Tetrahydroacridone analogs for treatment and prevention of malaria

Abstract

According to the purposes of the present disclosure, as embodied and broadly described herein, the present disclosure relates, in one aspect, to scaffold molecules that exhibit potent anti-malarial activity against a variety of Plasmodium strains at different stages of a parasite, such as the red and infrared stages, and pharmaceutical compositions comprising the scaffold molecules. In one aspect, these compounds are tetrahydroacridones having Structure I described herein. In another aspect, the compounds described herein may be used to treat or prevent malaria in a subject.

Description

Statement regarding federally funded research or development

[0001] This invention was made with government funding under license number R01AI144464 granted by the National Institutes of Health. The government holds certain rights to this invention. (37 CFR 401.14 f (4)). Cross-references to related applications

[0002] This application claims the benefit and priority of co-pending U.S. Application No. 63 / 507,750, filed June 13, 2023, the entire contents of which are incorporated herein by reference. Background Technology

[0003] The World Health Organization reports an estimated 247 million cases of malaria and approximately 619,000 deaths in 2021. Resistance to current treatments, including the combination of artemisinin derivatives with another blood-splitting agent, is spreading, highlighting the need for novel antimalarial drugs. 1,2,3,4-Tetrahydroacrylidine-9(10H)-one (THA) is a promising class of antimalarial drugs that do not induce the resistance faced by current antimalarial drugs, as evidenced by their equivalence against two clinically relevant multidrug-resistant strains of Plasmodium falciparum, W2 and TM90-C2B. Furthermore, THA exhibits activity against multiple stages of the parasite, such as the liver and the transmission stage. However, THA lacks water solubility, a crucial characteristic for the preparation of orally bioavailable compounds. Summary of the Invention

[0004] For the purposes of this disclosure, as embodied and broadly described herein, this disclosure relates in one aspect to a backbone molecule that exhibits potent antimalarial activity against a variety of Plasmodium strains at various stages of the parasite (e.g., intraerythrocytic and erythrocytic stages), and pharmaceutical compositions comprising the backbone molecule.

[0005] In one respect, a compound having the structural formula shown in Structure I, or a pharmaceutically acceptable salt thereof: I in n is an integer from 1 to 4, where each R 1 Independently hydrogen, halogen, substituted or unsubstituted straight-chain or branched alkyl or alkoxy groups, and m is an integer from 1 to 3, where each R 2 It is hydrogen, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0006] In other respects, the compounds described herein can be used to treat or prevent malaria in subjects.

[0007] Other systems, methods, features, and advantages of this disclosure will become apparent to those skilled in the art from the following drawings and detailed description. This description is intended to cover all such additional systems, methods, features, and advantages, making them all within the scope of this disclosure and protected by the appended claims. Furthermore, all optional and preferred features and modifications of the described embodiments can be used in all aspects of the disclosure taught herein. Moreover, the various features of the dependent claims, as well as all optional and preferred features and modifications of the described embodiments, are combinable and interchangeable. Attached Figure Description

[0008] Many aspects of this disclosure can be better understood by referring to the following accompanying drawings. The components in the drawings are not necessarily drawn to scale; the emphasis is on clearly illustrating the principles of this disclosure. Furthermore, in the drawings, the same reference numerals denote corresponding parts in all views.

[0009] Figure 1A and Figure 1B The pharmacokinetic data for the two compounds described in this article are shown.

[0010] Other advantages of the invention will be set forth in part in the description which follows, and in part will be apparent from the description, or may be learned by practicing the invention. The advantages of the invention will be realized and obtained by means of the elements and combinations particularly pointed out in the appended claims. It should be understood that the foregoing general description and the following detailed description are exemplary and explanatory only, and are not intended to limit the claimed invention. Detailed Implementation

[0011] Many modifications and other embodiments disclosed herein will become apparent to those skilled in the art upon taking into account the teachings of the foregoing description and the accompanying drawings. Therefore, it should be understood that the disclosure is not limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. Those skilled in the art will recognize many variations and adaptations of the aspects described herein. These variations and adaptations are intended to be included in the teachings of this disclosure and are covered by the claims herein.

[0012] Although specific terms are used in this article, they are used only in a general and descriptive sense, not for restrictive purposes.

[0013] Those skilled in the art will understand upon reading this disclosure that each individual embodiment described and illustrated herein has discrete components and features that can be readily separated from or combined with features of any of the other several embodiments without departing from the scope or spirit of this disclosure.

[0014] Any method described herein may be performed in the order of events described or in any other logically possible order. That is, unless expressly stated otherwise, no method or aspect described herein implies a requirement that its steps be performed in a particular order. Therefore, if a method claim does not specifically state in the claims or specification that the steps will be limited to a particular order, no order is intended to be inferred in any aspect. This applies to any possible non-express basis of interpretation, including logical questions relating to the arrangement of steps or operational procedures, simple meanings derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0015] All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials cited in those publications. The publications discussed herein are provided only for those published prior to the filing date of this application. Nothing herein should be construed as an admission that the invention is not entitled to precedence over such publications due to prior invention. Furthermore, the publication dates provided herein may differ from actual publication dates, which may require independent verification.

[0016] While aspects of this disclosure may be described and claimed in specific statutory categories, such as the systems statutory category, this is merely for convenience, and those skilled in the art will understand that each aspect of this disclosure may be described and claimed in any statutory category.

[0017] It should also be understood that the terminology used herein is for descriptive purposes only and is not intended to be limiting. 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 the disclosed compositions and methods pertain. It should be further understood that terms (as defined in common dictionaries) should be interpreted as having the same meaning as they have in the context of the specification and related art, and should not be interpreted in an idealized or overly formal sense unless explicitly defined herein.

[0018] Before describing various aspects of this disclosure, the following definitions are provided and should be used unless otherwise stated. Additional terms may be defined elsewhere in this disclosure. definition

[0019] As used herein, “comprising” should be interpreted as specifying the presence of the mentioned feature, integer, step, or component, but does not preclude the presence or addition of one or more features, integers, steps, or components, or combinations thereof. Furthermore, each of the terms “by,” “comprising,” “comprises,” “comprised of,” “includes,” “included,” “includes,” “involving,” “involves,” “involved,” and “for example” is used in an open, non-limiting sense and may be used interchangeably. Additionally, the term “comprising” is intended to include examples and aspects covered by the terms “substantially composed of” and “consisting of.” Similarly, the term “substantially composed of” is intended to include examples covered by the term “consisting of.”

[0020] In the specification and appended claims, unless the context clearly specifies otherwise, the singular forms “a,” “an,” and “the” include plural references. Thus, for example, reference to “an excipient” includes, but is not limited to, mixtures or combinations of two or more such excipients.

[0021] It should be noted that ratios, concentrations, amounts, and other numerical data may be expressed in range format herein. It will be further understood that each endpoint of a range is significant relative to and independent of the other endpoint. It should also be understood that many numerical values ​​are disclosed herein, and each numerical value is also disclosed herein as “about” that particular value, in addition to being the value itself. For example, if the value “10” is disclosed, then “about 10” will also be disclosed. A range may be expressed here as from “about” one particular value and / or to “about” another particular value. Similarly, when a numerical value is expressed as an approximation using the antecedent “about”, it can be understood that a particular numerical value forms another aspect. For example, if the value “about 10” is disclosed, then “10” will also be disclosed.

[0022] When referring to a range, another aspect includes from one specific value and / or to another specific numerical value. For example, if the range includes one or two endpoints, this disclosure also includes ranges that do not include one or both of these limits. For instance, the phrase "x to y" includes a range from "x" to "y" as well as a range greater than "x" and less than "y". The range can also be expressed as an upper limit, such as "about x, y, z or less", which should be interpreted as including the specific ranges of "about x", "about y", and "about z", as well as the ranges of "less than x", "less than y", and "less than z". Similarly, the phrase "about x, y, z or greater" should be interpreted as including the specific ranges of "about x", "about y", and "about z", as well as the ranges of "greater than x", "greater than y", and "greater than z". Furthermore, the phrase "about 'x' to 'y'", where 'x' and 'y' are numerical values, includes "about 'x' to about 'y'".

[0023] It should be understood that this range format is used for convenience and brevity, and therefore should be interpreted flexibly, including not only the numerical values ​​explicitly stated as range limits, but also all individual numerical values ​​or subranges contained within that range, as if each numerical value and subrange were explicitly listed. For example, the numerical range “about 0.1% to 5%” should be interpreted as including not only the explicitly referenced value of about 0.1% to about 5%, but also the individual values ​​(e.g., about 1%, about 2%, about 3%, and about 4%) and subranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2% and about 0.5% to about 4.4%, and other possible subranges). Thus, for example, if the amount of the component is about 1%, 2%, 3%, 4%, or 5%, where any value can be the lower or upper limit of the range, any range between 1% and 5% can be envisioned (e.g., 1% to 3%, 2% to 4%, etc.).

[0024] As used herein, the terms “approximately,” “approximately,” “equal to or approximately,” and “substantially” mean that the quantity or value in question may be an exact value or a value that provides an equivalent result or effect as described in the claims or taught herein. That is, it is understood that quantities, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and / or larger or smaller as needed, reflecting tolerances, conversion factors, rounding, measurement errors, and other factors known to those skilled in the art to obtain an equivalent result or effect. In some cases, it is not reasonable to determine a value that provides an equivalent result or effect. In such cases, as used herein, it is generally understood that “approximately” and “equal to or approximately” mean a variation of ±10% of the nominal value shown, unless otherwise stated or inferred. Generally, a quantity, size, formulation, parameter, or other quantity or characteristic is “approximately,” “approximately,” or “equal to or approximately,” whether explicitly stated or not. It should be understood that where “approximately,” “approximately,” or “equal to or approximately” is used before a quantitative value, unless otherwise specifically stated, the parameter also includes the specific quantitative value itself.

[0025] As used in this article, "IC" 50 "IC50" refers to the concentration of a substance (such as a compound or drug) that has a 50% inhibitory effect on a biological process or a component of that process. For example, IC50... 50 It refers to the half-maximum (50%) inhibition concentration (IC) of a substance as determined in an appropriate assay.

[0026] As used in the specification and concluding claims, a chemical residue refers to the product portion of a chemical substance in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether that portion is actually obtained from the chemical substance. Therefore, an ethylene glycol residue in a polyester refers to one or more -OCH2CH2O- units in the polyester, regardless of whether the polyester is prepared using ethylene glycol. Similarly, a sebacic acid residue in a polyester refers to one or more -CO(CH2)8CO- moieties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or its ester with the polyester.

[0027] 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, and aromatic and non-aromatic substituents of organic compounds. Exemplary substituents include, for example, those described below. Permissible substituents may be one or more, and may be the same or different for a suitable organic compound. For the purposes of this disclosure, heteroatoms, such as nitrogen, may have hydrogen substituents and / or any permissible substituents of organic compounds that satisfy the heteroatom valence as described herein. This disclosure is not intended to be limited in any way by the permissible substituents of organic compounds. Furthermore, the terms “substituted” or “substituted” include the implicit condition that such substitution conforms to the permissible valence of the substituted atom and the substituent, and that such substitution produces a stable compound, such as a compound that does not spontaneously undergo rearrangement, cyclization, elimination, or other transformations. It is also contemplated that, in some respects, unless explicitly stated to the contrary, a single substituent may be further optionally substituted (i.e., further substituted or unsubstituted).

[0028] The position of a substituent can be defined relative to the positions of other substituents in the aromatic ring. For example, as shown in the figure below, the second substituent can be "ortho," "para," or "meta" relative to the "R" group, meaning that the second substituent is bonded to the carbon-labeled ortho, para, or meta position, as shown below. Combinations of ortho, para, and meta substituents relative to a given group or substituent are also contemplated, and should be considered as having been disclosed.

[0029] When defining various terms, "A" 1 “A” 2 “A” 3 "and "A 4 "Used herein as general symbols to denote various specific substituents. These symbols can be any substituents, not limited to those disclosed herein, and while they are defined as certain substituents in one example, they can be defined as some other substituents in another example."

[0030] As used herein, the term "aliphatic" or "aliphatic group" means a hydrocarbon group that can be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridged, and spirofused polycyclic rings), and can be fully saturated or contain one or more unsaturated units but is not aromatic. Unless otherwise stated, an aliphatic group contains 1-20 carbon atoms. Aliphatic groups include, but are not limited to, straight-chain or branched alkyl, alkenyl, and alkynyl groups, and their hybrids such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0031] As used herein, the term "alkyl" refers to a branched or unbranched saturated hydrocarbon group having 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, etc. Alkyl groups can be cyclic or acyclic. Alkyl groups can be branched or unbranched. Alkyl groups can also be substituted or unsubstituted. For example, an alkyl group can be substituted with one or more groups, including but not limited to alkyl, cycloalkyl, alkoxy, amino, ether, halogen, hydroxyl, nitro, silyl, sulfonyl, or thiol as described herein. "Lower alkyl" refers to an alkyl group containing 1 to 6 (e.g., 1 to 4) carbon atoms. The term alkyl can also be C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, etc., up to and including C1-C24 alkyl.

[0032] Throughout this specification, "alkyl" is generally used to refer to both unsubstituted and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying a particular substituent on the alkyl group. For example, the term "haloalkyl" or "haloalkyl" specifically refers to an alkyl group substituted with one or more halogens, such as fluorine, chlorine, bromine, or iodine. Alternatively, the term "monohaloalkyl" specifically refers to an alkyl group substituted with a single halogen, such as fluorine, chlorine, bromine, or iodine. The term "polyhaloalkyl" specifically refers to an alkyl group independently substituted with two or more halogens, i.e., each halogen substituent does not need to be the same as another halogen substituent, and multiple examples of halogen substituents do not need to be on the same carbon. The term "alkoxyalkyl" specifically refers to an alkyl group substituted with one or more alkoxy groups, as described below. The term "aminoalkyl" specifically refers to an alkyl group substituted with one or more amino groups. The term "hydroxyalkyl" specifically refers to an alkyl group substituted with one or more hydroxyl groups. When the term "alkyl" is used in one context and "hydroxyalkyl" or similar specific terms are used in another context, this does not mean that the word "alkyl" does not refer to the specific term "hydroxyalkyl" or similar specific terms.

[0033] This convention also applies to other groups described herein. That is, while terms like "cycloalkyl" refer to both unsubstituted and substituted cycloalkyl moieties, substituted moieties may also be specifically identified herein; for example, a particular substituted cycloalkyl group may be referred to as, for example, "alkylcycloalkyl". Similarly, a substituted alkoxy group may be specifically referred to as, for example, "haloalkoxy", and a particular substituted alkenyl group may be, for example, "alkenyl alcohol", etc. Likewise, the convention of using general terms such as "cycloalkyl" and specific terms such as "alkylcycloalkyl" does not mean that general terms exclude specific terms.

[0034] As used herein, the term "cycloalkyl" refers to a non-aromatic carbonyl ring consisting of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, etc. The term "heterocyclic alkyl" is a cycloalkyl group as defined above and is included within the meaning of the term "cycloalkyl" in which at least one carbon atom in the ring is substituted with a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. Cycloalkyl and heterocyclic alkyl groups can be substituted or unsubstituted. Cycloalkyl and heterocyclic alkyl groups can be substituted with one or more groups, including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halogen, hydroxyl, nitro, silyl, sulfonyl, or thiol groups as described herein.

[0035] As used herein, the term "alkylene" refers to a divalent saturated aliphatic group having one or two saturated carbon atoms as connecting points, having a straight or branched, cyclic, cyclic or acyclic structure, without carbon-carbon double or triple bonds, and containing no atoms other than carbon and hydrogen. The groups -CH2- (methylene), -CH2CH2-, -CH2C(CH3)2CH2-, and -CH2CH2CH2- are non-limiting examples of alkyldiyl groups.

[0036] As used herein, the terms "alkoxy" and "alkoxy" can refer to alkyl or cycloalkyl groups linked by an ether bond; that is, "alkoxy" can be defined as -OA. 1 A 1 It is an alkyl or cycloalkyl group as described above. "Alkoxy" also includes alkoxy polymers just described; that is, the alkoxy group can be a polyether, such as -OA. 1 -OA 2 or -OA 1 -(OA 2 ) a -OA 3 Where "a" is an integer from 1 to 200, A 1 A 2 and A 3 It is an alkyl and / or cycloalkyl group.

[0037] The term "aryloxy group" used in this article refers to an aryl group linked by an ether bond; that is, "aryloxy group" can be defined as -OA. 1 A 1 It is an aryl group as defined in this article.

[0038] As used herein, the term "alkenyl" refers to a hydrocarbon group with 2 to 24 carbon atoms having at least one carbon-carbon double bond. Asymmetric structures, such as (A... 1 A 2 C=C(A) 3 A 4The designation aims to include E and Z isomers. This can be inferred from the structural formula herein in the presence of asymmetric alkenes, or explicitly indicated by the bond symbol C=C. The alkenyl group may be substituted with one or more groups, including but not limited to alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halogen, hydroxyl, ketone, azide, nitro, silyl, sulfonyl, or thiol as described herein.

[0039] As used herein, the term "cycloalkenyl" refers to a non-aromatic carbonyl ring consisting of at least three carbon atoms and containing at least one carbon-carbon double bond (i.e., C=C). Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornyl, etc. The term "heterocyclic alkenyl" is a cycloalkenyl group as defined above and is included within the meaning of the term "cycloalkenyl" in which at least one carbon atom of the ring is substituted by a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. Cycloalkenyl and heterocyclic alkenyl groups can be substituted or unsubstituted. Cycloalkenyl and heterocyclic alkenyl groups can be substituted by one or more groups, including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halogen, hydroxyl, ketone, azide, nitro, silyl, sulfonyl, or thiol.

[0040] As used herein, the term "alkynyl" refers to a hydrocarbon group having 2 to 24 carbon atoms and a structural formula containing at least one carbon-carbon triple bond. The alkynyl group may be unsubstituted or substituted with one or more groups, including but not limited to alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halogen, hydroxyl, ketone, azide, nitro, silyl, sulfonyl, or thiol as described herein.

[0041] As used herein, the term "cycloalkynyl" refers to a non-aromatic carbonyl ring consisting of at least seven carbon atoms and containing at least one carbon-carbon triple bond. Examples of cycloalkynyl groups include, but are not limited to, cyclooctynyl, cyclononynyl, etc. The term "heterocyclic alkynyl" is a cycloalkenyl group as defined above, included within the meaning of the term "cycloalkynyl," wherein at least one carbon atom of the ring is substituted by a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. Cycloalkynyl and heterocyclic alkynyl groups may be substituted or unsubstituted. Cycloalkynyl and heterocyclic alkynyl groups may be substituted by one or more groups, including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halogen, hydroxyl, ketone, azide, nitro, silyl, sulfonyl, or thiol.

[0042] As used herein, the term "aromatic group" refers to a ring structure with a delocalized π-electron ring cloud above and below the molecular plane, wherein the π-cloud contains (4n+2) π electrons. Further discussion of aromaticity can be found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled "Aromaticity," pp. 477–497, which is incorporated herein by reference. The term "aromatic group" includes aryl and heteroaryl groups.

[0043] As used herein, the term "aryl" refers to a group containing any carbonyl aromatic group, including but not limited to benzene, naphthalene, phenyl, biphenyl, anthracene, etc. Aryl groups can be substituted or unsubstituted. An aryl group can be substituted by one or more groups, including but not limited to alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, -NH2, carboxylic acid, ester, ether, halogen, hydroxyl, ketone, azide, nitro, silyl, sulfonyl, or thiol as described herein. The term "biaryl" is a specific type of aryl group included in the definition of "aryl." Furthermore, aryl groups can be monocyclic structures or can include fused-ring structures or multiple ring structures linked by one or more bridging groups (such as carbon-carbon bonds). For example, a biaryl refers to two aryl groups that are linked together by a fused-ring structure, such as naphthalene, or linked by one or more carbon-carbon bonds, such as biphenyl. Fused aryl groups may also be included, including but not limited to indene and naphthyl.

[0044] The term "aldehyde" as used herein is represented by the formula -C(O)H. In this specification, "C(O)" is short for carbonyl group, i.e., C=O.

[0045] The term "amine" or "amino" as used in this article is derived from the formula -NA. 1 A 2 It means that A 1 and A 2 It can be hydrogen independently or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A specific example of an amino group is -NH2.

[0046] As used herein, the term "alkylamino" is represented by the formulas -NH(-alkyl) and -N(-alkyl)2, where alkyl is the one described herein. Representative examples include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, (sec-butyl)amino, (tert-butyl)amino, pentylamino, isopentylamino, (tert-pentyl)amino, hexylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di(sec-butyl)amino, di(tert-butyl)amino, dipentylamino, diisopentylamino, di(tert-pentyl)amino, dihexylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino, N-ethyl-N-propylamino, etc.

[0047] The term "carboxylic acid" as used in this article is represented by the formula -C(O)OH.

[0048] The term "ester" used in this article is derived from the formula -OC(O)A 1 or -C(O)OA 1 It means that A 1 It can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, ynyl, cycloynyl, aryl, or heteroaryl as described herein.

[0049] The term "ether" as used in this article is derived from formula A. 1 OA 2 It means that A 1 and A 2 It can be independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl or heteroaryl as described herein.

[0050] The terms “halo,” “halogen,” or “halide” used in this article are used interchangeably to refer to F, Cl, Br, or I.

[0051] The terms “pseudohalide,” “pseudohalogen,” or “pseudohalo” used herein are used interchangeably and refer to functional groups that exhibit a substantially similarity to halogens. Examples of such functional groups include cyano, thiocyano, azide, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy.

[0052] As used herein, the term "heteroalkyl" refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P, and S, wherein nitrogen, phosphorus, and sulfur atoms are optionally oxidized, and nitrogen heteroatoms are optionally quaternized. Heteroalkyl groups may be substituted with alkyl groups as defined above.

[0053] As used herein, the term "heteroaryl" refers to an aromatic group incorporating at least one heteroatom into the ring of an aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, wherein N-oxides, sulfur oxides, and dioxides are permitted heteroatom substitutions. Heteroaryl groups may be substituted or unsubstituted. Heteroaryl groups may be substituted by one or more groups, including but not limited to alkyl, cycloalkyl, alkoxy, amino, ether, halogen, hydroxyl, nitro, silyl, sulfonyl, or thiol groups as described herein. Heteroaryl groups can be monocyclic or fused-ring systems. Heteroaryl groups include, but are not limited to, furanyl, imidazolyl, pyrimidinyl, tetrazolyl, thiophene, pyridinyl, pyrroleyl, N-methylpyrroleyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, pyrazinyl, benzofuranyl, benzodioxacyclopentenyl, benzothiophene, indolyl, inazolyl, benzimidazolyl, imidazopyridyl, pyrazolopyridyl, and pyrazolopyrimidinyl. Other non-limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, thiopheneyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazole, imidazo[1,2-b]pyridinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.

[0054] The terms “heterocycle” or “heterocyclyl” as used herein are used interchangeably to refer to monocyclic and polycyclic aromatic or non-aromatic ring systems in which at least one ring member is not carbon. Therefore, this term includes, but is not limited to, “heterocyclic alkyl,” “heteroaryl,” “bicyclic heterocycle,” and “polycyclic heterocycle.” Heterocyclic compounds include pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole (including 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole), thiadiazole (including 1,2,3-thiadiazole, 1,2,5-thiadiazole and 1,3,4-thiadiazole), triazole (including 1,2,3-triazole and 1,3,4-triazole), tetrazolium (including 1,2,3,4-tetrazolium and 1,2,4,5-tetrazolium), pyridazine, pyrazine, triazine (including 1,2,4-triazine and 1,3,5-triazine), tetraazine (including 1,2,4,5-tetrazine), pyrrolidine, piperidine, piperazine, morpholine, azacyclobutane, tetrahydropyran, tetrahydrofuran, dioxane, etc. The term "heterocyclic group" can also refer to C2 heterocyclic group, C2-C3 heterocyclic group, C2-C4 heterocyclic group, C2-C5 heterocyclic group, C2-C6 heterocyclic group, C2-C7 heterocyclic group, C2-C8 heterocyclic group, C2-C9 heterocyclic group, C2-C10 heterocyclic group, C2-C11 heterocyclic group, etc., up to and including C2-C18 heterocyclic group. For example, a C2 heterocyclic group includes a group having two carbon atoms and at least one heteroatom, including but not limited to aziridine, diazacyclobutyl, dihydrodiazacycloethyl, epoxyethyl, thiocyclopropyl, etc. Or, for example, a C5 heterocyclic group includes a group having five carbon atoms and at least one heteroatom, including but not limited to piperidinyl, tetrahydropyranyl, tetrahydrothiophene-pyranyl, diazacycloheptyl, pyridinyl, etc. It should be understood that heterocyclic groups can be bonded by heteroatoms in the ring (where chemically possible) or by one of the carbons that make up the heterocyclic group ring.

[0055] As used herein, the term "bicyclic heterocycle" or "bicyclic heterocyclic group" refers to a ring system in which at least one ring member is not carbon. Bicyclic heterocyclic groups include ring systems in which an aromatic ring is fused to another aromatic ring, or ring systems in which an aromatic ring and a non-aromatic ring are fused. Bicyclic heterocyclic groups include ring systems in which a benzene ring is fused to a 5- or 6-membered ring containing 1, 2, or 3 heteroatoms, or ring systems in which a pyridine ring is fused to a 5- or 6-membered ring containing 1, 2, or 3 heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indole, indazole, pyrazolo[1,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxacyclopentenyl, 2,3-dihydro-1,4-benzodioxenyl, 3,4-dihydro-2H-chromenyl, 1H-pyrazolo[4,3-c]pyridin-3-yl; 1H-pyrrolo[3,2-b]pyridin-3-yl; and 1H-pyrazolo[3,2-b]pyridin-3-yl.

[0056] As used herein, the term "heterocyclic alkyl" refers to aliphatic, partially unsaturated, or fully saturated 3- to 14-membered ring systems, including monocyclic, bicyclic, and tricyclic systems with 3 to 8 atoms. Heterocyclic alkyl ring systems comprise one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be substituted. Representative heterocyclic alkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, piperidinyl, piperazinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolinyl, isothiazolyl, and tetrahydrofuranyl.

[0057] The term “hydroxyl” or “hydroxyl” as used in this article is represented by the formula -OH.

[0058] The term "ketone" used in this article is derived from formula A. 1 C(O)A 2 It means that A 1 and A 2 It can be independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl or heteroaryl as described herein.

[0059] The term “azide” or “azido group” used in this article is represented by the formula -N3.

[0060] The term “nitro” as used in this article is represented by the formula -NO2.

[0061] The term “nitrile” or “cyano” as used in this article is represented by the formula -CN.

[0062] The term "silyl alkyl" as used in this article is derived from the formula -SiA 1 A 2 A 3 It means that A 1 A 2 and A 3 It can be hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, aryl, or heteroaryl group as described herein.

[0063] The term “sulfonyloxy” as used in this article is derived from the formula -S(O)A 1 -S(O)2A 1 -OS(O)2A 1 or -OS(O)2OA 1 It means that A 1 It can be hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, ynyl, cycloynyl, aryl, or heteroaryl groups as described herein. In this specification, "S(O)" is the abbreviation for S=O. The term "sulfonyl" is used herein to refer to the group derived from the formula -S(O)₂A. 1The sulfonyl group represents the sulfonyl group, where A 1 It can be hydrogen or, as described herein, alkyl, cycloalkyl, alkenyl, cycloalkenyl, ynyl, cycloynyl, aryl, or heteroaryl. The term "sulfone" as used herein is derived from formula A. 1 S(O)2A 2 It means that A 1 and A 2 It can be independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, ynyl, cycloynyl, aryl, or heteroaryl as described herein. The term "sulfoxide" as used herein is derived from formula A. 1 S(O)A 2 It means that A 1 and A 2 It can be independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl or heteroaryl as described herein.

[0064] The term “thiol” used in this article is represented by the formula -SH.

[0065] As used in this article, “R” 1 “R” 2 “R” 3 "...R" n ", where n is an integer and can independently have one or more of the groups listed above. For example, if R 1 If it is a straight-chain alkyl group, one hydrogen atom of the alkyl group can optionally be replaced by a hydroxyl, alkoxy, alkyl, halogen, etc. Depending on the chosen group, the first group can be incorporated into the second group, or the first group can be dangling (i.e., attached) to the second group. For example, using the phrase "alkyl group containing an amino group," the amino group can be incorporated into the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the chosen group will determine whether the first group is inserted into or attached to the second group.

[0066] As described herein, the compounds of the present invention may contain an "optionally substituted" portion. Generally, the term "substituted," whether or not preceded by the term "optionally," means that one or more hydrogens of the specified portion are substituted by suitable substituents. Unless otherwise stated, the "optionally substituted" group may have suitable substituents at each substituted position of the group, and when multiple positions in any given structure can be substituted by multiple substituents selected from a particular group, the substituents at each position may be the same or different. The combinations of substituents contemplated in this invention are preferably those that result in the formation of stable or chemically viable compounds. It is also contemplated that, in certain aspects, unless explicitly stated otherwise, the individual substituents may be further optionally substituted (i.e., further substituted or unsubstituted).

[0067] As used herein, the term "stable" means that a compound does not undergo substantial changes under conditions that allow it to be produced, detected, and in some respects recovered, purified, and used for one or more purposes disclosed herein.

[0068] The suitable monovalent substituent on the substituted carbon atom of the "optionally substituted" group is independently a halogen; –(CH2) 0– 4R°;–(CH2) 0–4 OR°; -O(CH2) 0-4 R o ;–O–(CH2) 0–4 C(O)OR°;–(CH2) 0–4 CH(OR°)2;–(CH2) 0–4 SR°;–(CH2) 0–4 Ph, which can be replaced by R°; –(CH2) 0–4 O(CH2) 0–1 Ph, which can be substituted by R°; –CH=CHPh, which can be substituted by R°; –(CH2) 0–4 O(CH2) 0–1 -, which can be replaced by R°; –NO2; –CN; –N3; -(CH2) 0–4 N(R°)2;–(CH2) 0–4 N(R°)C(O)R°; –N(R°)C(S)R°; –(CH2) 0–4 N(R°)C(O)NR°2; -N(R°)C(S)NR°2; –(CH2) 0–4 N(R°)C(O)OR°; –N(R°)N(R°)C(O)R°; –N(R°)N(R°)C(O)NR°2; –N(R°)N(R°)C(O)OR°; –(CH2) 0–4 C(O)R°; –C(S)R°; –(CH2) 0–4 C(O)OR°;–(CH2) 0–4 C(O)SR°;-(CH2) 0–4 C(O)OSiR°3;–(CH2) 0–4 OC(O)R°;–OC(O)(CH2) 0–4 SR–;SC(S)SR°;–(CH2) 0–4 SC(O)R°;–(CH2) 0–4 C(O)NR°2; –C(S)NR°2; –C(S)SR°; –(CH2) 0–4OC(O)NR°2; -C(O)N(OR°)R°; –C(O)C(O)R°; –C(O)CH2C(O)R°; –C(NOR°)R°; –(CH2) 0–4 SSR°; –(CH2) 0–4 S(O)2R°;–(CH2) 0–4 S(O)₂OR°;–(CH₂) 0–4 OS(O)2R°; –S(O)2NR°2; -(CH2) 0–4 S(O)R°; -N(R°)S(O)2NR°2; –N(R°)S(O)2R°; –N(OR°)R°; –C(NH)NR°2; –P(O)2R°; –P(O)R°2; –OP(O)R°2; –OP(O)(OR°)2; SiR°3; –(C 1-4 (linear or branched alkylene)O–N(R°)2; or –(C 1-4 (straight-chain or branched alkylene)C(O)O–N(R°)2, wherein each R° can be substituted as defined below and is independently hydrogen, C 1–6 Aliphatic, –CH2Ph, –O(CH2) 0–1 Ph, -CH2- (5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur, or, notwithstanding the foregoing definition, two independently occurring R° together with the atoms between them to form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0069] Suitable monovalent substituents on R° (or a ring formed by two independently occurring R° and their intermediate atoms) are independently halogens, –(CH2). 0–2 R ● - (halogenated R) ● ), –(CH2) 0–2 OH, –(CH2) 0–2 OR ● –(CH2) 0–2 CH(OR ● )2;-O(halogenated R ● -CN, -N3, –(CH2) 0–2 C(O)R ● –(CH2) 0–2 C(O)OH, –(CH2) 0–2 C(O)OR ● , –(CH2) 0–2 SR ● , –(CH2)0–2 SH, –(CH2) 0–2 NH2、–(CH2) 0–2 NHR ● –(CH2) 0–2 NR ● 2, –NO2, –SiR ● 3. –OSiR ● 3. -C(O)SR ● 、–(C 1–4 (straight-chain or branched alkylene)C(O)OR ● 、or –SSR ● Each R ● It is unsubstituted, or when it is preceded by the prefix "halogenated", it is substituted by only one or more halogens, each independently selected from C. 1–4 Aliphatic groups, –CH2Ph, –O(CH2) 0-1 Ph, or a 5–6 member saturated, partially unsaturated, or aromatic ring having 0–4 independent heteroatoms selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents for the saturated carbon atom at R° include =O and =S.

[0070] Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group include the following: =O, =S, =NNR * 2、=NNHC(O)R * =NNHC(O)OR * =NNHS(O)2R * =NR * =NOR * 、 –O(C(R) * 2)) 2–3 O – or –S(C(R) * 2)) 2–3 S–, where each independently occurring R * Selected from hydrogen, C can be substituted as described below 1–6 Aliphatic groups, or unsubstituted 5–6-membered saturated, partially unsaturated, or aromatic rings having 0–4 independent heteroatoms selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to adjacent substituted carbon atoms of the "optionally substituted" group include: –O(CR * 2) 2–3 O–, where each individually occurring R* is selected from hydrogen, C, which can be substituted as described below. 1-6 Aliphatic groups, or unsubstituted 5–6 saturated, partially unsaturated or aromatic rings having 0–4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0071] R * Suitable substituents on aliphatic groups include halogens, -R ●- (halogenated R) ● -OH, -OR ● -O (halogenated R) ● -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● -NR ● 2 or -NO2, where each R ● It is unsubstituted, or the place preceding "halogen" is replaced by only one or more halogens, and is independently C. 1-4 Aliphatic, -CH2Ph, -O-(CH2) 0-1 Ph, or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur.

[0072] Suitable substituents on the substituted nitrogen of the "optionally substituted" group include -R † -NR † 2. -C(O)R † -C(O)OR † –C(O)CH2C(O)R † –S(O)2R † -S(O)2NR † 2. –C(S)NR † 2. –C(NH)NR † 2 or –N(R) † )S(O)2R † ; where each R † Independently, hydrogen, and C that can be substituted as defined below. 1-6 Aliphatic, unsubstituted -OPh, or unsubstituted 5-6 member saturated, partially unsaturated, or aryl rings having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur, or notwithstanding the above definition, R † Two independent occurrences together with their intermediate atoms form unsubstituted 3-12 saturated, partially unsaturated, or aryl monocyclic or bicyclic rings with 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur.

[0073] Suitable substituents on the aliphatic group of R† are independently halogens, –R ● - (halogenated R) ● -OH, -OR ● -O (halogenated R) ● -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● -NR ● 2 or -NO2, where each R ●It is unsubstituted, or the place preceding "halogen" is replaced by only one or more halogens, and is independently C. 1-4 Aliphatic, -CH2Ph, -O-(CH2) 0- 1Ph, or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur.

[0074] The term "leaving group" refers to an atom (or group of atoms) with electron-withdrawing capabilities that can be substituted as a stable species and remove bonded electrons. Examples of suitable leaving groups include halogens and sulfonates, including but not limited to trifluoromethanesulfonates, methanesulfonates, p-toluenesulfonates, and bromobenzenesulfonates.

[0075] The compounds described herein may contain one or more double bonds, thus potentially yielding cis / trans (E / Z) isomers and other conformational isomers. Unless otherwise stated, the invention encompasses all such possible isomers, as well as mixtures of these isomers.

[0076] Unless otherwise stated, chemical bonds are shown only as solid lines, not wedges or dashed lines in the chemical formula, and should be understood to encompass every possible isomer, such as every enantiomer and diastereomer, as well as mixtures of isomers, such as racemic or non-racemic mixtures. The compounds described herein may contain one or more asymmetric centers, thus potentially yielding diastereomers and optical isomers. Unless otherwise stated, the invention includes all possible diastereomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts. It also includes mixtures of stereoisomers and isolated specific stereoisomers. In the synthesis of such compounds, or in the use of racemic or epimerization processes known to those skilled in the art, the products of such processes may be mixtures of stereoisomers.

[0077] Many organic compounds exist in optically active forms capable of rotating the plane of polarization of light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule around its chiral center. The prefixes D and L or (+) and (-) are used to indicate the rotation sign of the plane polarization of light by the compound, with (-) or L indicating that the compound is levorotatory. Compounds with the prefix (+) or D are dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-superimposed mirror images of each other. Specific stereoisomers can also be called enantiomers, and mixtures of such isomers are generally called enantiomeric mixtures. A 50:50 enantiomeric mixture is called a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, the chiral carbon can be indicated by an asterisk (*). When bonds to chiral carbons are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbons, and therefore enantiomers and mixtures thereof, are included in the formulas. As used in the art, when it is necessary to specify the absolute configuration of a chiral carbon, one bond to the chiral carbon can be represented as a wedge (bonded to an atom above the plane), and the other can be represented as a series of short parallel lines or wedge lines (bonded to an atom below the plane). The Cahn-Ingold-Prelog system can be used to specify the (R) or (S) configuration of chiral carbons.

[0078] The compounds described herein include atoms with natural and non-natural isotopic abundances. The disclosed compounds may be compounds with the same isotopic labeling or isotopic substitution as those described herein, but with one or more atoms substituted by atoms whose atomic mass or mass number differs from that commonly found in nature. Examples of isotopes that may be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine, respectively. 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 35 S, 18 F and 36 Cl. The compound also includes its prodrug and a pharmaceutically acceptable salt of said compound or said prodrug, which contains the aforementioned isotopes and / or other isotopes of other atoms, all within the scope of this invention. Certain isotope-labeled compounds of this invention, for example, those doped with radioactive isotopes such as 3 H and 14 Compounds of C can be used for the determination of drug and / or substrate tissue distribution. Particularly preferred are tritium isotopes, i.e. 3 H, and carbon-14 isotopes, namely14 C, which is easy to prepare and detect. In addition, heavier isotopes such as deuterium (i.e., 2 H) Substitution can provide certain therapeutic advantages, stemming from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements, and may therefore be preferred in some cases. The isotope-labeled compounds and their prodrugs of the present invention can generally be prepared by the following steps, i.e., replacing non-isotope-labeled reagents with readily available isotope-labeled reagents.

[0079] The compounds described in this invention can exist in the form of solvates. In some cases, the solvent used to prepare the solvates is an aqueous solution, and the solvates are generally referred to as hydrates. These compounds can exist in the form of hydrates, for example, by crystallization from a solvent or aqueous solution. In this respect, one, two, three, or any number of solvent or water molecules can combine with the compounds of this invention to form solvates and hydrates. Unless otherwise stated, this invention includes all possible solvates.

[0080] It should also be recognized that some of the compounds described herein can exist as a balance of tautomers. For example, ketones with α-hydrogen can exist in a balance of keto and enol forms. Similarly, having N -H amides can exist in a balance of amide and imide forms. Unless otherwise stated, the invention includes all possible tautomers.

[0081] As is well known, solids formed by chemical substances exist in different ordered states, known as polymorphs or crystal forms. Different crystal forms of polymorphic substances can exhibit significant differences in physical properties. The compounds of this invention can exist in different polymorphs, wherein a particular crystal form may be metastable. Unless otherwise stated, this invention includes all possible polymorphic forms.

[0082] In some respects, the structure of a compound can be represented by the following formula: ,

[0083] It is understood to be equivalent to the formula: ,

[0084] Where n is usually an integer. That is, R n It is understood to represent five independent substituents, R n(a) R n(b) R n (c) R n(d) and R n(e)"Independent substituents" means that each R substituent can be defined independently. For example, if in one example R n(a) If it is a halogen, then R n(b) In this example, it is not necessarily a halogen.

[0085] As used herein, “application” can mean oral, local, intravenous, subcutaneous, percutaneous, transdermal, intramuscular, intra-articular, parenteral, intra-arterial, intradermal, intravenous, intraosseous, intraocular, intracranial, intraperitoneal, intralesional, intranasal, intracardiac, intraperitoneal, intralesional, intranasal, intracardiac, intra-articular, intracavitary, intrathecal, intrasheathal, intraviral, intracerebral and lateral ventricles, intratympanic cavity, intracochlear cavity, rectum, vagina, by inhalation, catheter, stent, or by implanted reservoir or other device, actively or passively (e.g., by diffusion) to the perivascular space and adventitia. For example, medical devices such as stents may contain a composition or formulation disposed on their surface, which may then dissolve or otherwise distribute to the surrounding tissues and cells. The term “parenteral” can include subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrasheathal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Application can be continuous or intermittent. In various respects, the formulation can be administered therapeutically; that is, for the treatment of an existing disease or condition. In other respects, the preparation can be used preventively; that is, to prevent disease or ailment.

[0086] As used interchangeably in this text, “subject,” “individual,” or “patient” can refer to a vertebrate, such as a mammal (e.g., a human). “Subject” can also refer to a cell, cell group, tissue, organ, or organism, preferably a human being and its components.

[0087] As used herein, the terms “treating” and “treatment” can generally refer to achieving a desired pharmacological and / or physiological effect. An effect may be, but does not necessarily have to be, preventative in the prevention or partial prevention of a disease, symptom, or condition, such as hematologic malignancies, breast cancer, and / or other solid malignancies. An effect may be therapeutic in the context of partial or complete cure of a disease, condition, symptom, or adverse reaction attributable to that disease, disorder, or condition. The term “treatment” as used herein can include any treatment of a subject, particularly a human, with hematologic malignancies, breast cancer, and / or other solid tumors, and may include any one or more of the following: (a) prevention of the disease in subjects who may be susceptible to the disease but have not yet been diagnosed with it; (b) suppression of the disease, i.e., halting its development; and (c) alleviation of the disease, i.e., reducing or improving the disease and / or its symptoms or condition. The term “treatment” as used herein can refer to treatment alone, preventative treatment alone, or treatment and preventative treatment. Subjects requiring treatment (subjects requiring treatment) can include those who already have the disorder and / or require prevention of the disorder. As used herein, the term "treatment" can include inhibiting a disease, disorder, or condition, such as hindering its progression; and alleviating a disease, disorder, or condition, such as causing the remission of the disease, disorder, and / or condition. Treating a disease, disorder, or condition can include improving at least one symptom of a particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, for example, treating a subject's pain by administering an analgesic, even if the medication does not treat the cause of the pain.

[0088] As used in this article, "therapeutic" can refer to treating, curing, and / or improving a disease, disorder, symptom, or side effect, or slowing the progression of a disease, disorder, symptom, or side effect.

[0089] As used herein, "effective amount" can refer to an amount of the disclosed compound or pharmaceutical composition provided herein that is sufficient to affect a beneficial or desired biological, emotional, medical, or clinical response in cells, tissues, systems, animals, or humans. Effective amounts can be administered, applied, or dosed once or multiple times. The term may also include, within its scope, amounts that effectively enhance or restore substantially normal physiological function.

[0090] For example, those skilled in the art are fully capable of initiating administration of the compound at a dose below the level required to achieve the desired therapeutic effect and gradually increasing the dose until the desired effect is achieved. If necessary, the effective daily dose can be divided into multiple doses for administration purposes. Thus, a single-dose composition may contain such an amount or an approximation thereof to constitute the daily dose. If any contraindications exist, the dosage may be adjusted by the attending physician. Generally, the maximum dose of the pharmacological agent of the present invention (alone or in combination with other therapeutic agents) is preferred, i.e., the highest safe dose based on reasonable medical judgment. However, those skilled in the art will understand that patients may adhere to lower or tolerable doses for medical, psychological, or virtually any other reason.

[0091] For example, the response to a therapeutically effective dose of the disclosed compound and / or pharmaceutical composition can be measured by determining the physiological effect of the treatment or drug, such as the reduction or disappearance of disease symptoms after administration of the treatment or pharmacological agent. Other assay methods will be known to those skilled in the art and can be used to measure response levels. The dosage of the treatment can be varied, for example, by increasing or decreasing the amount of the disclosed compound and / or pharmaceutical composition, by changing the disclosed administration of the compound and / or pharmaceutical composition, by changing the route of administration, by changing the time of administration, etc. The dosage can be varied and can be administered once or multiple times daily, for one day or several days. Appropriate dosage guidelines for a given class of pharmaceuticals can be found in the literature.

[0092] As used in this article, the term "effective preventive dose" refers to the amount that effectively prevents the onset or onset of a disease or symptom.

[0093] As used herein, the term "prevent" or "preventing" means to exclude, avoid, eliminate, prevent, stop, or hinder the occurrence of something, especially through preemptive action. It should be understood that, unless otherwise specified, the use of "reduce," "suppress," or "prevent" herein also explicitly discloses the use of the other two terms.

[0094] The term “pharmaceutically acceptable” describes a material that is biologically or otherwise undesirable, meaning it will not cause unacceptable adverse biological effects or interact with the material in a harmful manner.

[0095] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of an active agent prepared from an acid or base that is tolerated by the biological system or by the subject, or that is tolerated by the biological system and by the subject when administered at an effective therapeutic dose. When the compounds of this disclosure contain relatively acidic functional groups, a base addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base (whether soda ash or in a suitable inert solvent). Examples of pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, ammonium, organic ammonium, magnesium, lithium, strontium, or similar salts. When the compounds of this disclosure contain relatively basic functional groups, an acid addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid (which may be pure or in a suitable inert solvent). Examples of pharmaceutically acceptable acid addition salts include, but are not limited to: salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, hydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, or phosphorous acid; and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, succinic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are amino acid salts, such as arginine salts, and organic acid salts, such as glucuronic acid or galacturonic acid.

[0096] The term "pharmaceutically acceptable prodrug" or "prodrug" refers to a prodrug of the compounds disclosed herein that, to a reasonable medical judgment, is suitable for use in human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., is commensurate with a reasonable benefit / risk ratio, and is effective for its intended use. The prodrugs of this disclosure can be rapidly converted in vivo into a parent compound having the structure of the disclosed compound, for example, by hydrolysis in the blood. T. Higuchi and V. Stella discussed this in detail in the ACS Symposium Pro-drugs as Novel Delivery Systems, Issue 14, and in *Bioreversible Carriers in Drug Design*, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press (1987).

[0097] As used herein, “dosage,” “unit dose,” or “dose” can refer to a physically discrete unit suitable for use in a subject, each unit containing a predetermined amount of the disclosed compound and / or its pharmaceutical composition, the calculation of which produces the desired response in relation to its administration.

[0098] Some of the materials, compounds, compositions, and components disclosed herein can be commercially available or readily synthesized using techniques generally known to those skilled in the art. For example, the starting materials and reagents used to prepare the disclosed compounds and compositions may be obtained from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wis), AcrosOrganics (Morris Plains, NJ), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.), or prepared by methods known to those skilled in the art according to the steps specified in the references, such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0099] Unless otherwise expressly stated, no method described herein shall be construed as requiring its steps to be performed in a particular order. Therefore, if a method claim does not actually describe the order in which its steps should be followed, or if the claims or specification do not specifically state that the steps should be limited to a particular order, then in no way is an order inferred. This applies to any possible non-express basis for interpretation, including: logical matters relating to the arrangement of steps or the flow of operations; simple meanings derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[0100] The components used to prepare the compositions of the present invention and the compositions themselves used in the methods disclosed herein are disclosed. These and other materials are disclosed herein, and it should be understood that while specific references to various individual and collective combinations and arrangements of these materials are not explicitly disclosed when combinations, subsets, interactions, groups, etc., of these materials are disclosed, each combination and arrangement is specifically considered and described herein. For example, if a particular compound is disclosed and discussed, and various modifications that can be made to multiple molecules including that compound are discussed, then every possible combination and arrangement of that compound with modifications is specifically considered, unless specifically indicated otherwise. Thus, if examples of classes of molecules A, B, and C, and classes of molecules D, E, and F, and a combination molecule AD are disclosed, then AE, AF, BD, BE, BF, CD, CE, and CF are considered disclosed even though each is not described individually, each is considered individually and collectively. Similarly, any subsets or combinations of these are also disclosed. Thus, for example, subgroups of AE, BF, and CE would be considered disclosed. This concept applies to all aspects of this application, including but not limited to the steps in methods for preparing and using the compositions of the present invention. Therefore, if various additional steps are available, it can be understood that each of these additional steps can be performed using any particular embodiment or combination of embodiments of the method of the present invention.

[0101] It should be understood that the compositions disclosed herein have certain functions. This document discloses certain structural requirements for performing the disclosed functions, and it is understood that multiple structures can perform the same functions associated with the disclosed structures, and these structures generally achieve the same results.

[0102] As used herein, the terms “optional” or “optionally” mean that an event or situation described below may or may not occur, and the description includes both the possibility that the event or situation occurs and the possibility that it does not occur.

[0103] Unless otherwise specified, the temperatures referred to in this article are based on atmospheric pressure (i.e., one standard atmosphere). Compounds and their preparation and use

[0104] In one respect, this article discloses a compound having a formula represented by structure I or a pharmaceutically acceptable salt thereof. I in n is an integer from 1 to 4, where each R 1 Independently hydrogen, halogen, substituted or unsubstituted straight-chain or branched alkyl or alkoxy groups, and m is an integer from 1 to 3, where each R 2It is hydrogen, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, substituted or unsubstituted biaryl or substituted or unsubstituted biaryl ether.

[0105] In one aspect, n in structure I is 1 or 2. In another aspect, R in structure I... 1 It is a C1-C6 alkyl group. In another aspect, R in structure I... 1 It is methyl or ethyl. In another aspect, R in structure I... 1 It is a halogen. In another aspect, R in structure I... 1 It is a bromide, chloride, iodide, or fluoride. In another aspect, R in structure I... 1 It is a C1-C6 alkoxy group. In another aspect, R in structure I... 1 It is either methoxy or ethoxy. On the other hand, m in structure I is 1. On yet another hand, R in structure I... 2 It is a substituted or unsubstituted phenyl group. In another aspect, R in structure I... 2 It is a phenyl group substituted with halogen, substituted or unsubstituted alkyl, alkoxy or aryloxy groups. In another aspect, R in structure I... 2 It is a substituted or unsubstituted heterocyclic alkyl group, such as a 5- or 6-membered ring. On the other hand, the unsubstituted heterocyclic alkyl group is tetrahydrofuranyl or tetrahydropyranyl. In another aspect, R in structure I... 2 It is a substituted or unsubstituted heteroaryl group. In another aspect, the heteroaryl group is pyridyl, thiophene, or thiazolyl. In another aspect, the heteroaryl group is substituted or unsubstituted with a phenyl group. In another aspect, the phenyl group is substituted with a halogen, a substituted or unsubstituted alkyl group, an alkoxy group, a fluoroalkoxy group, or a fluoroalkyl group. In another aspect, the phenyl group is substituted with -OCF3. In another aspect, R in structure I... 2 It is a C3-C7 cycloalkyl group.

[0106] In another aspect, the compound has structure II II

[0107] In one respect, R in Structure II 2 It is a substituted or unsubstituted phenyl group. In another aspect, R in structure II... 2 It is a phenyl group substituted with halogen, substituted or unsubstituted alkyl, alkoxy or aryloxy groups. In another aspect, R in structure II... 2 It is a substituted or unsubstituted heterocyclic alkyl group, such as a 5- or 6-membered ring. On the other hand, the unsubstituted heterocyclic alkyl group is tetrahydrofuranyl or tetrahydropyranyl. In another aspect, R in structure II... 2It is a substituted or unsubstituted heteroaryl group. In another aspect, the heteroaryl group is pyridyl, thiophene, or thiazolyl. In another aspect, the heteroaryl group is substituted or unsubstituted with a phenyl group. In another aspect, the phenyl group is substituted with a halogen, a substituted or unsubstituted alkyl group, an alkoxy group, a fluoroalkoxy group, or a fluoroalkyl group. In another aspect, the phenyl group is substituted with -OCF3. In another aspect, R in structure II... 2 It is a C3-C7 cycloalkyl group.

[0108] In another aspect, R in Structure II 2 yes Where o is 1 or 2, R 3 It is hydrogen, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryloxy.

[0109] In one respect, the substituent R 2 R in 3 It is a phenyl group substituted with fluorine, fluoroalkyl, and / or fluoroalkoxy groups. In another aspect, the substituent R... 2 R in 3 It is a phenyl group substituted with -F, -CF3 and / or -OCF3. Pharmaceutical Composition

[0110] In all respects, this disclosure relates to pharmaceutical compositions comprising an effective therapeutic amount of at least one disclosed compound, a product of at least one of the disclosed methods, or a pharmaceutically acceptable salt thereof. As used herein, "pharmaceutically acceptable carrier" means one or more pharmaceutically acceptable diluents, preservatives, antioxidants, solubilizers, emulsifiers, colorants, release agents, coating agents, sweeteners, flavorings, and fragrances, as well as adjuvants. The disclosed pharmaceutical compositions can be conveniently presented in unit dosage forms and prepared by pharmaceutical science and any method well known in the pharmaceutical field.

[0111] In another aspect, the disclosed pharmaceutical compositions comprise an effective therapeutic amount of at least one disclosed compound, at least one product of the disclosed method, or a pharmaceutically acceptable salt thereof as an active ingredient, a pharmaceutically acceptable carrier, optionally one or more other therapeutic agents, and optionally one or more adjuvants. The disclosed pharmaceutical compositions include those suitable for oral, rectal, topical, pulmonary, nasal, and parenteral administration, although the most suitable route in any given case will depend on the specific host and the nature and severity of the conditions under which the active ingredient is administered. In another aspect, the disclosed pharmaceutical compositions can be formulated for oral, nasal, inhalation, parenteral, adjacent to normal, mucosal, percutaneous, intramuscular, intravenous, intradermal, subcutaneous, intraperitoneal, intravenous, intracranial, and intratumoral administration.

[0112] As used herein, “parenteral administration” includes administration by bolus or infusion, as well as administration by intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, intradermal, intra-articular, subcapsular, subarachnoid, spinal, epidural, and intrasternal injection and infusion.

[0113] In various aspects, the present invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent, and an effective therapeutic amount of the disclosed compound, the product of the disclosed preparation method, a pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, or a stereochemical isomer thereof as the active ingredient. In another aspect, the disclosed compound, the product of the disclosed preparation method, its pharmaceutically acceptable salt, hydrate, solvate, polymorph, or stereochemical isomer thereof, or any subgroup or combination thereof, can be formulated into various pharmaceutical forms for administration purposes.

[0114] In practice, according to conventional pharmaceutical formulation techniques, the compounds of this disclosure or their pharmaceutically acceptable salts can be tightly mixed as active ingredients with a pharmaceutical carrier. The carrier can take various forms, depending on the desired dosage form, such as oral or injectable (including intravenous) administration. Therefore, the pharmaceutical compositions of this disclosure can be presented as discrete units suitable for oral administration, such as capsules, pouches, or tablets, each containing a predetermined amount of the active ingredient. Furthermore, the compositions can be in the form of powders, granules, solutions, aqueous liquid suspensions, non-aqueous liquids, oil-in-water emulsions, or water-in-oil emulsions. In addition to the common dosage forms described above, the compounds of this disclosure and / or their pharmaceutically acceptable salts can also be administered via controlled-release devices and / or delivery devices. The compositions can be prepared by any pharmaceutical method. Generally, this method involves the step of binding the active ingredient with a carrier constituting one or more essential components. Typically, the composition is prepared by uniformly and tightly mixing the active ingredient with a liquid carrier or a finely chopped solid carrier, or both. The product can then be conveniently shaped into the desired dosage form.

[0115] For ease of administration and dosage uniformity, it is particularly advantageous to formulate the above-mentioned pharmaceutical compositions in unit dosage forms. As used herein, the term "unit dosage form" refers to a physically discrete unit suitable as a unit dose, each unit containing a predetermined amount of the active ingredient, calculated to produce the desired therapeutic effect when combined with a desired drug carrier. In other words, a "unit dosage form" refers to a single dose in which all active and inactive ingredients are combined in a suitable system so that the patient or the person administering the medication to the patient can open a container or package containing the entire dose without having to mix any components from two or more containers or packages together. Typical examples of unit dosage forms are tablets (including scored or coated tablets), capsules, or pills; single-dose vials for injectable solutions or suspensions; rectal suppositories; powder packets; thin tablets; and multiple units thereof. This list of unit dosage forms is not intended to be limiting in any way, but merely represents typical examples of unit dosage forms.

[0116] The pharmaceutical compositions disclosed herein comprise a disclosed compound (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more other therapeutic agents. In various aspects, the disclosed pharmaceutical compositions may include a pharmaceutically acceptable carrier and the disclosed compound or a pharmaceutically acceptable salt thereof. In another aspect, the disclosed compound or a pharmaceutically acceptable salt thereof may also be included in the pharmaceutical composition in combination with one or more other therapeutically active compounds. The compositions of the present invention include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any particular case will depend on the specific host and the nature and severity of the conditions under which the active ingredient is administered. The pharmaceutical compositions can be conveniently presented in unit dosage forms and prepared by any method well known in the pharmaceutical field.

[0117] For example, techniques and compositions for preparing dosage forms that can be used with the materials and methods described herein are described in the following references: Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol 7 (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity)). McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: TherapeuticApplications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; JG Hardy, SS Davis, Clive G. Wilson, Eds.); Modern Pharmaceutics Drugs and thePharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes,Eds.). .

[0118] The compounds described herein are typically administered in combination with appropriate drug diluents, excipients, fillers, or carriers (referred to herein as pharmaceutically acceptable carriers or delivery systems), which are appropriately selected according to the intended form of administration and in accordance with standard pharmaceutical practice. Deliverable compounds will be in a form suitable for oral, rectal, topical, intravenous, or parenteral administration. Carriers may be solid or liquid, and the type of carrier is selected based on the type of administration used. Compounds may be administered in doses containing known amounts of the compound.

[0119] Oral administration is likely the preferred dosage form due to ease of application, with tablets and capsules being the most advantageous forms of oral dosage units, in which case a solid drug carrier is obviously used. However, other dosage forms may be suitable depending on the clinical population (e.g., age and severity of clinical condition), the solubility of the specific disclosed compound used, etc. Therefore, the disclosed compounds can be used in oral dosage forms such as pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Any convenient pharmaceutical medium can be used when preparing compositions for oral dosage forms. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., can be used to form oral liquid formulations such as suspensions, elixirs, and solutions; while carriers such as starch, sugars, microcrystalline cellulose, diluents, granulators, lubricants, binders, disintegrants, etc., can be used to form oral solid dosage forms such as powders, capsules, and tablets. Tablets and capsules are preferred oral dosage units using solid drug carriers due to their ease of application. Optionally, tablets can be coated using standard aqueous or non-aqueous techniques.

[0120] The disclosed oral dosage form pharmaceutical compositions may contain one or more pharmaceutical excipients and / or additives. Non-limiting examples of suitable excipients and additives include gelatin, natural sugars such as raw sugar or lactose, lecithin, pectin, starch (such as corn starch or amylose), dextran, polyvinylpyrrolidone, polyvinyl acetate, gum arabic, alginate, tylose, talc, lycopodium, silica gel (such as colloids), cellulose, cellulose derivatives (such as cellulose ethers with cellulose hydroxyl groups partially etherified with low-saturated fatty alcohols and / or low-saturated fatty oxygen alcohols, such as methoxypropyl cellulose, methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate), fatty acids having 12 to 22 carbon atoms and magnesium, calcium, or aluminum salts of these fatty acids, particularly saturated (e.g., stearates), emulsifiers, oils and fats, particularly vegetable oils (e.g., peanut oil, castor oil, olive oil, sesame oil, cottonseed oil, corn oil, wheat germ oil, sunflower oil, cod liver oil, optionally hydrated in each case); C 12 H 24 O2 to C 18 H 36 O2 saturated fatty acid glycerides and polyglycerides and mixtures thereof, wherein the glycerol hydroxyl groups may be fully or only partially esterified (e.g., monoglycerides, diglycerides and triglycerides); pharmaceutically acceptable monovalent or polyvalent alcohols and polyethylene glycols (such as polyethylene glycol and its derivatives), esters of aliphatic saturated or unsaturated fatty acids (2 to 22 carbon atoms, especially 10-18 carbon atoms) with monovalent fatty alcohols (1 to 20 carbon atoms) or polyols (e.g., glycols, glycerol, diethylene glycol, pentaerythritol, sorbitol, mannitol, etc.) (which may also be optionally etherified), esters of citric acid and primary alcohols, acetic acid, urea, benzyl benzoate, dioxolane, glyceryl formaldehyde, tetrahydrofurfuryl alcohol, polyethylene glycol ethers with C1-C12 alcohols, dimethylacetamide, lactams, lactates, ethyl carbonate, organosilicones (especially medium viscosity polydimethylsiloxanes), calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, magnesium carbonate, etc.

[0121] Other excipients that can be used to prepare oral dosage forms are those substances that cause disintegration (so-called disintegrants), such as croscarmellose, sodium carboxymethyl starch, sodium carboxymethyl cellulose, or microcrystalline cellulose. Conventional coating substances can also be used to produce oral dosage forms. For example, polymers and copolymers of acrylic acid and / or methacrylic acid and / or their esters can be considered; copolymers of acrylates and methacrylates with low ammonium content (e.g., Eudragit R / RS); copolymers of acrylates and methacrylates and trimethylammonium methacrylates (e.g., Eudragit R / RS); and copolymers of acrylates and methacrylates and trimethylammonium methacrylates (e.g., Eudragit R / RS). RL); polyvinyl acetate; fats, oils, waxes, fatty alcohols; hydroxypropyl methylcellulose phthalate or acetate succinate; cellulose acetate phthalate, starch acetate phthalate, and polyvinyl acetate phthalate, carboxymethyl cellulose; methylcellulose phthalate, methylcellulose succinate, phthalic acid succinate, and methylcellulose phthalate half-ester; zein; ethyl cellulose and ethyl cellulose succinate; shellac, gluten; ethyl carboxyethyl cellulose; ethyl acrylate-maleic anhydride copolymer; maleic anhydride vinyl methyl ether copolymer; styrene-maleic acid copolymer; 2-ethyl-hexyl-acrylic acid maleic anhydride; crotonic acid-vinyl acetate copolymer; glutamic acid / glutamate copolymer; carboxymethyl ethyl cellulose glycerol monooctanoate; cellulose acetate succinate; polyarginine.

[0122] Plasticizers that can be considered coating substances in the disclosed oral dosage forms are: citrates and tartrates (acetyl triethyl citrate, acetyl tributyl citrate, tributyl citrate, triethyl citrate); glycerols and glycerides (glyceryl diacetate, glyceryl triacetate, acetylated monoglyceride, castor oil); phthalates (dibutyl phthalate, diamyl phthalate, diethyl phthalate, dimethyl phthalate, dipropyl phthalate), di(2-methoxy or 2-ethoxyethyl)-phthalates, ethyl phthaloyl glycolate, butyl phthalate... Phthaloyl ethyl glycolate and butyl glycolate; alcohols (propylene glycol, polyethylene glycol of various chain lengths), adipates (diethyl adipate, di(2-methoxy) adipate or di(2-ethoxyethyl) adipate); benzophenone; diethyl benzophenone and dibutyl sebacate, dibutyl succinate, dibutyl tartrate; diethylene glycol dipropionate; ethylene glycol diacetate, ethylene glycol dibutyrate, ethylene glycol dipropionate; tributyl phosphate, glyceryl tartrate; polyethylene glycol sorbitan monooleate (polysorbate, such as polysorbate 50); sorbitan monooleate.

[0123] In addition, suitable binders, lubricants, disintegrants, colorants, flavoring agents, flow aids, and melts can serve as carriers. The drug carriers used can be, for example, solid, liquid, or gaseous. Examples of solid carriers include, but are not limited to, lactose, kaolin, sucrose, glucose, methylcellulose, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, talc, starch, gelatin, agar, pectin, gum arabic, magnesium stearate, and stearic acid. Examples of liquid carriers are syrups, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0124] In various aspects, binders can include, for example, starch, gelatin, natural sugars (such as glucose or beta-lactose), corn sweeteners, natural and synthetic gums (such as gum arabic, tragacanth, or sodium alginate), carboxymethyl cellulose, polyethylene glycol, waxes, etc. Lubricants used in these formulations include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. In another aspect, disintegrants can include, for example, starch, methyl cellulose, agar, bentonite, xanthan gum, etc.

[0125] In various aspects, oral dosage forms, such as solid dosage forms, may contain a disclosed compound attached to the polymer as a targeted drug carrier or prodrug. Suitable biodegradable polymers that can be used to achieve controlled drug release include, for example, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, and hydrogels, preferably covalently cross-linked hydrogels.

[0126] Tablets may contain an active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for tablet manufacturing. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginate; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated using known techniques to delay gastrointestinal breakdown and absorption, thereby providing sustained action over a longer period.

[0127] Tablets containing the disclosed compounds can be prepared by compression or molding, optionally using one or more excipients or adjuvants. Compressed tablets can be prepared by compressing the active ingredient, in its free-flowing form, such as powder or granules, in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, surfactant, or dispersant. Molded tablets can be made by molding in a suitable machine, wetting the mixture of powdered compounds with an inert liquid diluent.

[0128] In various aspects, solid oral dosage forms, such as tablets, can be coated with enteric coatings to prevent rapid disintegration in the stomach. Enteric coating agents include, but are not limited to, hydroxypropyl methylcellulose phthalate, methacrylate-methacrylate copolymer, polyvinyl acetate phthalate, and cellulose acetate phthalate. (Akihiko Hasegawa, “Application of solid dispersions of Nifedipine with enteric coating agent to prepare a sustained-release dosage form”, Chem. Pharm. Bull. 33:1615-1619 (1985)). Various enteric coating materials can be selected based on testing to achieve de novo enteric-coated dosage forms with an optimal combination of dissolution time, coating thickness, and radial compressive strength (e.g., see SC Porter et al., “The Properties of Enteric Tablet Coatings Made From Polyvinyl Acetate-phthalate and Cellulose acetate Phthalate”, J. Pharm. Pharmacol. 22:42p (1970)). In another aspect, enteric coatings may include hydroxypropyl methylcellulose phthalate, methacrylate-methacrylate copolymer, polyvinyl acetate phthalate, and cellulose acetate phthalate.

[0129] In all respects, oral dosage forms can be solid dispersions with water-soluble or water-insoluble carriers. Examples of water-soluble or water-insoluble carriers include, but are not limited to, polyethylene glycol, polyvinylpyrrolidone, hydroxypropyl methylcellulose, phosphatidylcholine, polyoxyethylene hydrogenated castor oil, hydroxypropyl methylcellulose phthalate, carboxymethyl ethyl cellulose or hydroxypropyl methylcellulose, ethyl cellulose or stearic acid.

[0130] In various respects, oral dosage forms can be liquid dosage forms, including those that are taken orally, or dosage forms applied as mouthwash or rinsing agents. For example, liquid dosage forms can include aqueous suspensions containing active materials mixed with excipients suitable for manufacturing aqueous suspensions. Furthermore, oily suspensions can be formulated by suspending the active ingredient in vegetable oils, such as peanut oil, olive oil, sesame oil, or coconut oil, or in mineral oils such as liquid paraffin. Oily suspensions may also contain a variety of excipients. The pharmaceutical compositions disclosed herein can also be in the form of oil-in-water emulsions, which may also contain excipients such as sweeteners and flavoring agents.

[0131] For the preparation of solutions or suspensions, water, especially sterile water, or physiologically acceptable organic solvents can be used, such as alcohols (ethanol, propanol, isopropanol, 1,2-propanediol, polyethylene glycol and its derivatives, fatty alcohols, partial esters of glycerol), oils (e.g., peanut oil, olive oil, sesame oil, almond oil, sunflower oil, soybean oil, castor oil, cow hoof oil), paraffin, dimethyl sulfoxide, triglycerides, etc.

[0132] In the case of liquid dosage forms such as drinkable solutions, the following substances may be used as stabilizers or solubilizers: lower aliphatic monohydric and polyhydric alcohols having 2-4 carbon atoms, such as ethanol, n-propanol, glycerol, polyethylene glycol with a molecular weight between 200 and 600 (e.g., 1 to 40% aqueous solution), diethylene glycol monoethyl ether, 1,2-propanediol, organic amides, such as amides of aliphatic C1-C6 carboxylic acids with ammonia or primary, secondary, or tertiary C1-C4 amines or C1-C4 hydroxyamines, such as urea, ethyl carbamate, acetamide, N-methylacetamide, N,N-diethylacetamide, N,N-dimethylacetamide, lower aliphatic amines and diamines having 2-6 carbon atoms, such as ethylenediamine, hydroxyethyltheophylline, tromethamine (e.g., 0.1 to 20% aqueous solution), and aliphatic amino acids.

[0133] In preparing the disclosed liquid dosage form, a solubilizer and emulsifier may be included, for example, the following non-limiting examples: polyvinylpyrrolidone, sorbitol fatty acid esters (such as sorbitol trioleate), phospholipids (such as lecithin), gum arabic, tragacanth, polyoxyethyleneized sorbitol monooleate and other ethoxylated fatty acid esters of sorbitol, polyoxyethyleneized fatty acids, polyoxyethyleneized oleic acid triglycerides, linoleic acid triglycerides, fatty alcohols, alkylphenols or polyoxyethylene condensation products of fatty acids, or 1-methyl-3-(2-hydroxyethyl)imidazolidon-(2). In this case, polyoxyethyleneization means that the substance under discussion contains polyoxyethylene chains, the degree of polymerization of which is generally between 2 and 40, particularly between 10 and 20. Such polyoxyethylene compounds can be obtained, for example, by reacting hydroxyl-containing compounds (e.g., mono- or diglycerides or unsaturated compounds, such as compounds containing oleic acid groups) with ethylene oxide (e.g., 40 moles of ethylene oxide for every 1 mole of glyceride). Examples of oleoglycerides include olive oil, peanut oil, castor oil, sesame oil, cottonseed oil, and corn oil. See also Dr. HP Fiedler's *Lexikon der Hillsstoffe für Pharmazie, Kostnetik und angrenzende Gebiete* (1971), pp. 191-195.

[0134] In various aspects, liquid dosage forms can also contain preservatives, stabilizers, buffers, flavor correctors, sweeteners, colorants, antioxidants, and chelating agents. For example, chelating agents that can be considered include ethylenediaminetetraacetic acid (EDTA), hypozinotriacetic acid (HTA), diethylenetriaminepentaacetic acid (DTA) and their salts.

[0135] The liquid formulation may need to be stabilized in a pH range of approximately 6 to 9 using physiologically acceptable bases or buffers. A pH that is as neutral or weakly alkaline as possible (up to pH 8) is preferred.

[0136] To improve the solubility and / or stability of the disclosed compounds in the disclosed liquid, parenteral, or intravenous dosage forms, the use of α-, β-, or γ-cyclodextrins or their derivatives may be advantageous, particularly hydroxyalkyl-substituted cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin or sulfobutyl ether-β-cyclodextrin. Furthermore, co-solvents such as alcohols can improve the solubility or stability of the compounds of the present invention in pharmaceutical compositions.

[0137] In various aspects, the disclosed liquid, parenteral, or intravenous dosage forms may also include liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilayer vesicles. Liposomes can be formed from various phospholipids, such as cholesterol, stearamine, or phosphatidylcholine.

[0138] The pharmaceutical compositions disclosed herein are suitable for injection, such as parenteral administration, intravenous administration, intramuscular administration, or subcutaneous administration. The injectable pharmaceutical compositions can be prepared as solutions or suspensions of the active compound in water. Suitable surfactants, such as hydroxypropyl cellulose, may be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oil. Furthermore, preservatives may be added to prevent harmful microbial growth.

[0139] Pharmaceutical compositions of this disclosure suitable for parenteral administration may include sterile aqueous or oily solutions, suspensions, or dispersions. Furthermore, the composition may be in the form of a sterile powder for ad hoc preparation of such sterile injectable solutions or dispersions. In some respects, the final injectable dosage form is sterile and must be an effective liquid for use in a syringe. The pharmaceutical composition should be stable under manufacturing and storage conditions; therefore, it is preferably protected against contamination by microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium comprising, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0140] For example, injectable solutions can be prepared in which the carrier includes physiological saline, glucose solution, or a mixture of physiological saline and glucose solution. Injectable suspensions can also be prepared, in which case a suitable liquid carrier, suspending agent, etc., can be used. In some aspects, the disclosed parenteral preparations may contain about 0.01-0.1 M, for example, about 0.05 M, phosphate buffer. In other aspects, the disclosed parenteral preparations may contain about 0.9% physiological saline.

[0141] In various aspects, the disclosed parenteral drug compositions may contain pharmaceutically acceptable carriers, such as aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils (olive oil), and injectable organic esters (ethyl oleate). Aqueous carriers include, but are not limited to, water, alcohol / aqueous solutions, emulsions, or suspensions, including physiological saline and buffer media. Parenteral carriers may include mannitol, normal serum albumin, sodium chloride solution, Ringer's glucose solution, glucose and sodium chloride, lactated Ringer's solution, and fixed oils. Intravenous carriers include liquids and nutritional supplements, electrolyte supplements, such as Ringer's glucose-based supplements, etc. Preservatives and other additives, such as antibacterial agents, antioxidants, chelating agents, inert gases, etc., may also be present. On the other hand, the disclosed parenteral drug compositions may contain small amounts of additives, such as substances that enhance isotonicity and chemical stability, such as buffers and preservatives. Injectable drug compositions are also contemplated in solid form formulations intended to be converted into liquid form shortly before use. In addition, other adjuvants can be added to make the formulation isotonic with the blood of the subject or patient.

[0142] In addition to the pharmaceutical compositions described above, the disclosed compounds can also be formulated into reservoir formulations. Such long-acting formulations can be administered via implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Thus, for example, these compounds can be formulated with suitable polymers or hydrophobic materials (e.g., as emulsions in acceptable oils) or ion exchange resins, or as slightly soluble derivatives, such as slightly soluble salts.

[0143] The pharmaceutical compositions disclosed herein can be in forms suitable for topical application. As used herein, the phrase "topical application" means application to a biological surface, including, for example, skin areas (e.g., hands, forearms, elbows, legs, face, nails, anus, and genital areas) or mucous membranes. By selecting suitable carriers and other ingredients that may optionally be included in the composition, as described below, the compositions of the present invention can be formulated into any form commonly used for topical application. Topical pharmaceutical compositions can be in the form of creams, ointments, pastes, gels, lotions, emulsions, suspensions, aerosols, sprays, foams, powders, pads, and patches. Furthermore, the compositions can be in forms suitable for use with transdermal devices. These formulations can be prepared using the compounds of the present disclosure or pharmaceutically acceptable salts thereof by conventional processing methods. For example, a cream or ointment with a desired consistency can be prepared by mixing a hydrophilic material and water with about 5 wt% to about 10 wt% of the compound.

[0144] In compositions suitable for transdermal application, the carrier optionally comprises a penetration enhancer and / or a suitable wetting agent, optionally combined with a small amount of suitable additives of any nature that do not have a significant adverse effect on the skin. The additives may facilitate skin application and / or aid in the preparation of the desired composition. These compositions can be applied in various ways, such as as a transdermal patch, as a liniment, or as an ointment.

[0145] Ointments are semi-solid formulations, typically based on petrolatum or petroleum derivatives. The specific ointment matrix used is the matrix that provides optimal delivery of the active agent selected for a given formulation, and preferably, also provides other desired properties (e.g., emollient properties). Like other carriers or excipients, ointment matrices should be inert, stable, non-irritating, and non-sensitizing. As explained in Remington: The Science and Practice of Pharmacy, 19th Ed., Easton, Pa.: Mack Publishing Co. (1995), pp. 1399-1404, ointment matrices can be classified into four categories: oily matrices; emulsified matrices; emulsion matrices; and water-soluble matrices. Oily ointment matrices include, for example, vegetable oils, animal fats, and petroleum semi-solid hydrocarbons. Emulsified ointment matrices, also known as absorbent ointment matrices, contain little or no water and include, for example, sulfated hydroxystearate, anhydrous lanolin, and hydrophilic petrolatum. The emulsified ointment base is a water-in-oil (W / O) emulsion or an oil-in-water (O / W) emulsion, including, for example, cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. Preferred water-soluble ointment bases are prepared from polyethylene glycols of varying molecular weights.

[0146] Lotions are preparations applied to the skin surface without friction. Emulsions are typically liquid or semi-liquid preparations in which solid particles, including active agents, are present in a water- or alcohol-based matrix. Lotions are generally more suitable for treating large areas of the body because they are easier to apply as a more fluid composition. Lotions are often solid suspensions, typically comprising oil-in-water liquid emulsions. It is usually necessary to finely break down insoluble substances in lotions. Lotions often contain suspending agents to create a better dispersion, as well as compounds that help position and maintain the active agents in contact with the skin, such as methylcellulose, sodium carboxymethylcellulose, etc.

[0147] Emulsions are viscous liquids or semi-solid emulsions, which can be oil-in-water or water-in-oil. The emulsion matrix is ​​typically washable and contains an oil phase, an emulsifier, and an aqueous phase. The oil phase, also known as the "internal" phase, is usually composed of petrolatum and / or fatty alcohols such as cetyl alcohol or stearyl alcohol. The aqueous phase is usually (but not necessarily) larger in volume than the oil phase and typically contains humectants. Emulsifiers in emulsion formulations are typically nonionic, anionic, cationic, or amphoteric surfactants. For more information, see Remington: The Science and Practice of Pharmacy, above.

[0148] Pastes are semi-solid dosage forms in which bioactive agents are suspended in a suitable matrix. Based on the nature of the matrix, pastes are classified as fatty pastes or pastes made from single-phase hydrogels. The matrix in fatty pastes is typically petrolatum, hydrophilic petrolatum, etc. Pastes made from single-phase hydrogels usually contain carboxymethyl cellulose, etc., as a matrix. For more information, please refer to Remington: The Science and Practice of Pharmacy, above.

[0149] Gel formulations are semi-solid suspension systems. A single-phase gel contains organic macromolecules that are substantially uniformly distributed throughout a carrier liquid, which is typically aqueous but preferably contains alcohols and optionally oils. Preferred organic macromolecules, i.e., gelling agents, are cross-linked acrylic polymers, such as the carbomer polymer family, for example, carboxylated polyalkylene compounds available under the trade name Carbopol™. In this context, other preferred types of polymers are hydrophilic polymers such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymers, and polyvinyl alcohol; modified celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalates, and methylcellulose; gums such as tragacanth gum and xanthan gum; sodium alginate; and gelatin. To prepare a homogeneous gel, dispersants such as alcohols or glycerols can be added, or the gelling agent can be dispersed by grinding, mechanical mixing, stirring, or a combination thereof.

[0150] Sprays typically deliver active ingredients in the form of aqueous and / or alcoholic solutions, which can be atomized and delivered to the skin. Such sprays include those formulated to provide a solution concentration of the active ingredient at the application site after delivery; for example, the spray solution may consist primarily of alcohol or other similar volatile liquids in which the active ingredient can be dissolved. Upon delivery to the skin, the carrier evaporates, leaving a concentrated active ingredient at the application site.

[0151] Foam compositions are typically formulated as single-phase or multi-phase liquids and packaged in suitable containers, optionally with a propellant that helps expel the composition from the container, thus transforming it into foam upon application. Other foaming techniques include, for example, "bag-in-can" formulations. Compositions thus formulated typically contain low-boiling-point hydrocarbons, such as isopropane. Applying and stirring such a composition at body temperature causes the isopropane to evaporate and produce foam, similar to pressurized aerosol foaming systems. The foam can be water-based or aqueous alkanol-based, but is often formulated with a high alcohol content, which evaporates rapidly when applied to the user's skin, facilitating the active ingredient's penetration through the upper skin layer to the treatment site.

[0152] Skin patches typically include a backing layer to which a reservoir containing the active ingredient is attached. The reservoir can be, for example, a pad that disperses or soaks the active ingredient or composition, or a liquid reservoir. Patches usually also include a water-permeable adhesive on the front side, which adheres and secures the device to the treatment area. Self-adhesive silicone rubber can also be used. In both cases, a protective permeable layer can be used to protect the adhesive side of the patch before application. Skin patches may also include a removable cover for protection during storage.

[0153] Examples of patch formulations that can be used in this invention include single-layer or multi-layer pharmaceutical products in an adhesive system, characterized in that the pharmaceutical product is directly contained in the skin-contact adhesive. In such transdermal patch designs, the adhesive serves not only to adhere the patch to the skin but also as a formulation base, containing the pharmaceutical product and all excipients under a single backing film. In multi-layer drug-adhesive patches, the film is disposed between two distinct drug-adhesive layers, or multiple drug-adhesive layers are combined under a single backing film.

[0154] Examples of pharmaceutically acceptable carriers suitable for topical application of pharmaceutical compositions include carrier materials well-known in the cosmetic and medical fields, serving as matrices for emulsions, creams, aqueous solutions, oils, ointments, pastes, gels, lotions, emulsions, foams, suspensions, aerosols, etc., depending on the final form of the composition. Therefore, representative examples of suitable carriers according to the invention include, but are not limited to, water, liquid alcohols, liquid glycols, liquid polyalkylene glycols, liquid esters, liquid amides, liquid protein hydrolysates, liquid alkylated protein hydrolysates, liquid lanolin and lanolin derivatives, and similar materials commonly used in cosmetic and pharmaceutical compositions. Other suitable carriers according to the invention include, but are not limited to, alcohols, such as monohydric and polyhydric alcohols, such as ethanol, isopropanol, glycerol, sorbitol, 2-methoxyethanol, diethylene glycol, ethylene glycol, hexanediol, mannitol, and propylene glycol; ethers, such as diethyl ether or dipropyl ether; polyethylene glycol and methoxypolyoxyethylene (carbon waxes with a molecular weight of 200 to 20,000); polyoxyethylene glycerol, polyoxyethylene sorbitol, glyceryl stearoyl diacetate, etc.

[0155] If desired, the topical compositions of this disclosure can be packaged in a packaging or dispenser device, such as an FDA-approved kit, which may contain one or more unit dosage forms containing the active ingredient. The dispenser device may, for example, comprise a tube. The packaging or dispenser device may be accompanied by instructions for use. The packaging or dispenser device may also be accompanied by a notification issued by a government agency regulating the manufacture, use, or sale of the drug, reflecting that agency's approval of the form of the composition for human or veterinary use. For example, such notification may include a label or approved product information for a prescription drug approved by the U.S. Food and Drug Administration. Compositions comprising the topical compositions of this invention formulated in a pharmaceutically acceptable carrier can also be prepared, placed in a suitable container, and labeled to treat a specified disease.

[0156] Another patch system configuration usable with this invention is a reservoir transdermal system design, characterized by comprising a liquid compartment containing a drug solution or suspension, separated from the release membrane by a semi-permeable membrane and an adhesive. The adhesive component of this patch system can be added as a continuous layer between the membrane and the release membrane, or it can be arranged in a concentric configuration around the membrane. Another patch system configuration usable with this invention is a matrix system design, characterized by comprising a semi-solid matrix containing a drug solution or suspension in direct contact with the release membrane. The component responsible for skin adhesion is incorporated into the overlay layer and forms a concentric structure around the semi-solid matrix.

[0157] The pharmaceutical compositions disclosed herein can be formulations suitable for rectal administration, wherein the carrier is solid. Preferably, the mixture forms a unit-dose suppository. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppository can be conveniently formed by first mixing the composition with a softened or melted carrier, then cooling and molding it in a mold.

[0158] Pharmaceutical compositions containing compounds disclosed herein and / or their pharmaceutically acceptable salts may also be prepared in the form of powders or liquid concentrates.

[0159] Pharmaceutical compositions (or formulations) can be packaged in a variety of ways. Typically, the articles used for dispensing include containers containing the pharmaceutical composition in its appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), pouches, and foil blister packs. Containers may also include tamper-evident components to prevent unauthorized access to the contents. Furthermore, containers are usually labeled with a description of their contents and any appropriate warnings or instructions.

[0160] If desired, the disclosed pharmaceutical composition may be packaged in a packaging or dispenser device, which may contain one or more unit dosage forms containing the active ingredient. The packaging may include, for example, metal or plastic foil, such as blister packs. The packaging or dispenser device may be accompanied by instructions for use. The packaging or dispenser may also be accompanied by a notification related to the container, in the form prescribed by the government agency regulating the manufacture, use, or sale of the drug, reflecting that agency's approval for human or veterinary use. For example, such a notification may be an FDA-approved prescription drug label or an approved product label. Pharmaceutical compositions comprising the disclosed compound formulated in a compatible drug carrier may also be prepared, placed in an appropriate container, and labeled to treat a specified disease.

[0161] The exact dosage and frequency of administration depend on the specific compound disclosed, the product of the disclosed preparation method, its pharmaceutically acceptable salt, solvate or polymorph, its hydrate, its solvate, its polymorph or its stereochemical isomer; the specific condition being treated and the severity of the condition; various factors specific to the patient's medical history, such as the age, weight, sex, disease severity and general physical condition of the individual subject, and other medications that the individual may be taking; furthermore, it is apparent that the effective daily dose may be reduced or increased based on the patient's response and / or the assessment of the physician prescribing the disclosed compound.

[0162] Depending on the method of administration, the pharmaceutical composition will contain 0.05 to 99 wt%, preferably 0.1 to 70 wt%, more preferably 0.1 to 50 wt% of the active ingredient, and 1 to 99.95 wt%, preferably 30 to 99.9 wt%, more preferably 50 to 99.9 wt% of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.

[0163] In one respect, an appropriate dose level is typically from about 0.01 to 1000 mg of the compound described herein per kilogram of patient body weight per day, which may be administered once or multiple times. In each respect, the dose level will be from about 0.1 to about 500 mg / kg per day, from about 0.1 to 250 mg / kg per day, or from about 0.5 to 100 mg / kg per day. Suitable dose levels may be from about 0.01 to 1000 mg / kg per day, from about 0.01 to 500 mg / kg per day, from about 0.01 to 250 mg / kg per day, from about 0.05 to 100 mg / kg per day, or from about 0.1 to 50 mg / kg per day. Within this range, the dose may be 0.05 to 0.5, 0.5 to 5.0, or 5.0 to 50 mg / kg per day. For oral administration, the composition is preferably provided in tablet form containing 1.0 to 1000 mg of the active ingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 mg of the active ingredient, for adjusting the dosage for the patient to be treated according to symptoms. The compound can be administered 1 to 4 times daily, preferably once or twice daily. This administration regimen can be adjusted to provide the best therapeutic response.

[0164] The unit doses described above and below can be administered more than once daily, for example, 2, 3, 4, 5, or 6 times daily. In each respect, such unit doses can be administered once or twice daily, so that the total dose administered to a 70 kg adult per administration ranges from 0.001 to approximately 15 mg / kg of subject body weight. In the other respect, the dose administered per administration is from 0.01 to approximately 1.5 mg per kg of subject body weight, and this treatment can continue for weeks or months, and in some cases even years. However, it is understood that the specific dose level for any particular patient will depend on a variety of factors, including the activity of the particular compound used; the individual's age, weight, general health condition, sex, and diet; the time and route of administration; the excretion rate; other medications previously taken; and the severity of the particular disease being treated, as is fully understood by those skilled in the art.

[0165] Typical dosages may be 1 mg to approximately 100 mg tablets or 1 mg to approximately 300 mg tablets, taken once or more daily, or as sustained-release capsules or tablets taken once daily, containing a high proportion of the active ingredient. Sustained-release effects can be achieved through capsule materials dissolved at different pH values, capsules that release slowly by osmotic pressure, or any other known controlled-release mechanism.

[0166] In some cases, it may be necessary to use doses outside this range, which will be apparent to those skilled in the art. Furthermore, it is important to note that clinicians or treating physicians will know how and when to begin, interrupt, adjust, or terminate treatment based on the individual patient's response.

[0167] The disclosed pharmaceutical compositions may also contain other therapeutically active compounds that are commonly used to treat the aforementioned pathological or clinical conditions.

[0168] It should be understood that the disclosed compositions can be prepared from the disclosed compounds. It should also be understood that the disclosed compositions can be used in the disclosed methods of application.

[0169] As previously stated, this invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the disclosed compound, the product of the disclosed preparation method, a pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, and a pharmaceutically acceptable carrier. Furthermore, this invention relates to a method for preparing such a pharmaceutical composition, characterized by thoroughly mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of the compound of the invention. Treatment and prevention methods for malaria in the subjects

[0170] Human malaria is caused by single-celled microorganisms of the genus Plasmodium. It is transmitted only through the bite of an infected female Anopheles mosquito. The mosquito bite introduces the parasite, which enters the liver, where it matures and multiplies. Host infection begins with sporozoites invading liver cells, followed by a rapid proliferation of the parasite in the liver stage (also known as the erythrocytic exotype (EEF)). After developing in the liver stage, the parasite enters the bloodstream (the hematogenous stage), where it invades red blood cells (erythrocytes). The proliferation of the hematogenous stage leads to the clinical manifestations of malaria, which may include fever, chills, headache, muscle and joint pain, abdominal pain, nausea and vomiting, and diarrhea.

[0171] In one aspect, this document discloses a method for treating or preventing malaria in a subject, the method comprising the step of administering to the subject an effective therapeutic amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof or a disclosed pharmaceutical composition. In some aspects, the subject is a human being. In another aspect, the subject has been diagnosed with a need for malaria treatment prior to the administration step. In some aspects, the method further includes the step of identifying a subject who needs malaria treatment.

[0172] In one respect, the compounds described herein exhibit potent antimalarial activity against one or more strains of Plasmodium at one or more stages of the parasite, such as the intraerythrocytic and erythrocytic stages. In another respect, the Plasmodium species is Plasmodium falciparum (…). Plasmodium falciparum ), Plasmodium vivax ( Plasmodium vivax ), Plasmodium norotri ( Plasmodium knowlesi ), Plasmodium ovale ( Plasmodium ovale ) or Plasmodium malariae ( Plasmodium malariae In another aspect, the compounds described herein inhibit or prevent the hepatic, hematogenous, or combined phases of malaria. Embodiments demonstrate that the compounds described herein are capable of inhibiting both the hepatic and hematogenous phases of malaria. The ability of the compounds described herein to inhibit both the hepatic and hematogenous phases of malaria makes them an attractive alternative for the treatment and prevention of malaria.

[0173] In one aspect, the compound is administered orally to the subject. In another aspect, the compound is administered at a dose of about 50 mg / day to about 1000 mg / day, or about 50 mg / day, 50 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, 350 mg / day, 400 mg / day, 450 mg / day, 500 mg / day, 550 mg / day, 600 mg / day, 650 mg / day, 700 mg / day, and 750 mg / day (100 mg / day to 300 mg / day).

[0174] Having now described aspects of this disclosure, the following examples illustrate some additional aspects of the invention. While aspects of this disclosure have been described in conjunction with the following examples and corresponding text and drawings, it is not intended to limit the aspects of this disclosure to those described herein. Rather, it is intended to cover all alternatives, modifications, and equivalents included within the spirit and scope of this disclosure. aspect

[0175] Aspect 1. A compound having the formula represented by structure I, or a pharmaceutically acceptable salt thereof: I in n is an integer from 1 to 4, where each R 1 Independently hydrogen, halogen, substituted or unsubstituted straight-chain or branched alkyl or alkoxy groups, and m is an integer from 1 to 3, where each R 2 It is hydrogen, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0176] Aspect 2. Compounds of aspect 1, where n is 1 or 2.

[0177] Aspect 3. Compounds of aspect 1 or 2, wherein R 1 It is a C1-C6 alkyl group.

[0178] Aspect 4. Compounds of aspect 1 or 2, wherein R 1 It is methyl or ethyl.

[0179] Aspect 5. Compounds of aspect 1 or 2, wherein R 1 It is halogen.

[0180] Aspect 6. Compounds of aspect 1 or 2, wherein R 1 It is fluorine, bromine, iodine, or chlorine.

[0181] Aspect 7. Compounds of aspect 1 or 2, wherein R 1 It is a C1-C6 alkoxy group.

[0182] Aspect 8. Compounds of aspect 1 or 2, wherein R 1 It is methoxy or ethoxy.

[0183] Aspect 9. A compound of any one of Aspects 1-8, where m is 1.

[0184] Aspect 10. A compound of any one of Aspects 1-9, wherein R 2 It is a substituted or unsubstituted phenyl group.

[0185] Aspect 11. A compound of any one of Aspects 1-9, wherein R 2 It is a phenyl group that has been substituted with halogen, substituted or unsubstituted alkyl, alkoxy or aryloxy groups.

[0186] Aspect 12. A compound of any one of Aspects 1-9, wherein R 2 It is a substituted or unsubstituted heterocyclic alkyl group.

[0187] Compounds of aspect 13 and aspect 12, wherein the substituted or unsubstituted heterocyclic alkyl group is a 5- or 6-membered ring.

[0188] Compounds of aspect 14 and aspect 12, wherein the unsubstituted heterocyclic alkyl group is tetrahydrofuranyl or tetrahydropyranyl.

[0189] Aspect 15. A compound of any one of Aspects 1-9, wherein R 2 It is a substituted or unsubstituted heteroaryl group.

[0190] Compounds of aspect 16 and aspect 15, wherein the heteroaryl group is pyridyl, thiophene or thiazolyl.

[0191] Compounds of aspect 17. or aspect 15 or 16, wherein the heteroaryl group is substituted or unsubstituted with a phenyl group.

[0192] Compounds of aspect 18 and aspect 17, wherein the phenyl group is substituted with a halogen, a substituted or unsubstituted alkyl group, an alkoxy group, a fluoroalkoxy group, or a fluoroalkyl group.

[0193] Compounds of aspect 19 and aspect 17, wherein the phenyl group is substituted with -F, -CF3, -OCF3 or any combination thereof.

[0194] Aspect 20. A compound of any one of Aspects 1-9, wherein R 2 It is a C3-C6 cycloalkyl group.

[0195] Aspect 21. The compound according to aspect 1, wherein the compound has structural formula II. II

[0196] Aspect 22. The compound described in aspect 21, wherein R 2 It is a substituted or unsubstituted phenyl group.

[0197] Aspect 23. The compound described in aspect 21, wherein R 2 It is a phenyl group that has been substituted with halogen, substituted or unsubstituted alkyl, alkoxy or aryloxy groups.

[0198] Compounds of aspect 24 and aspect 21, wherein R 2 It is a substituted or unsubstituted heterocyclic alkyl group.

[0199] Compounds of aspect 25 and aspect 24, wherein the substituted or unsubstituted heterocyclic alkyl group is a 5- or 6-membered ring.

[0200] Compounds of aspect 26 and aspect 24, wherein the unsubstituted heterocyclic alkyl group is tetrahydrofuranyl or tetrahydropyranyl.

[0201] Compounds of aspect 27 and aspect 21, wherein R 2 It is a substituted or unsubstituted heteroaryl group.

[0202] Compounds of aspect 28 and aspect 27, wherein the heteroaryl group is pyridyl, thiophene or thiazolyl.

[0203] Compounds of aspect 29. or aspect 27 or 28, wherein the heteroaryl group is substituted or unsubstituted with a phenyl group.

[0204] Compounds of aspect 30 and aspect 29, wherein the phenyl group is substituted with a halogen, a substituted or unsubstituted alkyl group, an alkoxy group, a fluoroalkoxy group, or a fluoroalkyl group.

[0205] Compounds of aspect 31 and aspect 29, wherein the phenyl group is substituted with -F, -CF3, -OCF3 or any combination thereof.

[0206] Compounds of aspect 32 and aspect 21, wherein R 2 It is a C3-C6 cycloalkyl group.

[0207] 33. The compound of aspect 21, wherein R 2 for Where o is 1 or 2, R 3 It is hydrogen, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryloxy.

[0208] Aspect 34. The compound described in aspect 33, wherein R 3 It is a phenyl group that has been substituted with a fluoroalkyl or fluoroalkoxy group.

[0209] Compounds of aspect 35 and aspect 33, wherein R 3 It is a phenyl group substituted with F, CF3, OCF3 or any combination thereof.

[0210] Aspect 36. The compound of aspect 1, wherein the compound has one of the following structures , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , Where R 1a R 1b R 1c and R 1d Each is independently hydrogen, halogen, substituted or unsubstituted straight-chain or branched alkyl or alkoxy.

[0211] Compounds of aspect 37 and aspect 36, wherein the alkyl group is methyl, the alkoxy group is methoxy, and the halogen is chlorine.

[0212] Compounds of aspect 38 and aspect 36, wherein R 1c It is a methoxy group.

[0213] Aspect 39. The compound of aspect 1, wherein the compound has the following structure Where R 1c It is a methoxy group.

[0214] Aspect 40. The compound of aspect 1, wherein the compound has the following structure Where R 1b It is chlorine, R 1c It is a methoxy group.

[0215] Aspect 41. The compound of aspect 1, wherein the compound has the following structure or Where R 1b It is chlorine, R 1c It is a methoxy group.

[0216] Aspect 42. The compound of aspect 1, wherein the compound has the following structure Where R 1c It is a methoxy group.

[0217] Aspect 43. The compound of aspect 1, wherein the compound has the following structure Where R 2a R 2b and R 2cEach is independently hydrogen, halogen, substituted or unsubstituted straight-chain or branched alkyl or alkoxy.

[0218] Compounds of aspect 44 and aspect 43, wherein R 2c It is a methoxy group.

[0219] Aspect 45. The compound of aspect 1, wherein the compound is THA-1839, THA-1840, THA-1994, THA-2111, THA-2209, THA-2220, THA-2224, THA-2224 or THA-2225.

[0220] Aspect 46. A pharmaceutical composition comprising a compound of any one of aspects 1 to 45 and a pharmaceutically acceptable carrier.

[0221] Aspect 47. A method for treating or preventing malaria in a subject, the method comprising administering to the subject an effective amount of any one of aspects 1 to 45.

[0222] Aspect 48. The method of aspect 47, wherein the compound inhibits or prevents the liver phase, blood phase, or combination thereof of malaria.

[0223] Aspect 49. The method of aspect 47, wherein the subject is infected with a strain of Plasmodium, the strain of Plasmodium causing the subject to contract malaria.

[0224] The method of aspect 50. aspect 49, wherein the malaria strain includes Plasmodium falciparum ( Plasmodium falciparum ), Plasmodium vivax ( Plasmodium vivax ), Plasmodium norotri ( Plasmodium knowlesi ), Plasmodium ovale ( Plasmodium ovale ) or Plasmodium malariae ( Plasmodium malariae ). Example

[0225] The following examples are provided to provide those skilled in the art with a complete disclosure and description of the compounds, compositions, articles, apparatuses, and / or methods described herein. These examples are intended purely as illustrations of this disclosure and are not intended to limit the scope of the disclosure as viewed by the inventors. Efforts have been made to ensure the accuracy of figures (such as quantities, temperatures, etc.), but some errors and deviations should be accounted for. Unless otherwise stated, parts are by weight, temperatures (°C) are or ambient temperatures, and pressures are at atmospheric pressure.

[0226] Synthesis steps

[0227] experiment

[0228] General Step A: Formation of Indocyanine Anhydride

[0229] Add 1 equivalent of anthranilic acid dissolved in 1,2-dichloroethane (485 mM) to a two-necked round-bottom flask. Add dropwise a solution of triphosgene (2 equivalents) in 1,2-dichloroethane (1.05 M) to the above solution at room temperature. Heat the resulting mixture to 80 °C and stir for 3 hours, then cool in ice water. Collect the precipitate by filtration, wash with ice-cold dichloromethane, and dry to give the product (75–95% yield).

[0230] General Step B: Oxidation of pyridinium chlorochromate (forming aldehydes)

[0231] Under inert conditions at 0°C, an alcohol (1 equivalent) was added to a solution of pyridinium chlorochromate (2 equivalents) in dichloromethane (300 mM). The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth stopper, and the solvent was evaporated under reduced pressure. The crude product was used directly without further purification.

[0232] General step C: Swern oxidation (formation of aldehydes)

[0233] At -78°C, a 2M solution of oxaloyl chloride (1.5 equivalents) in dichloromethane, dimethyl sulfoxide (3 equivalents), and an alcohol (1 equivalent) were added sequentially to a dried double-necked round-bottom flask. Then, N,N-diisopropylethylamine (5.5 equivalents) was added over 5 minutes. The flask was removed from the bath and heated to 0°C over 10 minutes. The reaction mixture was transferred to a separatory funnel containing ice-cold 1M hydrochloric acid solution. The two phases were separated, and the aqueous layer was further extracted with dichloromethane. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The crude product was used directly without further purification.

[0234] General Step D: Protecting Aldehydes with Cycloacetal

[0235] A solution of aldehyde (1 equivalent) in DCM (113 mM) was added to an oven-dried, double-necked round-bottom flask under inert conditions. Ethylene glycol (3 equivalents) and TMSCl (1 equivalent) were then added at room temperature. The reaction mixture was stirred at room temperature for 12 hours. The mixture was extracted with DCM. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The crude product was used directly without further purification.

[0236] General Step E: Deprotection of Aldehydes (Deprotection of Cycloacetals)

[0237] To a protected biaryl ether (1 equivalent) in acetonitrile (54 mM) and water (273 mM) solution, p-toluenesulfonic acid monohydrate (0.2 equivalents) was added at room temperature under inert conditions. The reaction mixture was stirred under reflux for 4 hours and cooled to room temperature. After the reaction was complete, the reaction was quenched with sodium bicarbonate. The mixture was extracted with ethyl acetate and brine. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The crude product was stored under inert conditions because it is unstable in air. The residue was purified by column chromatography to give the product.

[0238] General step F: Ullman coupling (formation of ether bonds)

[0239] Under inert conditions, a solution of aldehyde (1 equivalent) and phenol (1.1 equivalent) in anhydrous dimethyl sulfoxide (250 mM), potassium phosphate (2 equivalent), pyridinecarboxylic acid (0.4 equivalent), and cuprous iodide (0.2 equivalent) were added sequentially to a dried double-necked round-bottom flask. The reaction mixture was stirred under reflux overnight and cooled to room temperature. The mixture was extracted with ethyl acetate and brine. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography to give either the product or a product of 90% purity, depending on the substrate.

[0240] General step G: Suzuki coupling (formation of CH2-CH2 bonds)

[0241] In a flame-dried reflux apparatus, an aldehyde (1 equivalent), boric acid (1.3 equivalents), and cesium carbonate (2 equivalents) were added to a two-necked round-bottom flask. Anhydrous toluene (800 mM), anhydrous ethanol (800 mM), and deionized water (130 mM) were added. The solution was stirred at room temperature for 5 minutes. Tetra(triphenylphosphine)palladium(0) (0.11 equivalents) was added to the reaction mixture. The reaction mixture was stirred under reflux for 3 hours, and then cooled to room temperature. The mixture was filtered through a diatomaceous earth stopper and washed with ethyl acetate. Ethanol was evaporated under reduced pressure. The mixture was extracted with ethyl acetate, the combined organic layers were washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography to give either the product or a product of 90% purity, depending on the substrate.

[0242] General step H: Suzuki coupling (formation of CH2-CH2 bonds)

[0243] In an oven-dried double-necked round-bottom flask, potassium carbonate (3 equivalents) in anhydrous tetrahydrofuran (369 mM) and deionized water (986 mM), an aldehyde (1 equivalent), and tetra(triphenylphosphine)palladium (0) (0.08 equivalents) were added sequentially. The solution was stirred at room temperature for 1 hour under inert conditions. Boric acid (1.1 equivalents) was added to the reaction mixture. The reaction mixture was stirred under reflux overnight, and then cooled to room temperature. The mixture was filtered through a diatomaceous earth stopper and washed with ethyl acetate. The mixture was extracted with ethyl acetate, the combined organic layers were washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography to give either the product or a product of 90% purity, depending on the substrate.

[0244] General Step I: Suzuki Coupling (Formation of CH2-CH2 Bonds)

[0245] A solution of aldehyde (1 equivalent), boric acid (1.2 equivalent), potassium carbonate (3 equivalent), palladium acetate (0.004 equivalent), and tetrabutylammonium bromide (1 equivalent) in deionized water (250 mM) was placed in a microwave-safe container. The microwave reaction was set to 150 °C and maintained for 5 minutes. The reaction mixture was diluted with ethyl acetate and filtered through a diatomaceous earth stopper. The solution was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography to obtain either the product or a product with 90% purity, depending on the substrate.

[0246] General step J: for the formation of α,β-unsaturated ketones (Aldol condensation)

[0247] Add 5% sodium hydroxide aqueous solution (10M) to a solution of aldehyde (1 equivalent) in acetone (4M) and water (1M). Stir the reaction mixture at room temperature for 30 minutes. Extract the mixture with ethyl acetate. Wash the combined organic layers with brine and dry with anhydrous sodium sulfate. Evaporate the solvent under reduced pressure.

[0248] General step K: Used to form α,β-unsaturated ketones (Wittig reaction)

[0249] A 500 mM solution of aldehyde (1 equivalent) in toluene was added to a flame-drying reflux apparatus. (Acetylmethylene)triphenylphosphine (1.2 equivalent) was then added to the solution. The mixture was stirred overnight under reflux, cooled to room temperature, and evaporated under reduced pressure. The residue was purified by column chromatography to give an enone. dx.doi.org / 10.1021 / jo5006729

[0250] General step L: for the formation of α,β-unsaturated ketones (Wittig reaction)

[0251] Under inert conditions, an aldehyde (1 equivalent) dissolved in DCM (600 mM) was added to a round-bottom flask. Yeride (1.5 equivalents) was added to the solution. The resulting mixture was stirred overnight at room temperature. Extraction was performed with ethyl acetate, and the combined organic layers were washed with brine. The mixture was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure.

[0252] General step M: for the formation of α,β-unsaturated ketones (Wittig reaction)

[0253] The aldehyde (5 equivalents) was added to a suspension of ylide (1 equivalent) in toluene (113 mM). The mixture was stirred at room temperature for 4 days. Extraction was performed with ethyl acetate, and the combined organic layers were washed with brine. The mixture was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure.

[0254] General step N: for the formation of α,β-unsaturated ketones (Horner-Wadsworth-Emmons reaction)

[0255] Potassium carbonate (2.7 equivalents) and water (6 M) were added to a round-bottom flask. A phosphonate (0.9 equivalents) was added to the solution, followed by an aldehyde (1 equivalent). The resulting mixture was stirred overnight at room temperature. Extraction was performed with diethyl ether. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure at room temperature.

[0256] General step O: for the formation of α,β-unsaturated ketones (Horner-Wadsworth-Emmons reaction)

[0257] Under inert conditions at 0°C, a 200 mM solution of 1.05 equivalents of sodium hydride in tetrahydrofuran was added to a round-bottom flask. A 1.5 equivalent of phosphonate ester was added to the solution. The mixture was stirred at room temperature for 30 minutes. A 200 mM solution of 1 equivalent of aldehyde in tetrahydrofuran was added dropwise. The mixture was stirred overnight at room temperature. The mixture was extracted with ethyl acetate, and the combined organic layers were washed with brine. The layers were dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure.

[0258] General step P: for the formation of ethyl-2,4-dioxocyclohexane-1-carboxylate

[0259] Under inert conditions, diethyl malonate was added to a two-necked round-bottom flask. Sodium ethoxide, generated in situ, was added dropwise to the above solution. The mixture was stirred at room temperature for 20 minutes. Then, an ethanolic solution of the enone was added. The solution was refluxed for 5 minutes to 18 hours, and then cooled to room temperature. After the reaction was complete, the reaction mixture was acidified to pH 6 with 6 M HCl. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The mixture was purified by column chromatography to a purity of 85-95%. No further purification was required for subsequent steps.

[0260] General step Q: Used to form cyclic diketones

[0261] An ethanol solution of ethyl-2,4-dioxocyclohexane-1-carboxylate was added to a two-necked round-bottom flask. 2 M sodium hydroxide solution was added dropwise to the solution. The resulting mixture was refluxed for 2 hours. After confirming the formation of the intermediate carboxylic acid, 4 M hydrochloric acid solution was added and the mixture was refluxed further for 1 hour. After the reaction was complete, the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure.

[0262] General Step R: Synthesis of THAs

[0263] A solution of the corresponding diketone (0.9 equivalents) in anhydrous dimethylformamide (350 mM) was added to a two-necked round-bottom flask. Sodium hydride (1.1 equivalents) was added. The resulting mixture was heated at 50 °C for 30 minutes. After cooling, the corresponding indomethacin anhydride was added. The solution was refluxed for 2–4 hours, then cooled to room temperature. After the reaction was complete, the reaction mixture was acidified to pH 3 with 6 M HCl. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Purification was achieved by recrystallization.

[0264] Specific synthesis steps and characterization

[0265] 6-Chloro- 2H- Benzo[ d [1,3]Oxazine-2,4( 1H )-Diketone (2)

[0266] The title compound was prepared as a white powder following general procedure A.

[0267] LCMS (ESI-MS) m / z [M+H] of C8H5ClNO3 + Calculated value: 197.99; Measured value: 197.8. Retention time: 2.921 minutes.

[0268] TLC: (50% EtOAc hexane solution, R) f ): 0.34 (UV, 254 nm, 280 nm).

[0269] 1 H NMR (500 MHz, DMSO- d 6) δ 11.86 (s, 1H), 7.87 (d,J = 2.4 Hz, 1H), 7.78 (dd, J = 8.8, 2.4 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H).

[0270] 13 C NMR (126 MHz, DMSO- d 6) δ 158.9, 146.7, 140.3, 136.6, 127.6, 127.1,117.4, 112.0.

[0271] ( E )-4-(2,4-dichlorophenyl)but-3-en-2-one (4)

[0272] The title compound was prepared as a white powder following general procedure D.

[0273] LCMS (ESI-MS) m / z :C 10 [M+H] of H9Cl2O + Calculated value: 215.00; Measured value: 215.0. Retention time: 3.514 minutes.

[0274] TLC: (10% EtOAc hexane solution, R) f ): 0.24 (UV, 254 nm, 280 nm).

[0275] 1 H NMR (500 MHz, DMSO- d 6) δ 7.93 (d, J = 8.5 Hz, 1H), 7.77 – 7.69 (m,2H), 7.48 (dd, J = 8.5, 2.1 Hz, 1H), 6.93 (d, J = 16.3 Hz, 1H), 2.36 (s, 3H).

[0276] 13 C NMR (126 MHz, DMSO- d 6) δ 198.0, 136.4, 135.9, 135.1, 131.6, 130.6,129.9, 129.8, 128.4, 28.5.

[0277] 2',4'-Dichloro-5-hydroxy-1,6-dihydro-[1,1'-biphenyl]-3(2 H )-Ketone (6)

[0278] The title compound was prepared as a white powder following general steps J and K.

[0279] LCMS (ESI-MS) m / z :C 12 H 11 [M+H] of Cl2O2 + Calculated value: 257.01; Measured value: 256.7. Retention time: 3.836 minutes.

[0280] TLC: (5% methanol in dichloromethane solution, R) f ): 0.22 (UV, 254 nm, 280 nm).

[0281] 1 H NMR (500 MHz, DMSO- d 6) δ 11.28 (s, 1H), 7.59 (d, J = 2.2 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.41 (dd, J = 8.5, 2.2 Hz, 1H), 5.27 (s, 1H), 3.66 –3.58 (m, 1H), 2.68 – 2.53 (m, 2H), 2.44 – 2.28 (m, 2H).

[0282] 13 C NMR (126 MHz, DMSO- d 6) δ 144.0, 128.9, 127.3, 127.0, 104.0, 39.2.

[0283] Infrared spectroscopy (IR) (thin film, cm) -1 ): = 2468, 2160, 1558, 1474, 1387, 1251, 1202, 1154, 1095, 1052, 907, 865, 833, 755, 360, 570, 462.

[0284] 7-Chloro-3-(2,4-dichlorophenyl)-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (7)

[0285] The title compound was prepared as a white solid following general procedure L.

[0286] TLC: (5% methanol in dichloromethane solution, R) f ): 0.38 (UV, 254 nm, 280 nm).

[0287] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.50 (d, J = 2.0 Hz, 1H), 8.12 –8.01 (m, 2H), 7.50 (d, J = 2.1 Hz, 1H), 7.34 (dd, J = 8.4, 2.1 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 4.21 – 4.08 (m, 1H), 3.76 – 3.60 (m, 2H), 3.23 (ddd, J = 17.8,4.0, 1.5 Hz, 1H), 3.14 (dd, J = 17.8, 12.6 Hz, 1H).

[0288] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 202.2, 172.4, 161.0, 139.0,137.9, 136.5, 134.9, 134.8, 134.2, 130.4, 128.2, 127.6, 124.2, 122.1, 120.2,108.1, 42.5, 34.6, 33.4.

[0289] 7-Chloro-3-(2-chlorophenyl)-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (8)

[0290] The title compound was prepared as a white powder following general procedure L.

[0291] LCMS (ESI-MS) m / z :C 19 H14 [M+H] of Cl2NO2 + Calculated value: 358.03; Measured value: 358.0. Retention time: 2.877 minutes.

[0292] TLC: (5% methanol in dichloromethane solution, R) f ): 0.32 (UV, 254 nm, 280 nm).

[0293] 1 H NMR (500 MHz, CDCl3, 1 drop DMF-) d and 3 drops of TFA- d ) δ 8.49 (d, J = 2.1 Hz, 1H),8.13 – 8.03 (m, 2H), 7.47 (dd, J = 7.6, 1.7 Hz, 1H), 7.38 – 7.27 (m, 3H), 4.24– 4.14 (m, 1H), 3.79 – 3.63 (m, 2H), 3.26 (ddd, J = 17.8, 4.2, 1.6 Hz, 1H),3.16 (dd, J = 17.8, 12.5 Hz, 1H).

[0294] 13 C NMR (126 MHz, CDCl3, 1 drop DMF-) d and 3 drops of TFA- d ) δ 202.7, 172.4, 164.7,138.8, 138.1, 136.3, 136.2, 133.5, 130.6, 129.5, 127.9, 126.6, 124.1, 122.3,120.3, 108.2, 42.7, 34.9, 33.5.

[0295] 7-Chloro-3-(3-chlorophenyl)-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (9)

[0296] The title compound, a yellow solid, was prepared following general procedure L.

[0297] TLC: (5% methanol in dichloromethane solution, R) f ): 0.32 (UV, 254 nm, 280 nm).

[0298] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.49 (d, J = 2.0 Hz, 1H), 8.12 –8.03 (m, 2H), 7.40 – 7.32 (m, 2H), 7.27 (d, J = 2.3 Hz, 1H), 7.22 – 7.14 (m,1H), 3.82 – 3.51 (m, 3H), 3.30 – 3.07 (m, 2H).

[0299] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 202.4, 172.4, 161.1, 141.0,139.0, 138.0, 136.5, 135.3, 130.8, 128.7, 126.8, 124.7, 124.2, 122.2, 120.2,108.2, 43.8, 37.9, 35.0.

[0300] 7-Chloro-3-(4-chlorophenyl)-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (10)

[0301] The title compound was prepared as a white powder following general procedure L.

[0302] LCMS (ESI-MS) m / z :C 19 H 14 [M+H] of Cl2NO2 + Calculated value: 358.03; Measured value: 358.0. Retention time: 2.886 minutes.

[0303] TLC: (5% methanol in dichloromethane solution, R) f ): 0.32 (UV, 254 nm, 280 nm).

[0304] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.49 (d, J= 2.1 Hz, 1H), 8.12 –8.02 (m, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 3.79 – 3.66 (m,2H), 3.61 (dd, J = 18.4, 12.1 Hz, 1H), 3.26 – 3.11 (m, 2H).

[0305] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 202.6, 172.4, 161.2, 139.0,137.9, 137.5, 136.6, 134.4, 129.7, 127.8, 124.3, 122.2, 120.3, 108.2, 43.9,37.7, 35.2.

[0306] 7-Chloro-3-(o-Tolyl)-3,4-Dihydroacridine-1,9(2) H 10 H )-Diketone (11)

[0307] The title compound, a light brown solid, was prepared following general procedure L.

[0308] LCMS (ESI-MS) m / z :C 20 H 17 [M+H] of ClNO2 + Calculated value: 358.03; Measured value: 358.0. Retention time: 2.886 minutes.

[0309] TLC: (5% methanol in dichloromethane solution, R) f ): 0.35 (UV, 254 nm, 280 nm).

[0310] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.50 (d, J= 2.1 Hz, 1H), 8.09 –8.01 (m, 2H), 7.31 – 7.26 (m, 3H), 7.25 – 7.20 (m, 1H), 4.01 – 3.91 (m, 1H), 3.65 – 3.54 (m, 2H), 3.20 – 3.12 (m, 2H), 2.35 (s, 3H).

[0311] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 203.3, 172.5, 161.8, 139.0,137.9, 137.2, 136.5, 135.5, 131.5, 128.2, 127.1, 124.6, 124.2, 122.1, 120.3,108.2, 43.7, 34.7, 34.3, 19.0.

[0312] 7-Chloro-3-(m-Tolyl)-3,4-Dihydroacridine-1,9(2) H 10 H )-Diketone (12)

[0313] The title compound, a light brown solid, was prepared following general procedure L.

[0314] LCMS (ESI-MS) m / z :C 20 H 17 [M+H] of ClNO2 + Calculated value: 338.09; Measured value: 338.1. Retention time: 2.852 minutes.

[0315] TLC: (5% methanol in dichloromethane solution, R) f ): 0.38 (UV, 254 nm, 280 nm).

[0316] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.50 (d, J = 2.3 Hz, 1H), 8.12 –7.95 (m, 2H), 7.29 (dd, J = 8.8, 7.6 Hz, 1H), 7.17 (d, J= 7.6 Hz, 1H), 7.10 –6.99 (m, 2H), 3.77 – 3.56 (m, 3H), 3.29 – 3.14 (m, 2H), 2.37 (s, 3H).

[0317] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 203.0, 172.5, 161.5, 139.4,139.0, 138.8, 137.7, 136.5, 129.3, 129.1, 127.1, 124.2, 123.1, 121.8, 120.2,108.2, 43.9, 38.1, 35.4, 21.1.

[0318] 7-Chloro-3-(p-Tolyl)-3,4-Dihydroacridine-1,9(2) H 10 H )-Diketone (13)

[0319] The title compound was prepared as a yellowish-white powder following general procedure L.

[0320] LCMS (ESI-MS) m / z :C 20 H 17 [M+H] of ClNO2 + Calculated value: 338.09; Measured value: 338.1. Retention time: 2.867 minutes.

[0321] TLC: (5% methanol in dichloromethane solution, R) f ): 0.38 (UV, 254 nm, 280 nm).

[0322] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.48 (s, 1H), 8.09 – 8.02 (m, 2H), 7.21 (d, J = 7.9 Hz, 2H), 7.15 (d, J = 7.9 Hz, 2H), 3.77 – 3.55 (m, 3H), 3.28 –3.10 (m, 2H), 2.36 (s, 3H).

[0323] 13C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 203.2, 172.4, 161.6, 138.9,138.3, 137.9, 136.4, 136.1, 130.1, 126.3, 124.2, 122.2, 120.3, 108.3, 44.1,37.8, 35.5, 21.0.

[0324] 7-Chloro-3-(2,4-dimethylphenyl)-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (14)

[0325] The title compound, a brown solid, was prepared following general procedure L.

[0326] LCMS (ESI-MS) m / z :C 21 H 19 [M+H] of ClNO2 + Calculated value: 352.10; Measured value: 352.1. Retention time: 3.033 minutes.

[0327] TLC: (5% methanol in dichloromethane solution, R) f ): 0.32 (UV, 254 nm, 280 nm).

[0328] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.49 (d, J = 1.9 Hz, 1H), 8.09 –8.01 (m, 2H), 7.14 – 7.05 (m, 3H), 3.96 – 3.83 (m, 1H), 3.68 – 3.50 (m, 2H), 2.39 – 2.23 (m, 8H).

[0329] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d) δ 203.3, 172.4, 161.8, 138.9,138.0, 137.8, 136.4, 135.3, 134.2, 132.2, 127.6, 124.5, 124.2, 122.0, 120.2,108.2, 43.8, 34.8, 34.0, 20.8, 18.8.

[0330] 7-Chloro-3-(2-methoxyphenyl)-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (15)

[0331] The title compound, which is a brownish-brown solid, was prepared according to general procedure L.

[0332] LCMS (ESI-MS) m / z :C 20 H 17 [M+H] of ClNO3 + Calculated value: 354.08; Measured value: 354.1. Retention time: 2.791 minutes.

[0333] TLC: (5% methanol in dichloromethane solution, R) f ): 0.35 (UV, 254 nm, 280 nm).

[0334] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.48 (s, 1H), 8.09 – 8.01 (m, 2H), 7.34 (dd, J = 7.8, 7.2 Hz, 1H), 7.13 (d, J = 7.2 Hz, 1H), 7.00 – 6.94 (m, 2H), 4.01 – 3.91 (m, 1H), 3.85 (s, 3H), 3.77 (dd, J = 18.0, 12.2 Hz, 1H), 3.67 (dd, J = 17.9, 4.0 Hz, 1H), 3.37 (dd, J = 18.0, 12.2 Hz, 1H), 3.17 (dd, J = 17.9, 4.0Hz, 1H).

[0335] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 203.9, 172.4, 162.4, 157.0,138.7, 137.9, 136.2, 129.5, 127.1, 126.9, 124.1, 122.1, 121.1, 120.2, 111.1,108.2, 55.2, 42.2, 34.1, 33.3.

[0336] 7-Chloro-3-(3-methoxyphenyl)-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (16)

[0337] The title compound was prepared as a white solid following general procedure L.

[0338] LCMS (ESI-MS) m / z :C 20 H 17 [M+H] of ClNO3 + Calculated value: 354.08; Measured value: 354.1. Retention time: 2.666 minutes.

[0339] TLC: (5% methanol in dichloromethane solution, R) f ): 0.35 (UV, 254 nm, 280 nm).

[0340] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.49 (d, J = 1.9 Hz, 1H), 8.10 –8.02 (m, 2H), 7.34 (dd, J = 8.7, 8.2 Hz, 1H), 6.91 (dd, J = 8.2, 2.1 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 6.84 (d, J = 2.1 Hz, 1H), 3.85 (s, 3H), 3.78 – 3.58 (m, 3H), 3.27 – 3.15 (m, 2H).

[0341] 13C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 202.9, 172.4, 161.4, 159.9,140.8, 138.9, 137.9, 136.4, 130.7, 124.2, 122.2, 120.3, 119.0, 113.4, 112.9,108.3, 55.5, 43.9, 38.1, 35.3.

[0342] 7-Chloro-3-(4-methoxyphenyl)-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (17)

[0343] The title compound was prepared as a white powder following general procedure L.

[0344] TLC: (5% methanol in dichloromethane solution, R) f ): 0.35 (UV, 254 nm, 280 nm).

[0345] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.48 (s, 1H), 8.11 – 8.01 (m, 2H), 7.20 (d, J = 8.7 Hz, 2H), 6.95 (d, J = 8.7 Hz, 2H), 3.85 (s, 3H), 3.76 – 3.66 (m, 2H), 3.63 – 3.56 (m, 1H), 3.26 – 3.11 (m, 2H).

[0346] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 203.1, 172.4, 161.6, 159.1,138.9, 137.9, 136.4, 131.6, 127.6, 124.2, 122.2, 120.2, 114.9, 108.3, 55.5,44.2, 37.5, 35.6.

[0347] 7-Chloro-3-(2,4-dimethoxyphenyl)-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (18)

[0348] The title compound, a light brown solid, was prepared following general procedure L.

[0349] LCMS (ESI-MS) m / z :C 21 H 19 [M+H] of ClNO4 + Calculated value: 384.09; Measured value: 384.1. Retention time: 2.811 minutes.

[0350] TLC: (5% methanol in dichloromethane solution, R) f ): 0.47 (UV, 254 nm, 280 nm).

[0351] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.47 (s, 1H), 8.05 (s, 2H), 7.08 –6.99 (m, 1H), 6.55 (d, J = 2.2 Hz, 1H), 6.50 (dd, J = 8.4, 2.2 Hz, 1H), 3.92 –3.79 (m, 7H), 3.72 (dd, J = 17.8, 12.1 Hz, 1H), 3.63 (dd, J = 17.8, 3.3 Hz, 1H), 3.34 (dd, J = 17.8, 12.1 Hz, 1H), 3.14 (dd, J = 17.8, 3.3 Hz, 1H).

[0352] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 204.1, 172.4, 162.5, 158.1,138.7, 137.8, 136.2, 127.7, 124.1, 122.0, 120.2, 119.8, 108.2, 104.8, 99.3,55.6, 55.2, 42.4, 33.7, 33.6.

[0353] 7-Chloro-3-phenyl-3,4-dihydroacridine-1,9(2) H 10 H)-Diketone (19)

[0354] The title compound, which is a brownish-brown solid, was prepared according to general procedure L.

[0355] TLC: (5% methanol in dichloromethane solution, R) f ): 0.37 (UV, 254 nm, 280 nm).

[0356] 1 H NMR (500 MHz, DMSO- d 6) δ 12.22 (s, 1H), 8.04 (s, 1H), 7.74 (d, J =8.5 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.46 – 7.33 (m, 4H), 7.27 (t, J = 7.8 Hz, 1H), 3.52 (dd, J = 16.4, 14.3 Hz, 1H), 3.10 (d, J = 16.4 Hz, 1H), 2.79 (dd, J =16.4, 14.3 Hz, 1H), 2.59 (d, J = 16.4 Hz, 1H).

[0357] ( E )-4-(2-chlorophenyl)but-3-en-2-one (32)

[0358] The yellow, oily title compound was prepared following general procedure D.

[0359] LCMS (ESI-MS) m / z :C 10 H 10 ClO [M+H] + Calculated value: 181.03; Measured value: 180.8. Retention time: 3.206 minutes.

[0360] TLC: (20% EtOAc hexane solution, R) f ): 0.48 (UV, 254 nm, 280 nm).

[0361] 1H NMR (500 MHz, CDCl3) δ 7.93 (d, J = 16.3 Hz, 1H), 7.64 (dd, J = 7.6, 2.0 Hz, 1H), 7.43 (dd, J = 7.8, 1.5 Hz, 1H), 7.35 – 7.27 (m, 2H), 6.67 (d, J =16.3 Hz, 1H), 2.42 (s, 3H).

[0362] 13 C NMR (126 MHz, CDCl3) δ 198.3, 139.2, 135.1, 132.6, 131.2, 130.2,129.6, 127.5, 127.2, 27.2.

[0363] ( E )-4-(3-chlorophenyl)but-3-en-2-one (33)

[0364]

[0365] The transparent, oily title compound was prepared following general step D.

[0366] LCMS (ESI-MS) m / z :C 10 H 10 ClO [M+H] + Calculated value: 181.03; Measured value: 181.1. Retention time: 3.088 minutes.

[0367] TLC: (5% EtOAc hexane solution, R) f ): 0.28 (UV, 254 nm, 280 nm).

[0368] 1 H NMR (399 MHz, CDCl3) δ 7.54 – 7.24 (m, 5H), 6.65 (d, J = 16.4 Hz, 1H), 2.34 (s, 3H).

[0369] 13 C NMR (126 MHz, CDCl3) δ 197.8, 141.4, 136.2, 134.8, 130.2, 130.1, 128.1, 127.9, 126.3, 27.7.

[0370] ( E )-4-(4-chlorophenyl)but-3-en-2-one (34)

[0371] The title compound was prepared as a white powder following general procedure D.

[0372] LCMS (ESI-MS) m / z :C 10 H 10 ClO [M+H] + Calculated value: 181.03; Measured value: 181.0. Retention time: 3.079 minutes.

[0373] TLC: (10% EtOAc hexane solution, R) f ): 0.24 (UV, 254 nm, 280 nm).

[0374] 1 H NMR (500 MHz, DMSO- d 6) δ 7.72 (d, J = 8.2 Hz, 2H), 7.60 (d, J = 16.7Hz, 1H), 7.48 (d, J = 8.2 Hz, 2H), 6.81 (d, J = 16.7 Hz, 1H), 2.33 (s, 3H).

[0375] 13 C NMR (126 MHz, CDCl3) δ 197.9, 141.8, 136.3, 132.9, 129.3, 129.2,127.4, 27.6.

[0376] ( E )-4-(o-tolyl)but-3-en-2-one (35)

[0377] The title compound, which is a pale yellow oil, was prepared according to general step D.

[0378] LCMS (ESI-MS) m / z :C 11 H 13 O of [M+H] +Calculated value: 161.09; Measured value: 160.9. Retention time: 3.935 minutes.

[0379] TLC: (17% EtOAc hexane solution, R) f ): 0.60 (UV, 254 nm, 280 nm).

[0380] 1 H NMR (399 MHz, DMSO- d 6) δ 7.78 (d, J = 16.2 Hz, 1H), 7.67 (d, J = 7.6Hz, 1H), 7.42 – 7.14 (m, 3H), 6.70 (d, J = 16.2 Hz, 1H), 2.40 (s, 3H), 2.34 (s, 3H).

[0381] 13 C NMR (126 MHz, CDCl3) δ 198.2, 140.7, 137.8, 133.3, 130.8, 130.2, 128.0, 126.4, 126.3, 27.7, 19.7.

[0382] ( E )-4-(m-Tolyl)but-3-en-2-one (36)

[0383] The title compound, which is a pale yellow oil, was prepared according to general step D.

[0384] LCMS (ESI-MS) m / z :C 11 H 13 O of [M+H] + Calculated value: 161.09; Measured value: 161.0. Retention time: 3.981 minutes.

[0385] TLC: (17% EtOAc hexane solution, R) f ): 0.55 (UV, 254 nm, 280 nm).

[0386] 1 H NMR (399 MHz, DMSO- d 6) δ 7.57 (d, J= 16.1 Hz, 1H), 7.54 – 7.44 (m,2H), 7.30 (dd, J = 8.2 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 6.78 (d, J = 16.1 Hz,1H), 2.42 – 2.25 (m, 6H).

[0387] 13 C NMR (126 MHz, CDCl3) δ 198.3, 143.6, 138.6, 134.3, 131.3, 128.9,128.8, 126.9, 125.4, 27.4, 21.3.

[0388] ( E )-4-(p-Tolyl)but-3-en-2-one (37)

[0389] The title compound, which is a pale yellow oil, was prepared according to general step D.

[0390] LCMS (ESI-MS) m / z :C 11 H 13 O of [M+H] + Calculated value: 161.09; Measured value: 161.1. Retention time: 3.075 minutes.

[0391] TLC: (17% EtOAc hexane solution, R) f ): 0.35 (UV, 254 nm, 280 nm).

[0392] 1 H NMR (500 MHz, DMSO- d 6) δ 7.61 – 7.54 (m, 3H), 7.24 (d, J = 7.9 Hz, 2H), 6.73 (d, J = 16.4 Hz, 1H), 2.31 (s, 6H).

[0393] 13 C NMR (126 MHz, CDCl3) δ 198.4, 143.5, 141.0, 131.7, 129.7, 128.2,126.2, 27.4, 21.5.

[0394] ( E )-4-(2,4-dimethylphenyl)but-3-en-2-one (38)

[0395] The title compound, which is a pale yellow oil, was prepared according to general step D.

[0396] LCMS (ESI-MS) m / z :C 12 H 14 O of [M+H] + Calculated value: 175.10; Measured value: 175.1. Retention time: 3.307 minutes.

[0397] TLC: (20% EtOAc hexane solution, R) f ): 0.53 (UV, 254 nm, 280 nm)

[0398] 1 H NMR (500 MHz, CDCl3) δ 7.79 (d, J = 16.1 Hz, 1H), 7.48 (d, J = 8.3 Hz,1H), 7.06 – 6.99 (m, 2H), 6.63 (d, J = 16.1 Hz, 1H), 2.42 (s, 3H), 2.37 (s, 3H), 2.33 (s, 3H).

[0399] 13 C NMR (126 MHz, CDCl3) δ 198.2, 140.7, 140.5, 137.8, 131.6, 130.4,127.2, 127.0, 126.3, 27.6, 21.2, 19.6.

[0400] ( E )-4-(2-methoxyphenyl)but-3-en-2-one (39)

[0401] The title compound was prepared as a white powder following general procedure D.

[0402] LCMS (ESI-MS) m / z :C 11 H 13 O2's [M+H] +Calculated value: 177.08; Measured value: 177.1. Retention time: 2.866 minutes.

[0403] TLC: (17% EtOAc hexane solution, R) f ): 0.51 (UV, 254 nm, 280 nm).

[0404] 1 H NMR (399 MHz, DMSO- d 6) δ 7.78 (d, J = 16.6 Hz, 1H), 7.70 (d, J = 7.7Hz, 1H), 7.42 (dd, J = 9.6, 8.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.99 (dd, J =9.6, 7.7 Hz, 1H), 6.83 (d, J = 16.6 Hz, 1H), 3.87 (s, 3H), 2.31 (s, 3H).

[0405] 13 C NMR (126 MHz, CDCl3) δ 198.9, 158.2, 138.6, 131.8, 128.2, 127.6,123.2, 120.7, 111.1, 55.4, 27.1.

[0406] ( E )-4-(3-methoxyphenyl)but-3-en-2-one (40)

[0407] The title compound, which is a pale yellow oil, was prepared according to general step E.

[0408] LCMS (ESI-MS) m / z :C 11 H 13 O2's [M+H] + Calculated value: 177.08; Measured value: 177.1. Retention time: 2.844 minutes.

[0409] TLC: (17% EtOAc hexane solution, R) f ): 0.43 (UV, 254 nm, 280 nm).

[0410] 1H NMR (500 MHz, DMSO- d 6) δ 7.59 (d, J = 16.3 Hz, 1H), 7.34 (dd, J = 9.0,8.2 Hz, 1H), 7.30 – 7.24 (m, 2H), 6.98 (d, J = 9.0 Hz, 1H), 6.82 (d, J = 16.3 Hz,1H), 3.79 (s, 3H), 2.33 (s, 3H).

[0411] 13 C NMR (126 MHz, CDCl3) δ 198.3, 159.9, 143.3, 135.8, 129.9, 127.3,120.9, 116.3, 113.0, 55.2, 27.4.

[0412] ( E )-4-(4-methoxyphenyl)but-3-en-2-one (41)

[0413] The title compound was prepared as a white powder following general procedure D.

[0414] LCMS (ESI-MS) m / z :C 11 H 13 O2's [M+H] + Calculated value: 177.08; Measured value: 177.1. Retention time: 2.716 minutes.

[0415] TLC: (17% EtOAc hexane solution, R) f ): 0.52 (UV, 254 nm, 280 nm).

[0416] 1 H NMR (399 MHz, DMSO- d 6) δ 7.67 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 16.4Hz, 1H), 6.99 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 16.4 Hz, 1H), 3.80 (s, 3H), 2.30 (s, 3H).

[0417] 13 C NMR (126 MHz, CDCl3) δ 198.4, 161.6, 143.2, 129.9, 127.0, 125.0,114.4, 55.4, 27.4.

[0418] ( E )-4-(2,4-dimethoxyphenyl)but-3-en-2-one (42)

[0419] The yellow, oily title compound was prepared following general procedure D.

[0420] LCMS (ESI-MS) m / z :C 12 H 15 O3's [M+H] + Calculated value: 207.09; Measured value: 207.1. Retention time: 2.899 minutes.

[0421] TLC: (20% EtOAc hexane solution, R) f ): 0.22 (UV, 254 nm, 280 nm).

[0422] 1 H NMR (500 MHz, CDCl3) δ 7.81 (d, J = 16.4 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 6.68 (d, J = 16.4 Hz, 1H), 6.52 (dd, J = 8.6, 2.3 Hz, 1H), 6.46 (d, J = 2.3Hz, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 2.36 (s, 3H).

[0423] 13 C NMR (126 MHz, CDCl3) δ 199.1, 163.0, 159.8, 138.7, 129.8, 125.5,116.4, 105.4, 98.4, 55.53, 55.50, 27.0. ( E )-4-Phenylacet-3-en-2-one (43)

[0424] The title compound was prepared as a grayish-white powder following general procedure D.

[0425] LCMS (ESI-MS) m / z :C 10 H 11 O of [M+H] + Calculated value: 147.07; Measured value: 147.1. Retention time: 2.712 minutes.

[0426] TLC: (10% EtOAc hexane solution, R) f ): 0.24 (UV, 254 nm, 280 nm).

[0427] 1 H NMR (500 MHz, DMSO- d 6) δ 7.75 – 7.68 (m, 2H), 7.64 (d, J = 16.7 Hz,1H), 7.48 – 7.42 (m, 3H), 6.82 (d, J = 16.7 Hz, 1H), 2.35 (s, 3H).

[0428] 13 C NMR (126 MHz, DMSO- d 6) δ 198.1, 143.1, 134.4, 130.4, 128.9, 128.3,127.2, 27.3.

[0429] 2'-Chloro-5-hydroxy-1,6-dihydro-[1,1'-biphenyl]-3(2 H )-Ketone (56)

[0430] The title compound was prepared as a white solid following general steps J and K.

[0431] LCMS (ESI-MS) m / z :C 12 H 12 [M+H] of ClO2 + Calculated value: 223.04; Measured value: 223.2. Retention time: 2.687 minutes.

[0432] TLC: (3% methanol in dichloromethane solution, R) f): 0.23 (UV, 254 nm, 280 nm).

[0433] 1 H NMR (399 MHz, CD3COCD3) δ 11.06 (s, 1H), 7.52 (d, J = 7.4 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.36 (dd, J = 7.9, 7.4 Hz, 1H), 7.28 (dd, J = 8.5, 7.9Hz, 1H), 5.37 (s, 1H), 3.83 – 3.70 (m, 1H), 2.72 – 2.54 (m, 2H), 2.54 – 2.41(m, 2H).

[0434] 3'-Chloro-5-hydroxy-1,6-dihydro-[1,1'-biphenyl]-3(2 H )-Ketone (57)

[0435] The title compound was prepared as a white solid following general steps J and K.

[0436] LCMS (ESI-MS) m / z :C 12 H 12 [M+H] of ClO2 + Calculated value: 223.04; Measured value: 223.2. Retention time: 3.623 minutes.

[0437] TLC: (5% methanol in dichloromethane solution, R) f ): 0.25 (UV, 254 nm, 280 nm).

[0438] 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.22 (s, 1H), 7.44 (s, 1H), 7.39 – 7.27(m, 3H), 5.29 (s, 1H), 3.44 – 3.29 (m, 1H), 2.75 – 2.55 (m, 2H), 2.40 (d, J =16.8 Hz, 2H).

[0439] 13C NMR (126 MHz, DMSO- d 6 ) δ 146.6, 133.6, 130.8, 127.4, 127.0, 126.2,104.0, 38.8.

[0440] IR (thin film, cm) -1 ): = 2509, 1595, 1498, 1363, 1310, 1223, 1139, 1081, 998,886, 846, 781, 695, 612, 443.

[0441] 4'-Chloro-5-hydroxy-1,6-dihydro-[1,1'-biphenyl]-3(2) H )-Ketone (58)

[0442] The title compound was prepared as a white solid following general steps J and K.

[0443] LCMS (ESI-MS) m / z :C 12 H 12 [M+H] of ClO2 + Calculated value: 223.04; Measured value: 222.8. Retention time: 3.557 minutes.

[0444] TLC: (5% methanol in dichloromethane solution, R) f ): 0.14 (UV, 254 nm, 280 nm).

[0445] 1 H NMR (500 MHz, DMSO- d 6) δ 11.22 (s, 1H), 7.38 (s, 4H), 5.29 (s, 1H), 3.35 – 3.28 (m, 1H), 2.58 (s, 2H), 2.40 (s, 2H).

[0446] 13 C NMR (126 MHz, DMSO- d 6) δ 143.0, 131.6, 129.3, 128.8, 104.0, 38.5.

[0447] IR (thin film, cm) -1 ): = 2504, 1585, 1493, 1471, 1368, 1320, 1298, 1265,1216, 1142, 1092, 1015, 831, 697, 581, 507, 437.

[0448] 5-Hydroxy-2'-methyl-1,6-dihydro-[1,1'-biphenyl]-3(2) H )-Ketone (59)

[0449] The title compound was prepared as a white solid following general steps J and K.

[0450] LCMS (ESI-MS) m / z :C 13 H 15 O2's [M+H] + Calculated value: 203.10; Measured value: 202.9. Retention time: 3.409 minutes.

[0451] TLC: (5% methanol in dichloromethane solution, R) f ): 0.24 (UV, 254 nm, 280 nm).

[0452] 1 H NMR (500 MHz, DMSO- d 6) δ 11.20 (s, 1H), 7.35 (d, J = 7.6 Hz, 1H),7.22 – 7.08 (m, 3H), 5.31 (s, 1H), 3.53 – 3.45 (m, 1H), 2.66 – 2.52 (m, 2H), 2.39 – 2.24 (m, 5H).

[0453] 13 C NMR (126 MHz, DMSO- d 6) δ 141.9, 135.6, 130.8, 126.7, 126.7, 126.1,103.8, 35.1, 19.3.

[0454] IR (thin film, cm) -1 ): = 2948, 1561, 1402, 1310, 1211, 1142, 758, 449.

[0455] 5-Hydroxy-3'-methyl-1,6-dihydro-[1,1'-biphenyl]-3(2) H )-Ketone (60)

[0456] The title compound was prepared as a white powder following general steps J and K.

[0457] LCMS (ESI-MS) m / z :C 13 H 15 O2's [M+H] + Calculated value: 203.10; Measured value: 202.9. Retention time: 3.484 minutes.

[0458] TLC: (5% methanol in dichloromethane solution, R) f ): 0.17 (UV, 254 nm, 280 nm).

[0459] 1 H NMR (399 MHz, DMSO- d 6) δ 11.20 (s, 1H), 7.26 – 7.09 (m, 3H), 7.04(d, J = 7.5 Hz, 1H), 5.27 (s, 1H), 3.30 – 3.16 (m, 1H), 2.76 – 2.52 (m, 2H), 2.44 – 2.32 (m, 2H), 2.28 (s, 3H).

[0460] 13 C NMR (126 MHz, DMSO- d 6) δ 143.95, 138.00, 128.84, 128.07, 127.69, 124.38, 103.98, 39.17, 21.56.

[0461] IR (thin film, cm) -1 ): = 2892, 1570, 1400, 1315, 1222, 1140, 870, 784, 702,444.

[0462] 5-Hydroxy-4'-methyl-1,6-dihydro-[1,1'-biphenyl]-3(2) H )-Ketone (61)

[0463] The title compound was prepared as a white solid following general steps J and K.

[0464] LCMS (ESI-MS) m / z :C 13 H 15 O2's [M+H] + Calculated value: 203.10; Measured value: 202.9. Retention time: 3.490 minutes. C 26 H 29 O4's [M+H] + Calculated value: 405.20; Measured value: 404.8. Retention time: 3.490 minutes.

[0465] TLC: (5% methanol in dichloromethane solution, R) f ): 0.17 (UV, 254 nm, 280 nm).

[0466] 1 H NMR (500 MHz, DMSO-d6) δ 11.17 (s, 1H), 7.21 (d, J = 7.8 Hz, 2H), 7.12 (d, J = 7.8 Hz, 2H), 5.29 (s, 1H), 3.30 – 3.21 (m, 1H), 2.65 – 2.51 (m,2H), 2.37 (d, J = 15.0 Hz, 2H), 2.27 (s, 3H).

[0467] 13 C NMR (126 MHz, DMSO- d 6) δ 141.0, 136.0, 129.4, 127.2, 104.0, 38.8, 21.0.

[0468] IR (thin film, cm) -1 ): = 2859, 1578, 1514, 1425, 1366, 1323, 1301, 1219,1143, 812, 738, 583, 503, 441.

[0469] 5-(2,4-Dimethylphenyl)cyclohexane-1,3-dione (62)

[0470] The title compound was prepared as a white solid following general steps J and K.

[0471] LCMS (ESI-MS)m / z :C 14 H 17 O2's [M+H] + Calculated value: 217.12; Measured value: 216.9. Retention time: 432.8 minutes. C 28 H 33 O4's [M+H] + Calculated value: 433.24; Measured value: 432.8. Retention time: 3.689 minutes.

[0472] TLC: (5% methanol in dichloromethane solution, R) f ): 0.17 (UV, 254 nm, 280 nm).

[0473] 1 H NMR (500 MHz, CD3OD) δ 7.19 (d, J = 8.5 Hz, 1H), 7.06 – 6.97 (m, 2H), 4.92 (s, 2H), 3.62 – 3.52 (m, 1H), 2.65 (dd, J = 17.1, 11.9 Hz, 2H), 2.46 (dd, J = 17.1, 4.5 Hz, 2H), 2.32 (s, 3H), 2.28 (s, 3H).

[0474] 13 C NMR (126 MHz, CD3OD) δ 139.1, 137.2, 136.3, 132.3, 128.0, 126.3, 36.3, 20.9, 19.2.

[0475] IR (thin film, cm) -1 ): = 2946, 1557, 1402, 1313, 1213, 1141, 1030, 816, 737,590, 540, 448.

[0476] 5-(2-Methoxyphenyl)cyclohexane-1,3-dione (63)

[0477] The title compound was prepared as a white solid following general steps J and K.

[0478] LCMS (ESI-MS) m / z :C 13 H15 O3's [M+H] + Calculated value: 219.09; Measured value: 218.9. Retention time: 3.334 minutes. C 26 H 29 O6's [M+H] + Calculated value: 437.18; Measured value: 436.8. Retention time: 3.334 minutes.

[0479] TLC: (5% methanol in dichloromethane solution, R) f ): 0.17 (UV, 254 nm, 280 nm).

[0480] 1 H NMR (500 MHz, CD3OD) δ 7.29 – 7.20 (m, 2H), 6.99 (d, J = 8.1 Hz, 1H), 6.94 (dd, J = 8.3, 7.8 Hz, 1H), 4.91 (s, 2H), 3.87 (s, 3H), 3.75 – 3.66 (m,1H), 2.72 (dd, J = 16.9, 11.7 Hz, 2H), 2.52 (dd, J = 16.9, 4.5 Hz, 2H).

[0481] 13 C NMR (126 MHz, CD3OD) δ 158.5, 131.8, 129.1, 128.0, 121.7, 111.8, 55.7, 35.1.

[0482] IR (thin film, cm) -1 ): = 2942, 1559, 1492, 1462, 1401, 1320, 1294, 1220,1143, 1122, 1053, 1028, 835, 752, 646, 591, 442.

[0483] 5-Hydroxy-3'-methoxy-1,6-dihydro-[1,1'-biphenyl]-3(2) H )-Ketone (64)

[0484] The title compound was prepared as a white solid following general steps J and K.

[0485] LCMS (ESI-MS)m / z :C 13 H 15 O3's [M+H] + Calculated value: 219.09; Measured value: 218.9. Retention time: 3.212 minutes. C 26 H 29 O6's [M+H] + Calculated value: 437.18; Measured value: 436.8. Retention time: 3.212 minutes.

[0486] TLC: (5% methanol in dichloromethane solution, R) f ): 0.16 (UV, 254 nm, 280 nm).

[0487] 1 H NMR (500 MHz, DMSO- d 6) δ 11.19 (s, 1H), 7.23 (dd, J = 9.4, 8.0 Hz,1H), 6.95 – 6.88 (m, 2H), 6.80 (dd, J = 8.3, 2.4 Hz, 1H), 5.30 (s, 1H), 3.74(s, 3H), 3.31 – 3.23 (m, 1H), 2.71 – 2.53 (m, 2H), 2.48 – 2.28 (m, 2H).

[0488] 13 C NMR (126 MHz, DMSO- d 6) δ 159.8, 145.6, 129.9, 119.5, 113.3, 112.3,103.9, 55.4, 39.2.

[0489] IR (thin film, cm) -1 ): = 2943, 1583, 1488, 1400, 1365, 1309, 1268, 1223,1154, 1049, 867, 780, 698, 564, 447, 416.

[0490] 5-Hydroxy-4'-methoxy-1,6-dihydro-[1,1'-biphenyl]-3(2) H )-Ketone (65)

[0491] The title compound was prepared as a white solid following general steps J and K.

[0492] LCMS (ESI-MS) m / z :C 13 H 15 O3's [M+H] + Calculated value: 219.09; Measured value: 218.9. Retention time: 3.155 minutes.

[0493] TLC: (5% methanol in dichloromethane solution, R) f ): 0.22 (UV, 254 nm, 280 nm).

[0494] 1 H NMR (500 MHz, DMSO- d 6) δ 11.16 (s, 1H), 7.25 (d, J = 8.2 Hz, 2H), 6.88 (d, J = 8.2 Hz, 2H), 5.29 (s, 1H), 3.73 (s, 3H), 3.30 – 3.18 (m, 1H), 2.59– 2.51 (m, 2H), 2.37 (d, J = 16.6 Hz, 2H).

[0495] 13 C NMR (126 MHz, DMSO- d 6) δ 158.3, 136.0, 128.3, 114.3, 104.0, 55.4, 38.4.

[0496] IR (thin film, cm) -1 ): = 2835, 1596, 1512, 1367, 1321, 1293, 1220, 1181,1139, 1029, 829, 764, 597, 523, 443.

[0497] 5-(2,4-Dimethoxyphenyl)cyclohexane-1,3-dione (66)

[0498] Following general steps J and K, the title compound was prepared as a grayish-white and slightly yellow powder.

[0499] LCMS (ESI-MS) m / z :C 14 H 17O4's [M+H] + Calculated value: 249.10; Measured value: 248.9. Retention time: 3.350 minutes.

[0500] TLC: (5% methanol in dichloromethane solution, R) f ): 0.22 (UV, 254 nm, 280 nm).

[0501] 1 H NMR (500 MHz, CD3OD) δ 7.00 (d, J = 8.4 Hz, 1H), 6.43 (d, J = 2.5 Hz, 1H), 6.38 (dd, J = 8.4, 2.5 Hz, 1H), 4.76 (s, 2H), 3.72 (s, 3H), 3.67 (s, 3H), 3.52 – 3.41 (m, 1H), 2.55 (dd, J = 17.0, 11.7 Hz, 2H), 2.37 (dd, J = 17.0, 4.5Hz, 2H).

[0502] 13 C NMR (126 MHz, CD3OD) δ 161.3, 159.4, 128.5, 124.3, 105.5, 99.6, 55.8, 55.7, 39.4, 34.7.

[0503] 5-Hydroxy-1,6-dihydro-[1,1'-biphenyl]-3(2) H )-Ketone (67)

[0504] The title compound was prepared as a white solid following general steps J and K.

[0505] LCMS (ESI-MS) m / z :C 12 H 13 O2's [M+H] + Calculated value: 189.08; Measured value: 188.9. Retention time: 3.152 minutes.

[0506] TLC: (5% methanol in dichloromethane solution, R) f ): 0.24 (UV, 254 nm, 280 nm).

[0507] 1 H NMR (500 MHz, DMSO- d 6) δ 11.19 (s, 1H), 7.37 – 7.29 (m, 4H), 7.26 –7.20 (m, 1H), 5.29 (s, 1H), 3.33 – 3.25 (m, 1H), 2.68 – 2.53 (m, 2H), 2.47 –2.31 (m, 2H).

[0508] 13 C NMR (126 MHz, DMSO- d 6) δ 144.0, 128.9, 127.3, 127.0, 104.0, 39.2.

[0509] IR (thin film, cm) -1 ): = 3028, 2018, 1571, 1400, 1334, 1217, 1142, 833, 760,698, 498, 447.

[0510] 3-(2,4-dichlorophenyl)-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (68)

[0511] The title compound, which is a brownish-brown solid, was prepared according to general procedure L.

[0512] LCMS (ESI-MS) m / z :C 19 H 14 [M+H] of Cl2NO2 + Calculated value: 358.03; Measured value: 358.0. Retention time: 2.887 minutes.

[0513] TLC: (5% methanol in dichloromethane solution, R) f ): 0.34 (UV, 254 nm, 280 nm).

[0514] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.58 (d, J = 8.2 Hz, 1H), 8.17 (dd, J = 8.5, 7.8 Hz, 1H), 8.04 (d,J = 8.5 Hz, 1H), 7.91 (dd, J = 8.2, 7.8 Hz, 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.35 (dd, J = 8.3, 2.1 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 4.22 – 4.11 (m, 1H), 3.75 – 3.61 (m, 2H), 3.27 – 3.10 (m, 2H).

[0515] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 202.5, 161.1, 139.5, 138.8,135.1, 135.0, 134.4, 130.6, 129.9, 128.3, 127.7, 125.5, 120.4, 42.6, 34.8,33.6.

[0516] 8-Chloro-3-(2,4-dichlorophenyl)-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (69)

[0517] The title compound, a yellow solid, was prepared following general procedure L.

[0518] TLC: (5% methanol in dichloromethane solution, R) f ): 0.40 (UV, 254 nm, 280 nm).

[0519] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.04 – 7.94 (m, 2H), 7.87 (dd, J =7.4, 1.5 Hz, 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.35 (dd, J = 8.4, 2.1 Hz, 1H), 7.24(d, J = 8.4 Hz, 1H), 4.19 – 4.09 (m, 1H), 3.72 – 3.60 (m, 2H), 3.24 (ddd,J =17.7, 4.2, 1.4 Hz, 1H), 3.15 (dd, J = 17.7, 12.4 Hz, 1H).

[0520] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 202.8, 175.1, 161.3, 141.5,137.6, 135.2, 135.0, 134.8, 134.3, 132.6, 130.5, 128.2, 127.6, 119.6, 117.2,108.0, 42.6, 34.5, 33.2.

[0521] 6-Chloro-3-(2,4-dichlorophenyl)-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (70)

[0522] The title compound was prepared as a white solid following general procedure L.

[0523] LCMS (ESI-MS) m / z :C 19 H 13 [M+H] of Cl3NO2 + Calculated value: 391.99; Measured value: 392.0. Retention time: 3.230 minutes.

[0524] TLC: (5% methanol in dichloromethane solution, R) f ): 0.44 (UV, 254 nm, 280 nm).

[0525] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.48 (d, J = 8.9 Hz, 1H), 8.07 (d, J =1.8 Hz, 1H), 7.82 (dd, J = 8.9, 1.8 Hz, 1H), 7.50 (d, J = 2.2 Hz, 1H), 7.34 (dd, J = 8.4, 2.2 Hz, 1H), 7.25 (d, J= 8.4 Hz, 1H), 4.20 – 4.08 (m, 1H), 3.76 – 3.62(m, 2H), 3.22 (dd, J = 17.7, 3.6 Hz, 1H), 3.12 (dd, J = 17.7, 12.6 Hz, 1H).

[0526] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 202.3, 173.0, 162.2, 145.8,140.1, 134.98, 134.95, 134.2, 130.8, 130.4, 128.2, 127.7, 126.5, 120.2,117.6, 107.9, 42.6, 34.6, 33.4.

[0527] 5-Chloro-3-(2,4-dichlorophenyl)-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (71)

[0528] The title compound was prepared as a white solid following general procedure L.

[0529] LCMS (ESI-MS) m / z :C 19 H 13 [M+H] of Cl3NO2 + Calculated value: 391.99; Measured value: 392.0. Retention time: 3.402 minutes.

[0530] TLC: (5% methanol in dichloromethane solution, R) f ): 0.49 (UV, 254 nm, 280 nm).

[0531] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.53 (dd, J = 8.4, 1.3 Hz, 1H), 8.21(dd, J = 7.8, 1.3 Hz, 1H), 7.85 (dd, J = 8.4, 7.8 Hz, 1H), 7.49 (d, J= 2.1 Hz, 1H), 7.34 (dd, J = 8.4, 2.1 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 4.20 – 4.10 (m,1H), 3.96 (ddd, J = 18.2, 4.1, 1.3 Hz, 1H), 3.76 (dd, J = 18.1, 11.7 Hz, 1H), 3.28 – 3.13 (m, 2H).

[0532] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 202.6, 173.9, 163.4, 138.2,136.1, 134.99, 134.97, 134.2, 130.4, 129.7, 128.3, 127.7, 125.4, 124.3,121.0, 108.4, 34.4, 34.3, 33.5.

[0533] 3-(2,4-dichlorophenyl)-8-methyl-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (72)

[0534] The title compound, which is a brownish-brown solid, was prepared according to general procedure L.

[0535] TLC: (5% methanol in dichloromethane solution, R) f ): 0.43 (UV, 254 nm, 280 nm).

[0536] 1 H NMR (500 MHz, DMSO- d 6) δ 11.84 (s, 1H), 7.67 (d, J = 2.1 Hz, 1H),7.55 – 7.47 (m, 3H), 7.34 (d, J = 8.2 Hz, 1H), 7.08 (d, J = 7.3 Hz, 1H), 3.83 –3.75 (m, 1H), 3.30 (d, J = 11.4 Hz, 1H), 3.08 (d, J= 16.0 Hz, 1H), 2.79 – 2.68(m, 4H), 2.55 (d, J = 16.0 Hz, 1H).

[0537] 3-(2,4-Dichlorophenyl)-7-methyl-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (73)

[0538] The title compound was prepared as a white solid following general procedure L.

[0539] LCMS (ESI-MS) m / z :C 20 H 16 [M+H] of Cl2NO2 + Calculated value: 372.05; Measured value: 372.1. Retention time: 3.099 minutes.

[0540] TLC: (5% methanol in dichloromethane solution, R) f ): 0.45 (UV, 254 nm, 280 nm).

[0541] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d δ 8.34 (s, 1H), 8.00 (dd, J = 8.6, 1.9Hz, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.52 (d, J = 2.2 Hz, 1H), 7.36 (dd, J = 8.4, 2.2Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 4.21 – 4.12 (m, 1H), 3.75 – 3.61 (m, 2H), 3.29 – 3.10 (m, 2H), 2.68 (s, 3H).

[0542] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d) δ 202.4, 173.1, 159.8, 141.2,140.6, 137.8, 135.1, 135.0, 134.3, 130.5, 128.3, 127.6, 124.3, 120.1, 119.5,107.8, 42.6, 34.8, 33.5, 21.6.

[0543] 3-(2,4-Dichlorophenyl)-6-methyl-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (74)

[0544] The title compound, a yellow solid, was prepared following general procedure L.

[0545] LCMS (ESI-MS) m / z :C 20 H 16 [M+H] of Cl2NO2 + Calculated value: 372.05; Measured value: 371.7. Retention time: 4.040 minutes.

[0546] TLC: (5% methanol in dichloromethane solution, R) f ): 0.44 (UV, 254 nm, 280 nm).

[0547] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.42 (d, J = 8.5 Hz, 1H), 7.80 (s,1H), 7.69 (dd, J = 8.5, 1.5 Hz, 1H), 7.50 (d, J = 2.2 Hz, 1H), 7.34 (dd, J = 8.4, 2.2 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 4.20 – 4.08 (m, 1H), 3.73 – 3.59 (m,2H), 3.20 (dd, J = 17.6, 4.6 Hz, 1H), 3.10 (dd, J = 17.6, 12.5 Hz, 1H), 2.68 (s, 3H).

[0548] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 202.2, 172.9, 160.7, 151.7,139.9, 135.1, 134.8, 134.2, 131.7, 130.4, 128.2, 127.6, 124.9, 119.7, 117.2,107.4, 42.7, 34.7, 33.3, 22.6.

[0549] 3-(2,4-Dichlorophenyl)-5-methyl-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (75)

[0550] The title compound, a yellow solid, was prepared following general procedure L.

[0551] LCMS (ESI-MS) m / z :C 20 H 16 [M+H] of Cl2NO2 + Calculated value: 372.05; Measured value: 372.1. Retention time: 3.291 minutes.

[0552] TLC: (5% methanol in dichloromethane solution, R) f ): 0.41 (UV, 254 nm, 280 nm).

[0553] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.44 (d, J = 8.3 Hz, 1H), 7.98 (d, J =7.3 Hz, 1H), 7.79 (dd, J = 8.3, 7.3 Hz, 1H), 7.49 (d, J = 2.2 Hz, 1H), 7.33 (dd, J = 8.4, 2.2 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 4.17 – 4.07 (m, 1H), 3.87 (ddd, J =18.0, 4.1, 1.6 Hz, 1H), 3.69 (dd, J= 17.9, 11.6 Hz, 1H), 3.27 – 3.09 (m, 2H), 2.76 (s, 3H)).

[0554] 3-(2,4-dichlorophenyl)-8-methoxy-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (76)

[0555] The title compound, which is a brownish-brown solid, was prepared according to general procedure L.

[0556] TLC: (5% methanol in dichloromethane solution, R) f ): 0.42 (UV, 254 nm, 280 nm).

[0557] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.02 (dd, J = 8.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 2.1 Hz, 1H), 7.33 (dd, J = 8.4, 2.1 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 4.18 – 4.06 (m, 4H), 3.67 – 3.54 (m,2H), 3.19 (ddd, J = 17.6, 4.2, 1.3 Hz, 1H), 3.10 (dd, J = 17.6, 12.4 Hz, 1H).

[0558] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 202.4, 175.6, 160.88, 160.82,141.2, 139.5, 135.1, 134.8, 134.3, 130.4, 128.2, 127.6, 111.9, 110.6, 109.5,107.3, 57.0, 42.6, 34.5, 33.1.

[0559] 3-(2,4-dichlorophenyl)-7-methoxy-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (77)

[0560] The title compound, which is a brownish-brown solid, was prepared according to general procedure L.

[0561] LCMS (ESI-MS) m / z :C 20 H 16 [M+H] of Cl2NO3 + Calculated value: 388.04; Measured value: 388.1. Retention time: 3.022 minutes.

[0562] TLC: (5% methanol in dichloromethane solution, R) f ): 0.44 (UV, 254 nm, 280 nm).

[0563] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 7.98 (d, J = 9.1 Hz, 1H), 7.79 –7.70 (m, 2H), 7.50 (d, J = 2.2 Hz, 1H), 7.34 (dd, J = 8.4, 2.2 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 4.21 – 4.09 (m, 1H), 4.04 (s, 3H), 3.72 – 3.56 (m, 2H), 3.21(dd, J = 17.6, 3.5 Hz, 1H), 3.11 (dd, J = 17.7, 12.6 Hz, 1H).

[0564] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 202.4, 171.7, 160.2, 157.7,135.1, 134.87, 134.84, 134.2, 130.4, 130.3, 128.2, 127.6, 122.1, 120.9,107.6, 102.9, 56.3, 42.8, 34.7, 33.1.

[0565] 3-(2,4-Dichlorophenyl)-6-methoxy-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (78)

[0566] The title compound, which is a brownish-brown solid, was prepared according to general procedure L.

[0567] LCMS (ESI-MS) m / z :C 20 H 16 [M+H] of Cl2NO3 + Calculated value: 388.04; Measured value: 387.7. Retention time: 4.011 minutes.

[0568] TLC: (5% methanol in dichloromethane solution, R) f ): 0.44 (UV, 254 nm, 280 nm).

[0569] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.39 (d, J = 9.3 Hz, 1H), 7.49 (d, J =2.3 Hz, 1H), 7.40 (dd, J = 9.3, 2.3 Hz, 1H), 7.34 (dd, J = 7.9, 2.2 Hz, 2H), 7.25(d, J = 8.5 Hz, 1H), 4.19 – 4.08 (m, 1H), 4.08 – 4.00 (m, 3H), 3.67 – 3.59 (m,2H), 3.18 (dd, J = 17.6, 3.8 Hz, 1H), 3.07 (dd, J = 17.6, 12.6 Hz, 1H).

[0570] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.39 (d, J = 9.3 Hz, 1H), 7.49 (d, J =2.3 Hz, 1H), 7.40 (dd,J = 9.3, 2.3 Hz, 1H), 7.34 (dd, J = 7.9, 2.2 Hz, 2H), 7.25(d, J = 8.5 Hz, 1H), 4.19 – 4.08 (m, 1H), 4.08 – 4.00 (m, 3H), 3.67 – 3.59 (m,2H), 3.18 (dd, J = 17.6, 3.8 Hz, 1H), 3.07 (dd, J = 17.6, 12.6 Hz, 1H).

[0571] 3-(2,4-dichlorophenyl)-5-methoxy-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (79)

[0572] The title compound, which is a brownish-brown solid, was prepared according to general procedure L.

[0573] LCMS (ESI-MS) m / z :C 20 H 16 [M+H] of Cl2NO3 + Calculated value: 388.04; Measured value: 388.0. Retention time: 3.019 minutes.

[0574] TLC: (5% methanol in dichloromethane solution, R) f ): 0.45 (UV, 254 nm, 280 nm).

[0575] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.08 (dd, J = 8.4, 1.0 Hz, 1H), 7.80(dd, J = 8.8, 8.4 Hz, 1H), 7.55 – 7.47 (m, 2H), 7.34 (dd, J = 8.4, 2.2 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 4.19 – 4.03 (m, 4H), 3.88 (ddd, J= 17.9, 4.0, 1.6 Hz,1H), 3.68 (dd, J = 17.9, 11.8 Hz, 1H), 3.27 – 3.06 (m, 2H).

[0576] 3-(2,4-dichlorophenyl)-7-iodo-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (80)

[0577] The title compound was prepared as a white powder following general procedure L.

[0578] TLC: (5% methanol in dichloromethane solution, R) f ): 0.39 (UV, 254 nm, 280 nm).

[0579] 1 H NMR (500 MHz, CDCl3, 1 drop DMF-) d , and 3 drops of TFA- d ) δ 8.89 (d, J = 1.9 Hz, 1H), 8.38 (dd, J = 8.9, 1.9 Hz, 1H), 7.84 (d, J = 8.9 Hz, 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.34 (dd, J = 8.4, 2.1 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 4.19 – 4.09 (m, 1H), 3.71 (ddd, J = 17.7, 4.1, 1.6 Hz, 1H), 3.64 (dd, J = 17.8, 11.5 Hz, 1H), 3.23(ddd, J = 17.7, 4.1, 1.6 Hz, 1H), 3.17 – 3.07 (m, 1H).

[0580] 13 C NMR (126 MHz, CDCl3, 1 drop DMF-) d , and 3 drops of TFA- d) δ 202.2, 172.0, 164.7,161.2, 146.9, 138.7, 134.9, 134.2, 133.8, 130.4, 128.2, 127.6, 121.9, 120.6,108.2, 95.1, 42.6, 34.6, 33.4.

[0581] 7-Bromo-3-(2,4-dichlorophenyl)-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (81)

[0582] The title compound, which is a brownish-brown solid, was prepared according to general procedure L.

[0583] TLC: (5% methanol in dichloromethane solution, R) f ): 0.39 (UV, 254 nm, 280 nm).

[0584] 1 H NMR (500 MHz, CDCl3, 1 drop DMF-) d , and 3 drops of TFA- d ) δ 8.67 (d, J = 2.1 Hz, 1H), 8.21 (dd, J = 8.9, 2.1 Hz, 1H), 8.01 (d, J = 8.9 Hz, 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.34 (dd, J = 8.4, 2.1 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 4.21 – 4.08 (m, 1H), 3.76 – 3.60 (m, 2H), 3.23 (ddd, J = 17.7, 4.1, 1.6 Hz, 1H), 3.13 (dd, J = 17.8, 12.6 Hz, 1H).

[0585] 13 C NMR (126 MHz, CDCl3, 1 drop DMF-) d , and 3 drops of TFA- d) δ 202.3, 172.2, 164.6,161.1, 141.5, 138.4, 134.97, 134.91, 134.2, 130.4, 128.2, 127.6, 127.4,124.1, 122.3, 120.5, 37.8, 34.4, 32.5.

[0586] 3-(2,4-Dichlorophenyl)-7-fluoro-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (82)

[0587] The title compound was prepared as a white powder following general procedure L.

[0588] TLC: (5% methanol in dichloromethane solution, R) f ): 0.39 (UV, 254 nm, 280 nm).

[0589] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.17 (dd, J = 7.5, 2.8 Hz, 1H), 8.13(dd, J = 9.3, 4.2 Hz, 1H), 7.91 (ddd, J = 9.3, 7.5, 2.8 Hz, 1H), 7.50 (d, J = 2.1Hz, 1H), 7.35 (dd, J = 8.4, 2.1 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 4.22 – 4.10(m, 1H), 3.76 – 3.60 (m, 2H), 3.24 (ddd, J = 17.7, 4.1, 1.5 Hz, 1H), 3.15 (dd, J = 17.8, 12.5 Hz, 1H).

[0590] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 202.4, 173.0 (d, J = 4.3 Hz), 163.0, 160.5 (d, J= 1.9 Hz), 136.3, 135.1, 134.9, 134.3, 130.6, 128.38 (d, J =25.9 Hz), 128.38, 127.6, 123.4 (d, J = 9.0 Hz), 121.0 (d, J = 9.6 Hz), 110.0 (d, J = 24.6 Hz), 108.0, 42.7, 34.7, 33.5.

[0591] 19 F NMR (471 MHz, CDCl3 and 3 drops of TFA-) d ) δ -105.01.

[0592] 8-Chloro-2 H -benzo[ d [1,3]Oxazine-2,4(1 H )-Diketone (98)

[0593] The title compound was prepared as a white powder following general procedure A.

[0594] LCMS (ESI-MS) m / z [M+H] of C8H5ClNO3 + Calculated value: 197.99; Measured value: 197.8. Retention time: 1.418 minutes.

[0595] TLC: (20% EtOAc hexane solution, R) f ): 0.16 (UV, 254 nm, 280 nm).

[0596] 1 H NMR (500 MHz, DMSO- d 6) δ 11.40 (s, 1H), 7.91 (dd, J = 7.9, 1.4 Hz, 1H), 7.87 (dd, J = 8.0, 1.4 Hz, 1H), 7.25 (dd, J = 7.9, 8.0 Hz, 1H).

[0597] 13 C NMR (126 MHz, DMSO- d6) δ 159.6, 147.1, 138.8, 137.1, 128.4, 124.4,119.3, 113.3.

[0598] 7-Chloro-2 H -benzo[ d [1,3]Oxazine-2,4(1 H )-Diketone (99)

[0599] The title compound was prepared as a white powder following general procedure A.

[0600] LCMS (ESI-MS) m / z [M+H] of C8H5ClNO3 + Calculated value: 197.99; Measured value: 197.8. Retention time: 2.741 minutes.

[0601] TLC: (20% EtOAc hexane solution, R) f ): 0.16 (UV, 254 nm, 280 nm).

[0602] 1 H NMR (500 MHz, DMSO- d 6) δ 11.85 (s, 1H), 7.91 (d, J = 8.6 Hz, 1H), 7.29 (dd, J = 8.6, 2.0 Hz, 1H), 7.14 (d, J = 2.0 Hz, 1H).

[0603] 13 C NMR (126 MHz, DMSO- d 6) δ 159.5, 147.3, 142.9, 141.6, 131.3, 124.1,115.2, 109.9.

[0604] 5-Chloro-2 H -benzo[ d [1,3]Oxazine-2,4(1 H )-Diketone (100)

[0605] The title compound was prepared as a white powder following general procedure A.

[0606] LCMS (ESI-MS) m / z [M+H] of C8H5ClNO3 + Calculated value: 197.99; Measured value: 197.8. Retention time: 2.219 minutes.

[0607] TLC: (50% EtOAc hexane solution, R) f ): 0.28 (UV, 254 nm, 280 nm).

[0608] 1 H NMR (500 MHz, DMSO- d 6) δ 11.86 (s, 1H), 7.65 (dd, J = 8.8, 8.1 Hz, 1H), 7.30 (dd, J = 8.1, 0.8 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H).

[0609] 13 C NMR (126 MHz, DMSO- d 6) δ 156.9, 147.1, 144.4, 137.0, 135.4, 126.1,115.0, 108.5.

[0610] 8-Methyl-2 H -benzo[ d [1,3]Oxazine-2,4(1 H )-Diketone (101)

[0611] The title compound was prepared as a white powder following general procedure A.

[0612] LCMS (ESI-MS) m / z [M+H] of C9H8NO3 + Calculated value: 178.04; Measured value: 177.9. Retention time: 1.674 minutes.

[0613] TLC: (50% EtOAc hexane solution, R) f ): 0.29 (UV, 254 nm, 280 nm).

[0614] 1 H NMR (500 MHz, DMSO- d 6) δ 11.01 (s, 1H), 7.76 (d, J= 8.2 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.14 (dd, J = 8.2, 7.5 Hz, 1H), 2.32 (s, 3H).

[0615] 13 C NMR (126 MHz, DMSO- d 6) δ 160.4, 147.7, 140.1, 138.3, 127.1, 124.8,123.6, 110.8, 17.4.

[0616] 7-Methyl-2 H -benzo[ d [1,3]Oxazine-2,4(1 H )-Diketone (102)

[0617] The title compound was prepared as a white powder following general procedure A.

[0618] LCMS (ESI-MS) m / z [M+H] of C9H8NO3 + Calculated value: 178.04; Measured value: 177.9. Retention time: 2.263 minutes.

[0619] TLC: (50% EtOAc hexane solution, R) f ): 0.21 (UV, 254 nm, 280 nm).

[0620] 1 H NMR (500 MHz, DMSO- d 6) δ 11.68 (s, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.93 (s, 1H), 2.37 (s, 3H).

[0621] 13 C NMR (126 MHz, DMSO- d 6) δ 160.1, 148.6, 147.7, 141.9, 129.3, 125.2, 115.5, 108.1, 22.0.

[0622] 6-Methyl-2 H-benzo[ d [1,3]Oxazine-2,4(1 H )-Diketone (103)

[0623] The title compound was prepared as a grayish-white and slightly yellow powder according to general procedure A.

[0624] LCMS (ESI-MS) m / z [M+H] of C9H8NO3 + Calculated value: 178.04; Measured value: 177.9. Retention time: 2.508 minutes.

[0625] TLC: (50% EtOAc hexane solution, R) f ): 0.21 (UV, 254 nm, 280 nm).

[0626] 1 H NMR (500 MHz, DMSO- d 6) δ 11.63 (s, 1H), 7.70 (d, J = 2.2 Hz, 1H), 7.55 (dd, J = 8.4, 2.2 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 2.32 (s, 3H).

[0627] 13 C NMR (126 MHz, DMSO- d 6) δ 159.9, 147.1, 139.2, 137.9, 132.9, 128.3, 115.3, 110.0, 20.0.

[0628] 5-Methyl-2 H -benzo[ d [1,3]Oxazine-2,4(1 H )-Diketone (104)

[0629] The title compound was prepared as a white powder following general procedure A.

[0630] LCMS (ESI-MS) m / z [M+H] of C9H8NO3 + Calculated value: 178.04; Measured value: 177.9. Retention time: 2.555 minutes.

[0631] TLC: (50% EtOAc hexane solution, R) f ): 0.24 (UV, 254 nm, 280 nm).

[0632] 1 H NMR (500 MHz, DMSO- d 6) δ 11.59 (s, 1H), 7.56 (dd, J = 8.6, 7.9 Hz, 1H), 7.05 (d, J = 7.9 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 2.59 (s, 3H).

[0633] 13 C NMR (126 MHz, DMSO- d 6) δ 158.9, 147.1, 142.5 (2 × C), 135.8, 125.9, 113.3, 108.6, 21.7.

[0634] 8-Methoxy-2 H -benzo[ d [1,3]Oxazine-2,4(1 H )-Diketone (105)

[0635] The title compound was prepared as a white powder following general procedure A.

[0636] LCMS (ESI-MS) m / z [M+H] of C9H8NO4 + Calculated value: 194.04; Measured value: 193.9. Retention time: 1.284 minutes.

[0637] TLC: (50% EtOAc hexane solution, R) f ): 0.24 (UV, 254 nm, 280 nm).

[0638] 1 H NMR (500 MHz, DMSO- d 6) δ 11.26 (s, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.20 (dd,J = 8.1, 7.8 Hz, 1H), 3.89 (s, 3H).

[0639] 13 C NMR (126 MHz, DMSO- d 6) δ 159.8, 146.8, 146.2, 131.5, 123.4, 119.6,117.4, 110.8, 56.3.

[0640] 7-Methoxy-2 H -benzo[ d [1,3]Oxazine-2,4(1 H )-Diketone (106)

[0641] The title compound was prepared as a grayish-white, slightly yellowish-brown powder according to general step A.

[0642] LCMS (ESI-MS) m / z [M+H] of C9H8NO4 + Calculated value: 194.04; Measured value: 193.9. Retention time: 1.581 minutes.

[0643] TLC: (50% EtOAc hexane solution, R) f ): 0.24 (UV, 254 nm, 280 nm).

[0644] 1 H NMR (500 MHz, DMSO- d 6) δ 11.64 (s, 1H), 7.82 (d, J = 8.9 Hz, 1H), 6.82 (dd, J = 8.9, 2.4 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 3.85 (s, 3H).

[0645] 13 C NMR (126 MHz, DMSO- d 6) δ 165.8, 159.2, 147.4, 143.6, 131.0, 111.6,102.8, 98.5, 55.9.

[0646] 6-Methoxy-2 H -benzo[ d[1,3]Oxazine-2,4(1 H )-Diketone (107)

[0647] Following general step A, the title compound was prepared as a grayish-white, slightly yellowish-brown powder.

[0648] LCMS (ESI-MS) m / z [M+H] of C9H8NO4 + Calculated value: 194.04; Measured value: 193.9. Retention time: 1.295 minutes.

[0649] TLC: (50% EtOAc hexane solution, R) f ): 0.31 (UV, 254 nm, 280 nm).

[0650] 1 H NMR (500 MHz, DMSO- d 6) δ 11.61 (s, 1H), 7.38 (d, J = 9.4 Hz, 1H),7.34 (s, 1H), 7.11 (d, J = 9.4 Hz, 1H), 3.80 (s, 3H).

[0651] 13 C NMR (126 MHz, DMSO- d 6) δ 160.3, 155.6, 147.4, 135.9, 126.2, 117.4, 111.1, 110.3, 56.2.

[0652] 5-Methoxy-2 H -benzo[ d [1,3]Oxazine-2,4(1 H )-Diketone (108)

[0653] The title compound was prepared as a grayish-white, slightly yellowish-brown powder according to general step A.

[0654] LCMS (ESI-MS) m / z [M+H] of C9H8NO4 + Calculated value: 194.04; Measured value: 193.9. Retention time: 0.541 minutes.

[0655] TLC: (50% EtOAc hexane solution, R) f ): 0.14 (UV, 254 nm, 280 nm).

[0656] 1 H NMR (500 MHz, DMSO- d 6) δ 11.57 (s, 1H), 7.63 (dd, J = 8.6, 8.2 Hz, 1H), 6.82 (d, J = 8.6 Hz, 1H), 6.68 (d, J = 8.2 Hz, 1H), 3.88 (s, 3H).

[0657] 13 C NMR (126 MHz, DMSO- d 6) δ 161.1, 155.6, 147.3, 143.2, 137.6, 106.9,105.9, 99.3, 56.2.

[0658] 6-Iodine-2 H -benzo[ d [1,3]Oxazine-2,4(1 H Diketone (109)

[0659] The title compound was prepared as a white powder following general procedure A.

[0660] LCMS (ESI-MS) m / z [M+H] of C8H5INO3 + Calculated value: 289.92; Measured value: 289.6. Retention time: 3.294 minutes.

[0661] TLC: (50% EtOAc hexane solution, R) f ): 0.24 (UV, 254 nm, 280 nm).

[0662] 1 H NMR (500 MHz, DMSO- d 6) δ 11.82 (s, 1H), 8.13 (d, J = 2.0 Hz, 1H), 8.02 (dd, J = 8.6, 2.0 Hz, 1H), 6.96 (d, J= 8.6 Hz, 1H).

[0663] 13 C NMR (126 MHz, DMSO- d 6) δ 159.1, 147.2, 145.2, 141.4, 136.9, 118.0,113.1, 86.5.

[0664] 6-Bromo-2 H -benzo[ d [1,3]Oxazine-2,4(1 H )-Diketone (110)

[0665] The title compound was prepared as a white powder following general procedure A.

[0666] LCMS (ESI-MS) m / z [M+H] of C8H5BrNO3 + Calculated value: 241.94; Measured value: 241.7. Retention time: 3.093 minutes.

[0667] TLC: (50% EtOAc hexane solution, R) f ): 0.24 (UV, 254 nm, 280 nm).

[0668] 1 H NMR (500 MHz, DMSO- d 6) δ 11.86 (s, 1H), 7.99 (d, J = 2.3 Hz, 1H), 7.90 (dd, J = 8.7, 2.3 Hz, 1H), 7.10 (d, J = 8.7 Hz, 1H).

[0669] 13 C NMR (126 MHz, DMSO- d 6) δ 159.3, 147.2, 141.1, 139.8, 131.0, 118.1, 115.0, 112.9.

[0670] 6-Fluoro-2 H -benzo[ d [1,3]Oxazine-2,4(1 H )-Diketone (111)

[0671] The title compound was prepared as a white powder following general procedure A.

[0672] LCMS (ESI-MS) m / z [M+H] of C8H5FNO3 + Calculated value: 182.02; Measured value: 181.8. Retention time: 1.194 minutes.

[0673] TLC: (50% EtOAc hexane solution, R) f ): 0.35 (UV, 254 nm, 280 nm).

[0674] 1 H NMR (500 MHz, DMSO- d 6) δ 11.80 (s, 1H), 7.74 – 7.60 (m, 2H), 7.19(dd, J = 9.2, 4.6 Hz, 1H).

[0675] 13 C NMR (126 MHz, DMSO- d 6) δ 159.6 (d, J C–F = 3.3 Hz), 157.9 (d, J C–F =241.3 Hz), 147.2, 138.6 (d, J C–F = 1.5 Hz), 125.2 (d, J C–F = 24.5 Hz), 118.0 (d, J C–F = 8.4 Hz), 114.4 (d, J C–F = 24.3 Hz), 111.9 (d, J C–F = 24.4 Hz).

[0676] 19 F NMR (471 MHz, DMSO- d 6) δ -118.76 – -118.85 (m).

[0677] 2 H -Benzo [d [1,3]Oxazine-2,4(1 H )-Diketone (112)

[0678] The title compound was prepared as a white powder following general procedure A.

[0679] LCMS (ESI-MS) m / z [M+H] of C8H6NO3 + Calculated value: 164.03; Measured value: 163.9. Retention time: 0.711 minutes.

[0680] TLC: (50% EtOAc hexane solution, R) f ): 0.38 (UV, 254 nm, 280 nm).

[0681] 1 H NMR (500 MHz, DMSO- d 6) δ 11.72 (s, 1H), 7.91 (d, J = 7.9 Hz, 1H),7.78 – 7.69 (m, 1H), 7.25 (dd, J = 8.4, 7.9 Hz, 1H), 7.15 (d, J = 8.1 Hz, 1H).

[0682] 13 C NMR (126 MHz, DMSO- d 6) δ 160.3, 147.5, 141.8, 137.4, 129.4, 123.9,115.8, 110.7.

[0684] 3-Cyclopropyl-3,4-Dihydroacridine-1,9(2) H 10 H )-Diketone (113)

[0685] The title compound was prepared as a white powder following general procedure L.

[0686] LCMS (ESI-MS) m / z :C 16 H 16 NO2's [M+H] + Calculated value: 254.11; Measured value: 253.9. Retention time: 2.888 minutes.

[0687] TLC: (5% methanol in dichloromethane solution, R) f ): 0.34 (UV, 254 nm, 280 nm).

[0688] 1 H NMR (500 MHz, DMSO- d 6) δ 12.77 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H),7.75 – 7.65 (m, 2H), 7.41 – 7.32 (m, 1H), 3.16 (dd, J = 16.9, 3.9 Hz, 1H), 2.97(dd, J = 16.7, 10.4 Hz, 1H), 2.49 (dd, J = 16.9, 3.9 Hz, 1H), 2.41 (dd, J = 16.7,10.4 Hz, 1H), 1.50 – 1.37 (m, 1H), 0.82 – 0.71 (m, 1H), 0.51 – 0.39 (m, 2H), 0.27 – 0.13 (m, 2H).

[0689] 8-Chloro-3-cyclopropyl-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (114)

[0690] The title compound, which is a brownish-brown solid, was prepared according to general procedure L.

[0691] TLC: (5% methanol in dichloromethane solution, R) f ): 0.40 (UV, 254 nm, 280 nm).

[0692] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.04 – 7.93 (m, 2H), 7.84 (dd, J =5.7, 3.1 Hz, 1H), 3.59 (dd, J = 18.0, 4.1 Hz, 1H), 3.29 (dd, J = 18.0, 10.9 Hz,1H), 3.13 (dd, J= 18.0, 4.1 Hz, 1H), 2.87 (dd, J = 18.0, 10.9 Hz, 1H), 1.77 –1.59 (m, 1H), 0.86 – 0.74 (m, 1H), 0.74 – 0.56 (m, 2H), 0.38 – 0.19 (m, 2H).

[0693] 7-Chloro-3-cyclopropyl-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (115)

[0694] The title compound was prepared as a white powder following general procedure L.

[0695] TLC: (5% methanol in dichloromethane solution, R) f ): 0.40 (UV, 254 nm, 280 nm).

[0696] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.46 (s, 1H), 8.10 – 8.00 (m, 2H), 3.70 – 3.50 (m, 1H), 3.30 (dd, J = 18.0, 11.0 Hz, 1H), 3.17 – 3.09 (m, 1H), 2.85 (dd, J = 18.0, 11.0 Hz, 1H), 1.72 – 1.61 (m, 1H), 0.86 – 0.77 (m, 1H), 0.70 – 0.61 (m, 2H), 0.33 – 0.22 (m, 2H).

[0697] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 203.5, 172.4, 162.0, 138.8,137.9, 136.3, 124.2, 122.2, 120.2, 108.4, 43.4, 38.7, 34.3, 15.6, 3.9, 3.8.

[0698] 6-Chloro-3-cyclopropyl-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (116)

[0699] The title compound was prepared as a white powder following general procedure L.

[0700] LCMS (ESI-MS) m / z :C 16 H 15 [M+H] of ClNO2 + Calculated value: 288.07; Measured value: 287.9. Retention time: 3.412 minutes.

[0701] TLC: (5% methanol in dichloromethane solution, R) f ): 0.19 (UV, 254 nm, 280 nm).

[0702] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.45 (d, J = 8.9 Hz, 1H), 8.05 (d, J =1.8 Hz, 1H), 7.79 (dd, J = 8.9, 1.8 Hz, 1H), 3.61 (ddd, J = 18.0, 4.2, 1.4 Hz,1H), 3.31 (dd, J = 18.1, 11.0 Hz, 1H), 3.11 (ddd, J = 18.0, 4.2, 1.4 Hz, 1H),2.84 (dd, J = 18.1, 11.0 Hz, 1H), 1.71 – 1.59 (m, 1H), 0.89 – 0.75 (m, 1H), 0.70 – 0.60 (m, 2H), 0.32 – 0.22 (m, 2H).

[0703] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 203.57, 173.08, 163.09, 145.64,140.08, 130.65, 126.55, 120.06, 117.64, 108.2, 43.3, 38.7, 34.3, 15.6, 3.9,3.7.

[0704] 5-Chloro-3-cyclopropyl-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (117)

[0705] The title compound was prepared as a white powder following general procedure L.

[0706] LCMS (ESI-MS) m / z :C 16 H 15 [M+H] of ClNO2 + Calculated value: 288.07; Measured value: 287.8. Retention time: 3.500 minutes.

[0707] TLC: (5% methanol in dichloromethane solution, R) f ): 0.33 (UV, 254 nm, 280 nm).

[0708] 1 H NMR (500 MHz, DMSO- d 6) δ 8.08 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 7.4 Hz, 1H), 7.10 (dd, J = 7.9, 7.4 Hz, 1H), 3.01 (dd, J = 15.7, 3.9 Hz, 1H), 2.78 (dd, J =16.3, 10.6 Hz, 1H), 2.50 (dd, J = 15.7, 3.9 Hz, 1H), 2.36 (dd, J = 16.3, 10.6 Hz,1H), 1.37 – 1.26 (m, 1H), 0.78 – 0.67 (m, 1H), 0.47 – 0.35 (m, 2H), 0.24 –0.11 (m, 2H).

[0709] 3-Cyclopropyl-8-methyl-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (118)

[0710] The title compound, a brown solid, was prepared following general procedure L.

[0711] TLC: (5% methanol in dichloromethane solution, R) f ): 0.32 (UV, 254 nm, 280 nm).

[0712] 1 H NMR (500 MHz, DMSO- d 6) δ 11.81 (s, 1H), 7.46 (dd, J = 8.1, 7.3 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.04 (d, J = 7.3 Hz, 1H), 2.98 (dd, J = 16.5, 4.2Hz, 1H), 2.85 (dd, J = 16.5, 11.1 Hz, 1H), 2.74 (s, 3H), 2.45 (dd, J = 16.5, 4.2Hz, 1H), 2.33 (dd, J = 16.5, 11.1 Hz, 1H), 1.44 – 1.34 (m, 1H), 0.79 – 0.69 (m,1H), 0.48 – 0.38 (m, 2H), 0.26 – 0.10 (m, 2H).

[0713] 3-Cyclopropyl-7-methyl-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (119)

[0714] The title compound, a pale yellow solid, was prepared following general procedure L.

[0715] TLC: (5% methanol in dichloromethane solution, R) f ): 0.32 (UV, 254 nm, 280 nm).

[0716] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.28 (s, 1H), 7.99 – 7.89 (m, 2H), 3.58 (ddd, J = 17.8, 4.2, 1.4 Hz, 1H), 3.28 (dd, J = 17.9, 11.0 Hz, 1H), 3.11(ddd,J = 17.8, 4.2, 1.4 Hz, 1H), 2.84 (dd, J = 17.9, 11.0 Hz, 1H), 2.64 (s, 3H), 1.71 – 1.59 (m, 1H), 0.85 – 0.76 (m, 1H), 0.71 – 0.59 (m, 2H), 0.34 – 0.22(m, 2H).

[0717] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 203.7, 172.9, 160.7, 140.8,140.3, 137.7, 124.1, 120.1, 119.3, 108.0, 43.5, 38.8, 34.2, 21.6, 15.6, 3.8,3.7.

[0718] 3-Cyclopropyl-6-methyl-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (120)

[0719] The title compound was prepared as a white powder following general procedure L.

[0720] TLC: (5% methanol in dichloromethane solution, R) f ): 0.27 (UV, 254 nm, 280 nm).

[0721] 1 H NMR (500 MHz, CDCl3and 1 drop TFA- d ) δ 8.39 (d, J = 8.5 Hz, 1H), 7.79 (s,1H), 7.67 (dd, J = 8.5, 1.2 Hz, 1H), 3.58 (ddd, J = 17.9, 4.1, 1.3 Hz, 1H), 3.27(dd, J = 17.9, 11.1 Hz, 1H), 3.10 (ddd, J = 17.9, 4.1, 1.3 Hz, 1H), 2.82 (dd, J=17.9, 11.1 Hz, 1H), 2.66 (s, 3H), 1.71 – 1.56 (m, 1H), 0.90 – 0.74 (m, 1H), 0.70 – 0.60 (m, 2H), 0.34 – 0.18 (m, 2H).

[0722] 13 C NMR (126 MHz, CDCl3and 1 drop TFA- d ) δ 203.5, 173.0, 161.5, 151.4,139.8, 131.5, 124.9, 119.6, 117.1, 107.7, 43.4, 38.8, 34.2, 22.5, 15.6, 3.8,3.7.

[0723] 3-Cyclopropyl-5-methyl-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (121)

[0724] The title compound, a pale yellow solid, was prepared following general procedure L.

[0725] TLC: (5% methanol in dichloromethane solution, R) f ): 0.40 (UV, 254 nm, 280 nm).

[0726] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.40 (d, J = 8.2 Hz, 1H), 7.95 (d, J =7.3 Hz, 1H), 7.75 (dd, J = 8.2, 7.3 Hz, 1H), 3.75 (ddd, J = 17.8, 4.2, 1.4 Hz,1H), 3.35 (dd, J = 18.1, 10.2 Hz, 1H), 3.12 (ddd, J = 17.8, 4.2, 1.4 Hz, 1H), 2.91 – 2.72 (m, 4H), 1.70 – 1.56 (m, 1H), 0.87 – 0.77 (m, 1H), 0.71 – 0.55(m, 2H), 0.34 – 0.19 (m, 2H).

[0727] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 203.7, 173.6, 162.5, 139.3,138.4, 129.7, 129.1, 123.2, 119.7, 107.9, 43.3, 38.7, 34.1, 17.1, 15.6, 3.9,3.6.

[0728] 3-Cyclopropyl-8-methoxy-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (122)

[0729] The title compound was prepared as a grayish-white powder following general procedure L.

[0730] LCMS (ESI-MS) m / z :C 17 H 18 NO3's [M+H] + Calculated value: 284.12; Measured value: 283.9. Retention time: 2.839 minutes.

[0731] TLC: (5% methanol in dichloromethane solution, R) f ): 0.19 (UV, 254 nm, 280 nm).

[0732] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.00 (dd, J = 8.6, 7.9 Hz, 1H), 7.51(d, J = 7.9 Hz, 1H), 7.16 (d, J = 8.6 Hz, 1H), 4.11 (s, 3H), 3.52 (ddd, J = 17.9,4.3, 1.4 Hz, 1H), 3.23 (dd, J = 17.9, 11.1 Hz, 1H), 3.08 (ddd, J = 17.9, 4.3, 1.4Hz, 1H), 2.82 (dd, J= 17.9, 11.1 Hz, 1H), 1.67 – 1.57 (m, 1H), 0.85 – 0.75 (m,1H), 0.69 – 0.60 (m, 2H), 0.31 – 0.22 (m, 2H).

[0733] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 203.8, 175.7, 161.7, 160.7,141.1, 139.4, 111.7, 110.5, 109.4, 107.6, 57.0, 43.4, 38.6, 34.1, 15.6, 3.8,3.6.

[0734] 3-Cyclopropyl-7-methoxy-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (123)

[0735] The title compound was prepared as a white powder following general procedure L.

[0736] TLC: (5% methanol in dichloromethane solution, R) f ): 0.19 (UV, 254 nm, 280 nm).

[0737] 1 H NMR (500 MHz, DMSO- d 6) δ 12.04 (s, 1H), 7.52 – 7.46 (m, 2H), 7.30(dd, J = 8.9, 2.9 Hz, 1H), 3.83 (s, 3H), 3.01 (dd, J = 16.1, 4.3 Hz, 1H), 2.91(dd, J = 16.1, 11.1 Hz, 1H), 2.47 (dd, J = 16.1, 4.3 Hz, 1H), 2.36 (dd, J = 16.1,11.1 Hz, 1H), 1.49 – 1.37 (m, 1H), 0.79 – 0.70 (m, 1H), 0.49 – 0.35 (m, 2H), 0.26 – 0.14 (m, 2H).

[0738] 3-Cyclopropyl-6-methoxy-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (124)

[0739] The title compound was prepared as a white powder following general procedure L.

[0740] LCMS (ESI-MS) m / z :C 17 H 18 NO3's [M+H] + Calculated value: 284.12; Measured value: 283.9. Retention time: 3.225 minutes.

[0741] TLC: (5% methanol in dichloromethane solution, R) f ): 0.34 (UV, 254 nm, 280 nm).

[0742] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.35 (d, J = 9.2 Hz, 1H), 7.37 (dd, J = 9.2, 2.3 Hz, 1H), 7.33 (d, J = 2.3 Hz, 1H), 4.03 (s, 3H), 3.55 (ddd, J = 17.9,4.3, 1.4 Hz, 1H), 3.26 (dd, J = 17.8, 10.3 Hz, 1H), 3.07 (ddd, J = 17.9, 4.3, 1.4Hz, 1H), 2.80 (dd, J = 17.8, 10.3 Hz, 1H), 1.69 – 1.58 (m, 1H), 0.90 – 0.76 (m,1H), 0.70 – 0.59 (m, 2H), 0.33 – 0.21 (m, 2H).

[0743] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d) δ 203.4, 171.9, 167.9, 161.6,142.5, 126.8, 121.7, 113.1, 107.3, 99.9, 56.7, 43.4, 38.9, 34.2, 15.6, 3.8,3.7.

[0744] 3-Cyclopropyl-5-methoxy-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (125)

[0745] The title compound was prepared as a white powder following general procedure L.

[0746] LCMS (ESI-MS) m / z :C 17 H 18 NO3's [M+H] + Calculated value: 284.12; Measured value: 283.9. Retention time: 3.109 minutes.

[0747] TLC: (5% methanol in dichloromethane solution, R) f ): 0.29 (UV, 254 nm, 280 nm).

[0748] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.04 (dd, J = 8.4, 1.0 Hz, 1H), 7.76(dd, J = 8.4, 8.0 Hz, 1H), 7.49 (dd, J = 8.0, 1.0 Hz, 1H), 4.08 (s, 3H), 3.75(ddd, J = 17.8, 4.2, 1.4 Hz, 1H), 3.35 (dd, J = 18.1, 11.0 Hz, 1H), 3.12 (ddd, J =17.8, 4.2, 1.4 Hz, 1H), 2.84 (dd, J = 18.1, 11.0 Hz, 1H), 1.70 – 1.58 (m, 1H), 0.81 (s, 1H), 0.71 – 0.58 (m, 2H), 0.34 – 0.21 (m, 2H).

[0749] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 203.8, 173.4, 161.3, 149.3,130.4, 129.8, 120.2, 116.2, 116.0, 108.4, 56.8, 43.4, 38.7, 34.1, 15.6, 3.8,3.7.

[0750] 3-Cyclobutyl-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (126)

[0751] The title compound was prepared as a white powder following general procedure L.

[0752] LCMS (ESI-MS) m / z :C 17 H 18 NO2's [M+H] + Calculated value: 268.13; Measured value: 267.9. Retention time: 3.265 minutes.

[0753] TLC: (5% methanol in dichloromethane solution, R) f ): 0.44 (UV, 254 nm, 280 nm).

[0754] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.51 (d, J = 8.3 Hz, 1H), 8.18 –8.03 (m, 2H), 7.85 (dd, J = 8.3, 7.6 Hz, 1H), 3.50 (dd, J = 18.1, 3.8 Hz, 1H), 3.09 – 2.92 (m, 2H), 2.55 (dd, J = 17.7, 10.8 Hz, 1H), 2.46 – 2.27 (m, 2H), 2.21 – 2.08 (m, 2H), 2.03 – 1.70 (m, 4H).

[0755] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d) δ 203.6, 173.3, 161.9, 139.5,138.1, 129.4, 125.2, 120.5, 119.3, 108.0, 40.7, 39.6, 39.2, 31.5, 25.9, 25.8,17.6.

[0756] 3-Cyclobutyl-8-methyl-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (127)

[0757] The title compound was prepared as a grayish-white powder following general procedure L.

[0758] TLC: (5% methanol in dichloromethane solution, R) f ): 0.25 (UV, 254 nm, 280 nm).

[0759] 1 H NMR (500 MHz, DMSO- d 6) δ 11.65 (s, 1H), 7.42 (dd, J = 8.2, 7.3 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.00 (d, J = 7.3 Hz, 1H), 2.82 (d, J = 12.9 Hz, 1H), 2.69 (s, 3H), 2.55 (dd, J = 16.8, 8.9 Hz, 1H), 2.30 (d, J = 12.9 Hz, 1H), 2.16(dd, J = 16.8, 8.9 Hz, 1H), 2.07 – 1.88 (m, 4H), 1.82 – 1.59 (m, 4H).

[0760] 3-Cyclobutyl-7-methyl-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (128)

[0761] The title compound was prepared as a white powder following general procedure L.

[0762] TLC: (5% methanol in dichloromethane solution, R) f): 0.19 (UV, 254 nm, 280 nm).

[0763] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.27 (s, 1H), 7.99 – 7.91 (m, 2H), 3.45 (ddd, J = 17.9, 3.8, 1.6 Hz, 1H), 3.05 – 2.91 (m, 2H), 2.64 (s, 3H), 2.54(dd, J = 17.8, 10.9 Hz, 1H), 2.43 – 2.29 (m, 2H), 2.18 – 2.08 (m, 2H), 2.01 –1.72 (m, 4H).

[0764] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 203.7, 172.8, 160.7, 140.7,140.1, 137.8, 124.0, 120.2, 119.3, 108.0, 40.7, 39.6, 39.2, 31.4, 26.0, 25.8,21.6, 17.6.

[0765] 3-Cyclobutyl-6-methyl-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (129)

[0766] The title compound was prepared as a white powder following general procedure L.

[0767] LCMS (ESI-MS) m / z :C 18 H 20 NO2's [M+H] + Calculated value: 282.14; Measured value: 281.9. Retention time: 3.630 minutes.

[0768] TLC: (5% methanol in dichloromethane solution, R) f ): 0.19 (UV, 254 nm, 280 nm).

[0769] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-)d ) δ 8.39 (d, J = 8.5 Hz, 1H), 7.79 (s,1H), 7.67 (d, J = 8.5 Hz, 1H), 3.43 (dd, J = 17.9, 4.0 Hz, 1H), 3.04 – 2.91 (m,2H), 2.66 (s, 3H), 2.54 (dd, J = 17.7, 10.8 Hz, 1H), 2.44 – 2.28 (m, 2H), 2.18 – 2.09 (m, 2H), 2.00 – 1.71 (m, 4H).

[0770] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 203.7, 173.0, 161.6, 151.6,139.7, 131.6, 125.0, 119.5, 117.2, 107.8, 40.7, 39.6, 39.3, 31.5, 26.0, 25.8,22.5, 17.7.

[0771] 3-Cyclobutyl-5-methyl-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (130)

[0772] The title compound was prepared as a white powder following general procedure L.

[0773] LCMS (ESI-MS) m / z :C 18 H 20 NO2's [M+H] + Calculated value: 282.14; Measured value: 281.9. Retention time: 3.741 minutes.

[0774] TLC: (5% methanol in dichloromethane solution, R) f ): 0.42 (UV, 254 nm, 280 nm).

[0775] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.40 (d, J= 8.6 Hz, 1H), 7.93 (d, J =7.8 Hz, 1H), 7.75 (dd, J = 8.6, 7.8 Hz, 1H), 3.63 (ddd, J = 18.1, 3.7, 1.6 Hz,1H), 3.08 – 2.92 (m, 2H), 2.77 (s, 3H), 2.54 (dd, J = 17.7, 10.8 Hz, 1H), 2.41–2.28 (m, 2H), 2.17–2.07 (m, 2H), 2.02–1.69 (m, 4H).

[0776] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 203.7, 173.6, 162.5, 139.3,138.4, 129.7, 129.1, 123.2, 119.7, 108.0, 40.6, 39.6, 39.2, 31.4, 26.0, 25.8,17.6, 17.1.

[0777] 7-Chloro-3-cyclobutyl-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (131)

[0778] The title compound was prepared as a white powder following general procedure L.

[0779] LCMS (ESI-MS) m / z :C 17 H 17 [M+H] of ClNO2 + Calculated value: 302.09; Measured value: 301.9. Retention time: 3.705 minutes.

[0780] TLC: (5% methanol in dichloromethane solution, R) f ): 0.45 (UV, 254 nm, 280 nm).

[0781] 1 H NMR (500 MHz, DMSO- d 6) δ 7.98 (s, 1H), 7.53 – 7.40 (m, 2H), 2.81(d,J = 16.4 Hz, 1H), 2.48 (d, J = 10.9 Hz, 1H), 2.32 (d, J = 16.4 Hz, 1H), 2.20 –2.08 (m, 1H), 2.03 (dd, J = 16.1, 10.9 Hz, 1H), 1.99 – 1.86 (m, 3H), 1.80 –1.55 (m, 4H).

[0782] 3-Cyclobutyl-6-methoxy-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (132)

[0783] The title compound was prepared as a white powder following general procedure L.

[0784] LCMS (ESI-MS) m / z :C 18 H 20 NO3's [M+H] + Calculated value: 298.14; Measured value: 297.9. Retention time: 3.481 minutes.

[0785] TLC: (5% methanol in dichloromethane solution, R) f ): 0.39 (UV, 254 nm, 280 nm).

[0786] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.35 (d, J = 9.2 Hz, 1H), 7.37 (dd, J = 9.2, 2.3 Hz, 1H), 7.32 (d, J = 2.3 Hz, 1H), 4.02 (s, 3H), 3.46 – 3.32 (m,1H), 3.02 – 2.90 (m, 2H), 2.51 (dd, J = 17.6, 10.7 Hz, 1H), 2.43 – 2.28 (m,2H), 2.19 – 2.05 (m, 2H), 2.03 – 1.69 (m, 4H).

[0787] 13C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 203.5, 171.9, 167.9, 161.7,142.5, 126.8, 121.7, 113.1, 107.3, 99.9, 56.7, 40.6, 39.6, 39.3, 31.5, 26.0,25.8, 17.6.

[0788] 3-Cyclopentyl-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (133)

[0789] The title compound was prepared as a white powder following general procedure L.

[0790] LCMS (ESI-MS) m / z :C 18 H 20 NO2's [M+H] + Calculated value: 282.14; Measured value: 281.9. Retention time: 3.521 minutes.

[0791] TLC: (5% methanol in dichloromethane solution, R) f ): 0.39 (UV, 254 nm, 280 nm).

[0792] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.52 (d, J = 8.3 Hz, 1H), 8.14 (dd, J = 8.3, 7.7 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.87 (dd, J = 8.4, 7.7 Hz, 1H), 3.59 (ddd, J = 17.8, 4.0, 1.4 Hz, 1H), 3.17 (dd, J = 17.9, 11.7 Hz, 1H), 3.08(ddd, J = 17.8, 4.0, 1.4 Hz, 1H), 2.71 (dd, J= 17.9, 11.7 Hz, 1H), 2.32 – 2.20(m, 1H), 1.96 – 1.80 (m, 3H), 1.66 (dqd, J = 48.0, 9.6, 8.1, 4.9 Hz, 4H), 1.30– 1.17 (m, 2H).

[0793] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 203.8, 173.3, 162.1, 139.5,138.3, 129.5, 125.2, 120.5, 119.3, 108.0, 44.8, 42.8, 38.9, 33.6, 30.3, 30.2,25.05, 25.02.

[0794] 3-Cyclopentyl-8-methyl-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (134)

[0795] The title compound was prepared as a white powder following general procedure L.

[0796] LCMS (ESI-MS) m / z :C 19 H 22 NO2's [M+H] + Calculated value: 296.16; Measured value: 295.9. Retention time: 3.886 minutes.

[0797] TLC: (5% methanol in dichloromethane solution, R) f ): 0.39 (UV, 254 nm, 280 nm).

[0798] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.35 (d, J = 8.4 Hz, 1H), 7.90 (dd, J = 8.4, 7.3 Hz, 1H), 7.53 (d, J = 7.3 Hz, 1H), 3.90 (d, J = 17.7 Hz, 1H), 3.21(dd, J= 17.7, 10.7 Hz, 1H), 2.97 (s, 4H), 2.69 (dd, J = 17.7, 10.7 Hz, 1H), 2.29– 2.16 (m, 1H), 2.02 – 1.92 (m, 1H), 1.92 – 1.79 (m, 2H), 1.76 – 1.53 (m,4H), 1.34 – 1.15 (m, 2H).

[0799] 3-Cyclopentyl-7-methyl-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (135)

[0800] The title compound was prepared as a white powder following general procedure L.

[0801] TLC: (5% methanol in dichloromethane solution, R) f ): 0.42 (UV, 254 nm, 280 nm).

[0802] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.26 (s, 1H), 8.01 – 7.90 (m, 2H), 3.56 (ddd, J = 17.8, 4.0, 1.7 Hz, 1H), 3.14 (dd, J = 17.9, 11.0 Hz, 1H), 3.06(ddd, J = 17.8, 4.0, 1.7 Hz, 1H), 2.74 – 2.60 (m, 4H), 2.30 – 2.18 (m, 1H), 1.95 – 1.78 (m, 3H), 1.78 – 1.54 (m, 4H), 1.27 – 1.16 (m, 2H).

[0803] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 203.8, 172.7, 160.9, 140.6,140.1, 137.8, 124.0, 120.2, 119.3, 108.0, 44.8, 42.8, 38.9, 33.5, 30.3, 30.2,25.04, 25.02, 21.6.

[0804] 3-Cyclopentyl-6-methyl-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (136)

[0805] The title compound was prepared as a white powder following general procedure L.

[0806] LCMS (ESI-MS) m / z :C 19 H 22 NO2's [M+H] + Calculated value: 296.16; Measured value: 295.9. Retention time: 3.676 minutes.

[0807] TLC: (5% methanol in dichloromethane solution, R) f ): 0.42 (UV, 254 nm, 280 nm).

[0808] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.38 (d, J = 8.5 Hz, 1H), 7.81 (s,1H), 7.66 (d, J = 8.5 Hz, 1H), 3.55 (ddd, J = 17.8, 4.0, 1.5 Hz, 1H), 3.13 (dd, J =17.9, 11.0 Hz, 1H), 3.05 (ddd, J = 17.8, 4.0, 1.5 Hz, 1H), 2.74 – 2.62 (m, 4H), 2.30 – 2.18 (m, 1H), 1.96 – 1.79 (m, 3H), 1.76 – 1.54 (m, 4H), 1.31 – 1.14(m, 2H).

[0809] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d) δ 203.8, 172.9, 161.8, 151.4,139.8, 131.5, 124.9, 119.6, 117.1, 107.7, 44.8, 42.8, 38.9, 33.5, 30.3, 30.2,25.04, 25.02, 22.5.

[0810] 3-Cyclopentyl-5-methyl-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (137)

[0811] The title compound was prepared as a white powder following general procedure L.

[0812] TLC: (5% methanol in dichloromethane solution, R) f ): 0.42 (UV, 254 nm, 280 nm).

[0813] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.40 (d, J = 8.2 Hz, 1H), 7.95 (d, J =7.2 Hz, 1H), 7.75 (dd, J = 8.2, 7.2 Hz, 1H), 3.74 (ddd, J = 17.9, 3.9, 1.7 Hz,1H), 3.17 (dd, J = 17.7, 11.1 Hz, 1H), 3.07 (dd, J = 17.9, 3.9 Hz, 1H), 2.77 (s,3H), 2.70 (dd, J = 17.7, 11.1 Hz, 1H), 2.27 – 2.17 (m, 1H), 1.94 – 1.79 (m,3H), 1.75 – 1.52 (m, 4H), 1.26 – 1.14 (m, 2H).

[0814] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d) δ 203.9, 173.6, 162.7, 139.4,138.3, 129.6, 129.1, 123.3, 119.7, 108.0, 44.8, 42.8, 38.9, 33.4, 30.3, 30.1,25.05, 25.02, 17.1.

[0815] 7-Chloro-3-cyclopentyl-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (138)

[0816] The title compound was prepared as a white powder following general procedure L.

[0817] LCMS (ESI-MS) m / z :C 18 H 19 [M+H] of ClNO2 + Calculated value: 316.10; Measured value: 315.8. Retention time: 3.934 minutes.

[0818] TLC: (5% methanol in dichloromethane solution, R) f ): 0.39 (UV, 254 nm, 280 nm).

[0819] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.46 (s, 1H), 8.08 – 8.01 (m, 2H), 3.64 – 3.53 (m, 1H), 3.23 – 3.04 (m, 2H), 2.71 (dd, J = 17.9, 11.8 Hz, 1H), 2.31 – 2.20 (m, 1H), 1.95 – 1.76 (m, 3H), 1.77 – 1.54 (m, 4H), 1.28 – 1.14(m, 2H).

[0820] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d) δ 203.7, 172.2, 162.2, 138.7,137.9, 136.2, 124.1, 122.2, 120.2, 108.4, 44.8, 42.8, 38.8, 33.5, 30.3, 30.2,25.01, 24.99.

[0821] 3-Cyclopentyl-6-methoxy-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (139)

[0822] The title compound was prepared as a white powder following general procedure L.

[0823] TLC: (5% methanol in dichloromethane solution, R) f ): 0.17 (UV, 254 nm, 280 nm).

[0824] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.35 (d, J = 9.2 Hz, 1H), 7.37 (dd, J = 9.2, 2.3 Hz, 1H), 7.31 (d, J = 2.3 Hz, 1H), 4.02 (s, 3H), 3.49 (ddd, J = 17.8,3.9, 1.6 Hz, 1H), 3.11 (dd, J = 17.8, 11.8 Hz, 1H), 3.04 (ddd, J = 17.8, 3.9, 1.6Hz, 1H), 2.66 (dd, J = 17.8, 11.8 Hz, 1H), 2.29 – 2.16 (m, 1H), 1.99 – 1.77 (m,3H), 1.77 – 1.53 (m, 4H), 1.29 – 1.13 (m, 2H).

[0825] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d) δ 203.6, 171.8, 167.9, 161.9,142.5, 126.8, 121.6, 113.1, 107.3, 99.9, 56.7, 44.8, 42.7, 39.0, 33.5, 30.3,30.2, 25.04, 25.00.

[0827] 3-Cyclohexyl-7-methyl-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (140)

[0828] The title compound was prepared as a white powder following general procedure L.

[0829] TLC: (5% methanol in dichloromethane solution, R) f ): 0.22 (UV, 254 nm, 280 nm).

[0830] 3-Cyclohexyl-6-methyl-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (141)

[0831] The title compound was prepared as a grayish-white powder following general procedure L.

[0832] LCMS (ESI-MS) m / z :C 20 H 24 NO2's [M+H] + Calculated value: 310.17; Measured value: 309.9. Retention time: 4.029 minutes.

[0833] TLC: (5% methanol in dichloromethane solution, R) f ): 0.17 (UV, 254 nm, 280 nm).

[0834] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.37 (d, J = 8.5 Hz, 1H), 7.85 (s,1H), 7.65 (d, J = 8.5 Hz, 1H), 3.52 (ddd, J= 17.6, 4.0, 1.6 Hz, 1H), 3.16 (dd, J =17.8, 11.6 Hz, 1H), 2.99 (ddd, J = 17.6, 4.0, 1.6 Hz, 1H), 2.73 – 2.62 (m, 4H), 2.33 – 2.23 (m, 1H), 1.86 – 1.69 (m, 5H), 1.50 – 1.41 (m, 1H), 1.33 – 1.01(m, 5H).

[0835] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 204.1, 172.8, 162.2, 151.2,139.8, 131.4, 124.8, 119.7, 117.1, 107.7, 41.2, 41.0, 38.7, 31.8, 29.6, 29.5,26.15, 26.09, 26.05, 22.5.

[0836] 3-Cyclohexyl-5-methyl-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (142)

[0837] The title compound was prepared as a white powder following general procedure L.

[0838] TLC: (5% methanol in dichloromethane solution, R) f ): 0.32 (UV, 254 nm, 280 nm).

[0839] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.40 (d, J = 9.0 Hz, 1H), 7.95 (d, J =8.1 Hz, 1H), 7.75 (dd, J = 9.0, 8.1 Hz, 1H), 3.67 (ddd, J = 17.7, 4.0, 1.7 Hz,1H), 3.17 (dd, J = 18.0, 11.6 Hz, 1H), 3.01 (ddd, J= 17.7, 4.0, 1.7 Hz, 1H),2.79 – 2.66 (m, 4H), 2.31 – 2.21 (m, 1H), 1.86 – 1.67 (m, 5H), 1.49 – 1.39(m, 1H), 1.34 – 1.11 (m, 3H), 1.10 – 0.99 (m, 2H).

[0840] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 204.3, 173.6, 163.0, 139.4,138.3, 129.5, 129.1, 123.3, 119.7, 108.0, 41.3, 41.1, 38.6, 31.7, 29.7, 29.5,26.1, 26.0, 25.9, 16.9.

[0841] 7-Chloro-3-cyclohexyl-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (143)

[0842] The title compound was prepared as a white powder following general procedure L.

[0843] TLC: (5% methanol in dichloromethane solution, R) f ): 0.21 (UV, 254 nm, 280 nm).

[0844] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.46 (d, J = 1.7 Hz, 1H), 8.12 –7.99 (m, 2H), 3.52 (dd, J = 18.0, 3.1 Hz, 1H), 3.18 (dd, J = 17.9, 12.4 Hz, 1H),3.03 (dd, J = 18.0, 3.1 Hz, 1H), 2.72 (dd, J = 17.9, 12.4 Hz, 1H), 2.36 – 2.24(m, 1H), 1.89 – 1.67 (m, 5H), 1.54 – 1.42 (m, 1H), 1.36 – 0.99 (m, 5H).

[0845] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 204.14, 172.2, 162.6, 138.7,138.0, 136.1, 124.1, 122.2, 120.1, 108.4, 41.2, 41.0, 38.6, 31.8, 29.6, 29.4,26.0.

[0846] 3-Cyclohexyl-6-methoxy-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (144)

[0847] The title compound was prepared as a white powder following general procedure L.

[0848] TLC: (5% methanol in dichloromethane solution, R) f ): 0.36 (UV, 254 nm, 280 nm).

[0849] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.35 (d, J = 9.2 Hz, 1H), 7.37 (dd, J = 9.2, 2.3 Hz, 1H), 7.29 (d, J = 2.3 Hz, 1H), 4.02 (s, 3H), 3.42 (ddd, J = 17.8,4.1, 1.7 Hz, 1H), 3.13 (dd, J = 17.8, 12.4 Hz, 1H), 2.98 (ddd, J = 17.8, 4.1, 1.7Hz, 1H), 2.67 (dd, J = 17.8, 12.4 Hz, 1H), 2.33 – 2.22 (m, 1H), 1.89 – 1.65 (m,5H), 1.50 – 1.41 (m, 1H), 1.35 – 0.99 (m, 5H).

[0850] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d) δ 204.0, 171.8, 167.8, 162.3,142.5, 126.8, 121.6, 113.1, 107.3, 99.9, 56.6, 41.2, 40.9, 38.8, 31.8, 29.6,29.5, 26.14, 26.09, 26.04.

[0851] 7-Chloro-3-(tetrahydrofuran-3-yl)-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (145)

[0852] The title compound was prepared as a white powder following general procedure L.

[0853] LCMS (ESI-MS) m / z :C 17 H 17 [M+H] of ClNO3 + Calculated value: 318.08; Measured value: 317.8. Retention time: 2.777 minutes.

[0854] TLC: (5% methanol in dichloromethane solution, R) f ): 0.21 (UV, 254 nm, 280 nm).

[0855] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.51 – 8.44 (m, 1H), 8.19 – 8.01(m, 2H), 4.24 – 4.07 (m, 2H), 3.99 – 3.88 (m, 1H), 3.75 – 3.51 (m, 2H), 3.32– 3.18 (m, 1H), 3.14 – 2.92 (m, 1H), 2.83 – 2.69 (m, 1H), 2.54 – 2.38 (m,2H), 2.36 – 2.20 (m, 1H), 1.84 – 1.72 (m, 1H).

[0856] 7-Chloro-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (146)

[0857] The title compound was prepared as a white powder following general procedure L.

[0858] LCMS (ESI-MS) m / z :C 18 H 19 [M+H] of ClNO3 + Calculated value: 332.10; Measured value: 331.8. Retention time: 3.051 minutes.

[0859] TLC: (5% methanol in dichloromethane solution, R) f ): 0.21 (UV, 254 nm, 280 nm).

[0860] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.48 (d, J = 1.9 Hz, 1H), 8.12 –8.01 (m, 2H), 4.33 – 4.14 (m, 2H), 3.67 – 3.49 (m, 3H), 3.21 (dd, J = 17.9,12.5 Hz, 1H), 3.08 (ddd, J = 17.7, 3.8, 1.8 Hz, 1H), 2.70 (dd, J = 17.9, 12.5 Hz,1H), 2.42 – 2.29 (m, 1H), 1.86 – 1.72 (m, 3H), 1.64 – 1.47 (m, 2H).

[0861] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 203.0, 172.3, 161.8, 138.9,138.0, 136.4, 124.2, 122.2, 120.2, 108.3, 67.6, 67.5, 40.4, 38.2, 37.9, 31.6,29.2, 28.7.

[0862] 6-Methoxy-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroacryl-1,9(2) H 10 H )-Diketone (147)

[0863] The title compound was prepared as a white powder following general procedure L.

[0864] TLC: (5% methanol in dichloromethane solution, R) f ): 0.27 (UV, 254 nm, 280 nm).

[0865] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.35 (d, J = 9.3 Hz, 1H), 7.51 (d, J =2.0 Hz, 1H), 7.37 (dd, J = 9.3, 2.0 Hz, 1H), 4.31 – 4.15 (m, 2H), 4.04 (s, 3H), 3.67 (d, J = 17.2 Hz, 1H), 3.64 – 3.52 (m, 2H), 3.18 (dd, J = 17.7, 12.4 Hz, 1H),3.01 (dd, J = 17.2, 3.6 Hz, 1H), 2.64 (dd, J = 17.7, 12.4 Hz, 1H), 2.36 – 2.26 (m, 1H), 1.84 – 1.72 (m, 3H), 1.63 – 1.46 (m, 2H).

[0866] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 202.8, 171.6, 167.9, 161.3,142.7, 126.7, 121.8, 113.1, 107.1, 100.1, 67.7, 67.5, 56.8, 40.3, 38.2, 38.1,31.6, 29.4, 28.7.

[0867] 7-Chloro-3-(thiophen-2-yl)-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (148)

[0868] The title compound was prepared as a yellow powder following general procedure L.

[0869] LCMS (ESI-MS)m / z :C 17 H 13 [M+H] of ClNO2S + Calculated value: 330.03; Measured value: 329.8. Retention time: 3.540 minutes.

[0870] TLC: (5% methanol in dichloromethane solution, R) f ): 0.37 (UV, 254 nm, 280 nm).

[0871] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.47 (s, 1H), 8.09 – 8.05 (m, 2H), 7.28 – 7.24 (m, 1H), 6.98 (dd, J = 5.1, 3.5 Hz, 1H), 6.94 (d, J = 3.5 Hz, 1H), 4.14 – 4.05 (m, 1H), 3.89 (dd, J = 17.9, 4.3 Hz, 1H), 3.71 (dd, J = 17.9, 8.9 Hz, 1H), 3.38 (dd, J = 17.9, 4.3 Hz, 1H), 3.27 (dd, J = 17.9, 8.9 Hz, 1H).

[0872] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 202.0, 172.3, 160.6, 142.5, 139.0, 138.0, 136.5, 127.5, 125.2, 125.0, 124.2, 122.2, 120.3, 108.3, 44.5, 35.9, 33.6.

[0873] 7-Fluoro-3-(thiophene-2-yl)-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (149)

[0874] The title compound was prepared as a white powder following general procedure L.

[0875] TLC: (5% methanol in dichloromethane solution, R) f ): 0.40 (UV, 254 nm, 280 nm).

[0876] 1 H NMR (500 MHz, DMSO- d 6) δ 7.75 (d, J = 8.9 Hz, 1H), 7.63 – 7.50 (m,3H), 7.31 (s, 1H), 7.18 (d, J = 4.9 Hz, 1H), 3.62 – 3.52 (m, 1H), 3.26 – 3.18(m, 2H), 2.70 (d, J = 7.8 Hz, 2H).

[0877] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.20 – 8.09 (m, 2H), 7.89 (ddd, J =9.3, 7.6, 2.8 Hz, 1H), 7.40 (dd, J = 5.1, 2.9 Hz, 1H), 7.12 (dd, J = 2.9, 1.4 Hz, 1H), 7.04 (dd, J = 5.1, 1.4 Hz, 1H), 3.93 – 3.79 (m, 2H), 3.66 (dd, J = 17.9,10.0 Hz, 1H), 3.32 (dd, J = 17.9, 4.0 Hz, 1H), 3.21 (dd, J = 17.9, 10.0 Hz, 1H).

[0878] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 202.82, 172.63 (d, J C–F = 4.3 Hz), 161.84 (d, J C–F = 257.1 Hz), 160.57 (d, J C–F= 2.3 Hz), 140.10, 136.42, 128.08 (d, J C–F = 26.0 Hz), 127.88, 125.68, 123.52 (d, J C–F = 8.8 Hz), 121.49, 120.90 (d, J C–F =9.4 Hz), 109.88 (d, J C–F = 24.4 Hz), 108.07, 43.75, 34.91, 33.62.

[0879] 19 F NMR (471 MHz, CDCl3 and 3 drops of TFA-) d ) δ -105.48 – -105.55 (m).

[0881] 6-Methoxy-3-(thiophen-2-yl)-3,4-dihydroacryl-1,9(2) H 10 H )-Diketone (150)

[0882] The title compound was prepared as a white powder following general procedure L.

[0883] TLC: (5% methanol in dichloromethane solution, R) f ): 0.43 (UV, 254 nm, 280 nm).

[0884] 1 H NMR (500 MHz, DMSO- d 6) δ 11.92 (s, 1H), 8.01 (d, J = 8.7 Hz, 1H),7.56 – 7.50 (m, 1H), 7.31 (s, 1H), 7.18 (d, J = 4.9 Hz, 1H), 6.99 – 6.90 (m,2H), 3.86 (s, 3H), 3.60 – 3.52 (m, 1H), 3.26 – 3.14 (m, 2H), 2.75 – 2.64 (m,2H).

[0885] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-)d ) δ 8.37 (d, J = 9.2 Hz, 1H), 7.46 –7.34 (m, 2H), 7.31 (d, J = 2.4 Hz, 1H), 7.12 (s, 1H), 7.04 (d, J = 5.0 Hz, 1H), 4.02 (s, 3H), 3.90 – 3.80 (m, 1H), 3.75 (dd, J = 17.9, 4.3 Hz, 1H), 3.59 (dd, J =17.9, 10.3 Hz, 1H), 3.26 (dd, J = 17.9, 4.3 Hz, 1H), 3.15 (dd, J = 17.9, 10.3 Hz, 1H).

[0886] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 202.5, 171.8, 167.9, 160.8,142.5, 140.3, 127.6, 126.8, 125.6, 121.7, 121.2, 113.1, 107.2, 99.9, 56.6,43.6, 34.8, 33.7.

[0887] 7-Chloro-3-(thien-3-yl)-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (151)

[0888] The title compound was prepared as a yellow powder following general procedure L.

[0889] LCMS (ESI-MS) m / z :C 17 H 13 [M+H] of ClNO2S + Calculated value: 330.03; Measured value: 329.8. Retention time: 3.534 minutes.

[0890] TLC: (5% methanol in dichloromethane solution, R) f ): 0.37 (UV, 254 nm, 280 nm).

[0891] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.47 (d, J = 1.9 Hz, 1H), 8.13 –8.03 (m, 2H), 7.40 (dd, J = 5.0, 2.6 Hz, 1H), 7.12 (dd, J = 2.6, 1.5 Hz, 1H), 7.04 (dd, J = 5.0, 1.5 Hz, 1H), 3.93 – 3.79 (m, 2H), 3.67 (dd, J = 18.0, 9.5 Hz,1H), 3.31 (ddd, J = 18.0, 4.1, 1.4 Hz, 1H), 3.20 (dd, J = 18.0, 9.5 Hz, 1H).

[0892] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 202.7, 172.3, 161.1, 140.1,138.9, 138.0, 136.4, 127.8, 125.7, 124.2, 122.2, 121.4, 120.2, 108.3, 43.7,34.9, 33.5.

[0893] 6-Methoxy-3-(thiophen-3-yl)-3,4-dihydroacryl-1,9(2) H 10 H )-Diketone (152)

[0894] The title compound was prepared as a white powder following general procedure L.

[0895] TLC: (5% methanol in dichloromethane solution, R) f ): 0.43 (UV, 254 nm, 280 nm).

[0896] 1 H NMR (500 MHz, DMSO- d 6) δ 11.97 (s, 1H), 8.00 (d, J = 8.9 Hz, 1H), 7.40 (dd, J= 4.1, 2.1 Hz, 1H), 7.02 – 6.94 (m, 3H), 6.91 (d, J = 2.1 Hz, 1H), 3.86 (s, 3H), 3.85 – 3.76 (m, 1H), 3.29 – 3.19 (m, 2H), 2.81 – 2.66 (m, 2H).

[0897] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.37 (d, J = 9.2 Hz, 1H), 7.39 (dd, J = 9.2, 2.3 Hz, 1H), 7.32 (d, J = 2.3 Hz, 1H), 7.25 (dd, J = 5.0, 1.5 Hz, 1H), 6.98 (dd, J = 5.0, 3.4 Hz, 1H), 6.95 (d, J = 3.4 Hz, 1H), 4.10 – 4.01 (m, 4H), 3.82 (ddd, J = 17.8, 4.4, 1.1 Hz, 1H), 3.64 (dd, J = 17.8, 9.1 Hz, 1H), 3.32(ddd, J = 17.8, 4.4, 1.1 Hz, 1H), 3.20 (dd, J = 17.8, 9.1 Hz, 1H).

[0898] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 201.9, 171.9, 168.0, 160.3,142.9, 142.7, 127.5, 126.9, 125.1, 124.8, 121.9, 113.2, 107.3, 100.0, 56.7,44.5, 35.8, 33.8.

[0899] 7-Chloro-3-(thiazo-2-yl)-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (153)

[0900] The title compound was prepared as a yellow powder following general procedure L.

[0901] TLC: (5% methanol in dichloromethane solution, R) f ): 0.29 (UV, 254 nm, 280 nm).

[0902] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.53 (d, J = 2.2 Hz, 1H), 8.24 (d, J =3.8 Hz, 1H), 8.12 (dd, J = 9.0, 2.2 Hz, 1H), 8.01 (d, J = 9.0 Hz, 1H), 7.94 (d, J =3.8 Hz, 1H), 4.91 – 4.80 (m, 1H), 4.12 (ddd, J = 17.4, 4.2, 1.5 Hz, 1H), 3.99(dd, J = 17.3, 12.0 Hz, 1H), 3.55 – 3.39 (m, 2H).

[0903] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 198.4, 173.9, 172.8, 158.3,139.5, 137.9, 137.1, 135.6, 124.5, 123.3, 122.0, 120.4, 108.2, 34.2, 34.1,33.1.

[0904] 6-Methoxy-3-(thiazolyl-2-yl)-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (154)

[0905] The title compound was prepared as a white powder following general procedure L.

[0906] LCMS (ESI-MS) m / z :C 17 H 15 [M+H] of N2O3S+ Calculated value: 327.07; Measured value: 326.8. Retention time: 2.959 minutes.

[0907] TLC: (5% methanol in dichloromethane solution, R) f ): 0.29 (UV, 254 nm, 280 nm).

[0908] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.40 (d, J = 9.3 Hz, 1H), 8.19 (d, J =3.8 Hz, 1H), 7.83 (d, J = 3.8 Hz, 1H), 7.42 (dd, J = 9.2, 2.3 Hz, 1H), 7.32 (d, J =2.3 Hz, 1H), 4.80 – 4.69 (m, 1H), 4.04 (s, 4H), 3.93 (dd, J = 17.3, 11.6 Hz,1H), 3.47 – 3.33 (m, 2H).

[0909] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 199.2, 172.3, 171.8, 168.1,158.6, 142.8, 138.5, 126.8, 122.0, 121.7, 113.3, 107.0, 100.1, 56.7, 35.0,34.9, 33.3.

[0910] 7-Chloro-3-(thiazo-4-yl)-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (155)

[0911] The title compound was prepared as a yellow powder following general procedure L.

[0912] LCMS (ESI-MS) m / z :C 16 H 12 [M+H] of ClN2O2S +Calculated value: 331.02; Measured value: 330.7. Retention time: 2.877 minutes.

[0913] TLC: (5% methanol in dichloromethane solution, R) f ): 0.19 (UV, 254 nm, 280 nm).

[0914] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 9.81 (d, J = 2.2 Hz, 1H), 8.50 (d, J =2.2 Hz, 1H), 8.15 – 8.01 (m, 2H), 7.91 (d, J = 2.2 Hz, 1H), 4.46 – 4.35 (m,1H), 3.97 (dd, J = 17.6, 4.3 Hz, 1H), 3.88 (dd, J = 17.6, 12.2 Hz, 1H), 3.39(ddd, J = 17.6, 4.3, 1.6 Hz, 1H), 3.31 (dd, J = 17.6, 12.2 Hz, 1H).

[0915] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 200.3, 172.6, 159.6, 158.2, 150.0, 139.1, 138.0, 136.6, 124.3, 122.1, 120.4, 119.5, 108.2, 32.7, 32.4, 32.3.

[0916] 6-Methoxy-3-(thiazolyl-4-yl)-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (156)

[0917] The title compound was prepared as a white powder following general procedure L.

[0918] LCMS (ESI-MS) m / z :C 17 H 15 [M+H] of N2O3S +Calculated value: 327.07; Measured value: 326.8. Retention time: 1.838 minutes.

[0919] TLC: (5% methanol in dichloromethane solution, R) f ): 0.16 (UV, 254 nm, 280 nm).

[0920] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 9.88 (d, J = 2.1 Hz, 1H), 8.40 (d, J =9.2 Hz, 1H), 7.95 (d, J = 2.1 Hz, 1H), 7.42 (dd, J = 9.2, 2.4 Hz, 1H), 7.30 (d, J =2.4 Hz, 1H), 4.42 – 4.31 (m, 1H), 4.04 (s, 3H), 3.93 (dd, J = 17.5, 4.0 Hz, 1H), 3.83 (dd, J = 17.5, 11.6 Hz, 1H), 3.40 – 3.20 (m, 2H).

[0921] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 199.8, 172.1, 168.2, 159.0,158.4, 149.6, 142.6, 127.0, 122.0, 119.9, 113.3, 107.1, 99.9, 56.7, 41.4, 35.6, 32.4.

[0922] 7-Chloro-3-(thiazolyl-5-yl)-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (157)

[0923] The title compound was prepared as a yellow powder following general procedure L.

[0924] TLC: (5% methanol in dichloromethane solution, R) f ): 0.14 (UV, 254 nm, 280 nm).

[0925] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 9.90 (d, J = 0.9 Hz, 1H), 8.56 –8.47 (m, 2H), 8.23 ​​(d, J = 9.0 Hz, 1H), 8.11 (dd, J = 9.0, 2.3 Hz, 1H), 4.39 –4.17 (m, 2H), 3.85 (dd, J = 17.6, 11.0 Hz, 1H), 3.51 – 3.29 (m, 2H).

[0926] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 199.5, 172.6, 158.8, 156.9,142.9, 139.4, 138.0, 137.0, 132.7, 124.4, 122.2, 120.4, 108.0, 42.9, 34.7,31.5.

[0927] 6-Methoxy-3-(thiazolyl-5-yl)-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (158)

[0928] The title compound was prepared as a grayish-white powder following general procedure L.

[0929] TLC: (5% methanol in dichloromethane solution, R) f ): 0.19 (UV, 254 nm, 280 nm).

[0930] 1 H NMR (500 MHz, DMSO- d 6) δ 9.00 (d, J = 0.8 Hz, 1H), 8.01 (d, J = 9.5 Hz, 1H), 7.80 (dd, J= 1.3, 0.8 Hz, 1H), 7.01 – 6.96 (m, 2H), 3.97 – 3.89 (m, 1H), 3.87 (s, 3H), 3.38 – 3.24 (m, 2H), 2.84 – 2.67 (m, 2H).

[0931] ( E )-4-Cyclopropylbut-3-en-2-one (172)

[0932] The title compound, which is pale yellow and oily, was prepared according to general step F.

[0933] LCMS (ESI-MS) m / z C7H 11 O of [M+H] + Calculated value: 111.07; Measured value: 111.0. Retention time: 2.084 minutes.

[0934] TLC: (10% EtOAc hexane solution, R) f ): 0.25 (UV, 254 nm, 280 nm).

[0935] 1 H NMR (500 MHz, DMSO- d 6) δ 6.37 (dd, J = 16.1, 9.9 Hz, 1H), 6.12 (d, J =16.1 Hz, 1H), 2.13 (s, 3H), 1.67 – 1.58 (m, 1H), 0.99 – 0.92 (m, 2H), 0.71 –0.65 (m, 2H).

[0936] 13 C NMR (126 MHz, CDCl3) δ 197.7, 153.5, 128.2, 26.9, 14.6, 9.0.

[0937] ( E )-4-Cyclobutylbut-3-en-2-one (173)

[0938] The pale yellow, oily title compound was prepared following general steps B and F.

[0939] LCMS (ESI-MS) m / z C8H 13 O of [M+H] + Calculated value: 125.09; Measured value: 125.0. Retention time: 3.521 minutes.

[0940] TLC: (10% EtOAc hexane solution, R) f ): 0.36 (UV, 254 nm, 280 nm).

[0941] 1 H NMR (500 MHz, CDCl3) δ 6.86 (dd, J = 16.0, 6.7 Hz, 1H), 5.97 (dd, J =16.0, 1.4 Hz, 1H), 3.15 – 3.04 (m, 1H), 2.23 (s, 3H), 2.21 – 2.13 (m, 2H), 2.00 – 1.75 (m, 4H).

[0942] 13 C NMR (126 MHz, CDCl3) δ 198.9, 151.7, 128.8, 37.7, 27.8, 26.8,18.5.

[0943] ( E )-4-Cyclopentylalbumin-3-en-2-one (174)

[0944] The transparent, oily title compound was prepared following general step F.

[0945] LCMS (ESI-MS) m / z C9H 15 O of [M+H] + Calculated value: 139.10; Measured value: 139.0. Retention time: 3.961 minutes.

[0946] TLC: (10% EtOAc hexane solution, R) f ): 0.36 (UV, 254 nm, 280 nm).

[0947] 1 H NMR (500 MHz, DMSO- d 6) δ 6.83 (dd, J = 16.3, 8.1 Hz, 1H), 6.00 (d, J=16.3 Hz, 1H), 2.66 – 2.56 (m, 1H), 2.19 (s, 3H), 1.85 – 1.76 (m, 2H), 1.71 –1.52 (m, 4H), 1.45 – 1.33 (m, 2H).

[0948] 13 C NMR (126 MHz, DMSO- d 6) δ 198.5, 152.9, 129.6, 42.9, 32.4, 27.1,25.3.

[0949] ( E )-4-cyclohexyl-3-en-2-one (175)

[0950]

[0951] The transparent, oily title compound was prepared following general step F.

[0952] LCMS (ESI-MS) m / z :C 10 H 17 O of [M+H] + Calculated value: 153.12; Measured value: 153.2. Retention time: 3.452 minutes.

[0953] TLC: (10% EtOAc hexane solution, R) f ): 0.36 (UV, 254 nm, 280 nm).

[0954] 1 H NMR (500 MHz, CDCl3) δ 6.73 (dd, J = 16.1, 6.8 Hz, 1H), 6.02 (dd, J =16.1, 1.4 Hz, 1H), 2.24 (s, 3H), 2.19 – 2.11 (m, 1H), 1.80 – 1.65 (m, 5H), 1.35 – 1.10 (m, 5H).

[0955] 13 C NMR (126 MHz, CDCl3) δ 199.2, 153.4, 128.8, 40.6, 31.7, 26.8, 25.9, 25.7.

[0956] ( E)-4-(tetrahydrofuran-3-yl)but-3-en-2-one (176)

[0957]

[0958] The yellow-brown oily title compound was prepared according to general procedure G.

[0959] LCMS (ESI-MS) m / z C8H 13 O2's [M+H] + Calculated value: 141.08; Measured value: 141.1. Retention time: 1.216 minutes.

[0960] TLC: (33% EtOAc hexane solution, R) f ): 0.27 (UV, 254 nm, 280 nm).

[0961] 1 H NMR (500 MHz, CDCl3) δ 6.72 (dd, J = 15.9, 8.5 Hz, 1H), 6.13 (dd, J =15.9, 1.0 Hz, 1H), 4.00 – 3.91 (m, 2H), 3.87 – 3.80 (m, 1H), 3.57 (dd, J = 8.7, 6.8 Hz, 1H), 3.02 (m, J = 7.7 Hz, 1H), 2.26 (s, 3H), 2.24 – 2.13 (m, 1H), 1.87 – 1.76 (m, 1H).

[0962] 13 C NMR (126 MHz, CDCl3) δ 198.27, 147.5, 131.1, 72.2, 68.1, 42.3, 32.5, 27.1.

[0963] ( E )-4-(tetrahydro-2H-pyran-4-yl)but-3-en-2-one (177)

[0964] The light brown, oily title compound was prepared following the general steps C and H.

[0965] LCMS (ESI-MS) m / z C9H 15O2's [M+H] + Calculated value: 155.10; Measured value: 155.0. Retention time: 1.163 minutes.

[0966] TLC: (20% EtOAc hexane solution, R) f ): 0.32 (UV, 254 nm, 280 nm).

[0967] 1 H NMR (500 MHz, CDCl3) δ 6.72 (dd, J = 15.8, 6.5 Hz, 1H), 6.06 (d, J =15.8 Hz, 1H), 4.00 (dd, J = 11.5, 3.7 Hz, 2H), 3.45 (td, J = 11.8, 3.7 Hz, 2H), 2.47 – 2.37 (m, 1H), 2.26 (s, 3H), 1.69 (d, J = 11.5 Hz, 2H), 1.59 – 1.48 (m, 2H).

[0968] 13 C NMR (126 MHz, CDCl3) δ 198.7, 150.8, 129.4, 67.3, 37.7, 31.3, 27.0.

[0969] ( E )-4-(thien-2-yl)but-3-en-2-one (178)

[0970] The dark brown, oily title compound was prepared following general step I.

[0971] LCMS (ESI-MS) m / z [M+H] of C8H9OS + Calculated value: 153.03; Measured value: 152.9. Retention time: 3.147 minutes.

[0972] TLC: (20% EtOAc hexane solution, R) f ): 0.34 (UV, 254 nm, 280 nm).

[0973] 1 H NMR (500 MHz, CDCl3) δ 7.63 (d, J= 15.9 Hz, 1H), 7.40 (d, J = 5.2 Hz, 1H), 7.29 (d, J = 3.5 Hz, 1H), 7.07 (dd, J = 5.2, 3.5 Hz, 1H), 6.53 (d, J = 15.9Hz, 1H), 2.34 (s, 3H).

[0974] 13 C NMR (126 MHz, CDCl3) δ 197.7, 139.7, 135.7, 131.5, 128.9, 128.2,125.8, 27.6.

[0975] ( E )-4-(thien-3-yl)but-3-en-2-one (179)

[0976] The title compound was prepared as a grayish-white and slightly brown powder according to general step I.

[0977] LCMS (ESI-MS) m / z [M+H] of C8H9OS + Calculated value: 153.03; Measured value: 152.9. Retention time: 3.289 minutes.

[0978] TLC: (20% EtOAc hexane solution, R) f ): 0.34 (UV, 254 nm, 280 nm).

[0979] 1 H NMR (500 MHz, DMSO- d 6) δ 7.98 (d, J = 2.5 Hz, 1H), 7.67 – 7.59 (m,2H), 7.53 (dd, J = 5.1, 2.5 Hz, 1H), 6.65 (d, J = 16.1 Hz, 1H), 2.31 (s, 3H).

[0980] 13 C NMR (126 MHz, DMSO- d6) δ 198.7, 138.2, 137.5, 130.2, 128.2, 127.3,126.1, 27.6.

[0982] ( E )-4-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)but-3-en-2-one (180)

[0983] The title compound was prepared as a brown powder following general procedure I.

[0984] LCMS (ESI-MS) m / z [M+H] of C7H8NOS + Calculated value: 154.02; Measured value: 153.9. Retention time: 1.074 minutes.

[0985] TLC: (20% EtOAc hexane solution, R) f ): 0.17 (UV, 254 nm, 280 nm).

[0986] 1 H NMR (500 MHz, CDCl3) δ 7.94 (d, J = 3.2 Hz, 1H), 7.64 (d, J = 16.3 Hz, 1H), 7.46 (d, J = 3.2 Hz, 1H), 6.94 (d, J = 16.3 Hz, 1H), 2.40 (s, 3H).

[0987] 13 C NMR (126 MHz, CDCl3) δ 197.6, 163.9, 144.8, 134.3, 130.7, 121.6, 27.8.

[0988] ( E )-4-(thiazolyl-4-yl)but-3-en-2-one (181)

[0989] The title compound was prepared as a brown powder following general procedure I.

[0990] LCMS (ESI-MS) m / z [M+H] of C7H8NOS +Calculated value: 154.02; Measured value: 153.9. Retention time: 1.784 minutes.

[0991] TLC: (33% EtOAc hexane solution, R) f ): 0.23 (UV, 254 nm, 280 nm).

[0992] 1 H NMR (500 MHz, DMSO- d 6) δ 9.20 (s, 1H), 8.14 (s, 1H), 7.66 (d, J =16.2 Hz, 1H), 6.88 (d, J = 16.2 Hz, 1H), 2.34 (s, 3H).

[0993] 13 C NMR (126 MHz, DMSO- d 6) δ 198.7, 156.16, 152.4, 135.8, 128.9, 124.2, 27.8.

[0994] ( E )-4-(thiazolyl-5-yl)but-3-en-2-one (182)

[0995] The title compound was prepared as a yellow-brown powder following general procedure I.

[0996] LCMS (ESI-MS) m / z [M+H] of C7H8NOS + Calculated value: 154.02; Measured value: 153.9. Retention time: 0.828 minutes.

[0997] TLC: (33% EtOAc hexane solution, R) f ): 0.17 (UV, 254 nm, 280 nm).

[0998] 1 H NMR (500 MHz, DMSO- d 6) δ 9.21 (s, 1H), 8.29 (s, 1H), 7.89 (d, J =15.7 Hz, 1H), 6.57 (d, J = 15.7 Hz, 1H), 2.32 (s, 3H).

[0999] 13 C NMR (126 MHz, DMSO- d 6) δ 197.8, 157.3, 147.6, 135.4, 133.1, 129.5, 27.9.

[1000] 5-Cyclopropyl-3-hydroxycyclohexyl-2-en-1-one (194)

[1001] The title compound was prepared as a yellow powder following general steps J and K.

[1002] LCMS (ESI-MS) m / z C9H 13 O2's [M+H] + Calculated value: 153.08; Measured value: 153.0. Retention time: 1.991 minutes.

[1003] TLC: (5% methanol in dichloromethane solution, R) f ): 0.25 (UV, 254 nm, 280 nm).

[1004] 1 H NMR (500 MHz, DMSO- d 6) δ 11.02 (s, 1H), 5.18 (s, 1H), 2.41 – 2.06 (m, 4H), 1.32 – 1.19 (m, 1H), 0.78 – 0.66 (m, 1H), 0.39 (dd, J = 14.7, 5.3 Hz, 2H), 0.13 (dd, J = 12.0, 5.2 Hz, 2H).

[1005] 13 C NMR (126 MHz, DMSO- d 6) δ 104.0, 38.9, 16.2, 3.5.

[1006] 5-Cyclobutyl-3-hydroxycyclohexyl-2-en-1-one (195)

[1007] The title compound was prepared as a white powder following general steps J and K.

[1008] LCMS (ESI-MS) m / z:C 10 H 15 O2's [M+H] + Calculated value: 167.10; Measured value: 167.0. Retention time: 3.183 minutes.

[1009] TLC: (5% methanol in dichloromethane solution, R) f ): 0.25 (UV, 254 nm, 280 nm).

[1010] 1 H NMR (500 MHz, DMSO- d 6) δ 10.97 (s, 1H), 5.18 (s, 1H), 2.28 – 2.11 (m, 3H), 2.01 – 1.86 (m, 5H), 1.86 – 1.76 (m, 1H), 1.75 – 1.57 (m, 3H).

[1011] 13 C NMR (126 MHz, DMSO- d 6) δ 103.9, 40.0, 39.8, 26.1, 17.9.

[1012] 5-Cyclopentyl-3-hydroxycyclohexyl-2-en-1-one (196)

[1013] The title compound was prepared as a white powder following general steps J and K.

[1014] LCMS (ESI-MS) m / z :C 11 H 17 O2's [M+H] + Calculated value: 181.12; Measured value: 181.0. Retention time: 3.501 minutes.

[1015] TLC: (5% methanol in dichloromethane solution, R) f ): 0.25 (UV, 254 nm, 280 nm). TLC: (5% methanol in dichloromethane, R f ): 0.25 (UV, 254 nm, 280 nm).

[1016] 1 H NMR (500 MHz, DMSO- d6) δ 10.98 (s, 1H), 5.18 (s, 1H), 2.44 – 1.96 (m, 4H), 1.83 – 1.39 (m, 8H), 1.21 – 1.00 (m, 2H).

[1017] 13 C NMR (126 MHz, DMSO- d 6) δ 103.9, 45.2, 39.4, 30.3, 25.1.

[1018] 5-Hydroxy-[1,1'-bis(cyclohexane)]-4-en-3-one (197)

[1019] The title compound was prepared as a white powder following general steps J and K.

[1020] LCMS (ESI-MS) m / z :C 12 H 19 O2's [M+H] + Calculated value: 195.13; Measured value: 195.0. Retention time: 3.765 minutes.

[1021] TLC: (5% methanol in dichloromethane solution, R) f ): 0.25 (UV, 254 nm, 280 nm).

[1022] Keto form: 1 H NMR (500 MHz, CD3OD) δ 2.28 (dd, J = 16.9, 4.4 Hz, 2H), 2.08(dd, J = 16.9, 11.9 Hz, 2H), 1.84 – 1.73 (m, 1H), 1.73 – 1.63 (m, 4H), 1.58 (d, J = 12.5 Hz, 1H), 1.24 – 1.04 (m, 4H), 1.00 – 0.84 (m, 2H).

[1023] 13 C NMR (126 MHz, CD3OD) δ 43.0, 40.7, 31.1, 27.6, 27.5.

[1024] Enol form: 1 H NMR (500 MHz, DMSO-d 6) δ 10.98 (s, 1H), 5.18 (s, 1H), 2.22(dd, J = 16.6, 4.4 Hz, 2H), 2.15 – 1.97 (m, 2H), 1.84 – 1.75 (m, 1H), 1.75 –1.65 (m, 4H), 1.61 (d, J = 11.5 Hz, 1H), 1.27 – 1.05 (m, 4H), 1.01 – 0.88 (m, 2H).

[1025] 13 C NMR (126 MHz, DMSO- d 6) δ 103.88, 41.52, 39.13, 29.9, 26.5, 26.4.

[1026] IR (thin film, cm) -1 ): = 2921, 2850, 2534, 1613, 1518, 1475, 1317, 1221,1144, 817, 591, 441.

[1027] 3-Hydroxy-5-(tetrahydrofuran-3-yl)cyclohex-2-en-1-one (198)

[1028] The title compound was prepared as a yellow powder following general steps J and K.

[1029] LCMS (ESI-MS) m / z :C 10 H 15 O3's [M+H] + Calculated value: 183.09; Measured value: 182.9. Retention time: 0.450 minutes.

[1030] TLC: (5% methanol in dichloromethane solution, R) f ): 0.16 (UV, 254 nm, 280 nm).

[1031] 3-Hydroxy-5-(tetrahydro-2H-pyran-4-yl)cyclohex-2-en-1-one (199)

[1032] The title compound was prepared as a grayish-white and slightly yellow powder following general steps J and K.

[1033] LCMS (ESI-MS) m / z :C 11 H 17 O3's [M+H] + Calculated value: 197.11; Measured value: 196.9. Retention time: 0.563 minutes.

[1034] TLC: (5% methanol in dichloromethane solution, R) f ): 0.16 (UV, 254 nm, 280 nm).

[1035] 1 H NMR (500 MHz, DMSO- d 6) δ 11.14 (s, 1H), 5.20 (s, 1H), 3.98 – 3.76 (m, 2H), 3.36 – 3.15 (m, 2H), 2.26 (dd, J = 16.7, 4.4 Hz, 2H), 2.09 (dd, J =16.7, 11.8 Hz, 2H), 1.87 – 1.71 (m, 1H), 1.67 – 1.50 (m, 2H), 1.49 – 1.37 (m,1H), 1.30 – 1.12 (m, 2H).

[1036] 13 C NMR (126 MHz, DMSO- d 6) δ 103.9, 67.5, 39.0, 38.7, 30.1.

[1037] 5-(thien-2-yl)cyclohexane-1,3-dione (200)

[1038] The title compound was prepared as a white solid following general steps J and K.

[1039] LCMS (ESI-MS) m / z :C 10 H 11 O2S's [M+H] + Calculated value: 195.04; Measured value: 194.8. Retention time: 2.921 minutes.

[1040] TLC: (5% methanol in dichloromethane solution, R) f ): 0.19 (UV, 254 nm, 280 nm).

[1041] 1 H NMR (500 MHz, CD3OD) δ 7.27 (dd, J = 3.7, 3.3 Hz, 1H), 7.02 – 6.89(m, 2H), 4.91 (s, 2H), 3.78 – 3.65 (m, 1H), 2.79 – 2.71 (m, 2H), 2.70 – 2.62(m, 2H).

[1042] 13 C NMR (126 MHz, CD3OD) δ 148.0, 127.8, 124.6, 124.5, 36.0.

[1043] IR (thin film, cm) -1 ): = 2526, 1560, 1352, 1305, 1210, 1141, 1100, 865, 832,777, 648, 626, 557, 486, 440.

[1044] 5-(thiophen-3-yl)cyclohexane-1,3-dione (201)

[1045] The title compound was prepared as a white solid following general steps J and K.

[1046] LCMS (ESI-MS) m / z :C 10 H 11 O2S's [M+H] + Calculated value: 195.04; Measured value: 194.9. Retention time: 2.908 minutes.

[1047] TLC: (5% methanol in dichloromethane solution, R) f ): 0.19 (UV, 254 nm, 280 nm).

[1048] 1 H NMR (500 MHz, CD3OD) δ 7.41 – 7.37 (m, 1H), 7.19 (d, J = 2.9 Hz, 1H), 7.11 (d, J= 4.9 Hz, 1H), 4.91 (s, 2H), 3.54 – 3.43 (m, 1H), 2.77 – 2.56 (m, 4H).

[1049] 13 C NMR (126 MHz, CD3OD) δ 145.4, 127.5, 127.0, 121.0, 36.1.

[1050] IR (thin film, cm) -1 ): = 2890, 1566, 1401, 1352, 1302, 1221, 1140, 1103, 832,778, 651, 559, 443.

[1051] 5-(thiazolyl-2-yl)cyclohexane-1,3-dione (202)

[1052] The title compound was prepared as a brown powder following general steps J and K.

[1053] LCMS (ESI-MS) m / z C9H 10 NO2S [M+H] + Calculated value: 196.04; Measured value: 195.8. Retention time: 0.506 minutes.

[1054] TLC: (10% methanol in dichloromethane solution, R) f ): 0.29 (UV, 254 nm, 280 nm).

[1055] 1 H NMR (500 MHz, CD3OD) δ 7.75 (d, J = 3.3 Hz, 1H), 7.52 (d, J = 3.3 Hz, 1H), 4.93 (s, 2H), 3.94 – 3.83 (m, 1H), 2.89 – 2.77 (m, 4H).

[1056] 13 C NMR (126 MHz, CD3OD) δ 173.9, 143.1, 120.2, 38.5.

[1057] IR (thin film, cm) -1 ): = 2942, 1724, 1647, 1602, 1499, 1382, 1220, 1140, 998,872, 731.

[1058] 3-Hydroxy-5-(thiazolyl-4-yl)cyclohex-2-en-1-one (203)

[1059] The light brown powder title compound was prepared following general steps J and K.

[1060] LCMS (ESI-MS) m / z C9H 10 NO2S [M+H] + Calculated value: 196.04; Measured value: 195.9. Retention time: 0.504 minutes.

[1061] TLC: (10% methanol in dichloromethane solution, R) f ): 0.20 (UV, 254 nm, 280 nm).

[1062] 1 H NMR (500 MHz, DMSO- d 6) δ 11.17 (s, 1H), 9.06 (d, J = 1.9 Hz, 1H), 7.43 (d, J = 1.9 Hz, 1H), 5.26 (s, 1H), 3.54 (p, J = 7.6 Hz, 1H), 2.61 (s, 4H).

[1063] 13 C NMR (126 MHz, DMSO- d 6) δ 159.2, 154.4, 114.2, 104.1, 35.4.

[1064] 5-(thiazolyl-5-yl)cyclohexane-1,3-dione (204)

[1065] The dark brown, oily title compound was prepared following general steps J and K.

[1066] LCMS (ESI-MS) m / z C9H 10 NO2S [M+H] +Calculated value: 196.04; Measured value: 195.9. Retention time: 0.438 minutes. C9H 13 [M+H] of N2O2S + Calculated value: 213.07; Measured value: 213.8; Retention time: 0.438 minutes.

[1067] TLC: (10% methanol in dichloromethane solution, R) f ): 0.23 (UV, 254 nm, 280 nm).

[1068] 1 H NMR (500 MHz, CD3OD) δ 8.80 (s, 1H), 7.66 (s, 1H), 4.79 (s, 2H), 3.77 – 3.68 (m, 1H), 2.68 (dd, J = 16.9, 4.8 Hz, 2H), 2.56 (dd, J = 16.9, 10.1Hz, 2H).

[1069] 13 C NMR (126 MHz, CD3OD) δ 154.3, 143.4, 140.4, 33.5.

[1070] IR (thin film, cm) -1 ): = 2899, 1717, 1600, 1405, 1220, 1106, 871, 732, 605.

[1072] 7-Chloro-3-(2,4-dichlorophenyl)-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone(1)

[1073] The title compound was prepared as a white solid following general procedure L.

[1074] TLC: (5% methanol in dichloromethane solution, R) f ): 0.38 (UV, 254 nm, 280 nm).

[1075] 1 H NMR (500 MHz, CDCl3 and 3 drops TFA- d ) δ 8.50 (d, J= 2.0 Hz, 1H), 8.12 –8.01 (m, 2H), 7.50 (d, J = 2.1 Hz, 1H), 7.34 (dd, J = 8.4, 2.1 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 4.21 – 4.08 (m, 1H), 3.76 – 3.60 (m, 2H), 3.23 (ddd, J = 17.8,4.0, 1.5 Hz, 1H), 3.14 (dd, J = 17.8, 12.6 Hz, 1H).

[1076] 13 C NMR (126 MHz, CDCl3 and 3 drops TFA- d ) δ 202.2, 172.4, 161.0, 139.0,137.9, 136.5, 134.9, 134.8, 134.2, 130.4, 128.2, 127.6, 124.2, 122.1, 120.2,108.1, 42.5, 34.6, 33.4.

[1077] 7-Chloro-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (2)

[1078] The title compound was prepared as a white powder following general procedure L.

[1079] TLC: (5% methanol in dichloromethane solution, R) f ): 0.42 (UV, 254 nm, 280 nm).

[1080] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.49 (s, 1H), 8.08 (s, 2H), 7.26 –7.17 (m, 4H), 7.14 – 6.93 (m, 4H), 3.83 – 3.55 (m, 3H), 3.29 – 3.11 (m, 2H).

[1081] 13C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 202.8, 172.4, 161.4, 157.0,155.1, 144.9 (q, J C–F = 2.0 Hz), 139.0, 138.0, 136.5, 134.2, 128.0, 124.2,122.7, 122.3, 120.8 (q, J C–F = 256.8 Hz), 120.3, 120.1, 119.5, 108.3, 44.2, 37.7, 35.5.

[1082] 19 F NMR (471 MHz, CDCl3 and 3 drops of TFA-) d ) δ -59.09.

[1083] 7-Fluoro-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (3)

[1084] The title compound was prepared as a white powder following general procedure L.

[1085] TLC: (5% methanol in dichloromethane solution, R) f ): 0.42 (UV, 254 nm, 280 nm).

[1086] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.18 – 8.10 (m, 2H), 7.94 – 7.87(m, 1H), 7.26 – 7.18 (m, 4H), 7.07 – 7.00 (m, 4H), 3.78 – 3.67 (m, 2H), 3.62(dd, J = 18.3, 12.1 Hz, 1H), 3.30 – 3.12 (m, 2H).

[1087] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 202.9, 172.8 (d, J C–F= 4.2 Hz),162.9, 160.9, 160.8 (d, J C–F = 1.9 Hz), 156.1 (d, J C–F = 251.4 Hz), 145.0 (q, J C–F =2.4 Hz), 136.3, 134.2, 128.2 (d, J C–F = 25.9 Hz), 128.0, 123.4 (d, J C–F = 9.0 Hz), 122.8, 120.9 (d, J C–F = 9.6 Hz), 120.2, 119.9 (q, J = 264.5 Hz), 119.57, 119.53,109.9 (d, J C–F = 24.4 Hz), 108.0, 44.2, 37.7, 35.4.

[1088] 19 F NMR (471 MHz, CDCl3 and 3 drops of TFA-) d ) δ -59.08, -105.31.

[1089] 6-Methoxy-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (4)

[1090] The title compound was prepared as a white powder following general procedure L.

[1091] TLC: (5% methanol in dichloromethane solution, R) f ): 0.42 (UV, 254 nm, 280 nm).

[1092] 1 H NMR (500 MHz, DMSO- d 6) δ 12.68 (s, 1H), 8.03 (d, J = 8.9 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.39 (d,J = 8.4 Hz, 2H), 7.15 – 7.04 (m, 5H), 6.99(dd, J = 8.9, 2.4 Hz, 1H), 3.86 (s, 3H), 3.57 – 3.46 (m, 1H), 3.33 – 3.28 (m,1H), 3.19 (d, J = 16.2 Hz, 1H), 2.87 – 2.74 (m, 1H), 2.57 (d, J = 16.2 Hz, 1H).

[1093] 4-(4-(trifluoromethoxyphenoxy)benzaldehyde (6)

[1094] The title compound, a pale yellow, viscous, oily substance, was prepared according to general step D.

[1095] LCMS (ESI-MS) m / z :C 14 H 10 F3O3 [M+H] + Calculated value: 283.05; Measured value: 282.8. Retention time: 4.718 minutes.

[1096] TLC: (10% EtOAc hexane solution, R) f ): 0.30 (UV, 254 nm, 280 nm).

[1097] 1 H NMR (500 MHz, CDCl3) δ 9.94 (s, 1H), 7.87 (d, J = 8.7 Hz, 2H), 7.26(d, J = 8.2 Hz, 2H), 7.13 – 7.06 (m, 4H).

[1098] 13 C NMR (126 MHz, CDCl3) δ 190.6, 162.6, 153.6, 145.7 (q, J C–F = 1.9 Hz),132.0, 131.7, 122.9, 121.3, 120.4 (q, J C–F = 257.2 Hz), 117.8.

[1099] 19 F NMR (471 MHz, CDCl3) δ -58.21.

[1100] ( E )-4-(4-(4-(trifluoromethoxy)phenoxy)phenyl)but-3-en-2-one (7)

[1101] The title compound was prepared as a white powder following general procedure I.

[1102] LCMS (ESI-MS) m / z :C 17 H 14 F3O3 [M+H] + Calculated value: 323.08; Measured value: 323.1. Retention time: 4.083 minutes.

[1103] TLC: (20% EtOAc hexane solution, R) f ): 0.40 (UV, 254 nm, 280 nm).

[1104] 1 H NMR (500 MHz, DMSO- d 6) δ 7.76 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 16.5Hz, 1H), 7.42 (d, J = 8.9 Hz, 2H), 7.19 (d, J = 8.9 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 6.74 (d, J = 16.5 Hz, 1H), 2.32 (s, 3H).

[1105] 13 C NMR (126 MHz, CDCl3) δ 198.2, 159.1, 154.6, 145.1 (d, J C–F = 2.0 Hz),142.4, 130.0, 129.7, 126.3, 122.7, 120.5, 120.4 (q, J C–F = 256.9 Hz), 118.7, 27.5.

[1106] 19 F NMR (471 MHz, CDCl3) δ -58.23.

[1107] 5-Hydroxy-4'-(4-(trifluoromethoxy)phenoxy)-1,6-dihydro-[1,1'-biphenyl]-3(2 H )-Ketone (9)

[1108] The title compound was prepared as a grayish-white powder following general steps J and K.

[1109] LCMS (ESI-MS) m / z :C 19 H 16 [M+H] of F3O4 + Calculated value: 365.09; Measured value: 364.8. Retention time: 4.418 minutes.

[1110] TLC: (2% methanol in dichloromethane, R) f ): 0.23 (UV, 254 nm, 280 nm).

[1111] 1 H NMR (500 MHz, DMSO- d 6) δ 11.19 (s, 1H), 7.39 (dd, J = 9.2, 7.5 Hz,4H), 7.13 – 7.06 (m, 2H), 7.05 – 6.97 (m, 2H), 5.30 (s, 1H), 3.44 – 3.25 (m,1H), 2.81 – 2.52 (m, 2H), 2.49 – 2.11 (m, 2H).

[1112] 13 C NMR (126 MHz, DMSO- d 6) δ 156.3, 155.1, 144.0 (q, J C–F = 2.0 Hz),139.8, 129.1, 123.4, 120.6 (q, J C–F = 257.5 Hz), 120.0, 119.5, 104.0, 38.5.

[1113] 19 F NMR (471 MHz, DMSO- d6) δ -57.21.

[1114] IR (thin film, cm) -1 ): = 2896, 1596, 1498, 1240, 1189, 1013, 835, 515.

[1115] 6-Chloro-2 H -benzo[ d [1,3]Oxazine-2,4(1 H )-Diketone (13)

[1116] The title compound was prepared as a white powder following general procedure A.

[1117] LCMS (ESI-MS) m / z [M+H] of C8H5ClNO3 + Calculated value: 197.99; Measured value: 197.8. Retention time: 2.921 minutes.

[1118] TLC: (50% EtOAc hexane solution, R) f ): 0.34 (UV, 254 nm, 280 nm).

[1119] 1 H NMR (500 MHz, DMSO- d 6) δ 11.86 (s, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7.78 (dd, J = 8.8, 2.4 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H).

[1120] 13 C NMR (126 MHz, DMSO- d 6) δ 158.9, 146.7, 140.3, 136.6, 127.6, 127.1,117.4, 112.0.

[1121] 6-Fluoro-2 H -benzo[ d [1,3]Oxazine-2,4(1 H )-Diketone (14)

[1122] The title compound was prepared as a white powder following general procedure A.

[1123] LCMS (ESI-MS) m / z [M+H] of C8H5FNO3 + Calculated value: 182.02; Measured value: 181.8. Retention time: 1.194 minutes.

[1124] TLC: (50% EtOAc hexane solution, R) f ): 0.35 (UV, 254 nm, 280 nm).

[1125] 1 H NMR (500 MHz, DMSO- d 6) δ 11.80 (s, 1H), 7.74 – 7.60 (m, 2H), 7.19(dd, J = 9.2, 4.6 Hz, 1H).

[1126] 13 C NMR (126 MHz, DMSO- d 6) δ 159.6 (d, J C–F = 3.3 Hz), 157.9 (d, J C–F =241.3 Hz), 147.2, 138.6 (d, J C–F = 1.5 Hz), 125.2 (d, J C–F = 24.5 Hz), 118.0 (d, J C–F = 8.4 Hz), 114.4 (d, J C–F = 24.3 Hz), 111.9 (d, J C–F = 24.4 Hz).

[1127] 19 F NMR (471 MHz, DMSO- d 6) δ -118.76 – -118.85 (m).

[1128] 7-Methoxy-2 H -benzo[ d [1,3]Oxazine-2,4(1 H )-Diketone (15)

[1129] The title compound was prepared as a grayish-white, slightly yellowish-brown powder according to general step A.

[1130] LCMS (ESI-MS) m / z [M+H] of C9H8NO4 + Calculated value: 194.04; Measured value: 193.9. Retention time: 1.581 minutes.

[1131] TLC: (50% EtOAc hexane solution, R) f ): 0.24 (UV, 254 nm, 280 nm).

[1132] 1 H NMR (500 MHz, DMSO- d 6) δ 11.64 (s, 1H), 7.82 (d, J = 8.9 Hz, 1H), 6.82 (dd, J = 8.9, 2.4 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 3.85 (s, 3H).

[1133] 13 C NMR (126 MHz, DMSO- d 6) δ 165.8, 159.2, 147.4, 143.6, 131.0, 111.6,102.8, 98.5, 55.9.

[1134] 7-Chloro-3-(5-(4-(trifluoromethoxy)phenoxy)thiophen-2-yl)-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (16)

[1135] The title compound was prepared as a yellow powder following general procedure L.

[1136] TLC: (5% methanol in dichloromethane solution, R) f ): 0.32 (UV, 254 nm, 280 nm).

[1137] 1 H NMR (500 MHz, DMSO- d6) δ 12.28 (s, 1H), 8.03 (d, J = 2.5 Hz, 1H),7.73 (dd, J = 8.7, 2.5 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.41 (d, J = 9.1 Hz, 2H),7.21 (d, J = 9.1 Hz, 2H), 6.78 (d, J = 3.8 Hz, 1H), 6.62 (d, J = 3.8 Hz, 1H), 3.78– 3.68 (m, 1H), 3.30 – 3.20 (m, 2H), 2.81 – 2.67 (m, 2H).

[1138] 1 H NMR (500 MHz, CDCl3 and 3 drops of TFA- d ) δ 8.46 (d, J = 2.3 Hz, 1H), 8.16 (d, J =8.9 Hz, 1H), 8.06 (dd, J = 9.1, 2.3 Hz, 1H), 7.19 (d, J = 8.8 Hz, 2H), 7.12 –7.03 (m, 2H), 6.68 (d, J = 3.8 Hz, 1H), 6.43 – 6.38 (m, 1H), 3.98 – 3.87 (m,2H), 3.68 (dd, J = 18.0, 9.5 Hz, 1H), 3.33 (dd, J = 18.0, 3.8 Hz, 1H), 3.16 (dd, J = 18.0, 9.5 Hz, 1H).

[1139] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA- d ) δ 202.0, 172.0, 160.5, 159.0,156.8, 145.0 (q, J C–F= 2.3 Hz), 138.68, 138.62, 136.1, 133.9, 124.0, 122.9,122.6, 122.5, 120.4 (q, J C–F = 256.9 Hz), 120.3, 118.1, 113.3, 108.2, 44.4, 35.3, 34.1.

[1140] 19 F NMR (471 MHz, CDCl3 and 3 drops of TFA-) d ) δ -58.98.

[1141] 6-Methoxy-3-(5-(4-(trifluoromethoxy)phenoxy)thiophene-2-yl)-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (17)

[1142] The title compound was prepared as a light brown powder following general procedure L.

[1143] TLC: (5% methanol in dichloromethane solution, R) f ): 0.27 (UV, 254 nm, 280 nm).

[1144] 1 H NMR (500 MHz, DMSO- d 6) δ 11.92 (s, 1H), 8.01 (d, J = 8.9 Hz, 1H),7.44 – 7.37 (m, 2H), 7.24 – 7.17 (m, 2H), 6.97 (dd, J = 8.9, 2.3 Hz, 1H), 6.90(s, 1H), 6.77 (dd, J = 3.8, 1.1 Hz, 1H), 6.62 (d, J = 3.8 Hz, 1H), 3.86 (s, 3H), 3.77 – 3.67 (m, 1H), 3.30 – 3.17 (m, 2H), 2.79 – 2.64 (m, 2H).

[1145] 7-Chloro-3-(5-(3-(trifluoromethoxy)phenoxy)thiophene-2-yl)-3,4-dihydroacridine-1,9(2) H 10 H)-Diketone (18)

[1146] The title compound was prepared as a white powder following general procedure L.

[1147] TLC: (5% methanol in dichloromethane solution, R) f ): 0.32 (UV, 254 nm, 280 nm).

[1148] 1 H NMR (500 MHz, DMSO- d 6) δ 12.25 (s, 1H), 8.02 (d, J = 2.5 Hz, 1H), 7.73 (dd, J = 9.0, 2.5 Hz, 1H), 7.59 – 7.49 (m, 2H), 7.19 – 7.11 (m, 2H), 7.09(s, 1H), 6.79 (d, J = 3.8 Hz, 1H), 6.66 (d, J = 3.8 Hz, 1H), 3.80 – 3.70 (m, 1H), 3.31 – 3.21 (m, 2H), 2.82 – 2.67 (m, 2H).

[1149] 6-Methoxy-3-(5-(3-(trifluoromethoxy)phenoxy)thiophene-2-yl)-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (19)

[1150] The title compound was prepared as a yellow powder following general procedure L.

[1151] TLC: (5% methanol in dichloromethane solution, R) f ): 0.27 (UV, 254 nm, 280 nm).

[1152] 1 H NMR (500 MHz, DMSO- d 6) δ 11.94 (s, 1H), 8.01 (d, J = 9.1 Hz, 1H), 7.53 (dd, J= 8.8, 8.2 Hz, 1H), 7.19 – 7.11 (m, 2H), 7.09 (s, 1H), 6.97 (d, J =9.1 Hz, 1H), 6.90 (s, 1H), 6.79 (d, J = 3.8 Hz, 1H), 6.65 (d, J = 3.8 Hz, 1H), 3.86 (s, 3H), 3.78 – 3.69 (m, 1H), 3.31 – 3.17 (m, 2H), 2.79 – 2.64 (m, 2H).

[1153] 7-Chloro-3-(6-(4-(trifluoromethoxy)phenoxy)pyridin-3-yl)-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (20)

[1154] The title compound was prepared as a yellow powder following general procedure L.

[1155] TLC: (5% methanol in dichloromethane solution, R) f ): 0.33 (UV, 254 nm, 280 nm).

[1156] 1 H NMR (500 MHz, DMSO- d 6) δ 12.27 (s, 1H), 8.16 (s, 1H), 8.03 (s, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.42(d, J = 7.9 Hz, 2H), 7.27 (d, J = 7.9 Hz, 2H), 7.12 (d, J = 8.6 Hz, 1H), 3.62 –3.50 (m, 1H), 3.42 – 3.37 (m, 1H), 3.10 (d, J = 16.3 Hz, 1H), 2.86 – 2.74 (m,1H), 2.59 (d, J = 16.3 Hz, 1H).

[1157] 6-Methoxy-3-(6-(4-(trifluoromethoxy)phenoxy)pyridin-3-yl)-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (21)

[1158] The title compound was prepared as a yellow powder following general procedure L.

[1159] TLC: (5% methanol in dichloromethane solution, R) f ): 0.32 (UV, 254 nm, 280 nm).

[1160] 1 H NMR (500 MHz, DMSO- d 6) δ 11.93 (s, 1H), 8.16 (s, 1H), 8.02 (d, J =9.0 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.42 (d, J = 8.5 Hz, 2H), 7.27 (d, J = 8.4Hz, 2H), 7.11 (d, J = 8.2 Hz, 1H), 6.97 (d, J = 9.0 Hz, 1H), 6.92 (s, 1H), 3.86 (s, 3H), 3.58 – 3.49 (m, 1H), 3.06 (d, J = 16.4 Hz, 1H), 2.82 – 2.72 (m, 1H), 2.56 (d, J = 16.4 Hz, 1H).

[1161] 7-Chloro-3-(6-(3-(trifluoromethoxy)phenoxy)pyridin-3-yl)-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (22)

[1162] The title compound was prepared as a white powder following general procedure L.

[1163] TLC: (5% methanol in dichloromethane solution, R) f ): 0.33 (UV, 254 nm, 280 nm).

[1164] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.73 (s, 1H), 8.52 (d, J = 2.2 Hz, 1H), 8.42 (d, J = 8.8 Hz, 1H), 8.09 (dd, J = 9.1, 2.2 Hz, 1H), 8.02 (d, J = 9.1 Hz, 1H), 7.61 (dd, J = 9.1, 8.3 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.23 – 7.10 (m,3H), 4.07 – 3.90 (m, 1H), 3.90 – 3.65 (m, 2H), 3.40 – 3.18 (m, 2H).

[1165] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 200.7, 172.6, 160.0, 159.3,151.4, 150.8 (q, J C–F = 2.2 Hz), 148.3, 139.2, 138.9, 137.9, 136.8, 133.2,132.3, 124.4, 122.0, 120.7, 120.3, 120.2 (q, J C–F = 259.2 Hz), 118.8, 113.8,112.7, 108.1, 34.9, 34.8, 34.0.

[1166] 19 F NMR (471 MHz, CDCl3 and 3 drops of TFA-) d ) δ -58.98.

[1167] 6-Methoxy-3-(6-(3-(trifluoromethoxy)phenoxy)pyridin-3-yl)-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (23)

[1168] The title compound was prepared as a white powder following general procedure L.

[1169] TLC: (5% methanol in dichloromethane solution, R) f ): 0.33 (UV, 254 nm, 280 nm).

[1170] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 8.74 (d, J = 2.4 Hz, 1H), 8.43 –8.34 (m, 2H), 7.59 (dd, J = 9.1, 8.3 Hz, 1H), 7.41 (dd, J = 9.3, 2.3 Hz, 1H),7.36 – 7.29 (m, 2H), 7.18 (dd, J = 8.2, 2.1 Hz, 1H), 7.15 – 7.08 (m, 2H), 4.03(s, 3H), 3.98 – 3.88 (m, 1H), 3.81 (dd, J = 17.4, 3.1 Hz, 1H), 3.67 (dd, J =17.4, 12.1 Hz, 1H), 3.30 – 3.13 (m, 2H).

[1171] 19 F NMR (471 MHz, CDCl3 and 3 drops of TFA-) d ) δ -58.83.

[1172] 5-(4-(trifluoromethoxy)phenoxy)thiophene-2-carboxaldehyde (26)

[1173] The title compound, a brown solid, was prepared following general procedure D.

[1174] LCMS (ESI-MS) m / z :C 12 [M+H] of H8F3O3S + Calculated value: 289.01; Measured value: 288.8. Retention time: 3.774 minutes.

[1175] TLC: (7% EtOAc hexane solution, R) f ): 0.18 (UV, 254 nm, 280 nm).

[1176] 1 H NMR (500 MHz, CDCl3) δ 9.73 (s, 1H), 7.55 (d, J = 4.3 Hz, 1H), 7.29 –7.24 (m, 2H), 7.24 – 7.18 (m, 2H), 6.54 (d, J = 4.3 Hz, 1H).

[1177] 13 C NMR (126 MHz, CDCl3) δ 182.7, 171.2, 155.1, 146.3 (q, J C–F = 1.9 Hz),136.5, 133.4, 122.9, 120.4 (q, J C–F = 257.5 Hz), 120.3, 112.1.

[1178] 19 F NMR (471 MHz, CDCl3) δ -58.21.

[1179] 5-(3-(trifluoromethoxy)phenoxy)thiophene-2-carboxaldehyde (27)

[1180] The brown, oily title compound was prepared following general step D.

[1181] LCMS (ESI-MS) m / z :C 12 [M+H] of H8F3O3S + Calculated value: 289.01; Measured value: 288.8. Retention time: 3.771 minutes.

[1182] TLC: (7% EtOAc hexane solution, R) f ): 0.21 (UV, 254 nm, 280 nm).

[1183] 1 H NMR (500 MHz, CDCl3) δ 9.76 (s, 1H), 7.58 (d, J = 4.2 Hz, 1H), 7.45 (dd, J = 9.0, 8.3 Hz, 1H), 7.17 – 7.09 (m, 2H), 7.07 (s, 1H), 6.60 (d,J = 4.2Hz, 1H).

[1184] 13 C NMR (126 MHz, CDCl3) δ 182.7, 170.2, 157.6, 150.1 (q, J = 2.0 Hz),136.4, 133.8, 131.0, 120.3 (q, J = 258.3 Hz), 117.6, 116.9, 112.8, 111.9.

[1185] 19 F NMR (471 MHz, CDCl3) δ -57.95.

[1186] 6-(4-(trifluoromethoxy)phenoxy)nicotinamide (28)

[1187] The title compound was prepared as a pale yellow powder following general procedure D.

[1188] LCMS (ESI-MS) m / z :C 13 H9F3NO3's [M+H] + Calculated value: 284.05; Measured value: 283.8. Retention time: 4.384 minutes.

[1189] TLC: (10% EtOAc hexane solution, R) f ): 0.13 (UV, 254 nm, 280 nm).

[1190] 1 H NMR (500 MHz, CDCl3) δ 10.0 (s, 1H), 8.6 (d, J = 2.4 Hz, 1H), 8.2(dd, J = 8.8, 2.4 Hz, 1H), 7.3 (d, J = 9.1 Hz, 2H), 7.2 (d, J = 9.1 Hz, 2H), 7.1(d, J = 8.8 Hz, 1H).

[1191] 19 F NMR (471 MHz, CDCl3) δ -58.06.

[1192] 6-(3-(trifluoromethoxy)phenoxy)nicotinamide (29)

[1193] The title compound was prepared as a pale yellow powder following general procedure D.

[1194] LCMS (ESI-MS) m / z :C 13 H9F3NO3's [M+H] + Calculated value: 284.05; Measured value: 283.8. Retention time: 4.391 minutes.

[1195] TLC: (10% EtOAc hexane solution, R) f ): 0.13 (UV, 254 nm, 280 nm).

[1196] 1 H NMR (500 MHz, CDCl3) δ 10.02 (s, 1H), 8.65 (d, J = 2.3 Hz, 1H), 8.24(dd, J = 8.9, 2.3 Hz, 1H), 7.48 (dd, J = 9.3, 8.2 Hz, 1H), 7.19 – 7.08 (m, 4H).

[1197] 13 C NMR (126 MHz, CDCl3) δ 189.1, 166.4, 153.8, 152.4, 149.9 (d, J C–F =1.8 Hz), 139.0, 130.5, 128.2, 120.4 (q, J C–F = 257.9 Hz), 120.0, 117.8, 114.8,112.4.

[1198] 19 F NMR (471 MHz, CDCl3) δ -57.89.

[1199] ( E )-4-(5-(4-(trifluoromethoxy)phenoxy)thiophen-2-yl)but-3-en-2-one (30)

[1200] The dark brown, oily title compound was prepared following general procedure H.

[1201] LCMS (ESI-MS) m / z :C 15 H 12 F3O3S [M+H] + Calculated value: 329.04; Measured value: 328.9. Retention time: 4.018 minutes.

[1202] TLC: (25% EtOAc hexane solution, R) f ): 0.26 (UV, 254 nm, 280 nm).

[1203] 1 H NMR (500 MHz, CDCl3) δ 7.51 (d, J = 15.7 Hz, 1H), 7.25 – 7.19 (m,2H), 7.19 – 7.12 (m, 2H), 7.04 (d, J = 4.0 Hz, 1H), 6.47 (d, J = 4.0 Hz, 1H), 6.32 (d, J = 15.7 Hz, 1H), 2.31 (s, 3H).

[1204] 13 C NMR (126 MHz, CDCl3) δ 197.3, 163.3, 156.1, 145.5 (q, J C–F = 2.2 Hz),136.3, 130.8, 130.6, 124.0, 122.7, 120.4 (q, J C–F = 257.3 Hz), 119.0, 113.5, 27.8.

[1205] 19 F NMR (471 MHz, CDCl3) δ -58.24.

[1206] ( E )-4-(5-(3-(trifluoromethoxy)phenoxy)thiophen-2-yl)but-3-en-2-one (31)

[1207] The dark brown, oily title compound was prepared following general procedure H.

[1208] LCMS (ESI-MS)m / z :C 15 H 12 F3O3S [M+H] + Calculated value: 329.08; Measured value: 328.9. Retention time: 3.968 minutes.

[1209] TLC: (25% EtOAc hexane solution, R) f ): 0.24 (UV, 254 nm, 280 nm).

[1210] 1 H NMR (399 MHz, CDCl3) δ 7.52 (d, J = 15.8 Hz, 1H), 7.38 (t, J = 8.3 Hz,1H), 7.10 – 6.98 (m, 4H), 6.51 (d, J = 4.0 Hz, 1H), 6.34 (d, J = 15.8 Hz, 1H), 2.32 (s, 3H).

[1211] 13 C NMR (126 MHz, CDCl3) δ 197.3, 162.3, 158.6, 150.0 (q, J C–F = 2.1 Hz), 136.2, 131.1, 130.8 – 130.6 (m), 124.2, 120.3 (q, J C–F = 258.1 Hz), 116.6, 115.8, 114.2, 110.8, 27.7, 27.6.

[1212] 19 F NMR (471 MHz, CDCl3) δ -57.92.

[1213] ( E )-4-(6-(4-(trifluoromethoxy)phenoxy)pyridin-3-yl)but-3-en-2-one (32)

[1214] The title compound was prepared as a white powder following general procedure I.

[1215] LCMS (ESI-MS) m / z :C 16H 13 F3NO3 [M+H] + Calculated value: 324.08; Measured value: 323.8. Retention time: 4.520 minutes.

[1216] TLC: (20% EtOAc hexane solution, R) f ): 0.22 (UV, 254 nm, 280 nm).

[1217] 1 H NMR (500 MHz, CDCl3) δ 8.30 (d, J = 2.5 Hz, 1H), 7.92 (dd, J = 8.6, 2.5Hz, 1H), 7.46 (d, J = 16.3 Hz, 1H), 7.27 (d, J = 8.8 Hz, 2H), 7.21 – 7.15 (m,2H), 7.00 (d, J = 8.6 Hz, 1H), 6.67 (d, J = 16.3 Hz, 1H), 2.39 (s, 3H).

[1218] 13 C NMR (126 MHz, CDCl3) δ 197.7, 164.4, 151.7, 148.6, 145.9 (q, J C–F =1.7 Hz), 138.8, 137.6, 127.1, 125.8, 122.6, 122.4, 120.4 (q, J C–F = 257.2 Hz), 112.1, 27.6.

[1219] 19 F NMR (471 MHz, CDCl3) δ -58.07.

[1220] ( E )-4-(6-(3-(trifluoromethoxy)phenoxy)pyridin-3-yl)but-3-en-2-one (33)

[1221] The title compound was prepared as a grayish-white powder following general procedure I.

[1222] LCMS (ESI-MS) m / z :C 16 H 13 F3NO3 [M+H] + Calculated value: 324.08; Measured value: 323.8. Retention time: 3.685 minutes.

[1223] TLC: (20% EtOAc hexane solution, R) f ): 0.22 (UV, 254 nm, 280 nm).

[1224] 1 H NMR (500 MHz, CDCl3) δ 8.31 (d, J = 2.4 Hz, 1H), 7.93 (dd, J = 8.6, 2.4Hz, 1H), 7.50 – 7.40 (m, 2H), 7.15 – 7.08 (m, 2H), 7.06 (s, 1H), 7.00 (d, J =8.6 Hz, 1H), 6.68 (d, J = 16.2 Hz, 1H), 2.39 (s, 3H).

[1225] 13 C NMR (126 MHz, CDCl3) δ 197.7, 164.1, 154.3, 149.9 (q, J C–F = 1.9 Hz),148.6, 138.8, 137.7, 130.4, 127.3, 126.0, 121.4 (q, J C–F = 257.3 Hz), 119.6, 117.3, 114.5, 112.2, 27.7.

[1226] 19 F NMR (471 MHz, CDCl3) δ -57.83.

[1227] 3-Hydroxy-5-(5-(4-(trifluoromethoxy)phenoxy)thiophen-2-yl)cyclohex-2-en-1-one (38)

[1228] The title compound was prepared as a white powder following general steps J and K.

[1229] LCMS (ESI-MS) m / z :C17 H 14 [M+H] of F3O4S + Calculated value: 371.05; Measured value: 370.7. Retention time: 3.556 minutes.

[1230] TLC: (5% methanol in dichloromethane solution, R) f ): 0.20 (UV, 254 nm, 280 nm).

[1231] 1 H NMR (500 MHz, DMSO- d 6) δ 11.25 (s, 1H), 7.44 – 7.37 (m, 2H), 7.24 –7.17 (m, 2H), 6.74 (dd, J = 3.8, 1.0 Hz, 1H), 6.59 (d, J = 3.8 Hz, 1H), 5.28 (s,1H), 3.59 – 3.50 (m, 1H), 2.63 – 2.47 (m, 4H).

[1232] 13 C NMR (126 MHz, DMSO- d 6) δ 157.6, 156.6, 144.3 (q, J C–F = 2.0 Hz),139.4, 123.4, 121.6, 121.5, 120.2 (q, J C–F = 255 Hz), 118.5, 114.4, 104.2, 34.8.

[1233] 19 F NMR (471 MHz, DMSO- d 6) δ -57.24.

[1234] 3-Hydroxy-5-(5-(3-(trifluoromethoxy)phenoxy)thiophen-2-yl)cyclohex-2-en-1-one (39)

[1235] The title compound was prepared as a white powder following general steps J and K.

[1236] LCMS (ESI-MS) m / z :C 17 H 14[M+H] of F3O4S + Calculated value: 371.05; Measured value: 370.9. Retention time: 3.527 minutes.

[1237] TLC: (5% methanol in dichloromethane solution, R) f ): 0.20 (UV, 254 nm, 280 nm).

[1238] 1 H NMR (500 MHz, DMSO- d 6) δ 11.26 (s, 1H), 7.52 (dd, J = 8.6, 7.9 Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H), 7.12 (dd, J = 8.6, 2.4 Hz, 1H), 7.09 (s, 1H), 6.76(d, J = 3.8 Hz, 1H), 6.63 (d, J = 3.8 Hz, 1H), 5.27 (s, 1H), 3.60 – 3.50 (m, 1H), 2.77 – 2.51 (m, 4H).

[1239] 13 C NMR (126 MHz, DMSO- d 6) δ 159.8, 155.9, 149.6 (q, J C–F = 2.0 Hz),139.8, 132.0, 121.7, 120.4 (q, J C–F = 256.9 Hz), 116.3, 115.8, 114.8, 110.1,104.2, 34.8.

[1240] 19 F NMR (471 MHz, DMSO- d 6) δ -56.90.

[1241] 3-Hydroxy-5-(6-(4-(trifluoromethoxy)phenoxy)pyridin-3-yl)cyclohex-2-en-1-one (40)

[1242] The yellow, oily title compound was prepared following general steps J and K.

[1243] LCMS (ESI-MS) m / z :C 18 H 15 F3NO4's [M+H] + Calculated value: 366.09; Measured value: 365.7. Retention time: 4.076 minutes. C 18 H 13 [M+H] of F3N O4 + Calculated value: 364.09; Measured value: 364.0. Retention time: 3.233.

[1244] TLC: (5% methanol in dichloromethane solution, R) f ): 0.22 (UV, 254 nm, 280 nm).

[1245] 1 H NMR (500 MHz, DMSO- d 6) δ 11.24 (s, 1H), 8.12 (d, J = 2.5 Hz, 1H), 7.91 (dd, J = 8.5, 2.5 Hz, 1H), 7.41 (d, J = 8.5 Hz, 2H), 7.29 – 7.22 (m, 2H), 7.07 (d, J = 8.5 Hz, 1H), 5.30 (s, 1H), 3.40 – 3.30 (m, 1H), 2.66 – 2.57 (m, 2H), 2.44 – 2.36 (m, 2H).

[1246] 13 C NMR (126 MHz, DMSO- d 6) δ 162.0, 153.2, 146.3, 145.0 (q, J C–F = 1.8Hz), 139.5, 134.9, 123.3, 122.9, 120.5 (q, J C–F = 255.8 Hz), 111.8, 104.0, 36.0.

[1247] 19 F NMR (471 MHz, DMSO- d 6) δ -57.08.

[1248] 3-Hydroxy-5-(6-(3-(trifluoromethoxy)phenoxy)pyridin-3-yl)cyclohex-2-en-1-one (41)

[1249] The yellow, oily title compound was prepared following general steps J and K.

[1250] LCMS (ESI-MS) m / z :C 18 H 15 F3NO4's [M+H] + Calculated value: 366.09; Measured value: 365.7. Retention time: 4.080 minutes.

[1251] TLC: (5% methanol in dichloromethane solution, R) f ): 0.16 (UV, 254 nm, 280 nm).

[1252] Keto form: 1 H NMR (500 MHz, CD3OD) δ 8.15 (d, J = 2.5 Hz, 1H), 7.91 (dd, J =8.5, 2.5 Hz, 1H), 7.50 (dd, J = 9.1, 8.2 Hz, 1H), 7.18 – 7.08 (m, 2H), 7.07 (s,1H), 7.04 (d, J = 8.5 Hz, 1H), 4.89 (s, 2H), 3.52 – 3.42 (m, 1H), 2.72 (dd, J =16.9, 11.7 Hz, 2H), 2.60 (dd, J = 17.0, 4.7 Hz, 2H).

[1253] Enol form: 13 C NMR (126 MHz, DMSO- d 6) δ 161.7, 155.4, 149.3 (q, J C–F = 1.9Hz), 146.4, 139.5, 135.1, 131.4, 120.7, 120.4 (q, J C–F = 256.7 Hz), 117.2, 114.7, 112.0, 104.0, 36.0.

[1254] 19 F NMR (471 MHz, DMSO- d 6) δ -56.83.

[1255] 2-Bromo-5-(1,3-dioxolane-2-yl)thiazole (44)

[1256] Following general step B, a 90% pure, transparent, oily compound is obtained and can be used directly without further purification.

[1257] LCMS (ESI-MS) m / z [M+H] of C6H7BrNO2S + Calculated value: 235.93; Measured value: 236.0. Retention time: 2.440 minutes.

[1258] TLC: (20% EtOAc hexane solution, R) f ): 0.27 (UV, 254 nm, 280 nm).

[1259] 2-Bromo-4-(1,3-dioxolane-2-yl)thiazole (45)

[1260] Following general step B, a 90% pure, transparent, oily compound is obtained and can be used directly without further purification.

[1261] LCMS (ESI-MS) m / z [M+H] of C6H7BrNO2S + Calculated value: 235.93; Measured value: 235.96. Retention time: 2.024 minutes.

[1262] TLC: (20% EtOAc hexane solution, R) f ): 0.27 (UV, 254 nm, 280 nm).

[1263] 5-(1,3-dioxolane-2-yl)-2-(4-(trifluoromethoxy)phenoxy)thiazole (46)

[1264] The title compound was prepared as a white powder following general procedure D.

[1265] LCMS (ESI-MS) m / z :C 13 H11 F3NO4S [M+H] + Calculated value: 334.03; Measured value: 333.7. Retention time: 4.504 minutes.

[1266] TLC: (20% EtOAc hexane solution, R) f ): 0.31 (UV, 254 nm, 280 nm).

[1267] 1 H NMR (500 MHz, CDCl3) δ 7.34 – 7.29 (m, 2H), 7.29 – 7.24 (m, 3H), 5.98 (s, 1H), 4.14 – 4.05 (m, 2H), 4.05 – 3.97 (m, 2H).

[1268] 13 C NMR (126 MHz, CDCl3) δ 173.7, 153.1, 146.5 (q, J C–F = 2.2 Hz), 136.4,130.5, 122.6, 121.6, 120.4 (q, J C–F = 257.5 Hz), 98.9, 65.3.

[1269] 19 F NMR (471 MHz, CDCl3) δ -58.13.

[1270] 5-(1,3-dioxolane-2-yl)-2-(3-(trifluoromethoxy)phenoxy)thiazole (47)

[1271] The yellow, oily title compound was prepared following general procedure D.

[1272] LCMS (ESI-MS) m / z :C 13 H 11 F3NO4S [M+H] + Calculated value: 334.03; Measured value: 333.7. Retention time: 4.527 minutes.

[1273] TLC: (20% EtOAc hexane solution, R) f ): 0.31 (UV, 254 nm, 280 nm).

[1274] 1 H NMR (500 MHz, CDCl3) δ 7.43 (dd, J = 8.3, 7.8 Hz, 1H), 7.29 (s, 1H), 7.24 (ddd, J = 8.3, 2.3, 0.9 Hz, 1H), 7.21 – 7.18 (m, 1H), 7.14 – 7.10 (m, 1H), 5.99 (s, 1H), 4.14 – 4.06 (m, 2H), 4.06 – 3.97 (m, 2H).

[1275] 13 C NMR (126 MHz, CDCl3) δ 173.1, 155.5, 149.8 (q, J C–F = 2.2 Hz), 136.4,130.8, 130.8, 120.3 (q, J C–F = 258.1 Hz), 118.4, 118.0, 113.3, 98.9, 65.3.

[1276] 19 F NMR (471 MHz, CDCl3) δ -57.90.

[1277] 4-(1,3-dioxolane-2-yl)-2-(4-(trifluoromethoxy)phenoxy)thiazole (48)

[1278] The title compound was prepared as a white powder following general procedure D.

[1279] LCMS (ESI-MS) m / z :C 13 H 11 F3NO4S [M+H] + Calculated value: 334.03; Measured value: 334.1. Retention time: 3.78 minutes.

[1280] TLC: (20% EtOAc hexane solution, R) f ): 0.31 (UV, 254 nm, 280 nm).

[1281] 1 H NMR (500 MHz, CDCl3) δ 7.37 – 7.32 (m, 2H), 7.25 (d,J = 8.8 Hz, 2H), 6.96 (s, 1H), 5.84 (s, 1H), 4.17 – 4.09 (m, 2H), 4.05 – 3.97 (m, 2H).

[1282] 13 C NMR (126 MHz, CDCl3) δ 172.8, 153.3, 148.5, 146.3 (q, J C–F = 1.8 Hz),122.5, 121.2, 120.4 (q, J C–F = 257.4 Hz), 111.0, 99.8, 65.3.

[1283] 4-(1,3-dioxolane-2-yl)-2-(3-(trifluoromethoxy)phenoxy)thiazole (49)

[1284] Following general step D, a 90% pure white powder compound is obtained, which can be used directly without further purification.

[1285] LCMS (ESI-MS) m / z :C 13 H 11 F3NO4S [M+H] + Calculated value: 334.03; Measured value: 333.9. Retention time: 3.661 minutes.

[1286] TLC: (20% EtOAc hexane solution, R) f ): 0.31 (UV, 254 nm, 280 nm).

[1287] 2-(4-(trifluoromethoxy)phenoxy)thiazole-5-carboxaldehyde (50)

[1288] The title compound was prepared as a pale yellow powder following general procedure C.

[1289] LCMS (ESI-MS) m / z :C 11 H7F3NO3S's [M+H] + Calculated value: 290.00; Measured value: 289.8. Retention time: 3.526 minutes.

[1290] TLC: (20% EtOAc hexane solution, R) f ): 0.38 (UV, 254 nm, 280 nm).

[1291] 1 H NMR (500 MHz, CDCl3) δ 9.87 (s, 1H), 7.91 (s, 1H), 7.41 – 7.28 (m, 4H).

[1292] 13 C NMR (126 MHz, CDCl3) δ 181.9, 178.9, 152.2, 148.4, 147.2 (q, J C–F =2.0 Hz), 134.3, 122.7, 121.9, 120.3 (q, J C–F = 258.0 Hz).

[1293] 19 F NMR (471 MHz, CDCl3) δ -58.10.

[1294] 2-(3-(trifluoromethoxy)phenoxy)thiazole-5-carboxaldehyde (51)

[1295] The title compound, which is pale yellow and oily, was prepared according to general step C.

[1296] LCMS (ESI-MS) m / z :C 11 H7F3NO3S's [M+H] + Calculated value: 290.00; Measured value: 289.8. Retention time: 3.536 minutes.

[1297] TLC: (20% EtOAc hexane solution, R) f ): 0.41 (UV, 254 nm, 280 nm).

[1298] 1 H NMR (500 MHz, CDCl3) δ 9.87 (s, 1H), 7.92 (s, 1H), 7.50 (dd, J = 8.8, 8.3 Hz, 1H), 7.29 (ddd, J= 8.3, 2.4, 1.0 Hz, 1H), 7.25 – 7.23 (m, 1H), 7.22 –7.18 (m, 1H).

[1299] 13 C NMR (126 MHz, CDCl3) δ 181.9, 178.4, 154.6, 149.9 (q, J C–F = 1.9 Hz),148.3, 134.4, 130.9, 120.3 (q, J C–F = 258.7 Hz), 119.0, 118.8, 113.8.

[1300] 19 F NMR (471 MHz, CDCl3) δ -57.95, -58.46.

[1301] 2-(4-(trifluoromethoxy)phenoxy)thiazole-4-carboxaldehyde (52)

[1302] The title compound was prepared as a white powder following general procedure C.

[1303] LCMS (ESI-MS) m / z :C 11 H7F3NO3S's [M+H] + Calculated value: 290.00; Measured value: 289.7. Retention time: 4.254 minutes.

[1304] TLC: (20% EtOAc hexane solution, R) f ): 0.35 (UV, 254 nm, 280 nm).

[1305] 1 H NMR (500 MHz, CDCl3) δ 9.81 (s, 1H), 7.78 (s, 1H), 7.45 – 7.38 (m,2H), 7.31 (d, J = 8.7 Hz, 2H).

[1306] 13 C NMR (126 MHz, CDCl3) δ 183.8, 172.6, 152.7, 149.3, 146.6 (q, J C–F=2.2 Hz), 122.7, 122.6, 121.4, 120.4 (q, J C–F = 257.8 Hz).

[1307] 19 F NMR (471 MHz, CDCl3) δ -58.13.

[1308] 2-(3-(trifluoromethoxy)phenoxy)thiazole-4-carboxaldehyde (53)

[1309] The title compound was prepared as a white powder following general procedure C.

[1310] LCMS (ESI-MS) m / z :C 11 H7F3NO3S's [M+H] + Calculated value: 290.00; Measured value: 289.4. Dwell time: 4.268 minutes.

[1311] TLC: (20% EtOAc hexane solution, R) f ): 0.35 (UV, 254 nm, 280 nm).

[1312] 1 H NMR (500 MHz, CDCl3) δ 9.80 (s, 1H), 7.78 (s, 1H), 7.46 (dd, J = 8.8, 8.3 Hz, 1H), 7.33 (dd, J = 8.3, 2.3 Hz, 1H), 7.26 (d, J = 2.3 Hz, 1H), 7.16 (d, J =8.8 Hz, 1H).

[1313] 13 C NMR (126 MHz, CDCl3) δ 183.8, 172.1, 155.1, 149.9 (q, J C–F = 2.1 Hz),149.3, 130.8, 122.7, 120.3 (q, J C–F = 258.3 Hz), 118.3, 118.2, 113.2.

[1314] 19 F NMR (471 MHz, CDCl3) δ -57.92.

[1315] ( E )-4-(2-(4-(trifluoromethoxy)phenoxy)thiazolyl-5-yl)but-3-en-2-one (54)

[1316] The title compound, a brown solid, was prepared following general step I.

[1317] LCMS (ESI-MS) m / z :C 14 H 11 F3NO3S [M+H] + Calculated value: 330.03; Measured value: 329.8. Retention time: 3.729 minutes.

[1318] TLC: (20% EtOAc hexane solution, R) f ): 0.31 (UV, 254 nm, 280 nm).

[1319] 1 H NMR (500 MHz, CDCl3) δ 7.51 (d, J = 15.8 Hz, 1H), 7.41 (s, 1H), 7.38– 7.32 (m, 2H), 7.29 (d, J = 8.8 Hz, 2H), 6.30 (d, J = 15.8 Hz, 1H), 2.32 (s, 3H).

[1320] 13 C NMR (126 MHz, CDCl3) δ 197.0, 173.9, 152.5, 146.8 (q, J C–F = 1.8 Hz),142.2, 132.8, 129.9, 126.9, 122.6, 121.7, 120.4 (q, J C–F = 257.6 Hz), 27.8. 2.8, 129.9, 126.9, 122.6, 121.7, 120.4 (q, J C–F = 257.6 Hz), 27.8.

[1321] 19 F NMR (471 MHz, CDCl3) δ -58.11.

[1322] ( E )-4-(2-(3-(trifluoromethoxy)phenoxy)thiazolyl-5-yl)but-3-en-2-one (55)

[1323] The title compound, a brown solid, was prepared following general step I.

[1324] LCMS (ESI-MS) m / z :C 14 H 11 F3NO3S [M+H] + Calculated value: 330.03; Measured value: 329.8. Retention time: 3.702 minutes.

[1325] TLC: (20% EtOAc hexane solution, R) f ): 0.28 (UV, 254 nm, 280 nm).

[1326] 1 H NMR (500 MHz, CDCl3) δ 7.52 (d, J = 15.8 Hz, 1H), 7.47 (dd, J = 8.6,8.2 Hz, 1H), 7.42 (s, 1H), 7.28 (ddd, J = 8.6, 2.3, 0.9 Hz, 1H), 7.25 – 7.21(m, 1H), 7.19 – 7.14 (m, 1H), 6.30 (d, J = 15.8 Hz, 1H), 2.33 (s, 3H).

[1327] 13 C NMR (126 MHz, CDCl3) δ 197.0, 173.3, 154.9, 149.9 (q, J C–F = 2.0 Hz),142.1, 132.8, 130.8, 130.0, 127.0, 120.3 (q, J C–F = 258.2 Hz), 118.6, 118.5,113.6, 27.8.

[1328] 19 F NMR (471 MHz, CDCl3) δ -57.92.

[1329] ( E )-4-(2-(4-(trifluoromethoxy)phenoxy)thiazolyl-4-yl)but-3-en-2-one (56)

[1330] The title compound was prepared as a brown powder following general procedure I.

[1331] LCMS (ESI-MS) m / z :C 14 H 11 F3NO3S [M+H] + Calculated value: 330.03; Measured value: 330.1. Retention time: 3.711 minutes.

[1332] TLC: (20% EtOAc hexane solution, R) f ): 0.23 (UV, 254 nm, 280 nm).

[1333] 1 H NMR (500 MHz, CDCl3) δ 7.44 – 7.39 (m, 2H), 7.33 – 7.29 (m, 2H),7.26 (d, J = 15.6 Hz, 1H), 7.06 (s, 1H), 6.85 (d, J = 15.6 Hz, 1H), 2.35 (s, 3H).

[1334] 13 C NMR (126 MHz, CDCl3) δ 198.4, 172.3, 152.9, 146.8, 146.5 (q, J C–F =2.2 Hz), 134.3, 128.8, 122.5, 121.4, 120.4 (q, J C–F = 257.6 Hz), 116.9, 28.3.

[1335] 19 F NMR (471 MHz, CDCl3) δ -58.11.

[1336] ( E)-4-(2-(3-(trifluoromethoxy)phenoxy)thiazolyl-4-yl)but-3-en-2-one (57)

[1337] The title compound was prepared as a brown powder following general procedure I.

[1338] LCMS (ESI-MS) m / z :C 14 H 11 F3NO3S [M+H] + Calculated value: 330.03; Measured value: 330.0. Retention time: 3.737 minutes.

[1339] TLC: (20% EtOAc hexane solution, R) f ): 0.32 (UV, 254 nm, 280 nm).

[1340] 1 H NMR (500 MHz, CDCl3) δ 7.48 (dd, J = 8.5, 8.1 Hz, 1H), 7.36 – 7.30(m, 2H), 7.27 (d, J = 15.5 Hz, 1H), 7.19 – 7.15 (m, 1H), 7.07 (s, 1H), 6.86 (d, J = 15.6 Hz, 1H), 2.35 (s, 3H).

[1341] 13 C NMR (126 MHz, CDCl3) δ 198.3, 171.8, 155.2, 149.7 (q, J C–F = 2.0 Hz),146.8, 134.1, 130.6, 128.8, 120.3 (q, J C–F = 258.2 Hz), 118.2, 118.1, 117.0,113.3, 28.4.

[1342] 19 F NMR (471 MHz, CDCl3) δ -57.92.

[1343] 3-Hydroxy-5-(2-(4-(trifluoromethoxy)phenoxy)thiazolyl-5-yl)cyclohex-2-en-1-one (58)

[1344] The title compound was prepared as a white powder following general steps J and K.

[1345] LCMS (ESI-MS) m / z :C 16 H 13 F3NO4S [M+H] + Calculated value: 372.04; Measured value: 371.7. Retention time: 4.047 minutes.

[1346] TLC: (5% methanol in dichloromethane solution, R) f ): 0.17 (UV, 254 nm, 280 nm).

[1347] Keto form: 1 H NMR (500 MHz, CD3OD) δ 7.45 – 7.35 (m, 4H), 7.10 (d, J = 0.9 Hz,1H), 4.90 (s, 2H), 3.76 – 3.62 (m, 1H), 2.75 (dd, J = 17.0, 4.7 Hz, 2H), 2.62(dd, J = 16.9, 9.9 Hz, 2H).

[1348] Enol form: 1 H NMR (500 MHz, DMSO- d 6) δ 11.32 (s, 1H), 7.48 (s, 4H), 7.13(d, J = 1.0 Hz, 1H), 5.28 (s, 1H), 3.65 – 3.55 (m, 1H), 2.64 – 2.45 (m, 4H).

[1349] 13 C NMR (126 MHz, DMSO- d 6) δ 170.7, 153.8, 145.9 (q, J C–F = 2.1 Hz),136.7, 133.6, 123.4, 122.5, 120.5 (q, J C–F = 256.4 Hz), 104.2, 32.5.

[1350] 19F NMR (471 MHz, CD3OD) δ -59.80.

[1351] IR (thin film, cm) -1 ): = 2885, 1600, 1545, 1499, 1367, 1284, 1221, 1174, 843.

[1352] 3-Hydroxy-5-(2-(3-(trifluoromethoxy)phenoxy)thiazolyl-5-yl)cyclohex-2-en-1-one (59)

[1353] The title compound was prepared as a white powder following general steps J and K.

[1354] LCMS (ESI-MS) m / z :C 16 H 13 F3NO4S [M+H] + Calculated value: 372.04; Measured value: 371.7. Retention time: 4.053 minutes.

[1355] TLC: (5% methanol in dichloromethane solution, R) f ): 0.17 (UV, 254 nm, 280 nm).

[1356] 1 H NMR (500 MHz, CD3OD) δ 7.44 (dd, J = 9.9, 8.2 Hz, 1H), 7.23 – 7.15(m, 2H), 7.11 (d, J = 8.2 Hz, 1H), 7.00 (s, 1H), 4.77 (s, 2H), 3.63 – 3.47 (m,1H), 2.64 (dd, J = 17.0, 4.7 Hz, 2H), 2.51 (dd, J = 17.0, 10.0 Hz, 2H).

[1357] 19 F NMR (471 MHz, CD3OD) δ -59.58.

[1358] 5-(2-(4-(trifluoromethoxy)phenoxy)thiazolyl-4-yl)cyclohexane-1,3-dione (60)

[1359] The title compound was prepared as a white powder following general steps J and K.

[1360] LCMS (ESI-MS) m / z :C 16 H 13 F3NO4S [M+H] + Calculated value: 372.04; Measured value: 371.7. Retention time: 4.159 minutes.

[1361] TLC: (5% methanol in dichloromethane solution, R) f ): 0.25 (UV, 254 nm, 280 nm).

[1362] 1 H NMR (500 MHz, CD3OD) δ 7.48 – 7.41 (m, 2H), 7.41 – 7.36 (m, 2H), 6.82 (d, J = 1.0 Hz, 1H), 4.89 (s, 2H), 3.47 – 3.37 (m, 1H), 2.67 (d, J = 7.6 Hz, 4H).

[1363] 13 C NMR (126 MHz, CD3OD) δ 174.2, 155.2, 153.7, 147.7 (q, J C–F = 2.1 Hz),123.8, 122.6, 121.8 (q, J C–F = 256.9 Hz), 109.1, 37.4.

[1364] 19 F NMR (471 MHz, CD3OD) δ -59.79.

[1365] IR (thin film, cm) -1 ): = 2890, 1571, 1534, 1493, 1207, 1178, 844.

[1366] 5-(2-(3-(trifluoromethoxy)phenoxy)thiazolyl-4-yl)cyclohexane-1,3-dione (61)

[1367] The title compound was prepared as a white powder following general steps J and K.

[1368] LCMS (ESI-MS) m / z :C 16 H 13 F3NO4S [M+H] + Calculated value: 372.04; Measured value: 371.7. Retention time: 4.159 minutes.

[1369] TLC: (5% methanol in dichloromethane solution, R) f ): 0.22 (UV, 254 nm, 280 nm).

[1370] Keto form: 1 H NMR (500 MHz, CD3OD) δ 7.44 (dd, J = 9.1, 8.3 Hz, 1H), 7.26 –7.18 (m, 2H), 7.14 – 7.08 (m, 1H), 6.73 (s, 1H), 4.77 (s, 2H), 3.36 – 3.26(m, 1H), 2.55 (d, J = 7.6 Hz, 4H).

[1371] Enol form: 1 H NMR (500 MHz, DMSO- d 6) δ 11.18 (s, 1H), 7.62 (dd, J = 8.7, 8.1Hz, 1H), 7.50 (s, 1H), 7.44 (dd, J = 8.3, 2.3 Hz, 1H), 7.38 – 7.20 (m, 1H), 6.95 (d, J = 1.0 Hz, 1H), 5.25 (s, 1H), 3.33 – 3.26 (m, 1H), 2.73 – 2.54 (m,2H), 2.46 – 2.28 (m, 2H).

[1372] 13 C NMR (126 MHz, DMSO- d 6) δ 171.5, 155.9, 152.9, 149.3 (q, J C–F = 1.8Hz), 132.1, 120.4 (q, J C–F= 257.0 Hz), 119.5, 118.8, 113.8, 109.0, 104.0, 35.8.

[1373] 19 F NMR (471 MHz, CD3OD) δ -59.57.

[1374] IR (thin film, cm) -1 ): = 2895, 1598, 1483, 1250, 1208, 1163, 869.

[1375] 6-Methoxy-3-(2-(4-(trifluoromethoxy)phenoxy)thiazolyl-5-yl)-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (62)

[1376] The title compound, in the form of a brown powder, was prepared following general procedure L.

[1377] TLC: (5% methanol in dichloromethane solution, R) f ): 0.33 (UV, 254 nm, 280 nm).

[1378] 1 H NMR (500 MHz, CDCl3 and 3 drops TFA- d ) δ 8.38 (d, J = 9.3 Hz, 1H), 7.44 –7.30 (m, 7H), 4.03 (s, 3H), 3.99 – 3.89 (m, 1H), 3.86 (dd, J = 17.7, 4.2 Hz, 1H), 3.57 (dd, J = 17.6, 10.2 Hz, 1H), 3.28 (dd, J = 17.7, 4.2 Hz, 1H), 3.12 (dd, J = 17.6, 10.2 Hz, 1H).

[1379] 13 C NMR (126 MHz, CDCl3 and 3 drops TFA- d) δ 200.4, 175.4, 171.8, 168.0,159.2, 152.5, 147.9, 142.8, 131.7, 131.6, 126.8, 123.1, 122.08, 122.00,121.8, 120.3 (q, J C–F = 258.6 Hz), 113.2, 106.9, 100.1, 56.7, 43.1, 34.9, 32.0.

[1380] 19 F NMR (471 MHz, CDCl3 and 3 drops TFA- d ) δ -59.00.

[1381] 6-Methoxy-3-(2-(3-(trifluoromethoxy)phenoxy)thiazolyl-5-yl)-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (63)

[1382] The title compound was prepared as a grayish-white or brownish-brown powder following general procedure L.

[1383] TLC: (5% methanol in dichloromethane solution, R) f ): 0.33 (UV, 254 nm, 280 nm).

[1384] 1 H NMR (500 MHz, CDCl3 and 3 drops TFA- d ) δ 8.37 (d, J = 9.2 Hz, 1H), 7.51 (dd, J = 9.2, 8.3 Hz, 1H), 7.42 – 7.33 (m, 2H), 7.28 (s, 1H), 7.27 – 7.19 (m, 3H), 7.16 (s, 1H), 4.04 (s, 3H), 3.99 – 3.90 (m, 1H), 3.87 (dd, J = 17.8, 4.2 Hz, 1H), 3.58 (dd, J = 17.6, 9.9 Hz, 1H), 3.29 (dd, J = 17.8, 4.2 Hz, 1H), 3.11 (dd, J= 17.6, 9.9 Hz, 1H).

[1385] 13 C NMR (126 MHz, CDCl3 and 3 drops TFA- d ) δ 200.5, 174.3, 171.7, 168.0,159.3, 154.9, 150.1 (q, J C–F = 2.1 Hz), 142.9, 132.5, 132.0, 131.4, 126.7,121.9, 120.2 (q, J C–F = 258.7 Hz), 119.5, 118.5, 113.5, 113.2, 106.9, 100.2, 56.7, 43.3, 35.0, 32.0.

[1386] 19 F NMR (471 MHz, CDCl3 and 3 drops TFA- d ) δ -58.82.

[1387] 7-Chloro-3-(2-(4-(trifluoromethoxy)phenoxy)thiazo-4-yl)-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (64)

[1388] The title compound was prepared as a white powder following general procedure L.

[1389] TLC: (5% methanol in dichloromethane solution, R) f ): 0.34 (UV, 254 nm, 280 nm).

[1390] 1 H NMR (500 MHz, CDCl3 and 3 drops TFA- d ) δ 8.43 (s, 1H), 8.14 – 7.98 (m, 2H), 7.23 – 7.10 (m, 4H), 6.73 (s, 1H), 3.90 – 3.77 (m, 2H), 3.68 (dd, J = 17.8, 7.8Hz, 1H), 3.29 – 3.14 (m, 2H).

[1391] 13 C NMR (126 MHz, CDCl3 and 3 drops TFA- d ) δ 202.2, 174.5, 171.4, 160.8,152.8, 148.7, 146.7 (q, J = 2.2 Hz), 138.3, 138.0, 136.1, 124.0, 122.3, 121.6,120.3 (q, J = 257.6 Hz), 120.1, 108.9, 108.8, 42.2, 34.5, 33.39, 33.37.

[1392] 19 F NMR (471 MHz, CDCl3 and 3 drops TFA- d ) δ -58.84.

[1393] 6-Methoxy-3-(2-(4-(trifluoromethoxy)phenoxy)thiazolyl-4-yl)-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (65)

[1394] The title compound was prepared as a grayish-white or brownish-brown powder following general procedure L.

[1395] TLC: (5% methanol in dichloromethane solution, R) f ): 0.34 (UV, 254 nm, 280 nm).

[1396] 1 H NMR (500 MHz, CDCl3 and 3 drops TFA- d ) δ 8.36 (d, J = 9.2 Hz, 1H), 7.39 (dd, J = 9.2, 2.4 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.28 (s, 4H), 6.82 (s, 1H), 4.03(s, 3H), 3.95 – 3.86 (m, 1H), 3.78 (dd, J = 17.6, 4.6 Hz, 1H), 3.67 (dd, J =17.6, 9.8 Hz, 1H), 3.24 (dd,J = 17.6, 4.6 Hz, 1H), 3.16 (dd, J = 17.6, 9.8 Hz, 1H).

[1397] 13 C NMR (126 MHz, CDCl3 and 3 drops TFA- d ) δ 201.3, 176.7, 171.6, 167.9,160.0, 152.7, 147.7 (q, J C–F = 1.8 Hz), 147.2, 142.5, 126.8, 122.9, 121.8,121.6, 120.3 (q, J C–F = 258.1 Hz), 113.1, 108.9, 107.2, 99.8, 56.6, 41.8, 34.2,32.8.

[1398] 19 F NMR (471 MHz, CDCl3 and 3 drops TFA- d ) δ -58.90.

[1399] 7-Chloro-3-(2-(3-(trifluoromethoxy)phenoxy)thiazo-4-yl)-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (66)

[1400] The title compound, a yellow solid, was prepared following general procedure L.

[1401] TLC: (5% methanol in dichloromethane solution, R) f ): 0.33 (UV, 254 nm, 280 nm).

[1402] 1 H NMR (500 MHz, CDCl3 and 3 drops TFA- d ) δ 8.44 (s, 1H), 8.07 – 8.03 (m, 2H), 7.38 (dd, J= 9.4, 8.4 Hz, 1H), 7.16 – 7.10 (m, 2H), 7.07 (s, 1H), 6.77 (s,1H), 3.93 – 3.85 (m, 1H), 3.82 (dd, J = 17.8, 4.5 Hz, 1H), 3.69 (dd, J = 17.8, 8.4 Hz, 1H), 3.26 (dd, J = 17.8, 4.5 Hz, 1H), 3.19 (dd, J = 17.8, 8.4 Hz, 1H).

[1403] 13 C NMR (126 MHz, CDCl3 and 3 drops TFA- d ) δ 202.1, 174.4, 171.6, 160.8,155.2, 149.8, 148.6, 138.5, 138.0, 136.1, 130.7, 124.1, 122.3, 120.28 (q, J C–F =258.4 Hz), 120.23, 118.6, 118.5, 113.4, 109.2, 108.7 (q, J C–F = 1.9 Hz), 42.2, 34.5, 33.3.

[1404] 19 F NMR (471 MHz, CDCl3 and 3 drops TFA- d ) δ -58.80.

[1405] 7-Chloro-3-(6-(2-fluoro-4-(trifluoromethyl)phenyl)pyridin-3-yl)-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (67)

[1406] The title compound, a pale yellow solid, was prepared following general procedure L.

[1407] TLC: (5% methanol in dichloromethane solution, R) f ): 0.21 (UV, 254 nm, 280 nm).

[1408] 1¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 9.28 (s, 1H), 8.72 (dd, J = 8.5, 2.0Hz, 1H), 8.54 (d, J = 2.0 Hz, 1H), 8.26 (d, J = 8.3 Hz, 1H), 8.12 (dd, J = 9.0, 2.2Hz, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.86 (dd, J = 9.0, 7.6 Hz, 1H), 7.72 (d, J = 8.3Hz, 1H), 7.64 (d, J = 10.3 Hz, 1H), 4.24 – 4.11 (m, 1H), 4.00 – 3.79 (m, 2H), 3.46 – 3.26 (m, 2H).

[1409] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 200.3, 172.8, 159.9, 159.6 (d, J =256.8 Hz), 146.4, 146.2, 142.1, 140.2, 139.4, 137.8, 137.5 (qd, J = 34.4, 8.3Hz), 137.0, 131.2, 128.7 (d, J = 4.5 Hz), 124.5, 123.0 – 122.8 (m), 122.3 (qd, J = 276.2, 2.2 Hz), 121.9, 121.0 (d, J = 11.7 Hz), 120.4, 115.0 (dq, J C–F = 24.8, 3.7 Hz), 108.2 (d, J C–F = 1.9 Hz), 41.9, 35.5, 33.7.

[1410] 19 F NMR (471 MHz, CDCl3 and 3 drops of TFA-) d) δ -64.47.

[1411] 3-(6-(2-fluoro-4-(trifluoromethyl)phenyl)pyridin-3-yl)-6-methoxy-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (68)

[1412] The title compound, a brown solid, was prepared following general procedure L.

[1413] TLC: (5% methanol in dichloromethane solution, R) f ): 0.21 (UV, 254 nm, 280 nm).

[1414] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 9.37 (s, 1H), 8.71 (d, J = 7.8 Hz, 1H), 8.42 (d, J = 9.1 Hz, 1H), 8.25 (d, J = 8.3 Hz, 1H), 7.91 (dd, J = 10.2, 9.2Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 10.2 Hz, 1H), 7.43 (dd, J = 9.3, 2.3 Hz, 1H), 7.40 (d, J = 2.3 Hz, 1H), 4.21 – 4.09 (m, 1H), 4.09 – 3.95 (m,4H), 3.83 (dd, J = 17.4, 12.2 Hz, 1H), 3.38 (dd, J = 17.4, 12.2 Hz, 1H), 3.29(dd, J = 17.4, 3.5 Hz, 1H).

[1415] 19 F NMR (471 MHz, CDCl3 and 3 drops of TFA-) d ) δ -64.48.

[1416] 7-Chloro-3-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (69)

[1417] The title compound, a grayish-white peach-colored solid, was prepared according to general procedure L.

[1418] TLC: (5% methanol in dichloromethane solution, R) f ): 0.36 (UV, 254 nm, 280 nm).

[1419] 1 H NMR (500 MHz, DMSO- d 6) δ 12.27 (s, 1H), 8.71 (s, 1H), 8.22 (d, J =8.5 Hz, 2H), 8.06 – 8.00 (m, 2H), 7.95 (dd, J = 8.3, 2.2 Hz, 1H), 7.74 (dd, J =8.6, 2.5 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.48 (d, J = 8.5 Hz, 2H), 3.70 – 3.61(m, 1H), 3.45 (dd, J = 16.1, 11.6 Hz, 1H), 3.15 (dd, J = 16.1, 4.1 Hz, 1H), 2.87(dd, J = 16.1, 11.6 Hz, 1H), 2.65 (dd, J = 16.1, 4.1 Hz, 1H).

[1420] 6-Methoxy-3-(6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (70)

[1421] The title compound was prepared as a brownish-brown powder following general procedure L.

[1422] TLC: (5% methanol in dichloromethane solution, R) f): 0.36 (UV, 254 nm, 280 nm).

[1423] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 9.25 (s, 1H), 8.66 (d, J = 8.4 Hz, 1H), 8.39 (d, J = 9.3 Hz, 1H), 8.18 (d, J = 8.3 Hz, 1H), 8.03 – 7.94 (m, 2H), 7.52 – 7.43 (m, 3H), 7.41 (dd, J = 9.3, 2.2 Hz, 1H), 4.18 – 4.00 (m, 5H), 3.85(dd, J = 18.1, 12.9 Hz, 1H), 3.41 (dd, J = 18.1, 12.9 Hz, 1H), 3.27 (d, J = 16.5Hz, 1H).

[1424] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 200.4, 172.0, 168.0, 159.6,153.0, 150.8, 146.3, 141.3, 139.0, 132.1, 129.9, 127.4, 126.9, 125.8, 121.9,120.2 (q, J C–F = 259.8 Hz), 114.0, 113.3, 107.0, 100.1, 56.7, 42.0, 35.7, 33.7.

[1425] 19 F NMR (471 MHz, CDCl3 and 3 drops of TFA-) d ) δ -58.51.

[1426] 7-Chloro-3-(6-(3-(trifluoromethoxy)phenyl)pyridin-3-yl)-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (71)

[1427] The title compound was prepared as a white powder following general procedure L.

[1428] TLC: (5% methanol in dichloromethane solution, R) f ): 0.24 (UV, 254 nm, 280 nm).

[1429] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 9.17 (d, J = 2.1 Hz, 1H), 8.66 (dd, J = 8.5, 2.1 Hz, 1H), 8.53 (d, J = 2.2 Hz, 1H), 8.21 (d, J = 8.5 Hz, 1H), 8.10 (dd, J = 9.0, 2.2 Hz, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.72(dd, J = 8.7, 8.3 Hz, 1H), 7.67 (s, 1H), 7.57 (d, J = 8.3 Hz, 1H), 4.16 – 4.07(m, 1H), 3.91 (ddd, J = 17.6, 4.3, 1.7 Hz, 1H), 3.83 (dd, J = 17.5, 13.1 Hz, 1H),3.39 (dd, J = 17.5, 13.1 Hz, 1H), 3.30 (ddd, J = 17.6, 4.3, 1.7 Hz, 1H).

[1430] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 200.5, 172.6, 159.9, 151.1, 150.4(q, J C–F= 2.2 Hz), 146.2, 141.4, 139.3, 139.2, 137.9, 136.8, 132.1, 131.2,126.4, 126.0, 125.5, 124.4, 122.0, 120.39, 120.33 (q, J C–F = 259.2 Hz), 120.32, 108.1, 35.4, 35.3, 33.7.

[1431] 19 F NMR (471 MHz, CDCl3 and 3 drops of TFA-) d ) δ -58.86.

[1432] 6-Methoxy-3-(6-(3-(trifluoromethoxy)phenyl)pyridin-3-yl)-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (72)

[1433] The title compound was prepared as a brownish-brown powder following general procedure L.

[1434] TLC: (5% methanol in dichloromethane solution, R) f ): 0.24 (UV, 254 nm, 280 nm).

[1435] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 9.17 (s, 1H), 8.67 (d, J = 8.2 Hz, 1H), 8.43 (d, J = 9.4 Hz, 1H), 8.22 (d, J = 8.3 Hz, 1H), 7.82 – 7.65 (m, 3H), 7.58 (d, J = 8.2 Hz, 1H), 7.44 (dd, J = 9.4, 2.3 Hz, 1H), 7.30 (d, J = 2.3 Hz, 1H), 4.21 – 4.02 (m, 4H), 3.93 – 3.72 (m, 2H), 3.41 – 3.22 (m, 2H).

[1436] 19F NMR (471 MHz, CDCl3 and 3 drops of TFA-) d ) δ -58.99.

[1437] 7-Chloro-3-(5-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)-3,4-dihydroacridine-1,9(2) H 10 H )-Diketone (73)

[1438] The title compound was prepared as a white powder following general procedure L.

[1439] TLC: (5% methanol in dichloromethane solution, R) f ): 0.28 (UV, 254 nm, 280 nm).

[1440] 1 H NMR (500 MHz, DMSO- d 6) δ 8.87 (d, J = 2.4 Hz, 1H), 8.13 – 8.02 (m,2H), 7.86 (d, J = 8.7 Hz, 2H), 7.62 – 7.43 (m, 5H), 3.69 – 3.60 (m, 1H), 3.33(dd, J = 16.2, 11.2 Hz, 1H), 3.20 (d, J = 15.7 Hz, 1H), 2.87 (dd, J = 16.2, 11.2Hz, 1H), 2.70 (d, J = 15.7 Hz, 1H).

[1441] 1 ¹H NMR (500 MHz, CDCl₃ and 3 drops of TFA-) d ) δ 9.00 (d, J = 2.3 Hz, 1H), 8.70 (dd, J = 8.4, 2.3 Hz, 1H), 8.52 (d, J = 2.3 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 8.10 (dd, J = 9.0, 2.3 Hz, 1H), 8.01 (d, J= 9.0 Hz, 1H), 7.74 – 7.63 (m, 2H), 7.45 (d, J =8.3 Hz, 2H), 4.58 – 4.46 (m, 1H), 4.07 – 3.96 (m, 2H), 3.48 – 3.34 (m, 2H).

[1442] 13 C NMR (126 MHz, CDCl3 and 3 drops of TFA-) d ) δ 199.3, 172.6, 159.1, 152.1, 151.4(q, J C–F = 1.3 Hz), 145.3, 140.2, 139.7, 139.2, 137.9, 136.8, 130.6, 128.9,126.0, 124.4, 122.2, 122.0, 120.43, 120.39 (q, J C–F = 258.9 Hz), 108.2, 41.1, 36.1, 32.4.

[1443] 19 F NMR (471 MHz, CDCl3 and 3 drops of TFA-) d ) δ -58.45.

[1444] 6-Methoxy-3-(5-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)-3,4-dihydroacridine-1,9(2 H 10 H )-Diketone (74)

[1445] The title compound was prepared as a white powder following general procedure L.

[1446] TLC: (5% methanol in dichloromethane solution, R) f ): 0.28 (UV, 254 nm, 280 nm).

[1447] 1 H NMR (500 MHz, DMSO- d 6) δ 8.87 (s, 1H), 8.10 (d, J = 8.8 Hz, 1H), 8.01(d, J = 8.8 Hz, 1H), 7.87 (d, J= 8.2 Hz, 2H), 7.59 – 7.42 (m, 3H), 6.95 (d, J =10.2 Hz, 2H), 3.86 (s, 3H), 3.78 – 3.64 (m, 1H), 3.45 (t, J = 16.3, 10.2 Hz,2H), 3.24 (dd, J = 16.1, 4.5 Hz, 1H), 2.84 (t, J = 16.3, 10.2 Hz, 1H), 2.73 (dd, J = 16.1, 4.5 Hz, 1H).

[1448] 7-Chloro-3-(5-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)-3,4-dihydroacryl-1,9(2 H 10 H )-Diketone (75)

[1449] The title compound was prepared as a grayish-white powder following general procedure L.

[1450] TLC: (5% methanol in dichloromethane solution, R) f ): 0.25 (UV, 254 nm, 280 nm).

[1451] 1 H NMR (500 MHz, DMSO- d 6) δ 8.91 (d, J = 1.7 Hz, 1H), 8.15 (dd, J = 8.3, 1.7 Hz, 1H), 8.04 (d, J = 2.5 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.77 – 7.69 (m,2H), 7.67 – 7.51 (m, 3H), 7.42 (d, J = 8.3 Hz, 1H), 3.81 – 3.72 (m, 1H), 3.48(dd, J = 16.7, 10.8 Hz, 2H), 3.26 (dd, J = 16.3, 4.4 Hz, 1H), 2.86 (dd, J= 16.7,10.8 Hz, 1H), 2.76 (dd, J = 16.3, 4.4 Hz, 1H).

[1452] 6-Methoxy-3-(5-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)-3,4-dihydroacryl-1,9(2 H 10 H )-Diketone (76)

[1453] The title compound, which is a brownish-brown solid, was prepared according to general procedure L.

[1454] TLC: (5% methanol in dichloromethane solution, R) f ): 0.25 (UV, 254 nm, 280 nm).

[1455] 1 H NMR (500 MHz, DMSO- d 6) δ 8.91 (d, J = 2...

Claims

1. A compound having the structure of a compound represented by Structure I or a pharmaceutically acceptable salt thereof: wherein I 2. The compound of claim 1, wherein n is 1 or 2. n is an integer from 1 to 4, wherein each R 1 independently is hydrogen, halogen, substituted or unsubstituted linear or branched alkyl or alkoxy, and m is an integer from 1 to 3, wherein each R 2 is hydrogen, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

9. The compound of claim 1, wherein m is 1.

3. The compound of claim 1, wherein R 1 is Ci-C6alkyl.

4. The compound of claim 1, wherein R 1 is methyl or ethyl.

5. The compound of claim 1, wherein R 1 is halogen.

6. The compound of claim 1, wherein R 1 is fluoro, bromo, iodo, or chloro.

7. The compound of claim 1, wherein R 1 is Ci-C6alkoxy.

8. The compound of claim 1, wherein R 1 is methoxy or ethoxy.

13. The compound of claim 12, wherein the substituted or unsubstituted heterocycloalkyl is a 5- or 6-membered ring.

10. The compound of claim 1, wherein R 2 is substituted or unsubstituted phenyl.

11. The compound of claim 1, wherein R 2 is phenyl substituted with halo, substituted or unsubstituted alkyl, alkoxy, or aryloxy.

12. The compound of claim 1, wherein R 2 is substituted or unsubstituted heterocycloalkyl.

14. The compound of claim 12, wherein the unsubstituted heterocycloalkyl is tetrahydrofuranyl or tetrahydropyranyl.

16. The compound of claim 15, wherein the heteroaryl is pyridyl, thienyl, or thiazolyl.

15. The compound of claim 1, wherein R 2 is substituted or unsubstituted heteroaryl.

17. The compound of claim 15, wherein the heteroaryl is substituted with substituted or unsubstituted phenyl.

18. The compound of claim 17, wherein the phenyl is substituted with halogen, substituted or unsubstituted alkyl, alkoxy, fluoroalkoxy, or fluoroalkyl.

19. The compound of claim 17, wherein phenyl is substituted with -F, -CF3, -OCF3, or any combination thereof.

21. The compound of claim 1, wherein the compound has the structural formula II 20. The compound of claim 1, wherein R 2 is C3-C6cycloalkyl. II.

25. The compound of claim 24, wherein the substituted or unsubstituted heterocycloalkyl is a 5- or 6-membered ring.

22. The compound of claim 21, wherein R 2 is substituted or unsubstituted phenyl.

23. The compound of claim 21, wherein R 2 is phenyl substituted with halo, substituted or unsubstituted alkyl, alkoxy, or aryloxy.

24. The compound of claim 21, wherein R 2 is substituted or unsubstituted heterocycloalkyl.

26. The compound of claim 24, wherein the unsubstituted heterocycloalkyl is tetrahydrofuranyl or tetrahydropyranyl.

28. The compound of claim 27, wherein the heteroaryl is pyridyl, thienyl, or thiazolyl.

27. The compound of claim 21, wherein R 2 is substituted or unsubstituted heteroaryl.

29. The compound of claim 27, wherein the heteroaryl is substituted with substituted or unsubstituted phenyl.

30. The compound of claim 29, wherein the phenyl is substituted with halogen, substituted or unsubstituted alkyl, alkoxy, fluoroalkoxy, or fluoroalkyl.

31. The compound of claim 29, wherein phenyl is substituted with -F, -CF3, -OCF3, or any combination thereof.

36. The compound of claim 1, wherein the compound has one of the following structures:

32. The compound of claim 21, wherein R 2 is C3-C6cycloalkyl.

33. The compound of claim 21, wherein R 2 is wherein o is 1 or 2, R 3 is hydrogen, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryloxy.

34. The compound of claim 33, wherein R 3 is phenyl substituted with fluoroalkyl or fluoroalkoxy.

35. The compound of claim 33, wherein R 3 is phenyl substituted with F, CF3, OCF3, or any combination thereof.

37. The compound of claim 36, wherein the alkyl is methyl, the alkoxy is methoxy, and the halogen is chlorine. 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , or , wherein R 1a , R 1b , R 1c and R 1d are each independently hydrogen, halogen, substituted or unsubstituted linear or branched alkyl or alkoxy.

39. The compound of claim 1, wherein the compound has the following structure:

38. The compound of claim 36, wherein R 1c is methoxy.

40. The compound of claim 1, wherein the compound has the following structure: wherein R 1c is methoxy.

41. The compound of claim 1, wherein the compound has the following structure: wherein R 1b is chloro, R 1c is methoxy.

42. The compound of claim 1, wherein the compound has the following structure: or wherein R 1b is chloro, R 1c is methoxy.

43. The compound of claim 1, wherein the compound has the following structure: wherein R 1c is methoxy.

45. The compound of claim 1, wherein the compound is THA-1839, THA-1840, THA-1994, THA-2111, THA-2209, THA-2220, THA-2224, THA-2224, or THA-2225. wherein R 2a , R 2b , and R 2c are each independently hydrogen, halogen, substituted or unsubstituted linear or branched alkyl or alkoxy.

44. The compound of claim 43, wherein R 2c is methoxy. ​ 46. A pharmaceutical composition comprising a compound of any one of claims 1 to 45 and a pharmaceutically acceptable carrier.

47. A method of treating or preventing malaria in a subject, the method comprising administering to the subject an effective amount of a compound of any one of claims 1 to 45.

48. The method of claim 47, wherein the compound inhibits or prevents the intrahepatic stage, the intraerythrocytic stage, or a combination thereof, of malaria.

49. The method of claim 47, wherein the subject is infected with a Plasmodium strain that infects the subject with malaria.

50. The method of claim 49, wherein the Plasmodium strain comprises P. falciparum, P. vivax, P. knowlesi, P. ovale, or P. malariae.

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