in toluene (10 mL), and the resulting mixture was heated overnight at 70 °C. The reaction mixture was filtered through silica, washed with DCM, and concentrated under vacuum. The residue was purified by column chromatography (silica, 0%–25% DCM / cyclohexane) to give the desired ether (411 mg, 90%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.48 (dd, J = 8.5, 4.1Hz, 2H), 6.80 (dd, J = 8.4, 2.5 Hz, 1H), 6.61 (dd, J = 2.4, 0.8 Hz, 1H), 6.52(dd, J = 8.4, 2.4 Hz, 1H), 6.47 (d, J = 2.4 Hz, 1H), 5.17 (q, J = 6.5 Hz,1H), 1.00 (s, 9H), 0.98 (s, 9H) 0.92 – 0.84 (m, 3H), 0.21 (s, 6H), 0.20 (s,6H).

[1135] GP L5

[1136] 6-Methyl-6H-benzo[c]chromene-3,8-diol (119)

[1137] Acetyl chloride (96 mL, 1.35 mmol) was slowly added to a solution of ((6-methyl-6H-benzo[c]chromene-3,8-diyl)bis(oxy))bis(tert-butyldimethylsilane) (intermediate 23) (411 mg, 0.90 mmol) in anhydrous MeOH (10 mL) at 0 °C, and the resulting mixture was stirred overnight. The solvent was removed under vacuum, and the residue was purified by column chromatography (silica, 0%–100% EtOAc / cyclohexane) to provide the title compound (202 mg, 98%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 9.47 (s, 1H), 9.45 (s, 1H), 7.49 (t, J = 8.7 Hz, 2H), 6.73 (dd, J = 8.4, 2.5 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H), 6.43 (dd, J = 8.4, 2.4Hz, 1H), 6.30 (d, J = 2.4 Hz, 1H), 5.14 (q, J = 6.5 Hz, 1H), 1.44 (d, J = 6.5Hz, 3H).

[1138] The following examples in Table 2 were prepared using a method similar to that described above by utilizing the general procedure (GP) shown.

[1139] Table 2.

[1140]

[1141]

[1142] Unless otherwise stated, NMR spectra in DMSO- d 6 Obtained from.

[1143] Program M

[1144] 10-Fluoro-3,9-Dihydroxydibenzo[c,e]oxacon-5(7H)-one(132)

[1145]

[1146] GP M1

[1147] Methyl 5'-fluoro-2'-formyl-4,4'-dimethoxy-[1,1'-biphenyl]-2-carboxylate (Intermediate 24)

[1148] A mixture of 2-bromo-4-fluoro-5-methoxybenzaldehyde (250 mg, 1.07 mmol), methyl 5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzoate (345 mg, 1.18 mmol), and potassium phosphate (683 mg, 3.22 mmol) in dioxane (4 mL) and water (0.4 mL) was placed in a tube and degassed by purging with argon for 10 min. XPhos-Pd-G3 (45 mg, 0.05 mmol) was then added, and the mixture was sealed, degassed, and purged with argon. The mixture was heated at 50 °C for 1 h. The resulting cooled mixture was diluted with water, extracted with EtOAc (x 3), and the combined organic extracts were washed with brine, dried, and concentrated under vacuum. The residue was purified by silica chromatography using 0%–25% EtOAc in cyclohexane as the eluent to give the title compound (280 mg, 82% yield) as a light brown solid. ¹H NMR (400 MHz, CDCl₃) δ 9.66 (1H, s), 7.59 (1H, d, J=8.8 Hz), 7.55 (1H, d, J=2.8 Hz), 7.19 (1H, d, J=8.4 Hz), 7.14–7.08 (1H, m), 6.97 (1H, d, J=11.2 Hz), 3.99 (3H, s), 3.91 (3H, s), 3.67 (3H, s).

[1149] GP M2

[1150] 10-Fluoro-3,9-Dimethoxydibenzo[c,e]oxacon-5(7H)-one (Intermediate 25)

[1151] Sodium borohydride (32 mg, 0.85 mmol) was added fractionally to a solution of methyl 5'-fluoro-2'-formyl-4,4'-dimethoxy-[1,1'-biphenyl]-2-carboxylate (intermediate 24) (270 mg, 0.85 mmol) in MeOH (4 mL). The solution was stirred for 30 min, then quenched with water and evaporated. The resulting mixture was diluted with water and EtOAc; this resulted in a large precipitate at the interface, which was separated by filtration and dissolved in a large amount of ethyl acetate. The combined organic extracts were concentrated under vacuum. The solid residue was dissolved in CHCl3 / MeOH and evaporated to half volume, resulting in crystallization of the product as a white solid. The mother liquor was adsorbed onto HMN and purified by chromatography on silica using 0%–5% EtOAc in DCM as the eluent to obtain an additional product. The two batches of products were combined to give the title compound as a white solid (150 mg, 61% yield).

[1152] ¹H NMR (400 MHz, CDCl3) δ 7.47 (1H, d, J=2.7 Hz), 7.44 (1H, d, J=8.6Hz), 7.33 (1H, d, J=11.9 Hz), 7.21 (1H, dd, J=2.7, 8.8 Hz), 7.04 (1H, d, J=8.2 Hz), 5.03 - 4.89 (2H, m), 3.96 (3H, s), 3.91 (3H, s).

[1153] GP M3

[1154] 10-Fluoro-3,9-Dihydroxydibenzo[c,e]oxacon-5(7H)-one(132)

[1155] 10-Fluoro-3,9-Dimethoxydibenzo[c,e]oxacon-5(7H)-one (intermediate 25) (145 mg, 0.5 mmol) was suspended in DCM (10 mL), and boron tribromide (2 mL. 1 M solution in DCM, 2.0 mmol) was added dropwise at room temperature. The resulting yellow solution was stirred overnight to give a yellow suspension. The mixture was cooled in ice water, and isopropanol (5 mL) was added dropwise to quench the reactants. The solvent was removed under vacuum. The resulting beige powder was dissolved in MeOH and adsorbed onto HMN, and purified by chromatography on silica using 0%–30% Et0Ac in DCM to give an impure product. The impure product was further purified on silica using 0%–5% MeOH in DCM as the eluent to give the title compound (25 mg, 19%) as a grayish-white solid.

[1156] 1 H NMR (400 MHz, DMSO- d 6) δ 10.59 - 9.60 (2H, m), 7.50 (1H, d, J=4.6Hz), 7.47 (1H, d, J=8.3 Hz), 7.19 (1H, d, J=2.7 Hz), 7.16 (1H, d, J=8.9 Hz), 7.11 (1H, dd, J=2.7, 8.6 Hz), 5.10 - 4.74 (2H, m). LCMS (Method 3): R t =2.96 min; m / z=259.0 [MH] - .

[1157] The other compounds were prepared according to a method adapted from the above procedure.

[1158] Example 3: Synthesis of additional representative compounds of the present invention

[1159] Unless otherwise specified, all reactions were carried out using oven-dried glassware and under an inert atmosphere (nitrogen). Unless otherwise specified, all solvents were used as is. Commercial reagents were used as is without further purification. Organic solutions were concentrated under reduced pressure using a Büchi rotary evaporator.

[1160] Thin-layer chromatography was performed using Merck Kieselgel 60 F254 (230-400 mesh) fluorescently treated silica, and visualized under UV light (254 and 366 nm) and / or by staining with an aqueous potassium permanganate solution. ¹H NMR spectra were recorded in deuterated solvents at 400 MHz on a Bruker spectrometer or at 60 MHz on a Nanalysis NMReady-60PRO spectrometer, with the residual proton solvent serving as an internal standard. ¹³C NMR spectra were recorded in deuterated solvents at 100 MHz on a Bruker spectrometer, with the central peak of the deuterated solvent serving as an internal standard. Chemical shifts (δ) are given in parts per million (ppm), and coupling constants (J) are given rounded to the nearest 0.1 Hz in Hertz (Hz). ¹H NMR spectra are reported as δ / ppm (multiplicity, proton number, coupling constant J / Hz) relative to the low field of tetramethylsilane. 13 C10 NMR spectra are reported as δ / ppm. TLC-MS data were obtained on an Advion Expression CMS coupled with a Plate Express TLC reader. Medium-pressure liquid chromatography (MPLC) was performed on a Biotage Isolera Four with a built-in UV detector and a fraction collector with an Interchim silica column.

[1161] 1. ((8-(benzyloxy)-2,6,6,9-tetramethyl-6H-benzo[c]chromen-3-yl)oxy)(tert-butyl)dimethyl Synthesis of silanes

[1162]

[1163] ((8-(benzyloxy)-2,6,6,9-tetramethyl-6H-benzo[c]chromen-3-yl)oxy)(tert-butyl)dimethylsilane was prepared from 3-hydroxy-4-methylbenzoic acid in 7 steps.

[1164] Option 1.

[1165]

[1166] Step 1: Synthesis of methyl 3-hydroxy-4-methylbenzoate

[1167]

[1168] Sulfuric acid (1.3 g, 0.70 mL, 0.2 equivalents, 13 mmol) was added to a suspension of 3-hydroxy-4-methylbenzoic acid (10 g, 1 equivalent, 66 mmol) in methanol (2.1 g, 0.16 L, 0.4 mol, 1 equivalent, 66 mmol), and the mixture was refluxed overnight. The methanol was evaporated under vacuum, and the crude material was extracted with a saturated solution of EtOAc and Na₂CO₃. The organic phase was washed with water, dried over sodium sulfate, and concentrated under vacuum to give methyl 3-hydroxy-4-methylbenzoate (8.7 g, 52 mmol, 80%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 9.73 (d, J = 0.5 Hz, 1H), 7.39 (d, J =1.7 Hz, 1H), 7.31 (dd, J = 7.7, 1.7 Hz, 1H), 7.19 (d, J = 7.7 Hz, 1H), 3.80 (s,3H), 2.17 (d, J = 0.6 Hz, 3H).

[1169] Step 2: Synthesis of methyl 3-(benzyloxy)-4-methylbenzoate

[1170]

[1171] Methyl 3-hydroxy-4-methylbenzoate (8.7 g, 1 equivalent, 52 mmol) was dissolved in acetonitrile (2.1 g, 0.13 L, 0.4 mol, 1 equivalent, 52 mmol). Potassium carbonate (7.2 g, 1 equivalent, 52 mmol) was added, followed by benzyl bromide (9.0 g, 6.2 mL, 1 equivalent, 52 mmol), and the mixture was heated overnight at 50 °C. Water was added and the aqueous phase was extracted with EtOAc. The organic phase was washed successively with water and brine, dried over sodium sulfate, and evaporated under vacuum to give methyl 3-(benzyloxy)-4-methylbenzoate (10.9 g, 42.5 mmol, 81%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.61 –7.57 (m, 2H), 7.51 – 7.30 (m, 6H), 7.23 – 7.19 (m, 1H), 5.14 (s, 2H), 3.91(s, 3H), 2.33 (d, J = 0.7 Hz, 3H).

[1172] Step 3: Synthesis of methyl 5-(benzyloxy)-2-bromo-4-methylbenzoate

[1173]

[1174] Bromine (8.16 g, 2.63 mL, 1.2 equivalents, 51.0 mmol) was added to a suspension of methyl 3-(benzyloxy)-4-methylbenzoate (10.9 g, 1 equivalent, 42.5 mmol) in acetic acid (51.1 g, 48.7 mL, 20 equivalents, 851 mmol) and water (38.3 g, 38.3 mL, 50 equivalents, 2.13 mol) at room temperature, and the resulting mixture was heated to 60 °C overnight. After cooling to room temperature, ice was added, and the reaction mixture was stirred at room temperature for 2 hours. The precipitate was filtered off and washed with cold water, and dried under vacuum to give methyl 5-(benzyloxy)-2-bromo-4-methylbenzoate (13 g, 39 mmol, 91%) as a white solid. 1 HNMR (400 MHz, CDCl3) δ 7.46 – 7.32 (m, 7H), 5.09 (s, 2H), 3.92 (s, 3H), 2.27(d, J = 0.8 Hz, 3H).

[1175] Step 4: Synthesis of 5-(benzyloxy)-2-bromo-4-methylbenzoic acid

[1176]

[1177] Methyl 5-(benzyloxy)-2-bromo-4-methylbenzoate (3000.00 mg, 1 equivalent, 8.950 mmol) was dissolved in methanol (286.8 mg, 17.90 mL, 0.5 mol, 1 equivalent, 8.950 mmol) and THF (645.4 mg, 44.75 mL, 0.2 mol, 1 equivalent, 8.950 mmol) at room temperature. The solution was then cooled to 0 °C. LiOH (643.0 mg, 3 equivalent, 26.85 mmol) was added dropwise to a solution of water (161.3 mg, 17.90 mL, 0.5 mol, 1 equivalent, 8.950 mmol) with stirring overnight. The methanol and THF were evaporated under vacuum. The resulting crude product was extracted twice with ethyl acetate and 1M HCl. The combined organic phases were washed once with brine, dried over sodium sulfate, and concentrated under vacuum to give 5-(benzyloxy)-2-bromo-4-methylbenzoic acid (2.7 g, 8.4 mmol, 94%) as a white solid. 1H NMR (400 MHz, DMSO) δ 13.26 (s,1H), 7.52 (d, J = 0.9 Hz, 1H), 7.48 – 7.44 (m, 2H), 7.43 – 7.38 (m, 3H), 7.36 –7.31 (m, 1H), 5.17 (s, 2H), 2.26 – 2.19 (m, 3H).

[1178] Step 5: Synthesis of 8-(benzyloxy)-3-hydroxy-2,9-dimethyl-6H-benzo[c]chromene-6-one

[1179]

[1180] Sodium carbonate (2.970 g, 3.0 Eq, 28.02 mmol) was dissolved in water (168.3 mg, 46.70 mL, 0.2 mol, 1 equivalent, 9.341 mmol) at room temperature. 4-Methylphenyl-1,3-diol (2.319 g, 2.0 equivalent, 18.68 mmol) was added in portions and the mixture was heated at 60 °C for 30 min. 5-(benzyloxy)-2-bromo-4-methylbenzoic acid (3000 mg, 1 equivalent, 9.341 mmol) was added in portions and the mixture was stirred at 60 °C for 1 h. CuI (1.245 g, 0.7 equivalent, 6.539 mmol) was added and the reaction mixture was heated overnight at the same temperature. A precipitate formed after the addition of CuI. The precipitate was filtered off and washed successively with water and 1M HCl. The solid was dried under high vacuum to obtain a beige solid of 8-(benzyloxy)-3-hydroxy-2,9-dimethyl-6H-benzo[c]chromene-6-one (1.8 g, 5.2 mmol, 56%). 1 H NMR (400 MHz, DMSO) δ 10.16 (s,1H), 8.12 (s, 1H), 7.97 (s, 1H), 7.63 (s, 1H), 7.51 (d, J = 7.0 Hz, 2H), 7.42(t, J = 7.4 Hz, 2H), 7.36 – 7.32 (m, 1H), 6.74 (s, 1H), 5.26 (s, 2H), 2.39 (s, 3H), 2.21 (s, 3H).

[1181] Step 6: Synthesis of 8-(benzyloxy)-3-((tert-butyldimethylsilyl)oxy)-2,9-dimethyl-6H-benzo[c]chromen-6-one

[1182]

[1183] 8-(benzyloxy)-3-hydroxy-2,9-dimethyl-6H-benzo[c]chromen-6-one (1.7 g, 1 equivalent, 4.9 mmol) was dissolved in DMF (0.36 g, 49 mL, 0.1 mol, 1 equivalent, 4.9 mmol) at room temperature. Triethylamine (1.2 g, 1.7 mL, 2.5 equivalent, 12 mmol) was added and the mixture was cooled to 0 °C. TBDMS-Cl (0.89 g, 1.2 equivalent, 5.9 mmol) was added and stirring continued overnight at room temperature. The reaction mixture was extracted with 1 M HCl and EtOAc. The combined organic phases were washed successively with water and brine, dried over sodium sulfate, and concentrated under vacuum. The crude material was purified by rapid column chromatography on silica (0%-50% EtOAc in Hex) to obtain 8-(benzyloxy)-3-((tert-butyldimethylsilyl)oxy)-2,9-dimethyl-6H-benzo[c]chromen-6-one (1.18 g, 2.56 mmol, 52%). f = 0.7 (EtOAc / cyclohexane 20%). 1 H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 1.0 Hz, 1H), 7.78 (s, 1H), 7.73 (s, 1H),7.51 – 7.47 (m, 2H), 7.45 – 7.39 (m, 2H), 7.38 – 7.33 (m, 1H), 6.79 (s, 1H),5.20 (s, 2H), 2.46 (d, J = 0.8 Hz, 3H), 2.30 (d, J = 0.7 Hz, 3H), 1.04 (s, 9H), 0.28 (s, 6H).

[1184] Step 7: Synthesis of ((8-(benzyloxy)-2,6,6,9-tetramethyl-6H-benzo[c]chromen-3-yl)oxy)(tert-butyl)dimethylsilane

[1185]

[1186] 8-(benzyloxy)-3-((tert-butyldimethylsilyl)oxy)-2,9-dimethyl-6H-benzo[c]chromen-6-one (1170 mg, 1 equivalent, 2.540 mmol) was dissolved in THF (183.2 mg, 25.40 mL, 0.1 mol, 1 equivalent, 2.540 mmol), and the reaction mixture was cooled to 0°C in an ice bath. Then, methyl magnesium bromide (1.333 g, 3.725 mL, 3 mol, 4.4 equivalent, 11.18 mmol) was added in a single dose. The reaction mixture was stirred at 0°C for 10 minutes, then heated to room temperature. Stirring was continued at room temperature for 1 hour, after which the reaction mixture was quenched with water and extracted with EtOAc (3x). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude substance was dissolved in 20 mL of EtOAc, and PTSOH (48.31 mg, 0.1 equivalent, 254.0 µmol) was added in a single dose. The mixture was heated at 60 °C for 1 hour. The reaction mixture was extracted once with a saturated solution of EtOAc and sodium bicarbonate, dried over sodium sulfate, and concentrated under vacuum to give a light brown solid ((8-(benzyloxy)-2,6,6,9-tetramethyl-6H-benzo[c]chromen-3-yl)oxy)(tert-butyl)dimethylsilane (1100 mg, 2.317 mmol, 91.23%). f = 0.6 (EtOAc / cyclohexane 20%). 1 H NMR (400 MHz, CDCl3) δ 7.57 –7.46 (m, 2H), 7.45 – 7.38 (m, 2H), 7.37 – 7.30 (m, 1H), 7.21 (s, 1H), 6.85(d, J = 0.9 Hz, 1H), 6.44 (s, 1H), 5.14 (s, 2H), 2.24 (d, J = 0.8 Hz, 3H), 2.14 (s, 3H), 1.51 (s, 3H), 1.40 (s, 3H), 1.03 (s, 9H), 0.26 (s, 3H), 0.25 (s, 3H).

[1187] 2. Synthesis of 2,6,6,9-Tetramethyl-8-(methylamino)-6H-benzo[c]chromen-3-ol (2a)

[1188]

[1189] 2a was synthesized in four steps starting with ((8-(benzyloxy)-2,6,6,9-tetramethyl-6H-benzo[c]chromen-3-yl)oxy)(tert-butyl)dimethylsilane.

[1190] Option 2.

[1191]

[1192] Step 1: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-2,6,6,9-tetramethyl-6H-benzo[c]chromen-8-ol

[1193]

[1194] ((8-(benzyloxy)-2,6,6,9-tetramethyl-6H-benzo[c]chromen-3-yl)oxy)(tert-butyl)dimethylsilane (400 mg, 1 equivalent, 843 μmol) was dissolved in methanol (27.0 mg, 8.43 mL, 0.1 mol, 1 equivalent, 843 μmol) and dichloromethane (71.6 mg, 4.21 mL, 0.2 mol, 1 equivalent, 843 μmol). Carbon-supported palladium hydroxide (118 mg, 20% Wt, 0.2 equivalent, 169 μmol) was added in a single addition, and the suspension was hydrogenated overnight at atmospheric pressure. After completion, the reaction mixture was filtered through a diatomaceous earth mat. p-Toluenesulfonic acid monohydrate (16.0 mg, 12.9 μL, 0.1 equivalent, 84.3 μmol) was added, and the mixture was then concentrated and loaded onto silica for purification by rapid column chromatography (SiO2, 12 g, 0%–5% MeOH in DCM) to give 3-((tert-butyldimethylsilyl)oxy)-2,6,6,9-tetramethyl-6H-benzo[c]chromen-8-ol (150 mg, 390 μmol, 46.3%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 9.35 (s, 1H), 7.49 (s, 1H), 7.44 (s, 1H), 6.67 (s, 1H), 6.26 (s, 1H), 2.15 (s, 3H), 2.13 (s, 3H), 1.47 (s, 6H), 0.98 (s, 9H), 0.20 (s, 6H).

[1195] Step 2: Synthesis of 3,3-((tert-butyldimethylsilyl)oxy)-2,6,6,9-tetramethyl-6H-benzo[c]chromene-8-yl ester of trifluoromethanesulfonic acid

[1196]

[1197] Trifluoromethanesulfonic anhydride (165 mg, 98.8 μL, 1.5 equivalents, 585 μmol) was added dropwise to a solution of 3-((tert-butyldimethylsilyl)oxy)-2,6,6,9-tetramethyl-6H-benzo[c]chromen-8-ol (150 mg, 1 equivalent, 390 μmol) and pyridine (309 mg, 315 μL, 10 equivalents, 3.90 mmol) in 10 mL of DCM at 0 °C, and the mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC using EtOAc / cyclohexane 10% eluent. Dichloromethane was evaporated under vacuum, and the crude product was extracted with HCl 1M and EtOAc. The organic phase was washed once with water, dried over sodium sulfate, and concentrated under vacuum to give 3-((tert-butyldimethylsilyl)oxy)-2,6,6,9-tetramethyl-6H-benzo[c]chromene-8-yl trifluoromethanesulfonic acid (140 mg, 271 μmol, 69.5%), which could be used in the next step without further purification. f 0.6 (EtOAc / cyclohexane 40%).

[1198] Step 3: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-N,2,6,6,9-pentamethyl-6H-benzo[c]chromene-8-amine

[1199]

[1200] t-Bu XPhos (23 mg, 0.4 equivalents, 54 µmol) was added to a suspension of tris(dibenzylacetone)dipalladium (25 mg, 0.2 equivalents, 27 µmol) in 8 mL of dioxane, and the ...

Claims

1. A method of treating amyotrophic lateral sclerosis (ALS), the method comprising administering to a subject in need thereof an effective amount of a compound of Formula (la), (Ia) wherein A is ; X1is selected from O and S; Y1is O; R1, R4, R5, and R8are independently selected from H and halo; R3and R6are independently selected from H, CN, OH, CF3, halo, and alkyl; one of R2and R7is H, OH, or OAc and the other of R2and R7is halo, CN, CF3, CO2H, NO2, NHAc, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylamino, alkyl-R9, alkenyl-R9, alkynyl-R9, OR 10 , NHR 10 , NR 11 C(O)R 12 , C(O)NR 11 R 12 , and NR 11 SO2R 12 ; each occurrence of R9is independently selected from OH, NH2, O-alkyl, O-alkyl- O-alkyl, alkylamino, NHC(O)-alkyl, N(CH3)C(O)-alkyl, NHSO2-alkyl, N(CH3)SO2-alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; R 10 selected from C2-C 12 alkyl, C(O)-alkyl, hydroxyalkyl, aminoalkyl, alkyl-O-alkyl, alkyl-O-alkyl-OH, alkyl-O-alkyl-O-alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, alkyl-heterocycloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, SO3H, SO2-alkyl, and SO2-haloalkyl; each occurrence of R is selected from the group consisting of H and alkyl; and 11 is selected from the group consisting of H and alkyl; and each occurrence of R 12 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, and alkyl-heterocycloalkyl; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein A is .

3. The method of claim 1 or 2, wherein R2is H.

4. The method of claim 1 or 2, wherein R2is OH.

5. The method of claim 1 or 2, wherein R2is OAc.

6. The method of claim 1 or 2, wherein R2is selected from haloalkyl, substituted cycloalkyl, alkynyl-R9, OR 10 and C(O)NR 11 R 12 ; R9is selected from OH, substituted cycloalkyl, and heterocycloalkyl; R 10 is selected from alkyl, substituted cycloalkyl, heterocycloalkyl, and alkylheterocycloalkyl; and R 11 is H and R 12 is alkyl-heterocycloalkyl.

7. The method of any one of claims 1-6, wherein R7is H.

8. The method of any one of claims 1-6, wherein R7is OH.

9. The method of any one of claims 1-6, wherein R7is OAc.

10. The method of any one of claims 1-5, wherein R7is selected from haloalkyl, substituted cycloalkyl, alkynyl-R9, OR 10 and C(O)NR 11 R 12 ; R9is selected from OH, substituted cycloalkyl, and heterocycloalkyl; R 10 is selected from the group consisting of alkyl, substituted cycloalkyl, heterocycloalkyl, and alkylheterocycloalkyl; and R 11 is H and R 12 is alkyl-heterocycloalkyl.

11. The method of claim 6 or 10, wherein each occurrence of substituted cycloalkyl is independently substituted with OH, halo, or hydroxyalkyl.

12. The method of any one of claims 1-11, wherein R1, R3, R4, R5, R6, and R8are each H.

13. The method of any one of claims 1-11, wherein one of R1, R3, R4, R5, R6, and R8is not H.

14. The method of any one of claims 1-11, wherein two of R1, R3, R4, R5, R6, and R8are not H.

15. The method of claim 13, wherein one of R1, R3, R4, R5, R6, and R8is alkyl or halo.

16. The method of claim 14, wherein two of R1, R3, R4, R5, R6, and R8are independently alkyl or halo.

17. The method of claim 15 or 16, wherein the compound is selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and .

18. The method of claim 1, wherein the compound is selected from:

19. The method of claim 1, wherein the compound is selected from:

20. The method of claim 1, wherein the compound is selected from:

21. The method of claim 1, wherein the compound is selected from:

22. A method of treating amyotrophic lateral sclerosis (ALS), the method comprising administering to a subject in need thereof an effective amount of a compound of Formula (Ic), (Ic) wherein A is ; n and m one of n and m the other is 1; X1and Y1are each O; R1, R2, R3, R6, R7, and R8are independently selected from H, OH, OCH3, OAc, NH2, halogen, CN, CF3, CO2H, NO2, NHAc, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylamino, alkyl-R9, alkenyl-R9, alkynyl-R9, OR 10 , NHR 10 , NR 11 C(O)R 12 , C(O)NR 11 R 12 , and NR 11 SO2R 12 ; R4and R5are independently selected from H, halo, and alkyl; each occurrence of R9is independently selected from the group consisting of OH, NH2, O-alkyl, O-alkyl-O-alkyl, alkylamino, NHC(O)-alkyl, N(CH3)C(O)-alkyl, NHSO2-alkyl, N(CH3)SO2-alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; R 10 selected from C2-C 12 alkyl, hydroxyalkyl, aminoalkyl, alkyl-O-alkyl, alkyl-O-alkyl-OH, alkyl-O-alkyl-O-alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, alkyl-heterocycloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, SO3H, SO2-alkyl, and SO2-haloalkyl; each occurrence of R is selected from the group consisting of H and alkyl; and 11 is selected from the group consisting of H and alkyl; and each occurrence of R 12 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, and alkyl-heterocycloalkyl, or a pharmaceutically acceptable salt thereof.

23. The compound of claim 39, wherein A is selected from and .

24. The compound of claim 22 or 23, wherein R2and R7are each OH.

25. The compound of claim 22 or 23, wherein R2and R7are each O-alkyl.

26. The compound of claim 22 or 23, wherein R2is OH; and R7is H or O-alkyl.

27. The compound of claim 22 or 23, wherein R2is H or O-alkyl; and R7is OH.

28. The compound of any one of claims 22-27, wherein R1, R3, R4, R5, R6, and R8are each H.

29. The compound of any one of claims 22-27, wherein one of R1, R3, R4, R5, R6, and R8is not H.

30. The compound of any one of claims 22-27, wherein two of R1, R3, R4, R5, R6, and R8are not H.

31. The compound of claim 29, wherein one of R1, R3, R4, R5, R6, and R8is alkyl or halo.

32. The compound of claim 30, wherein two of R1, R3, R4, R5, R6, and R8are alkyl or halo.

33. The compound of claim 31 or 32, wherein the compound is selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and .

34. The compound of claim 22, wherein the compound is selected from the group consisting of:

35. The compound of claim 22, wherein the compound is:

36. A method of treating amyotrophic lateral sclerosis (ALS), the method comprising administering to a subject in need thereof an effective amount of a compound of Formula (Id) (Id) wherein A is ; Y2is O; Y3and Y4are independently selected from the group consisting of H, halo, and alkyl; or, taken together with the carbon to which they are bonded, combine to form a cycloalkyl or heterocycloalkyl; R1, R4, R5, and R8are independently selected from the group consisting of H and halo; R2, R3, R6, and R7 are independently selected from H, OH, OCH3, OAc, NH2, halogen, CN, CF3, CO2H, NO2, NHAc, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylamino, alkyl-R9, alkenyl-R9, alkynyl-R9, OR 10 , NHR 10 , NR 11 C(O)R 12 , C(O)NR 11 R 12 , and NR 11 SO2R 12 ; each occurrence of R9is independently selected from the group consisting of OH, NH2, O-alkyl, O-alkyl-O-alkyl, alkylamino, NHC(O)-alkyl, N(CH3)C(O)-alkyl, NHSO2-alkyl, N(CH3)SO2-alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; R 10 selected from C2-C 12 alkyl, hydroxyalkyl, aminoalkyl, alkyl-O-alkyl, alkyl-O-alkyl-OH, alkyl-O-alkyl-O-alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, alkyl-heterocycloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, SO3H, SO2-alkyl, and SO2-haloalkyl; each occurrence of R is selected from the group consisting of H and alkyl; and 11 is selected from the group consisting of H and alkyl; and each occurrence of R 12 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, and alkyl-heterocycloalkyl; or a pharmaceutically acceptable salt thereof.

37. The compound of claim 36, wherein A is selected from , , , , , , , , and .

38. The compound of claim 36 or 37, wherein R2and R7are each OH.

39. The compound of claim 36 or 37, wherein one of R2and R7is OH, and the other of R2and R7is O-alkyl.

40. The compound of any one of claims 36-39, wherein one of R1, R3, R4, R5, R6, and R8is alkyl or halo.

41. The compound of any one of claims 36-39, wherein two of R1, R3, R4, R5, R6, and R8 are alkyl or halogen.

42. The compound of claim 40 or 41, wherein the compound is selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and .

43. The compound of claim 36, wherein the compound is selected from:

44. The compound of claim 36, wherein the compound is selected from:

45. A method of treating amyotrophic lateral sclerosis (ALS), the method comprising administering to a subject in need thereof an effective amount of a compound of Formula (Ie), (Ie) wherein A is ; n and m both are 0; or n and m one of them is 0, and n and m the other is 1; X1is O; Y1is selected from NH, N-CH3, N- t N-alkyl, N-alkenyl, N-alkynyl, N-aryl, N-heteroaryl, N-cycloalkyl, and N-heterocycloalkyl; R1, R2, R3, R6, R7, and R8are independently selected from H, OH, OCH3, OAc, NH2, halogen, CN, CF3, CO2H, NO2, NHAc, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylamino, alkyl-R9, alkenyl-R9, alkynyl-R9, OR 10 , NHR 10 , NR 11 C(O)R 12 , C(O)NR 11 R 12 , and NR 11 SO2R 12 ; R4and R5are independently selected from H, alkyl, and halogen; each occurrence of R9is independently selected from OH, NH2, O-alkyl, O-alkyl-O-alkyl, alkylamino, NHC(O)-alkyl, N(CH3)C(O)-alkyl, NHSO2-alkyl, N(CH3)SO2-alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; R 10 selected from C2-C 12 alkyl, hydroxyalkyl, aminoalkyl, alkyl-O-alkyl, alkyl-O-alkyl-OH, alkyl-O-alkyl-O-alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, alkyl-heterocycloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, SO3H, SO2-alkyl, and SO2-haloalkyl; each occurrence of R is selected from the group consisting of H and alkyl; and 11 is selected from the group consisting of H and alkyl; and each occurrence of R 12 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, and alkyl-heterocycloalkyl; or a pharmaceutically acceptable salt thereof.

46. The compound of claim 45, wherein n and m is also 0.

47. The compound of claim 46, wherein A is selected from , and .

48. The compound of claim 45, wherein one of n and m is 0, and n and m the other is 1.

49. The compound of claim 48, wherein A is selected from , , and .

50. The compound of any one of claims 45-49, wherein R2and R7are each OH.

51. The compound of any one of claims 45-49, wherein one of R2and R7is OH and the other of R2and R7is not OH.

52. The compound of any one of claims 45-49, wherein R2and R7are each O-alkyl.

53. The compound of any one of claims 45-49, wherein R2is OH and R7is O-alkyl; or R2is O-alkyl and R7is OH.

54. The compound of any one of claims 45-53, wherein R1, R3, R4, R5, R6, and R8are each H.

55. The compound of any one of claims 45-53, wherein one of R1, R3, R4, R5, R6, and R8is not H.

56. The compound of any one of claims 45-53, wherein two of R1, R3, R4, R5, R6, and R8are not H.

57. The compound of any one of claims 45-53, wherein one of R1, R3, R4, R5, R6, and R8is alkyl or halogen.

58. The compound of any one of claims 45-53, wherein two of R1, R3, R4, R5, R6, and R8are alkyl or halogen.

59. The compound of claim 57 or 58, wherein the compound is selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and .

60. The compound of claim 45, wherein the compound is selected from:

61. The compound of claim 45, wherein the compound is selected from:

62. The compound of claim 45, wherein the compound is selected from:

63. A method of treating amyotrophic lateral sclerosis (ALS), the method comprising administering to a subject in need thereof an effective amount of a compound of Formula (If), (If) wherein A is selected from , , , , , , , , , and ; n and m both are 0; or n and m one of them is 0, and n and m the other is 1; o and p while o and p one of o and p the other is 1; q is 0 or 1 ; r and s while r and s one of r and s the other is 1; X1and X2are each O; X3is O or N(alkyl); Y1is S; Y2is selected from O, CH2, NH, N-alkyl, S, S(O), and SO2; Y3and Y4are independently selected from H, halo, OH, and alkyl, or combine together with the carbon to which they are bonded to form a cycloalkyl or cycloheteroalkyl; Y5is selected from CH2, NH, N-alkyl, N-arylalkyl, N-cycloalkyl, and N-heterocycloalkyl; each occurrence of Y6is independently selected from O, S, S(O), SO2, NH, N-alkyl, N-alkylaryl, and N-cycloalkyl; Y7is selected from O, NH, and N-alkyl; Y8is selected from O and S; R1, R2, R3, R6, R7, and R8are independently selected from H, OH, OCH3, OAc, NH2, halogen, CN, CF3, CO2H, NO2, NHAc, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylamino, alkyl-R9, alkenyl-R9, alkynyl-R9, OR 10 , NHR 10 , NR 11 C(O)R 12 , C(O)NR 11 R 12 , and NR 11 SO2R 12 , R4and R5are independently selected from H, alkyl, and halo; each occurrence of R9is independently selected from OH, NH2, O-alkyl, O-alkyl-O-alkyl, alkylamino, NHC(O)-alkyl, N(CH3)C(O)-alkyl, NHSO2-alkyl, N(CH3)SO2-alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; R 10 selected from C2-C 12 alkyl, hydroxyalkyl, aminoalkyl, alkyl-O-alkyl, alkyl-O-alkyl-OH, alkyl-O-alkyl-O-alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, alkyl-heterocycloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, SO3H, SO2-alkyl, and SO2-haloalkyl; each occurrence of R is selected from the group consisting of H and alkyl; and 11 is selected from the group consisting of H and alkyl; and each occurrence of R 12 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, and alkyl-heterocycloalkyl; or a pharmaceutically acceptable salt thereof.

64. The compound of claim 63, wherein A is ; and n and m is also 0.

65. The compound of claim 64, wherein A is .

66. The compound of claim 63, wherein A is .

67. The compound of claim 66, wherein A is selected from , , , , , and .

68. The compound of claim 63, wherein A is .

69. The compound of claim 68, wherein A is selected from , , , , , , , , , , , , , , , , , , , , , and .

70. The compound of claim 63, wherein A is selected from , , , , and .

71. The compound of claim 70, wherein A is selected from , , , , , , , , , , , , , and .

72. The compound of any one of claims 63-71, wherein R2and R7are each OH.

73. The compound of any one of claims 63-71, wherein one of R2and R7is OH, and the other of R2and R7is not OH.

74. The compound of any one of claims 63-71, wherein R2and R7are each O-alkyl.

75. The compound of any one of claims 63-71, wherein R2is OH and R7is O-alkyl; or R2is O-alkyl and R7is OH.

76. The compound of any one of claims 63-71, wherein R1, R3, R4, R5, R6, and R8are each H.

77. The compound of any one of claims 63-71, wherein one of R1, R3, R4, R5, R6, and R8is not H.

78. The compound of any one of claims 63-71, wherein two of R1, R3, R4, R5, R6, and R8are not H.

79. The compound of any one of claims 63-71, wherein one of R1, R3, R4, R5, R6, and R8is alkyl or halo.

80. The compound of any one of claims 63-71, wherein two of R1, R3, R4, R5, R6, and R8are alkyl or halo.

81. The compound of claim 79 or 80, wherein the compound is selected from: , , , , , , , , , , , , , , , , , , , , , , and .

82. The compound of claim 63, wherein the compound is selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and .

83. The compound of claim 63, wherein the compound is selected from: 、 、 、 、 and .

84. A method of treating amyotrophic lateral sclerosis (ALS), the method comprising administering to a subject in need thereof an effective amount of a compound of Formula (Ih), (Ih) wherein A is selected from or ; n and m one of the other is 0, and n and m one of the other is 0, and n and m one of the other is 1. r and s both are 0; or r and s one of them is 0, and r and s the other one is 1; X1is O; Y1is selected from O, NH, N-alkyl, and N-cycloalkyl; Y2is O; Y3and Y4are independently selected from H, halo, and alkyl, or combine together with the carbon to which they are bonded to form a cycloalkyl or cycloheteroalkyl; R1, R4, R5, and R8are independently selected from H and halo; and R2and R7are each OH. R3and R6are independently selected from H, CN, OH, CF3, halogen, and alkyl; one of R2and R7is selected from NH2, NHCH3, and N(CH3)2, and the other of R2and R7is selected from H, halogen, OCH3, CN, CF3, CO2H, NO2, NHAc, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylamino, alkyl-R9, alkenyl-R9, alkynyl-R9, OR 10 , NHR 10 , NR 11 C(O)R 12 , C(O)NR 11 R 12 , and NR 11 SO2R 12 ; each occurrence of R9is independently selected from OH, NH2, O-alkyl, O-alkyl-O-alkyl, alkylamino, NHC(O)-alkyl, N(CH3)C(O)-alkyl, NHSO2-alkyl, N(CH3)SO2-alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; R 10 selected from H, C2-C 12 alkyl, hydroxyalkyl, aminoalkyl, alkyl-O-alkyl, alkyl-O-alkyl-OH, alkyl-O-alkyl-O-alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, alkyl-heterocycloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, SO3H, SO2-alkyl, and SO2-haloalkyl; Each occurrence of R 11 Selected from H and alkyl groups; and each occurrence of R 12 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, and alkyl-heterocycloalkyl; or a pharmaceutically acceptable salt thereof.

85. The compound of claim 84, wherein Y1is selected from O, NH, and N-alkyl.

86. The compound of claim 84 or 85, wherein A is ; and n and m is also 0.

87. The compound of claim 84 or 85, wherein A is .

88. The compound of claim 84 or 85, wherein A is or .

89. The compound of claim 84 or 85, wherein A is ; and n or m one of n or m is 0, and the other is 1.

90. The compound of claim 89, wherein A is or .

91. The compound of claim 89, wherein A is selected from , , and .

92. The compound of claim 84, wherein A is ; and r and s is also 0.

93. The compound of claim 92, wherein A is selected from , , , , , , , and .

94. The compound of claim 93, wherein A is selected from , and .

95. The compound of any one of claims 84-94, wherein R2is selected from NH2, NHCH3, and N(CH3)2.

96. The compound of any one of claims 84-94, wherein R7is selected from H, OH, halogen, O-alkyl, and haloalkyl.

97. The compound of any one of claims 84-94, wherein R7is selected from alkynyl-R9and OR 10 ; R9is OH; and R 10 is alkyl-heterocycloalkyl.

98. The compound of any one of claims 84-97, wherein R1, R3, R4, R5, R6, and R8are each H.

99. The compound of any one of claims 84-97, wherein one of R1, R3, R4, R5, R6, and R8is not H.

100. The compound of any one of claims 84-97, wherein two of R1, R3, R4, R5, R6, and R8are not H.

101. The compound of any one of claims 84-97, wherein one of R1, R3, R4, R5, R6, and R8is alkyl or halogen.

102. The compound of any one of claims 84-97, wherein two of R1, R3, R4, R5, R6, and R8are independently alkyl or halogen.

103. The compound of claim 101 or 102, wherein the compound is selected from: , , , , , , , , , , , , , , , , , , , , , , and .

104. The compound of claim 84, wherein the compound is selected from:

105. The compound of claim 84, wherein the compound is selected from:

106. The compound of claim 84, wherein the compound is selected from: or a pharmaceutically acceptable salt thereof.

107. A method of treating amyotrophic lateral sclerosis (ALS), the method comprising administering to a subject in need thereof an effective amount of a compound of Formula (IIa) (IIa) wherein Y1and Y2are each alkyl; or, taken together with the carbons to which they are bonded, combine to form an unsubstituted or substituted spirocycloalkyl; R1, R4, R5, and R8are independently selected from -H and halogen; R2and R7are independently selected from -H, -OH, -OAc, -NH2, halogen, -CN, -CF3, -CO2H, -NO2, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylamino, alkyl-R9, alkenyl-R9, alkynyl-R9, -OR 10 , -NHR 10 , -NR 11 C(O)R 12 , -C(O)NR 11 R 12 , and -NR 11 SO2R 12 ; R3and R6are alkyl; each occurrence of R9is independently selected from OH, NH2, O-alkyl, O-alkyl-O-alkyl, alkylamino, NHC(O)-alkyl, N(CH3)C(O)-alkyl, NHSO2-alkyl, N(CH3)SO2-alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; R 10 selected from alkyl, hydroxyalkyl, aminoalkyl, alkyl-O-alkyl, alkyl-O-alkyl-OH, alkyl-O-alkyl-O-alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, alkyl-heterocycloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, SO3H, SO2-alkyl, and SO2-haloalkyl; each occurrence of R is selected from the group consisting of H and alkyl; and 11 is selected from the group consisting of H and alkyl; and each occurrence of R 12 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, and alkyl-heterocycloalkyl; provided that when R1, R 4、 R5and R8are each -H, R2and R7are each -OH, and R3and R6are each CH3, then Y1and Y2are not each -Me or together with the carbon to which they are bonded do not form an unsubstituted spirocyclobutyl; or a pharmaceutically acceptable salt thereof.

108. The method of claim 107, wherein Y1and Y2are each independently C1-C4alkyl.

109. The method of claim 107, wherein Y1and Y2are each -CH3.

110. The method of claim 107, wherein Y1and Y2, together with the carbon to which they are bonded, combine to form an unsubstituted spirocycloalkyl.

111. The method of claim 110, wherein Y1and Y2, together with the carbon to which they are bonded, combine to form an unsubstituted spirocyclopropyl, cyclobutyl, or cyclopentyl.

112. The method of any one of claims 107-111, wherein R3and R6are each independently C1-C4alkyl.

113. The method of any one of claims 107-112, wherein R3and R6are each independently selected from -CH3and -CH2CH3.

114. The method of any one of claims 107-112, wherein R3and R6are each -CH3.

115. The method of any one of claims 107-112, wherein R3and R6are each -CH2CH3.

116. The method of any one of claims 107-112, wherein one of R3and R6is -CH3and the other of R3and R6is -CH2CH3.

117. The method of any one of claims 107-116, the compound having a structure selected from:

118. The method of any one of claims 107-117, wherein R2and R7are independently selected from -OH, -NH2, alkylamino, and -OR 10 .

119. The method of any one of claims 107-117, wherein R2and R7are each OH.

120. The method of any one of claims 107-117, wherein R2is -OH; and R7is -OCH3.

121. The method of any one of claims 107-117, wherein R7is -OH; and R2is -OCH3.

122. The method of any one of claims 107-117, wherein R2is selected from -NH2, -NHCH3, and -NH(CH3)2; and R7is OH.

123. The method of any one of claims 107-117, wherein R7is selected from -NH2, -NHCH3, and -NH(CH3)2; and R2is OH.

124. The method of any one of claims 118-123, wherein R1, R 4、 R5and R8are each -H.

125. The method of claim 107, wherein the compound is selected from: or a pharmaceutically acceptable salt thereof.

126. A method of treating amyotrophic lateral sclerosis (ALS), the method comprising administering to a subject in need thereof an effective amount of a compound of Formula (IIb), (IIb) wherein X1and X2are each alkyl; or, together with the carbon to which they are bonded, combine to form an unsubstituted or substituted spirocycloalkyl; R1', R4' 、 R5' and R8' are independently selected from -H, -OH, -NH2, alkyl, and halogen; R2', R3', R6', and R7' are independently selected from -H, -OH, -OAc, -NH2, halogen, -CN, -CF3, -CO2H, -NO2, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylamino, and -OR8'; and R8' is selected from alkyl, hydroxyalkyl, aminoalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; or a pharmaceutically acceptable salt thereof.

127. The method of claim 126, wherein X1and X2are each independently C1-C4alkyl.

128. The method of claim 126, wherein X1and X2are each -CH3.

129. The method of claim 126, wherein X1and X2, together with the carbon to which they are bonded, combine to form an unsubstituted spirocycloalkyl.

130. The method of claim 129, wherein X1and X2, together with the carbon to which they are bonded, combine to form an unsubstituted spirocyclopropyl, cyclobutyl, or cyclopentyl.

131. The method of any one of claims 126-130, the compound having a structure selected from:

132. The method of any one of claims 126-131, wherein R2' and R7' are independently selected from -OH, -NH2, alkylamino, and -OR 10 .

133. The method of any one of claims 126-131, wherein R2’ and R7’ are each OH.

134. The method of any one of claims 126-131, wherein R2’ is -OH; and R7’ is -OCH3.

135. The method of any one of claims 126-131, wherein R7’ is -OH; and R2’ is -OCH3.

136. The method of any one of claims 126-131, wherein R2’ is selected from -NH2, -NHCH3, and -NH(CH3)2; and R7’ is OH.

137. The method of any one of claims 126-131, wherein R7’ is selected from -NH2, -NHCH3, and -NH(CH3)2; and R2’ is OH.

138. The method of any one of claims 126-137, wherein R3’ and R6’ are each independently -H or C1-C4alkyl.

139. The method of claim 138, wherein R3’ and R6’ are each independently -H or -CH3.

140. The method of any one of claims 126-137, wherein R1’ and R8’ are each independently -H or C1-C4alkyl.

141. The method of claim 140, wherein R1’ and R8’ are each independently -H or -CH3.

142. The method of any one of claims 126-137, wherein R4’ and R5’ are each independently -H or -OH.

143. The method of claim 126, wherein the compound is selected from: or a pharmaceutically acceptable salt thereof.

144. The method of any one of claims 1, 22, 36, 45, 63, and 83, wherein the compound is a compound selected from Table A.

145. The method of any one of claims 1-144, wherein amyotrophic lateral sclerosis (ALS) is C9orf72 amyotrophic lateral sclerosis (C9-ALS).

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