WO2018081612A1

WO2018081612A1 - Compounds and methods for treating cancer

Info

Publication number: WO2018081612A1
Application number: PCT/US2017/058831
Authority: WO
Inventors: Elena V. DNEPROVSKAIA; Michael S. HOLZWARTH
Original assignee: Actavalon, Inc.
Priority date: 2016-10-31
Filing date: 2017-10-27
Publication date: 2018-05-03

Abstract

Substituted hydrazone compounds, methods of making such compounds and metal complexes thereof, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds and metal complexes to treat, prevent or ameliorate cancer are provided.

Description

COMPOUNDS AND METHODS FOR TREATING CANCER

BACKGROUND

Field

[0001] Substituted hydrazone compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds to treat, prevent or ameliorate cancer are provided.

Description

[0002] Over the past decade, cancer researchers have been primarily focusing on inhibiting the functions of various growth- and survival-promoting oncoproteins. While inhibition of various kinases involved in mitogenic signaling cascades initially proved to be very successful in treatment of cancer, the rapidly evolving cancer cells deploy various mechanisms to evade drug inhibition and eventually develop resistance to this targeted therapy. Such acquired resistance results in clinical relapse and resurgence of therapy-resistant tumors. The emergence of multi-drug resistant cancers requires development of novel approaches to their treatment.

[0003] p53 is a tumor suppressor protein that controls cell growth and tissue maintenance and plays a central role in preventing tumor suppression and development. The p53 pathway is activated in response to a broad variety of stress signals, such as gamma and UV irradiation, DNA damage, oncogene signaling, lack of nutrients, and oxidative damage. The level of the p53 response is carefully attenuated by post-translational modifications of the amino acid residues of the p53 protein, such as phosphorylation, acetylation, methylation, ubiquitination, sumoylation, neddylation and glutathionylation. These modifications affect p53 conformation, stability and its ability to form protein complexes with its various partners. The p53 response to stress signals can proceed via a transcription-dependent pathway and a transcription-independent pathway. The p53 transcription- dependent pathway relies on transcriptional up-regulation of genes involved in cell cycle arrest or apoptosis. The p53 transcription-independent pathway exerts its action in part via interactions with the Bcl-2 family of proteins affecting the polarization of the mitochondrial membrane. Other transcription-independent activities of the p53 protein are currently the focus of scientific investigations.

[0004] When assembled into a tetramer, or more specifically into a dimer of dimers, p53 shows sequence specific DNA-binding activity and activates expression of a number of genes involved in the DNA-repair mechanism, metabolism, cell cycle arrest, apoptosis and/or senescence of incipient cancer cells. In cancer cells the normal function of p53 is inactivated, which results in uncontrolled proliferation and genomic instability. In approximately 50% of cancers, p53 is inactivated by a missense mutation, a single base-pair substitution that results in translation of a different amino acid. 100+ different mutations have been identified in the p53 DNA-binding domain. p53 mutant proteins are broadly categorized into 3 main types - 1) DNA-contact mutants, 2) structural mutants and 3) conformational mutants. The DNA-contact mutants seem to preserve the wild-type conformation, but lose the ability to form strong contacts with DNA, thus losing transcriptional activity either completely or partially. Structural mutants exhibit localized structural distortions of the amino acid residues, but mostly maintain native-like thermodynamic properties. Conformational mutants are thermodynamically unstable and are prone to rapid unfolding and aggregation. Both structural and conformational mutations are known to destabilize the active conformation of this highly flexible protein and disrupt its normal function. Furthermore, partially unfolded mutant p53 proteins accumulate to high levels in cancer cells and their aggregates exhibit oncogenic gain-of-function properties. As a zinc-binding protein and a sensor of ROS stress in cells, p53 protein is very sensitive to the levels and redox activity of various metal ions, such as zinc 2+, copper 2+ and copper 1+ ions. Small molecules, classified as metal chelators and/or metallochaperones, have been shown to affect the intracellular levels of metal ions and form the redox-active complexes with these metal ions. The redox activities of these complexes lead to the increased levels of reactive oxygene species (ROS) in cells and affect post-translational modifications of p53 protein, such as glutathionylation or oxidation-reduction of cysteine residues at or near the p53-DNA interface and formation of intra- and intermolecular disulfide bonds. These post-translational modifications affect the conformation and increase the stability of p53 mutant protein and affect its interactions with DNA and protein partners. As a result, these compounds modulate both the p53 transcription-dependent and transcription-independent activities by stabilizing the active conformation of mutant p53 proteins and slowing down its degradation via ubiquitin- proteasome pathway, thereby restoring tumor suppression activity and preventing oncogenic gain-of- function activity.

SUMMARY

[0005] Some embodiments of the present disclosure relate to compounds having the structure of formula (A):

or a pharmaceutically acceptable salt thereof, wherein

ring B is selected from

; wherein

Y¹ is selected from N and CR¹;

Y² is selected from N and CR²;

Y³ is selected from N and CR³;

Y^2a is CR^2a;

Y^3a is selected from NR^A, O, and S; and

each R¹, R², R^2a, and R³, is independently selected from the group consisting of H, C_1- ₆ alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)C_1- ₆ alkyl, halo, -CN, -NO₂, -NR^6aR^6b, -OR⁷, -C(O)R⁸, -C(O)OR⁹, -C(O)NR¹⁰R¹¹, -NR¹²C(O)R¹³, and -SO₂R¹⁴;

R^A is selected from the group consisting of H, C_1-6 alkyl, C_2-6 alkenyl and C_2-6 alkynyl; R⁴ is 5 to 10 membered heteroaryl or 5 to 10 membered heterocyclyl, each optionally substituted with one or more R¹⁵;

R⁵ is selected from the group consisting of H, C_1-6 alkyl and C_3-7 cycloalkyl;

ring A is an optionally substituted 5 to 8 membered monocyclic heterocyclyl or 5 to 8 membered monocyclic carbocyclyl, each optionally substituted with one or more R¹⁶;

each R^6a, R^6b, R¹⁰, R¹¹ and R¹² is independently selected from the group consisting of H, optionally substituted C_1-6 alkyl, optionally substituted C_6-10 aryl, optionally substituted C_7-14 aralkyl, and optionally substituted C_3-7 cycloalkyl; or R^6a and R^6b together with the nitrogen atom to which they are attached forms an optionally substituted 4 to 6 membered heterocyclyl;

each R⁷, R⁸, R⁹, R¹³ and R¹⁴ is independently selected from the group consisting of H, optionally substituted C_1-6 alkyl, optionally substituted C_2-6 alkenyl, optionally substituted C_2- ₆ alkynyl, optionally substituted C_6-10 aryl, optionally substituted C_7-14 aralkyl, and optionally substituted C_3-7 cycloalkyl;

each R¹⁵ and R¹⁶ is independently selected from the group consisting of C_1-6 alkyl, C_2- ₆ alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)C_1-6 alkyl, C_6- ₁₀ aryl, C_7-14 aralkyl, 4 to 6 membered heterocyclyl, C_3-7 cycloalkyl, halo, oxo, -CN, -NO₂, - NR^6aR^6b, -OR⁷, -C(O)R⁸, -C(O)OR⁹, -C(O)NR¹⁰R¹¹, -NR¹²C(O)R¹³, and -SO₂R¹⁴, and wherein each of C_6-10 aryl, C_7-14 aralkyl, 4 to 6 membered heterocyclyl, and C_3-7 cycloalkyl of R¹⁵ is optionally substituted with one to four R¹⁷;

or independently, two adjacent R¹⁵ together with the atoms to which they are attached form a fused 5 or 6 membered heteroaryl or heterocyclyl optionally substituted with one to four R¹⁷,

R¹⁷ is selected from the group consisting of halo, hydroxy, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, oxo, -CN, -NO_2, -NR^6aR^6b, -OR⁷, -C(O)OR⁹, -C(O)NR¹⁰R¹¹, - NR¹²C(O)R¹³, and -SO₂R¹⁴; provided that

when each of Y¹, Y², and Y³ is CH, R⁵ is H, ring A is a 6 membered carbocyclyl, and

R⁴ is selected

, then R⁴ is substituted with at least one R¹⁵; and when Y¹ is CR¹, R¹ is H or CH₃, Y² is CR², R² is H or

-C(O)OR⁹, Y³ is CH, R⁵ is H, and R⁴ is selected from

, and

.

[0006] In some embodiments, when each of Y¹, Y², and Y³ is CH, R⁵ is H, R⁴ is selected

then ring A is selected from optionally substituted 5 to 8 membered heterocyclyl and optionally substituted 5, 7 or 8 membered carbocyclyl. In some embodiments, the compound of formula (A) is selected from Table 1.

[0007] Some embodiments of the present disclosure relate to compounds of formula (A) having the stru

or a pharmaceutically acceptable salt thereof, wherein

Y¹ is selected from N and CR¹;

Y² is selected from N and CR²;

Y³ is selected from N and CR³;

each R¹, R² and R³ is independently selected from the group consisting of H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)C_1-6 alkyl, halo, -CN, -NO₂, -NR^6aR^6b, -OR⁷, -C(O)R⁸, -C(O)OR⁹, -C(O)NR¹⁰R¹¹, -NR¹²C(O)R¹³, and -SO₂R¹⁴;

R⁴ is 5 to 10 membered heteroaryl or 5 to 10 membered heterocyclyl, each optionally substituted with one or more R¹⁵;

each R¹⁵ and R¹⁶ is independently selected from the group consisting of C_1-6 alkyl, C_2- ₆ alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)C_1-6 alkyl, C_6- ₁₀ aryl, C_7-14 aralkyl, C_3-7 cycloalkyl, halo, oxo, -CN, -NO₂, -NR^6aR^6b, -OR⁷, -C(O)R⁸, - C(O)OR⁹, -C(O)NR¹⁰R¹¹, -NR¹²C(O)R¹³, and -SO₂R¹⁴, and wherein each of C_6-10 aryl, C_7-14 aralkyl, and C_3-7 cycloalkyl of R¹⁵ is optionally substituted with one to four R¹⁷;

is substituted with at least one R¹⁵; and

when Y¹ is CR¹, R¹ is H or CH₃, Y² is CR², R² is H or -C(O)OR⁹, Y³ is CH, R⁵ is H, and R⁴

then ring A is selected from optionally substituted 5 to 8 membered heterocyclyl and optionally substituted 5, 7 or 8 membered carbocyclyl. In some embodiments, the compound of formula (I) is selected from Table 1.

[0009] Some embodiments of the present disclosure relate to compounds of Formula (A) having the stru

(II)

or a pharmaceutically acceptable salt thereof, wherein Y^2a is CR^2a;

Y^3a is selected from NR^A, O, and S; and

R^2a is independently selected from the group consisting of H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)C_1-6 alkyl, halo, -CN, - NO₂, -NR^6aR^6b, -OR⁷, -C(O)R⁸, -C(O)OR⁹, -C(O)NR¹⁰R¹¹, -NR¹²C(O)R¹³, and -SO₂R¹⁴;

or independently, two adjacent R¹⁵ together with the atoms to which they are attached form a fused 5 or 6 membered heteroaryl or heterocyclyl optionally substituted with one to four R¹⁷; and

R¹⁷ is selected from the group consisting of halo, hydroxy, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, oxo, -CN, -NO_2, -NR^6aR^6b, -OR⁷, -C(O)OR⁹, -C(O)NR¹⁰R¹¹, -NR¹²C(O)R¹³, and -SO₂R¹⁴. In some embodiments, the compound of formula (I) is selected from Table 1.

[0010] Some embodiments of the present disclosure relate to pharmaceutical compositions comprising a compound of formula (A), formula (I), or formula (II) described herein, or a pharmaceutically acceptable salt thereof, a specific compound selected from Table 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0011] Some embodiments of the present disclosure relate to a metal complex comprising a metal cation and a compound of formula (A), formula (I), or formula (II) as described herein, a specific compound selected from Table 1, or an anion or solvate thereof. In some embodiments, the metal cation is selected from the group consisting of copper (I), copper (II), zinc (II), iron (III), gallium (III), nickel (II), cobalt (II), cobalt (III), gold (I), gold (III), platinum (II), platinum (IV), manganese (II), palladium (II), titanium (IV), vanadium (IV) and vanadium (V). In one embodiment, the metal cation is copper (II).

[0012] Some further embodiments of the present disclosure relate to a method of treating cancer, comprising selecting a subject having a p53 mutation in the DNA-binding domain; and administering an therapeutically effective amount of a compound of formula (A), formula (I), or formula (II) as described herein, or a pharmaceutically acceptable salt thereof, a specific compound selected from Table 1, or a pharmaceutically acceptable salt thereof, or a metal complex thereof as described herein to a subject in need thereof. The p53 DNA-binding domain includes amino acid residues 101-306 of the p53 protein.

[0013] Some further embodiments of the present disclosure relate to a method of inhibiting cancer cell growth, comprising contacting a cancer cell with an effective amount of a compound of formula (A), formula (I), or formula (II) as described herein, or a pharmaceutically acceptable salt thereof, a specific compound selected from Table 1, or a pharmaceutically acceptable salt thereof, or a metal complex thereof as described herein.

[0014] Some further embodiments of the present disclosure relate to a method of modulating or activating p53 signaling pathway in a mammal, administering a therapeutically effective amount of a compound of formula (A), formula (I), or formula (II) as described herein, or a pharmaceutically acceptable salt thereof, a specific compound selected from Table 1, or a pharmaceutically acceptable salt thereof, or a metal complex thereof as described herein to the mammal in need thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] In addition to the features described above, additional features and variations will be readily apparent from the following descriptions of the drawings and exemplary embodiments. It is to be understood that these drawings depict typical embodiments, and are not intended to be limiting in scope.

[0016] FIGs.1– 6 illustrate various substituted hydrazone compounds.

[0017] FIG.7 illustrates the structure of Compound 105.

DETAILED DESCRIPTION

[0018] p53 is a tumor suppressor protein that controls cell growth and tissue maintenance and plays a central role in preventing tumor suppression and development. The p53 pathway is activated in response to a broad variety of stress signals, such as gamma and UV irradiation, DNA damage, oncogene signaling, lack of nutrients, and oxidative damage, amongst many others. Indeed, studies have demonstrated that p53 plays an important role in the development and progression of cancer, including involvement in cell cycle checkpoints, cellular senescence, autophagy, and apoptosis. Thus, the involvement of p53 in oncogenesis is not limited to a specific cell or tissue type, but rather p53 has broad implications in cellular transformation, independent of other oncongenic drivers and independent of a cancer’s cell type or tissue of origin.

[0019] The level of the p53 response is carefully attenuated by post-translational modifications of the amino acid residues of the p53 protein, such as phosphorylation, acetylation, methylation, ubiquitination, sumoylation, neddylation and glutathionylation. These modifications affect p53 conformation, stability and its ability to form protein complexes with its various partners. The p53 response to stress signals can proceed via a transcription-dependent pathway and a transcription-independent pathway. The p53 transcription-dependent pathway relies on transcriptional up-regulation of genes involved in cell cycle arrest or apoptosis. The p53 transcription-independent pathway exerts its action in part via interactions with the Bcl-2 family of proteins affecting the polarization of the mitochondrial membrane. Other transcription-independent activities of the p53 protein are currently the focus of scientific investigations.

[0020] When assembled into a tetramer, or more specifically into a dimer of dimers, p53 has sequence specific DNA-binding activity and activates expression of a number of genes involved in the DNA-repair mechanism, metabolism, cell cycle arrest, apoptosis and/or senescence of incipient cancer cells. In cancer cells the normal function of p53 is inactivated, which results in uncontrolled proliferation and genomic instability. In approximately 50% of cancers, p53 is inactivated by a missense mutation, a single base-pair substitution that results in translation of a different amino acid. 100+ different mutations have been identified in the p53 DNA-binding domain. p53 mutant proteins are broadly categorized into 3 main types - 1) DNA-contact mutants, 2) structural mutants and 3) conformational mutants. The DNA-contact mutants seem to preserve the wild-type conformation, but lose the ability to form strong contacts with DNA, thus losing transcriptional activity either completely or partially. Structural mutants exhibit localized structural distortions of the amino acid residues, but mostly maintain native-like thermodynamic properties. Conformational mutants are thermodynamically unstable and are prone to rapid unfolding and aggregation. Both structural and conformational mutations are known to destabilize the active conformation of this highly flexible protein and disrupt its normal function. Furthermore, partially unfolded mutant p53 proteins accumulate to high levels in cancer cells and their aggregates exhibit oncogenic gain-of-function properties. As a zinc-binding protein and a sensor of ROS stress in cells, p53 protein is very sensitive to the levels and redox activity of various metal ions, such as iron 3+, iron 2+, zinc 2+, copper 2+ and copper 1+ ions. Small molecules, classified as metal chelators and/or metallochaperones, have been shown to affect the intracellular levels of metal ions and form the redox-active complexes with these metal ions. The redox activities of these complexes lead to the increased levels of reactive oxygene species (ROS) in cells and affect post-translational modifications of p53 protein, such as glutathionylation or oxidation-reduction of cysteine residues at or near the p53-DNA interface and formation of intra- and intermolecular disulfide bonds. These post-translational modifications affect both the conformation and stability of p53 mutant protein and its interactions with DNA and protein partners.

[0021] The present application discloses novel hydrazone derivatives that affect the overall conformation and stability of mutant p53 proteins. The mechanisms of stabilization are 1) increasing intracellular concentration of zinc 2+, copper 2+ and copper 1+ ions by acting as zinc and copper metallochaperones and chelators of metal ions, and 2) by having an effect on the post- translational modifications of p53 protein, such as glutathionylation or oxidation-reduction of cysteine residues at or near the p53-DNA interface and formation of intra- and intermolecular disulfide bonds, via redox activity of their corresponding metal complexes. These post-translational modifications increase the stability of p53 mutant proteins and improve their interactions with DNA and protein partners. As a result, these compounds modulate both the p53 transcription-dependent and transcription-independent activities by stabilizing the active conformation of p53 protein and slowing down its degradation via ubiquitin-proteasome pathway, thereby restoring tumor suppression activity and preventing oncogenic gain-of-function activities of mutant p53 protein Definitions

[0022] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. As used in the specification and the appended claims, the singular forms“a,”“an” and“the” include plural referents unless the context clearly dictates otherwise. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed. Furthermore, use of the term“including” as well as other forms, such as“include”,“includes,” and“included,” is not limiting. As used in this specification, whether in a transitional phrase or in the body of the claim, the terms“comprise(s)” and“comprising” are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases“having at least” or“including at least.” When used in the context of a process, the term“comprising” means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition, or device, the term “comprising” means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components.

[0023] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0024] As used herein, common organic abbreviations are defined as follows:

Ac Acetyl

aq. Aqueous

Bn Benzyl

Bz Benzoyl

BOC or Boc tert-Butoxycarbonyl

Bu n-Butyl

°C Temperature in degrees Centigrade

DCM Methylene chloride

DMF N,N'-Dimethylformamide

DMSO Dimethylsulfoxide

ee% Enantiomeric excess

EtOH Ethanol Et Ethyl

EtOAc Ethyl acetate

g Gram(s)

h or hr Hour(s)

iPr Isopropyl

m or min Minute(s)

MeOH MeOH

mL Milliliter(s)

PG Protecting group

Ph Phenyl

ppt Precipitate

rt Room temperature

Tert, t tertiary

TLC Thin-layer chromatography

µL Microliter(s)

[0025] As used herein, the phrase“p53 signaling pathway” refers to signal transduction cascades that include the p53 protein. These signal transduction cascades include, but not limited to, response to irradiation (for example, gamma or UV exposure), response to DNA damage (for example, missense mutations, nonsense mutation, oxidation, deamination, alkylation, single-strand breaks, and double-strand breaks), response to nutrient depletion, response to oxidative damage (for example, by reactive oxygen species), hypoxia, and response to oncogene signaling (for example, oncogenic Ras and oncogenic Myc signaling).

[0026] “Solvate” refers to the compound formed by the interaction of a solvent and a compound described herein or salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates.

[0027] The term“pharmaceutically acceptable salt” refers to salts that retain the biological effectiveness and properties of a compound and, which are not biologically or otherwise undesirable for use in a pharmaceutical. In many cases, the compounds disclosed herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87/05297, Johnston et al., published September 11, 1987 (incorporated by reference herein in its entirety).

[0028] As used herein,“C_a to C_b” or“C_a-b” in which“a” and“b” are integers refer to the number of carbon atoms in the specified group. That is, the group can contain from“a” to“b”, inclusive, carbon atoms. Thus, for example, a“C₁ to C₄ alkyl” or“C_1-4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH₃-, CH₃CH₂-, CH₃CH₂CH₂-, (CH₃)₂CH-, CH₃CH₂CH₂CH₂-, CH₃CH₂CH(CH₃)- and (CH₃)₃C-.

[0029] The term“halogen” or“halo,” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.

[0030] As used herein,“alkyl” refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds). The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as“1 to 20” refers to each integer in the given range; e.g.,“1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term“alkyl” where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 9 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 4 carbon atoms. The alkyl group may be designated as“C_1-4 alkyl” or similar designations. By way of example only,“C_1-4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl.

[0031] As used herein,“alkoxy” refers to the formula–OR wherein R is an alkyl as is defined above, such as“C_1-9 alkoxy”, including but not limited to methoxy, ethoxy, n-propoxy, 1- methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.

[0032] As used herein,“alkylthio” refers to the formula–SR wherein R is an alkyl as is defined above, such as“C_1-9 alkylthio” and the like, including but not limited to methylmercapto, ethylmercapto, n-propylmercapto, 1-methylethylmercapto (isopropylmercapto), n-butylmercapto, iso-butylmercapto, sec-butylmercapto, and tert-butylmercapto.

[0033] As used herein,“alkenyl” refers to a straight or branched hydrocarbon chain containing one or more double bonds. The alkenyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term“alkenyl” where no numerical range is designated. The alkenyl group may also be a medium size alkenyl having 2 to 9 carbon atoms. The alkenyl group could also be a lower alkenyl having 2 to 4 carbon atoms. The alkenyl group may be designated as“C_2-4 alkenyl” or similar designations. By way of example only,“C_2-4 alkenyl” indicates that there are two to four carbon atoms in the alkenyl chain, i.e., the alkenyl chain is selected from the group consisting of ethenyl, propen-1-yl, propen-2-yl, propen-3-yl, buten-1-yl, buten-2-yl, buten-3-yl, buten-4-yl, 1-methyl-propen-1-yl, 2-methyl-propen-1-yl, 1-ethyl-ethen-1-yl, 2-methyl-propen-3-yl, buta-1,3-dienyl, buta-1,2,-dienyl, and buta-1,2-dien-4-yl. Typical alkenyl groups include, but are in no way limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0034] As used herein,“alkynyl” refers to a straight or branched hydrocarbon chain containing one or more triple bonds. The alkynyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term“alkynyl” where no numerical range is designated. The alkynyl group may also be a medium size alkynyl having 2 to 9 carbon atoms. The alkynyl group could also be a lower alkynyl having 2 to 4 carbon atoms. The alkynyl group may be designated as“C_2-4 alkynyl” or similar designations. By way of example only,“C_2-4 alkynyl” indicates that there are two to four carbon atoms in the alkynyl chain, i.e., the alkynyl chain is selected from the group consisting of ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-3-yl, butyn-4-yl, and 2-butynyl. Typical alkynyl groups include, but are in no way limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0035] As used herein,“heteroalkyl” refers to a straight or branched hydrocarbon chain containing one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the chain backbone. The heteroalkyl group may have 1 to 20 carbon atom, although the present definition also covers the occurrence of the term“heteroalkyl” where no numerical range is designated. The heteroalkyl group may also be a medium size heteroalkyl having 1 to 9 carbon atoms. The heteroalkyl group could also be a lower heteroalkyl having 1 to 4 carbon atoms. The heteroalkyl group may be designated as“C_1-4 heteroalkyl” or similar designations. The heteroalkyl group may contain one or more heteroatoms. By way of example only,“C_1-4 heteroalkyl” indicates that there are one to four carbon atoms in the heteroalkyl chain and additionally one or more heteroatoms in the backbone of the chain.

[0036] The term“aromatic” refers to a ring or ring system having a conjugated pi electron system and includes both carbocyclic aromatic (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of atoms) groups provided that the entire ring system is aromatic.

[0037] As used herein,“aryl” refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent carbon atoms) containing only carbon in the ring backbone. When the aryl is a ring system, every ring in the system is aromatic. The aryl group may have 6 to 18 carbon atoms, although the present definition also covers the occurrence of the term“aryl” where no numerical range is designated. In some embodiments, the aryl group has 6 to 10 carbon atoms. The aryl group may be designated as“C_6-10 aryl,”“C₆ or C₁₀ aryl,” or similar designations. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.

[0038] As used herein,“aryloxy” and“arylthio” refers to RO- and RS-, in which R is an aryl as is defined above, such as“C_6-10 aryloxy” or“C_6-10 arylthio”, including but not limited to phenyloxy.

[0039] An“aralkyl” or“arylalkyl” is an aryl group connected, as a substituent, via an alkylene group, such as“C_7-14 aralkyl”, including but not limited to benzyl, 2-phenylethyl, 3- phenylpropyl, and naphthylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., a C_1-4 alkylene group).

[0040] As used herein,“heteroaryl” refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent atoms) that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the ring backbone. When the heteroaryl is a ring system, every ring in the system is aromatic. The heteroaryl group may have 5-18 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term“heteroaryl” where no numerical range is designated. In some embodiments, the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members. The heteroaryl group may be designated as“5-7 membered heteroaryl,”“5-10 membered heteroaryl,” or similar designations. Examples of heteroaryl rings include, but are not limited to, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinlinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.

[0041] A“heteroaralkyl” or“heteroarylalkyl” is heteroaryl group connected, as a substituent, via an alkylene group. Examples include but are not limited to 2-thienylmethyl, 3- thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazollylalkyl, and imidazolylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., a C_1-4 alkylene group).

[0042] As used herein,“carbocyclyl” means a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system backbone. When the carbocyclyl is a ring system, two or more rings may be joined together in a fused, bridged or spiro-connected fashion. Carbocyclyls may have any degree of saturation provided that at least one ring in a ring system is not aromatic. Thus, carbocyclyls include cycloalkyls, cycloalkenyls, and cycloalkynyls. The carbocyclyl group may have 3 to 20 carbon atoms, although the present definition also covers the occurrence of the term“carbocyclyl” where no numerical range is designated. The carbocyclyl group may also be a medium size carbocyclyl having 3 to 10 carbon atoms. The carbocyclyl group could also be a carbocyclyl having 3 to 6 carbon atoms. The carbocyclyl group may be designated as“C_3-6 carbocyclyl” or similar designations. Examples of carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicycle[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.

[0043] A“(carbocyclyl)alkyl” is a carbocyclyl group connected, as a substituent, via an alkylene group, such as“C_4-10 (carbocyclyl)alkyl” and the like, including but not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, and cycloheptylmethyl. In some cases, the alkylene group is a lower alkylene group.

[0044] As used herein,“cycloalkyl” means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0045] As used herein,“cycloalkenyl” means a carbocyclyl ring or ring system having at least one double bond, wherein no ring in the ring system is aromatic. An example is cyclohexenyl.

[0046] As used herein,“heterocyclyl” means a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. Heterocyclyls may be joined together in a fused, bridged or spiro-connected fashion. Heterocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. The heteroatom(s) may be present in either a non-aromatic or aromatic ring in the ring system. The heterocyclyl group may have 3 to 20 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term “heterocyclyl” where no numerical range is designated. The heterocyclyl group may also be a medium size heterocyclyl having 3 to 10 ring members. The heterocyclyl group could also be a heterocyclyl having 3 to 6 ring members. The heterocyclyl group may be designated as“3-6 membered heterocyclyl” or similar designations. In preferred six membered monocyclic heterocyclyls, the heteroatom(s) are selected from one up to three of O, N and S, and in preferred five membered monocyclic heterocyclyls, the heteroatom(s) are selected from one or two heteroatoms selected from O, N, and S. Examples of heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxanyl, hexahydro- 1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

[0047] A“(heterocyclyl)alkyl” is a heterocyclyl group connected, as a substituent, via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

[0048] As used herein,“acyl” refers to–C(=O)R, wherein R is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 carbocyclyl, C_6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl.

[0049] An“O-carboxy” group refers to a“-OC(=O)R” group in which R is selected from hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 carbocyclyl, C_6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0050] A“C-carboxy” group refers to a“-C(=O)OR” group in which R is selected from hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 carbocyclyl, C_6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein. A non-limiting example includes carboxyl (i.e., -C(=O)OH).

[0051] A“cyano” group refers to a“-CN” group.

[0052] A“sulfonyl” group refers to an“-SO₂R” group in which R is selected from hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 carbocyclyl, C_6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0053] An“S-sulfonamido” group refers to a“-SO₂NR_AR_B” group in which R_A and R_B are each independently selected from hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 carbocyclyl, C_6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0054] An“N-sulfonamido” group refers to a“-N(R_A)SO₂R_B” group in which R_A and R_b are each independently selected from hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 carbocyclyl, C_6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0055] A“C-amido” group refers to a“-C(=O)NR_AR_B” group in which R_A and R_B are each independently selected from hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 carbocyclyl, C_6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0056] An“N-amido” group refers to a“-N(R_A)C(=O)R_B” group in which R_A and R_B are each independently selected from hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 carbocyclyl, C_6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0057] An“amino” group refers to a“-NR_AR_B” group in which R_A and R_B are each independently selected from hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 carbocyclyl, C_6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein. A non-limiting example includes free amino (i.e., -NH₂).

[0058] An“aminoalkyl” group refers to an amino group connected via an alkylene group.

[0059] An“alkoxyalkyl” group refers to an alkoxy group connected via an alkylene group, such as a“C_2-8 alkoxyalkyl” and the like.

[0060] As used herein, a substituted group is derived from the unsubstituted parent group in which there has been an exchange of one or more hydrogen atoms for another atom or group. Unless otherwise indicated, when a group is deemed to be“substituted,” it is meant that the group is substituted with one or more substituents independently selected from C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₁-C₆ heteroalkyl, C₃-C₇ carbocyclyl (optionally substituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), C₃-C₇-carbocyclyl-C₁-C₆-alkyl (optionally substituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 5-10 membered heterocyclyl (optionally substituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 5-10 membered heterocyclyl-C₁-C₆-alkyl (optionally substituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), aryl (optionally substituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), aryl(C₁- C₆)alkyl (optionally substituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 5-10 membered heteroaryl (optionally substituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 5-10 membered heteroaryl(C₁-C₆)alkyl (optionally substituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), halo, cyano, hydroxy, C₁-C₆ alkoxy, C₁-C₆ alkoxy(C₁-C₆)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(C₁-C₆)alkyl (e.g., –CF₃), halo(C₁-C₆)alkoxy (e.g., –OCF₃), C₁-C₆ alkylthio, arylthio, amino, amino(C₁-C₆)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (=O). Wherever a group is described as“optionally substituted” that group can be substituted with the above substituents.

[0061] It is to be understood that certain radical naming conventions can include either a mono-radical or a di-radical, depending on the context. For example, where a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a di- radical. For example, a substituent identified as alkyl that requires two points of attachment includes di-radicals such as–CH₂–,–CH₂CH₂–,–CH₂CH(CH₃)CH₂–, and the like. Other radical naming conventions clearly indicate that the radical is a di-radical such as“alkylene” or“alkenylene.”

[0062] When two R groups are said to form a ring (e.g., a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring)“together with the atom to which they are attached,” it is meant that the collective unit of the atom and the two R groups are the recited ring. The ring is not otherwise limited by the definition of each R group when taken individually. For example, when the following substructure is present:

and R¹ and R² are defined as selected from the group consisting of hydrogen and alkyl, or R¹ and R² together with the nitrogen to which they are attached form a heterocyclyl, it is meant that R¹ and R² can be selected from hydrogen or alkyl, or alternatively, the substructure has structure:

where ring A is a heteroaryl ring containing the depicted nitrogen.

[0063] Similarly, when two“adjacent” R groups are said to form a ring“together with the atom to which they are attached,” it is meant that the collective unit of the atoms, intervening bonds, and the two R groups are the recited ring. For example, when the following substructure is present:

and R¹ and R² are defined as selected from the group consisting of hydrogen and alkyl, or R¹ and R² together with the atoms to which they are attached form an aryl or carbocylyl, it is meant that R¹ and R² can be selected from hydrogen or alkyl, or alternatively, the substructure has structure:

where A is an aryl ring or a carbocylyl containing the depicted double bond.

[0064] Wherever a substituent is depicted as a di-radical (i.e., has two points of attachment to the rest of the molecule), it is to be understood that the substituent can be attached in any directional configuration unless otherwise indicated. Thus, for example, a substituent depicted

A

as–AE– or E includes the substituent being oriented such that the A is attached at the leftmost attachment point of the molecule as well as the case in which A is attached at the rightmost attachment point of the molecule.

[0065] As used herein, "isosteres" of a chemical group are other chemical groups that exhibit the same or similar properties. For example, tetrazole is an isostere of carboxylic acid because it mimics the properties of carboxylic acid even though they both have very different molecular formulae. Tetrazole is one of many possible isosteric replacements for carboxylic acid. Other carboxylic acid isosteres contemplated include -SO₃H, -SO₂HNR, -PO₂(R)₂, -PO₃(R)₂, - CONHNHSO₂R, -COHNSO₂R, and–CONRCN, where R is selected from hydrogen, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-7 carbocyclyl, C_6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein. In addition, carboxylic acid isosteres can include 5-7 membered carbocycles or heterocycles containing any combination of CH₂, O, S, or N in any chemically stable oxidation state, where any of the atoms of said ring structure are optionally substituted in one or more positions. The following structures are non-limiting examples of carbocyclic and heterocyclic isosteres contemplated. The atoms of said ring structure may be optionally substituted at one or more positions with R as defined above.

[0066] It is also contemplated that when chemical substituents are added to a carboxylic isostere, the compound retains the properties of a carboxylic isostere. It is contemplated that when a carboxylic isostere is optionally substituted with one or more moieties selected from R as defined above, then the substitution and substitution position is selected such that it does not eliminate the carboxylic acid isosteric properties of the compound. Similarly, it is also contemplated that the placement of one or more R substituents upon a carbocyclic or heterocyclic carboxylic acid isostere is not a substitution at one or more atom(s) that maintain(s) or is/are integral to the carboxylic acid isosteric properties of the compound, if such substituent(s) would destroy the carboxylic acid isosteric properties of the compound.

[0067] Other carboxylic acid isosteres not specifically exemplified in this specification are also contemplated.

[0068] “Subject” as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate.

[0069] The term“mammal” is used in its usual biological sense. Thus, it specifically includes, but is not limited to, primates, including simians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rodents, rats, mice guinea pigs, or the like.

[0070] The term“pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. In addition, various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press.

[0071] A therapeutic effect relieves, to some extent, one or more of the symptoms of a disease or condition, and includes curing a disease or condition.“Curing” means that the symptoms of a disease or condition are eliminated; however, certain long-term or permanent effects may exist even after a cure is obtained (such as extensive tissue damage).

[0072] “Treat,”“treatment,” or“treating,” as used herein refers to administering a compound or pharmaceutical composition to a subject for prophylactic and/or therapeutic purposes. The term“prophylactic treatment” refers to treating a subject who does not yet exhibit symptoms of a disease or condition, but who is susceptible to, or otherwise at risk of, a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition. The term“therapeutic treatment” refers to administering treatment to a subject already suffering from a disease or condition.

[0073] Where the compounds disclosed herein have at least one chiral center, they may exist as individual enantiomers and diastereomers or as mixtures of such isomers, including racemates. Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included in the scope of the compounds disclosed herein. Furthermore, compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included in the scope of the compounds disclosed herein including any polymorphic forms. In addition, some of the compounds disclosed herein may form solvates with water (i.e., hydrates) or common organic solvents. Unless otherwise indicated, such solvates are included in the scope of the compounds disclosed herein. [0074] The skilled artisan will recognize that some structures described herein may be resonance forms or tautomers of compounds that may be fairly represented by other chemical structures, even when kinetically; the artisan recognizes that such structures may only represent a very small portion of a sample of such compound(s). Such compounds are considered within the scope of the structures depicted, though such resonance forms or tautomers are not represented herein.

[0075] Isotopes can be present in the compounds described. Each chemical element as represented in a compound structure can include any isotope of said element. For example, at any position of the compound that a hydrogen atom is be present, the hydrogen atom encompasses any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise. Deuteration replacement of a hydrogen-1 at a metabolically labile position of a compound may improve the pharmacokinetic properties of the compound. Compounds

Formula (A)

[0076] Some embodiments of the present disclosure relate to compounds having the structure of

(A)

or a pharmaceutically acceptable salt thereof, wherein

rin B is selected from

; wherein

Y¹ is selected from N and CR¹;

Y² is selected from N and CR²;

Y³ is selected from N and CR³;

Y^2a is CR^2a; Y^3a is selected from NR^A, O, and S; and

each R¹, R², R^2a, and R³ is independently selected from the group consisting of H, C_1- ₆ alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)C_1- ₆ alkyl, halo, -CN, -NO₂, -NR^6aR^6b, -OR⁷, -C(O)R⁸, -C(O)OR⁹, -C(O)NR¹⁰R¹¹, -NR¹²C(O)R¹³, and -SO₂R¹⁴;

R¹⁷ is selected from the group consisting of halo, hydroxy, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, oxo, -CN, -NO_2, -NR^6aR^6b, -OR⁷, -C(O)OR⁹, -C(O)NR¹⁰R¹¹, - NR¹²C(O)R¹³, and -SO₂R¹⁴; provided that when each of Y¹, Y², and Y³ is CH, R⁵ is H, ring A is a 6 membered carbocyclyl, and

is substituted with at least one R¹⁵; and

is selected from

. Formula I

[0077] Some embodiments of the present disclosure relate to compounds of formula (A) having the stru

or a pharmaceutically acceptable salt thereof, wherein

Y¹ is selected from N and CR¹;

Y² is selected from N and CR²;

Y³ is selected from N and CR³;

each R¹, R² and R³ is independently selected from the group consisting of H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)C_1-6 alkyl, halo, -CN, - NO ¹⁴

2, -NR^6aR^6b, -OR⁷, -C(O)R⁸, -C(O)OR⁹, -C(O)NR¹⁰R¹¹, -NR¹²C(O)R¹³, and -SO₂R ;

each R^6a, R^6b, R¹⁰, R¹¹ and R¹² is independently selected from the group consisting of H, optionally substituted C_1-6 alkyl, optionally substituted C_6-10 aryl, optionally substituted C_7-14 aralkyl, and optionally substituted C_3-7 cycloalkyl; or R^6a and R^6b together with the nitrogen atom to which they are attached forms optionally substituted 4 to 6 membered heterocyclyl; each R⁷, R⁸, R⁹, R¹³ and R¹⁴ is independently selected from the group consisting of H, optionally substituted C_1-6 alkyl, optionally substituted C_2-6 alkenyl, optionally substituted C_2-6 alkynyl, optionally substituted C_6-10 aryl, optionally substituted C_7-14 aralkyl, and optionally substituted C_3-7 cycloalkyl;

each R¹⁵ and R¹⁶ is independently selected from the group consisting of C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)C_1-6 alkyl, C_6-10 aryl, C_7-14 aralkyl, C_3-7 cycloalkyl, halo, oxo, -CN, -NO₂, -NR^6aR^6b, -OR⁷, -C(O)R⁸, -C(O)OR⁹, - C(O)NR¹⁰R¹¹, -NR¹²C(O)R¹³, and -SO₂R¹⁴, and wherein each of C_6-10 aryl, C_7-14 aralkyl, and C_3-7 cycloalkyl of R¹⁵ is optionally substituted with one to four R¹⁷;

R¹⁷ is selected from the group consisting of halo, hydroxy, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, oxo, -CN, -NO_2, -NR^6aR^6b, -OR⁷, -C(O)OR⁹, -C(O)NR¹⁰R¹¹, -NR¹²C(O)R¹³, and -SO₂R¹⁴; provided that

carbocyclyl, and R⁴ is

selected

then R⁴ is substituted with at least one R¹⁵;

when each of Y¹, Y², and Y³ is CH, R⁵ is H, and R⁴ is selected from

and

,

t en r ng s not .

heterocyclyl and optionally substituted 5, 7 or 8 membered carbocyclyl. In some further embodiments, ring A is selected from selected from optionally substituted 5 to 8 membered monocyclic heterocyclyl.

[0079] In some e

Y³ is CH, R⁵ is H, ring A

,

, then R⁴ is substituted with at least one R¹⁵.

[0080] In some embodiments of the com ounds of formula I when ring A is a six

membered carbocyclyl with the structure

substituted with one or more R¹⁶, then R¹⁶ is not oxo.

[0081] In some embodiments of the compounds of formula (I), each R^6a, R^6b, R¹⁰, R¹¹ and R¹² is independently selected from the group consisting of H, C_1-6 alkyl, C_6-10 aryl, C_7-14 aralkyl, and C_3-7 cycloalkyl; and each C_1-6 alkyl, C_6-10 aryl, C_7-14 aralkyl, and C_3-7 cycloalkyl is optionally substituted with one to four substituents selected from the group consisting of amino, halo, hydroxy, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, (C_1-6 alkoxy)C_1-6 alkyl, C_1-6 haloalkoxy, (C_1-6 haloalkoxy)C_1-6 alkyl, oxo, -CN, -NO_2, thiol, C_1-6 alkylthiol, and sulfonyl. In some other embodiments, R^6a and R^6b together with the nitrogen atom to which they are attached forms an optionally substituted 4 to 6 membered heterocyclyl, for example, azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl.

[0082] In some embodiments of the compounds of formula (I), each R⁷, R⁸, R⁹, R¹³ and R¹⁴ is independently selected from the group consisting of H, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_7-14 aralkyl, and C_3-7 cycloalkyl; and each C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_6-10 aryl, C_7-14 aralkyl, and C_3-7 cycloalkyl is optionally substituted with one to four substituents selected from the group consisting of amino, halo, hydroxy, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, (C_1-6 alkoxy)C_1-6 alkyl, C_1-6 haloalkoxy, (C_1-6 haloalkoxy)C_1-6 alkyl, oxo, -CN, -NO_2, thiol, C_1-6 alkylthiol, and sulfonyl.

[0083] In some embodiments of the compounds of formula (I), Y¹ is CR¹. In some such embodiments, Y² is CR² and Y³ is CR³.

[0084] In some embodiments of the compounds of formula (I), Y¹ is N. In some such embodiments, Y² is CR² and Y³ is CR³.

[0085] In some embodiments of the compounds of formula (I), Y² is N. In some such embodiments, Y¹ is CR¹ and Y³ is CR³.

[0086] In some embodiments of the compounds of formula (I), Y³ is N. In some such embodiments, Y¹ is CR¹ and Y² is CR².

[0087] In some embodiments of the compounds of formula (I), R⁵ is selected from H and C_1-6 alkyl. In some further embodiments, R⁵ is H.

[0088] In some embodiments of the compounds of formula (I), the compounds are also represen f rm l I I I r I

wherein each X is independently selected from CH₂, NR¹⁸, O and S;

R¹⁸ is independently selected from the group consisting of H, optionally substituted C_1-6 alkyl, and optionally substituted C_3-7 cycloalkyl;

each m is independently selected from 0 to 3; and

wherein is optionally substituted with one or more R¹⁶. In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic) or (Id), ring A is not substituted. In some embodiments, ring A is substituted with one or more R¹⁶, provided that if R¹⁶ is oxo, R¹⁶ is not at the corresponding X position of formula (Ia) through (Id).

[0089] In some embodiments of the compounds of formula (Ia), (Ib), (Ic) or (Id), X is CH₂. In some such embodiments of the compounds of formula (Ia), (Ib), (Ic) or (Id), m is 1. The comounds of formula Ia Ib Ic or Id are also reresented b formula Ia1 Ib1 Ic1 or

I I I r I r l r r n f rml I2 I 2 I2 r I2 r i l

[0090] In some embodiments of the compounds of formula (Ia), (Ib), (Ic) or (Id), X is O. In some such embodiments of the compounds of formula (Ia), (Ib), (Ic) or (Id), m is 1. The compounds of formula (Ia), (Ib), (Ic) or (Id) are also represented by formula (Ia3), (Ib3), (Ic3) or

(Id3) respectively:

(Ic3), or

(Id3). In some other embodiments, m is 2. The compounds of formula I I I r I r l r r n f rm l I 4 I 4 I 4 r I 4 r i l

[0091] In some embodiments of the compounds of formula (Ia), (Ib), (Ic) or (Id), X is NR¹⁸. In some such embodiments, R¹⁸ is independently selected from H, C_1-6 alkyl, and substituted C_1-6 alkyl, for example, aralalkyl or alkyl substituted with halo, C_3-7 cycloalkyl, C_1-6 alkoxy, or –NR^6aR^6b.

[0092] In some embodiments of the compounds of formula (I), (Ia) through (Id), (Ia1) through (Id1), (Ia2) through (Id2), (Ia3) through (Id3), and (Ia4) through (Id4), R¹ is H. In some such embodiments, R² is H. In some such embodiments, R³ is H. In some further embodiments, both R² and R³ are H. In some other embodiments, at least one of R¹, R² and R³ is not H.

[0093] In some embodiments of the compounds of formula (I), (Ia) through (Id), (Ia1) through (Id1), (Ia2) through (Id2), (Ia3) through (Id3), and (Ia4) through (Id4), R⁴ is selected from the group consisting of phenyl, 5 or 6 membered heteroaryl, and 9 or 10 membered heteroaryl, each optionally substituted with one or more R¹⁵. In some such embodiments, the 6 membered heteroaryl is selected from the group consisting of pyridyl, pyrimidyl, and pyridazinyl. In some such embodiments, the 5 membered heteroaryl is selected from the group consisting of oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, and thienyl. In some such embodiments, the 9 membered heteroaryl is selected from the group consisting of benzothiazolyl, benzimidazolyl, benzoxazolyl, benzothienyl, indolyl, isoindolyl and indazolyl. In some such embodiments, the 10 membered heteroaryl is selected from quinolinyl, isoquinolinyl, and quinazolinyl. In some particular embodiments, R⁴ is selected from the group c

,

, each optionally substituted with one or more R¹⁵, and wherein R¹⁹ is selected from the group consisting of H, optionally substituted C_1-6 alkyl, and optionally substituted C_3-7 cycloalkyl. In some embodiments, R¹⁹ is selected from H, C_1-6 alkyl, and substituted C_1-6 alkyl, for example, aralalkyl or alkyl substituted with halo, C_3-7 cycloalkyl, C_1-6 alkoxy, or–NR^6aR^6b. In one embodiment, R¹⁹ is CH₃.

[0094] In some embodiments of the compounds of formula (I), (Ia) through (Id), (Ia1) through (Id1), (Ia2) through (Id2), (Ia3) through (Id3), and (Ia4) through (Id4), R⁴ is unsubstituted. In some other embodiments, R⁴ is substituted with one or more R¹⁵. In some such embodiments, R¹⁵ is selected from halo, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, 4 to 6 membered heterocyclyl, and phenyl optionally substituted with one to four R¹⁷. In some embodiments, R¹⁵ is selected from halo, meth l, trifluoromethyl, trifluoromethoxy, N-morpholino, or phenyl. In one embodiment, R⁴ is

substituted with a phenyl optionally substituted with one to four R¹⁷. In some other embodiments, two adjacent R¹⁵ together with the atoms to which they are attached form a 6 membered heterocyclyl optionally with one to four R¹⁷. In one particular

embodiment, the 6 membered heterocyclyl

h n h m n r l fr m f rm l Ia1), and R⁴ is selected from

R⁴ is substituted with at least one R¹⁵. In some other embodiments, when compounds are selected from formula (Ia), each R¹, R²,

R³ is H, and R⁴ is selected from

, then ring A is selected from the group consisting of optionally substituted 5 to 8 membered monocyclic heterocyclyl and optionally substituted monocyclic 5, 7 or 8 membered carbocyclyl. In some further embodiments, ring A is selected from selected from the group consisting of optionally substituted monocyclic 5 to 8 membered heterocyclyl.

Formula (II)

[0096] Some embodiments of the present disclosure relate to compounds of formula (A) having the stru

or a pharmaceutically acceptable salt thereof, wherein

Y^2a is CR^2a;

Y^3a is selected from NR^A, O, and S; and

each R⁷, R⁸, R⁹, R¹³ and R¹⁴ is independently selected from the group consisting of H, optionally substituted C_1-6 alkyl, optionally substituted C_2-6 alkenyl, optionally substituted C_2- ₆ alkynyl, optionally substituted C_6-10 aryl, optionally substituted C_7-14 aralkyl, and optionally substituted C_3-7 cycloalkyl; each R¹⁵ and R¹⁶ is independently selected from the group consisting of C_1-6 alkyl, C_2- ₆ alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, (C_1-6 alkoxy)C_1-6 alkyl, C_6- ₁₀ aryl, C_7-14 aralkyl, 4 to 6 membered heterocyclyl, C_3-7 cycloalkyl, halo, oxo, -CN, -NO₂, - NR^6aR^6b, -OR⁷, -C(O)R⁸, -C(O)OR⁹, -C(O)NR¹⁰R¹¹, -NR¹²C(O)R¹³, and -SO₂R¹⁴, and wherein each of C_6-10 aryl, C_7-14 aralkyl, 4 to 6 membered heterocyclyl, and C_3-7 cycloalkyl of R¹⁵ is optionally substituted with one to four R¹⁷;

R¹⁷ is selected from the group consisting of halo, hydroxy, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, oxo, -CN, -NO_2, -NR^6aR^6b, -OR⁷, -C(O)OR⁹, -C(O)NR¹⁰R¹¹, -NR¹²C(O)R¹³, and -SO₂R¹⁴.

[0097] In some embodiments of the compounds of formula (II), Y^3a is S. In some embodiments of the compounds of formula (II), Y^3a is O. In some embodiments of the compounds of formula (II), Y^3a is NR^A. In some embodiments of the compounds of formula (II), R^A is H or C_1-6 alkyl. In some embodiments of the compounds of formula (II), R^2a is selected from H and C_1-6 alkyl. In some embodiments of the compounds of formula (II), Y^3a is S and R^2a is H. In some embodiments of the compounds of formula (II), R⁵ is selected from H or C_1-6 alkyl.

[0098] In some embodiments of the compounds of formula (II),

selected from the rou consistin of:

wherein each X i

independently selected from the group consisting of H, optionally substituted C_1-6 alkyl, and optionally substituted C_3-7 cycloalkyl; and each n is independently selected from 0 to 3.

[0099] In some embodiments of the compounds of formula (II), X¹ is CH₂.

[0100] In some embodiments, the compound of formula (II) is also represented by formula (IIa1), (IIb1) or (IIc1):

(IIc1).

[0101] In some embodiments, the compound of formula (II) is also represented by formula (IIa2), (IIb2) or (IIc2):

[0102] In some embodiments of the compounds of formula (II), X¹ is O.

[0103] In some embodiments, the compound of formula (II) is also represented by formula (IIa3), (IIb3) or (Ic3):

[0104] In some embodiments, the compound of formula (II) is also represented by formula (IIa4), (IIb4) or (IIc4):

[0105] In some embodiments of the compounds of formula (II), (IIa1) through (IIc1), (IIa2) through (IIc2), (IIa3) through (IIc3), and (IIa4) through (IIc4), R^2a is H.

[0106] In some embodiments of the compounds of formula (II), (IIa1) through (IIc1), (IIa2) through (IIc2), (IIa3) through (IIc3), and (IIa4) through (IIc4), R⁴ is 5 or 6 membered heteroaryl or 9 or 10 membered heteroaryl, each optionally substituted with one or more R¹⁵.

[0107] In some embodiments of the compounds of formula (II), (IIa1) through (IIc1), (IIa2) through (IIc2), (IIa3) through (IIc3), and (IIa4) through (IIc4), the 6 membered heteroaryl is selected from the group consisting of pyridyl, pyrimidyl, and pyridazinyl.

[0108] In some embodiments of the compounds of formula (II), (IIa1) through (IIc1), (IIa2) through (IIc2), (IIa3) through (IIc3), and (IIa4) through (IIc4), the 5 membered heteroaryl is selected from the group consisting of oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, and thienyl.

[0109] In some embodiments of the compounds of formula (II), (IIa1) through (IIc1), (IIa2) through (IIc2), (IIa3) through (IIc3), and (IIa4) through (IIc4), the 9 membered heteroaryl is selected from the group consisting of benzothiazolyl, benzimidazolyl, benzoxazolyl, benzothienyl, indolyl, isoindolyl and indazolyl.

[0110] In some embodiments of the compounds of formula (II), (IIa1) through (IIc1), (IIa2) through (IIc2), (IIa3) through (IIc3), and (IIa4) through (IIc4), the 10 membered heteroaryl is selected from quinolinyl, isoquinolinyl, and quinazolinyl.

[0111] In some embodiments of the compounds of formula (II), (IIa1) through (IIc1), (IIa2) through (IIc2), (IIa3) through (IIc3), and (IIa4) through (IIc4), R⁴ is selected from the group

the group consisting of H, optionally substituted C_1-6 alkyl, and optionally substituted C_3-7 cycloalkyl.

[0112] In some embodiments of the compounds of formula (II), (IIa1) through (IIc1), (IIa2) through (IIc2), (IIa3) through (IIc3), and (IIa4) through (IIc4), R¹⁵ is selected from halo, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, 4 to 6 membered heterocyclyl, and phenyl optionally substituted with one to four R¹⁷.

[0113] In some embodiments of the compounds of formula (II), (IIa1) through (IIc1), (IIa2) through (IIc2), (IIa3) through (IIc3), and (IIa4) through (IIc4), two adjacent R¹⁵ together with the atoms to which they are attached form a 6 membered heterocyclyl optionally substituted with one to four R¹⁷. [0114] In some embodiments of the compounds of formula (II), (IIa1) through (IIc1), (IIa2) through (IIc2), (IIa3) through (IIc3), and (IIa4) through (IIc4), the 6 membered heterocyclyl is

[0115] In some embodiments, the compound of formula (A), formula (I), or formula (II) is selected from Compounds 1 through 104, 107 through 110, and 112 through 117 of Table 1, or pharmaceutically acceptable salts thereof.

compounds selected from compounds D, I, L, M, N, O, R, S, V, W, Y, Z, AA, AB, AD, AE, AG, AH, AI, AJ, AK, AL, AM, AN, AO, AP of Table 2, or pharmaceutically acceptable salts thereof.

[0117] In any embodiments of the compounds of formula (A), formula (I), formula (II) or any substructures thereof, including but not limited to formulae (Ia) through (Id), formulae (Ia1) through (Id1), formulae (Ia2) through (Id2), formulae (Ia3) through (Id3), formulae (Ia4) through (Id4), formulae (IIa1) through (IIc1), formulae (IIa2) through (IIc2), formulae (IIa3) through (IIc3), formulae (IIa4) through (IIc4), and the individual compounds disclosed in Table 1 and Table 2, the substituted hydrazones may encompass of the compounds in

the E isomerization form, for exampl do not exclude the

corresponding Z isomer of formula (Ia’)

Metal Complexes of Substituted Hydrazone Compounds

[0118] Some embodiments described herein relate to metal complexes comprising a metal cation selected from the group consisting of copper (I), copper (II), zinc (II), iron (III), gallium (III), nickel (II), cobalt (II), cobalt (III), gold (I), gold (III), platinum (II), platinum (IV), manganese (II), palladium (II), titanium (IV), vanadium (IV) and vanadium (V), and a compound of formula (A), formula (I), formula (II) described herein, a specific compound selected from Table 1, a specific compound selected from Table 2, or an anion or solvate of any of the foregoing. In one embodiment, the metal cation is Cu²⁺. In another embodiment, the metal cation is Zn²⁺. In some embodiments, the metal complex is charge neutral.

[0119] Some further embodiments described herein relate to metal complexes comprising a metal cation selected from the group consisting of copper (I), copper (II), zinc (II), iron (III), gallium (III), nickel (II), cobalt (II), cobalt (III), gold (I), gold (III), platinum (II), platinum (IV), manganese (II), palladium (II), titanium (IV), vanadium (IV) and vanadium (V), and a substituted hydrazone compound selected from Table 2. In some embodiments, the metal complexes comprise a substituted hydrazone compound selected from the group consisting of compounds A, C, D, I, L, M, N, O, R, S, V, W, Y, Z, AA, AB, AD, AE, AG, AH, AI, AJ, AK, AL, AM, AN, AO, AP of Table 2, or an anion or solvate thereof. In one embodiment, the metal cation is Cu²⁺. In another embodiment, the metal cation is Zn²⁺. In some embodiments, the metal complex is charge neutral.

[0120] Some further embodiments described herein relate to copper (II) metal complexes comprising Cu²⁺ and a compound selected from Table 2, or an anion or solvate thereof. In some embodiments, the metal complex is charge neutral.

[0121] In some embodiments, the metal cation and the substituted hydrazone compound described herein forms the metal complex in a molar ratio of 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, or 1:2. In one particular embodiment, Cu²⁺ and the substituted hydrazone compound described herein forms a metal complex in a ratio of 1:1. In another embodiment, Zn²⁺ and the substituted hydrazone compound described herein forms a metal complex in a ratio of 1:2. Depending on the synthetic procedure, a particular metal complex may contain different ratios of the metal cation to the substituted hydrazone. For example, the majority of a metal complex may exist in a ratio of 1:1 metal cation to the substituted hydrazone and also exist in a ratio of 1:2 metal cation to the substituted hydrazone.

[0122] Various embodiments of the present disclosure, including but not limited to substituted hydrazone compounds, pharmaceutical salts, compositions and metal complexes thereof, and methods of treating cancer do not include the specific compounds of FIGs. 1-6 as disclosed in PCT Publications No. WO 2016/123250 A1 and WO 2016/123253 A1, both of which are hereby incorporated by reference, and particularly for the purpose of describing such disclosed compounds of FIGs.1-6.

Administration and Pharmaceutical Compositions

[0123] Some embodiments include pharmaceutical compositions comprising: (a) a therapeutically effective amount of a compound described herein (including enantiomers, diastereoisomers, tautomers, polymorphs, and solvates thereof), or pharmaceutically acceptable salts thereof; or a metal complex comprising a compound described herein and (b) a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

[0124] The compounds are administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for the disease states previously described. While human dosage levels have yet to be optimized for the compounds of the preferred embodiments, generally, a daily dose for most of the compounds described herein is from about 0.25 mg/kg to about 120 mg/kg or more of body weight, from about 0.5 mg/kg or less to about 70 mg/kg, from about 1.0 mg/kg to about 50 mg/kg of body weight, or from about 1.5 mg/kg to about 10 mg/kg of body weight. Thus, for administration to a 70 kg person, the dosage range would be from about 17 mg per day to about 8000 mg per day, from about 35 mg per day or less to about 7000 mg per day or more, from about 70 mg per day to about 6000 mg per day, from about 100 mg per day to about 5000 mg per day, or from about 200 mg to about 3000 mg per day. The amount of active compound administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician.

[0125] Administration of the compounds disclosed herein or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, or intraocularly. Oral and parenteral administrations are customary in treating the indications that are the subject of the preferred embodiments.

[0126] The compounds useful as described above can be formulated into pharmaceutical compositions for use in treatment of these conditions. Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005), incorporated by reference in its entirety.

[0127] In addition to the selected compound useful as described above, come embodiments include compositions containing a pharmaceutically-acceptable carrier. The term "pharmaceutically-acceptable carrier", as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances, which are suitable for administration to a mammal. The term "compatible", as used herein, means that the components of the composition are capable of being commingled with the subject compound, and with each other, in a manner such that there is no interaction, which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations. Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration preferably to an animal, preferably mammal being treated.

[0128] Some examples of substances, which can serve as pharmaceutically-acceptable carriers or components thereof, are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0129] The choice of a pharmaceutically-acceptable carrier to be used in conjunction with the subject compound is basically determined by the way the compound is to be administered.

[0130] The compositions described herein are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition containing an amount of a compound that is suitable for administration to an animal, preferably mammal subject, in a single dose, according to good medical practice. The preparation of a single or unit dosage form however, does not imply that the dosage form is administered once per day or once per course of therapy. Such dosage forms are contemplated to be administered once, twice, thrice or more per day and may be administered as infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), or administered as a continuous infusion, and may be given more than once during a course of therapy, though a single administration is not specifically excluded. The skilled artisan will recognize that the formulation does not specifically contemplate the entire course of therapy and such decisions are left for those skilled in the art of treatment rather than formulation.

[0131] The compositions useful as described above may be in any of a variety of suitable forms for a variety of routes for administration, for example, for oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, or other parental routes of administration. The skilled artisan will appreciate that oral and nasal compositions include compositions that are administered by inhalation, and made using available methodologies. Depending upon the particular route of administration desired, a variety of pharmaceutically-acceptable carriers well-known in the art may be used. Pharmaceutically- acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropies, surface-active agents, and encapsulating substances. Optional pharmaceutically-active materials may be included, which do not substantially interfere with the inhibitory activity of the compound. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods described herein are described in the following references, all incorporated by reference herein: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004).

[0132] Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Liquid oral dosage forms include aq. solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.

[0133] The pharmaceutically-acceptable carriers suitable for the preparation of unit dosage forms for peroral administration is well-known in the art. Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical, and can be readily made by a person skilled in the art.

[0134] Peroral compositions also include liquid solutions, emulsions, suspensions, and the like. The pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include EtOH, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above. [0135] Such compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.

[0136] Compositions described herein may optionally include other drug actives.

[0137] Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.

[0138] For ophthalmic application, solutions or medicaments are often prepared using a physiological saline solution as a major vehicle. Ophthalmic solutions should preferably be maintained at a comfortable pH with an appropriate buffer system. The formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants. Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor. Other excipient components, which may be included in the ophthalmic preparations, are chelating agents. A useful chelating agent is edetate disodium, although other chelating agents may also be used in place or in conjunction with it.

[0139] For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compound disclosed herein are employed. Topical formulations may generally be comprised of a pharmaceutical carrier, co-solvent, emulsifier, penetration enhancer, preservative system, and emollient.

[0140] For intravenous administration, the compounds and compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent, such as a saline or dextrose solution. Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HCl, and citric acid. In various embodiments, the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7. Antioxidant excipients may include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition may include sodium or potassium phosphates, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. Further acceptable excipients are described in Powell, et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52238-311 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of which are incorporated herein by reference in their entirety. Antimicrobial agents may also be included to achieve a bacteriostatic or fungistatic solution, including but not limited to phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.

[0141] The compositions for intravenous administration may be provided to caregivers in the form of one more solids that are reconstituted with a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration. In other embodiments, the compositions are provided in solution ready to administer parenterally. In still other embodiments, the compositions are provided in a solution that is further diluted prior to administration. In embodiments that include administering a combination of a compound described herein and another agent, the combination may be provided to caregivers as a mixture, or the caregivers may mix the two agents prior to administration, or the two agents may be administered separately.

[0142] The actual dose of the active compounds described herein depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.

Methods of Treatment

[0143] The mutations of p53 tumor suppressor proteins that lead to loss of wild-type p53 activity are frequently detected in many different tumor types. Perturbations in p53 signaling pathways are believed to be required for the development of most cancers, and therefore restoration or reactivation of p53 function will have significant therapeutic benefit. See Muller et al., Cancer Cell, 2014; 24:304-317.

[0144] Some embodiments of the present disclosure relate to a method of treating cancer, comprising selecting a subject having a p53 mutation in the DNA-binding domain; and administering an therapeutically effective amount of a compound of formula (A), formula (I), formula (II) as described herein, or a pharmaceutically acceptable salt thereof, a specific compound selected from Table 1, a pharmaceutically acceptable salt thereof, a metal complex thereof, or a pharmaceutical composition thereof to a subject in need thereof. In some embodiments, the metal complex is copper (II) complex. [0145] Some embodiments of the present disclosure relate to methods of modulating or activating a p53 signaling pathway in a subject, comprising administering a therapeutically effective amount of a compound a compound a compound of formula (A), formula (I), formula (II) as described herein, or a pharmaceutically acceptable salt thereof, a specific compound selected from Table 1, a pharmaceutically acceptable salt thereof, a metal complex thereof, or a pharmaceutical composition thereof to a subject in need thereof. In some embodiments, the metal complex is copper (II) complex.

[0146] Some embodiments of the present disclosure relate to methods of inhibiting cancer cell growth, comprising contacting a cancer cell with an effective amount of a compound of formula (A), formula (I), formula (II) as described herein, or a pharmaceutically acceptable salt thereof, a specific compound selected from Table 1, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, or a metal complex thereof. In some embodiments, the metal complex is copper (II) complex.

[0147] Some embodiments of the present disclosure relate to a method of treating cancer, comprising selecting a subject having a p53 mutation in the DNA-binding domain; and administering an therapeutically effective amount of a compound selected from Compounds A, C through I and L through AP in Table 2, a pharmaceutically acceptable salt thereof, a metal complex thereof, or a pharmaceutical composition thereof to a subject in need thereof. In some embodiments, the metal complex is copper (II) complex.

[0148] Some embodiments of the present disclosure relate to methods of modulating or activating p53 signaling pathway in a subject, comprising administering a therapeutically effective amount of a compound a compound a compound selected from Compounds A, C through I and L through AP in Table 2, a pharmaceutically acceptable salt thereof, a metal complex thereof, or a pharmaceutical composition thereof to a subject in need thereof. In some embodiments, the metal complex is copper (II) complex.

[0149] Some embodiments of the present disclosure relate to methods of inhibiting cancer cell growth, comprising contacting a cancer cell with an effective amount of a compound selected from Compounds A, C through I and L through AP in Table 2, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, or a metal complex thereof. In some embodiments, the metal complex is copper (II) complex.

[0150] Non-limiting examples of cancer that may be treated include breast cancer, lung cancer, colon cancer, prostate cancer, liver cancer, cervical cancer, ovarian cancer, bladder cancer, brain cancer, esophageal cancer, kidney cancer, leukemia, melanoma, non-hodgkin lymphoma, pancreatic cancer, skin cancer, thyroid cancer, and endometrial cancer.

[0151] Non-limiting examples of cancer cells that may have their growth inhibited include a breast cancer cell, a lung cancer cell, a colon cancer cell, a prostate cancer cell, a liver cancer cell, a cervical cancer cell, an ovarian cancer cell, a bladder cancer cell, a brain cancer cell, an esophageal cancer cell, a kidney cancer cell, a leukemia cell, a melanoma cell, a non-hodgkin lymphoma cell, a pancreatic cancer cell, a skin cancer cell, a thyroid cancer cell, and an endometrial cancer cell.

[0152] In some embodiments, the cancer cell has been identified as possessing wild-type p53. In some embodiments, the cancer cell has been identified as underexpressing p53. In some embodiments, the cancer cell has been identified as possessing a p53 mutation.

[0153] In some embodiments, the subject is a human. In some embodiments, the subject has been identified as possessing a p53 mutation. In some embodiments, the p53 mutation is in the p53 DNA-binding domain. Non-limiting examples of p53 mutations include, but are not limited to, mutations in amino acid residues 175, 176, 179, 220, 238, 242, 245, 248, 249, 273, 280, and 282, for example, R273H, R273C, R175H, R175L, G245S, G245D, R249S, R282W, C242W, R248Q, R248W, Y220C, and R280K. In an embodiment, the p53 mutation affects an amino acid involved in binding Zn²⁺ ion. Non-limiting examples of p53 mutations that affect an amino acid involved in binding Zn²⁺ ion include those in which the the p53 mutation is in an amino acid residue selected from 175, 176, 179, 238, 242 and 245.

[0154] The terms“therapeutically effective amount,” as used herein, refer to an amount of a compound sufficient to cure, ameliorate, slow progression of, prevent, or reduce the likelihood of onset of the identified disease or condition, or to exhibit a detectable therapeutic, prophylactic, or inhibitory effect. The effect can be detected by, for example, the assays disclosed in the following examples. The precise effective amount for a subject will depend upon the subject's body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically and prophylactically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0155] For any compound, the therapeutically or prophylactically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.

[0156] Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., IC₅₀ is a measure of how effective a drug is. It indicates how much of a particular drug compound is needed to inhibit a given biological process (e.g., a cancer cell line) by half. It is commonly used as a measure of antagonist drug potency in pharmacological research. ED₅₀ (the dose therapeutically effective in 50% of the population) and LD₅₀ (the dose lethal to 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index, and it can be expressed as the ratio, ED₅₀/LD₅₀. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. However, pharmaceutical compositions that exhibit narrow therapeutic indices are also within the scope of the invention. The data obtained from cell culture assays and animal studies may be used in formulating a range of dosage for human use. The dosage contained in such compositions is preferably within a range of circulating concentrations that include an ED₅₀ with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.

[0157] The exact dosage will be determined by the practitioner, in light of factors related to the subject that requires treatment. Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.

[0158] In one aspect, treating a condition described herein results in an increase in average survival time of a population of treated subjects in comparison to a population of untreated subjects. Preferably, the average survival time is increased by more than about 30 days; more preferably, by more than about 60 days; more preferably, by more than about 90 days; and even more preferably by more than about 120 days. An increase in survival time of a population may be measured by any reproducible means. In a preferred aspect, an increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound. In an another preferred aspect, an increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.

[0159] In another aspect, treating a condition described herein results in a decrease in the mortality rate of a population of treated subjects in comparison to a population of subjects receiving carrier alone. In another aspect, treating a condition described herein results in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. In a further aspect, treating a condition described herein results a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound of the embodiments, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof. Preferably, the mortality rate is decreased by more than about 2%; more preferably, by more than about 5%; more preferably, by more than about 10%; and most preferably, by more than about 25%. In a preferred aspect, a decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means. In another preferred aspect, a decrease in the mortality rate of a population may be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with an active compound. In another preferred aspect, a decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease related deaths per unit time following completion of a first round of treatment with an active compound.

[0160] In another aspect, treating a condition described herein results in a reduction in the rate of cellular proliferation. Preferably, after treatment, the rate of cellular proliferation is reduced by at least about 5%; more preferably, by at least about 10%; more preferably, by at least about 20%; more preferably, by at least about 30%; more preferably, by at least about 40%; more preferably, by at least about 50%; even more preferably, by at least about 60%; and most preferably, by at least about 75%. The rate of cellular proliferation may be measured by any reproducible means of measurement. In a preferred aspect, the rate of cellular proliferation is measured, for example, by measuring the number of dividing cells in a tissue sample per unit time.

[0161] In another aspect, treating a condition described herein results in a reduction in the proportion of proliferating cells. Preferably, after treatment, the proportion of proliferating cells is reduced by at least about 5%; more preferably, by at least about 10%; more preferably, by at least about 20%; more preferably, by at least about 30%; more preferably, by at least about 40%; more preferably, by at least about 50%; even more preferably, by at least about 60%; and most preferably, by at least about 75%. The proportion of proliferating cells may be measured by any reproducible means of measurement. In a preferred aspect, the proportion of proliferating cells is measured, for example, by quantifying the number of dividing cells relative to the number of nondividing cells in a tissue sample. In another preferred aspect, the proportion of proliferating cells is equivalent to the mitotic index.

[0162] In another aspect, treating a condition described herein results in a decrease in size of an area or zone of cellular proliferation. Preferably, after treatment, size of an area or zone of cellular proliferation is reduced by at least 5% relative to its size prior to treatment; more preferably, reduced by at least about 10%; more preferably, reduced by at least about 20%; more preferably, reduced by at least about 30%; more preferably, reduced by at least about 40%; more preferably, reduced by at least about 50%; even more preferably, reduced by at least about 60%; and most preferably, reduced by at least about 75%. Size of an area or zone of cellular proliferation may be measured by any reproducible means of measurement. In a preferred aspect, size of an area or zone of cellular proliferation may be measured as a diameter or width of an area or zone of cellular proliferation.

[0163] The methods described herein may include identifying a subject in need of treatment. In a preferred embodiment, the methods include identifying a mammal in need of treatment. In a highly preferred embodiment, the methods include identifying a human in need of treatment, where the human has p53 mutation in the DNA-binding domain. Identifying a subject in need of treatment may be accomplished by any means that indicates a subject who may benefit from treatment. For example, identifying a subject in need of treatment may occur by clinical diagnosis, laboratory testing such as genomic sequencing, or any other means known to one of skill in the art, including any combination of means for identification. In some embodiments, a subject in need of treatment has been identified as possessing a p53 mutation. In some embodiments, p53 mutations include, but are not limited to, R273H, R273C, R175H, R175L, G245S, G245D, R249S, R282W, C242W, R248Q, R248W, Y220C, and R280K.

[0164] In some embodiments, the cancer cell has been identified as possessing low levels of wild-type p53. In some embodiments, the subject has been identified as possessing a p53 mutation. In some embodiments, the subject has been identified as possessing high levels of p53 protein having the p53 mutation. The terms“low levels” and“high levels” of p53, as used herein, refers to a lower than normal amount of p53 protein and a higher than normal amount of p53 protein, respectively. The normal amount of p53 protein refers to the p53 levels found in a normal cell of the same cell type, a normal tissue of the same tissue type, and/or a normal human subject. Thus, a low level of p53 refers to a lower level of p53 relative to the normal amount of p53. Similarly, a high level of p53 refers to a higher level of p53 relative to the normal amount of p53. [0165] As described elsewhere herein, the compounds described herein may be formulated in pharmaceutical compositions, if desired, and can be administered by any route that permits treatment of the disease or condition. A preferred route of administration is oral administration. Administration may take the form of single dose administration, or the compound of the embodiments can be administered over a period of time, either in divided doses or in a continuous-release formulation or administration method (e.g., a pump). However the compounds of the embodiments are administered to the subject, the amounts of compound administered and the route of administration chosen should be selected to permit efficacious treatment of the disease condition.

[0166] Further embodiments include administering a combination of compounds to a subject in need thereof. A combination can include a compound, composition, pharmaceutical composition described herein with an additional medicament.

[0167] Some embodiments include co-administering a compound, composition, and/or pharmaceutical composition described herein, with an additional medicament. By “co- administration,” it is meant that the two or more agents may be found in the patient’s bloodstream at the same time, regardless of when or how they are actually administered. In some embodiments, the agents are administered simultaneously. In some such embodiments, administration in combination is accomplished by combining the agents in a single dosage form. In some embodiments, the agents are administered sequentially. In some embodiments the agents are administered through the same route, such as orally. In some other embodiments, the agents are administered through different routes, such as one being administered orally and another being administered i.v. Thus, for example, the combination of active ingredients may be: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by any other combination therapy regimen known in the art. When delivered in alternation therapy, the methods described herein may comprise administering or delivering the active ingredients sequentially, e.g., in separate solution, emulsion, suspension, tablets, pills or capsules, or by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in simultaneous therapy, effective dosages of two or more active ingredients are administered together. Various sequences of intermittent combination therapy may also be used.

Synthesis

[0168] The compounds disclosed herein may be synthesized by methods described below, or by modification of these methods. Ways of modifying the methodology include, among others, temperature, solvent, reagents etc., known to those skilled in the art. In general, during any of the processes for preparation of the compounds disclosed herein, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (ed. J.F.W. McOmie, Plenum Press, 1973); and P.G.M. Green, T.W. Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999), which are both hereby incorporated herein by reference in their entirety. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. Synthetic chemistry transformations useful in synthesizing applicable compounds are known in the art and include e.g. those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989, or L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995, which are both hereby incorporated herein by reference in their entirety. The routes shown and described herein are illustrative only and are not intended, nor are they to be construed, to limit the scope of the claims in any manner whatsoever. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise alternate routes based on the disclosures herein; all such modifications and alternate routes are within the scope of the claims.

EXAMPLES

[0169] Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims.

General Procedure I for the syntheses of the substituted hydrazones

[0170] Scheme 1 illustrates a general synthetic route for the preparation of the substituted hydrazone compounds described herein. The corresponding ketone (1.1 eq.) and the corresponding hydrazine (1.0 eq.) are dissolved in MeOH (0.24 M), followed by a catalytic amount of glacial acetic acid. The mixture is heated to 80°C until full conversion was observed by means of thin layer chromatography (TLC silica gel 60 F₂₅₄). Then the mixture is cooled to approx. 5°C and kept at 5°C for 16 hours. The formed precipitate is isolated by filtration or centrifugation. The isolated solid was washed with DI water, a small amount of cold MeOH, followed by a small amount of diethyl ether, and then dried in vacuo. If no precipitate forms, water is added to the mixture and it is stored at about 5°C for another 16 hours. The isolated solid is recrystallized from a mixture of EtOH and water. In cases when no precipitation is observed, the volatiles are removed in vacuo and the crude mixture is purified by column chromatography on silica gel using a gradient of EtOAc in hexanes as an eluent.

General Procedure II for the syntheses of the substituted hydrazones

[0171] The corresponding ketone (1.1 eq.) and the corresponding hydrazine (1.0 eq.) were dissolved in MeOH (0.24 M), followed by the addition of a catalytic amount of glacial acetic acid. The mixture was heated to 80 °C until full conversion was observed by means of thin layer chromatography (TLC silica gel 60 F254). After cooling down to rt, a small amount of water was added and the mixture was cooled to approx.5 °C and kept at 5 °C for 16 h. Formed precipitate was isolated by centrifugation, and the isolated solid was recrystallized from a mixture of EtOH and water and then dried in vacuo.

General Procedure III: syntheses of the metal complexes

[0172] The corresponding metal salt (1 eq.) is dissolved in MeOH (0.1 M) and then a solution of the corresponding substituted hydrazone compound (1 eq.) in MeOH (0.1 M) is added dropwise at rt. The mixture is refluxed for 2 hours. Partial evaporation of the MeOH gives the desired metal complex as a powder. Crystals that are suitable for X-ray analysis are obtained by slow evaporation from EtOH.

[0173] Following the general procedure, copper (II) complexes of the compounds described herein are prepared by reacting copper (II) acetate or copper (II) chloride with the corresponding substituted hydrazone.

[0174] The copper (II) acetate complex of Compound A was obtained according to the general procedure II as dark green crystals in about 52% yield. The structural composition of the complex was confirmed by SEM-EDX analysis as a 1:1 ratio of Cu²⁺ and Compound A.

[0175] The copper (II) acetate complex of Compound B was obtained according to the general procedure II as dark red crystals in about 77% yield. The structural composition of the complex was confirmed by SEM-EDX analysis as a 1:1 ratio of Cu²⁺ and Compound B.

Example 1: Compounds 1-3

No. Structure Chemical Name (E)-5-Chloro-2-(2-(5,6-dihydro-7H-cyclopenta[b]pyridin- 1 7-ylidene)hydrazinyl) benzo[d]thiazole

[0176] Compounds 1-3 were synthesized according to the general procedure I, with the exception that no diethyl ether wash was performed during the work-up of 3.

[0177] Compound 1 was obtained as a white solid in 63% yield. ¹H-NMR (400 MHz, DMSO-d₆): δ 11.80 (bs, 1H), 8.55 (d, J = 4.6 Hz, 1H), 7.81 (dd, J = 7.3, 3.8 Hz, 2H), 7.49 (s, 1H), 7.33 (dd, J = 7.7, 4.7 Hz, 1H), 7.15 (dd, J = 8.4, 2.0 Hz, 1H), 3.08 (t, J = 6.0 Hz, 2H), 2.93 (t, J = 6.3 Hz, 2H).

[0178] Compound 2 was obtained as a pale pink solid in 66% yield.¹H-NMR (400 MHz, DMSO-d₆): δ 11.75 (bs, 1H), 8.55 (dd, J = 4.7, 1.5 Hz, 1H), 7.94 (s, 1H), 7.81 (dd, J = 7.7, 1.4 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.36-7.30 (m, 2H), 3.10-3.05 (m, 2H), 2.94-2.91 (m, 2H).

[0179] Compound 3 was obtained as a yellow solid in 51% yield. ¹H-NMR (400 MHz, DMSO-d₆): δ 14.68 (bs, 1H), 8.40 (dd, J = 4.5, 1.4 Hz, 1H), 8.18 (dd, J = 4.7, 1.4 Hz, 1H), 7.81 (dd, J = 7.7, 1.5 Hz, 1H), 7.55 (dd, J = 8.4, 1.4 Hz, 1H), 7.47 (dd, J = 8.4, 4.5 Hz, 1H), 6.86 (dd, J = 7.8, 4.8 Hz, 1H), 4.44 (t, J = 5.8 Hz, 2H), 2.94 (t, J = 5.8 Hz, 2H). Example 2: Compound 4

[0180] Compound 4 was synthesized according to the general procedure I. Since no precipitate formed, the mixture was evaporated to dryness, and the residue was dissolved in hot EtOH. Water was added and the solution was stored at +4 °C for 16 hr. An orange precipitate formed, which was isolated by centrifugation, washed with diethyl ether and dried in vacuo. The product was obtained as an orange solid in 41% yield as mixture of E/Z-isomers (89:11). Major isomer: ¹H-NMR (400 MHz, DMSO-d₆): δ 9.91 (bs, 1H), 8.28 (dd, J = 4.3, 1.5 Hz, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.31 (dd, J = 8.3, 1.5 Hz, 1H), 7.24 (dd, J = 8.3, 4.3 Hz, 1H), 7.17 (s, 1H), 6.67 (d, J = 5.0 Hz, 1H), 4.29 (t, J = 6.1 Hz, 2H), 3.00 (t, J = 6.2 Hz, 2H), 2.31 (s, 3H). Minor isomer: ¹H-NMR (400 MHz, DMSO-d₆): δ 13.69 (bs, 1H), 8.39 (dd, J = 4.5, 1.4 Hz, 1H), 7.99 (d, J = 5.1 Hz, 1H), 7.54-7.50 (m, 1H), 7.43 (dd, J = 8.4, 4.6 Hz, 1H), 7.13 (s, 1H), 6.67-6.64 (m, 1H), 4.41 (t, J = 5.7 Hz, 2H), 2.90 (t, J = 6.0 Hz, 2H), 2.29 (s, 3H). Example 3: Compounds 5-7

[0181] Compounds 5-7 were synthesized according to the general procedure I.

[0182] Compound 5 was obtained as an orange solid in 41% yield as a mixture of E/Z- isomers (90:10).¹H-NMR (400 MHz, DMSO-d₆): δ 8.26 (dd, J = 4.3, 1.5 Hz, 1H), 7.37 (dd, J = 8.3, 1.5 Hz, 1H), 7.30 (dd, J = 8.3, 4.3 Hz, 1H), 6.84 (dd, J = 7.5, 1.4 Hz, 1H), 6.76 (td, J = 7.6, 1.5 Hz, 1H), 6.58-6.53 (m, 2H), 6.17 (d, J = 1.9 Hz, 1H), 4.82 (dd, J = 10.9, 5.7 Hz, 1H), 4.70 (dd, J = 11.3, 2.1 Hz, 1H), 3.98 (dd, J = 12.3, 11.1 Hz, 1H), 3.65-3.53 (m, 1H), 3.50 (s, 3H).

[0183] Compound 6 was obtained as a light yellow solid in 73% yield as a mixture of E/Z-isomers (95:5). ¹H-NMR (400 MHz, DMSO-d₆): δ 11.38 (bs, 1H), 8.29 (dd, J = 4.2, 1.7 Hz, 1H), 7.47 (bs, 1H), 7.39-7.24 (m, 3H), 7.19 (t, J = 7.7 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 4.32 (t, J = 6.2 Hz, 2H), 3.07 (t, J = 5.9 Hz, 2H).

[0184] Compound 7 was obtained as a yellow solid in 67% yield. ¹H-NMR (400 MHz, DMSO-d₆): δ 12.15 (bs, 1H), 8.31 (dd, J = 4.2, 1.6 Hz, 1H), 7.78 (d, J = 6.6 Hz, 1H), 7.39-7.30 (m, 3H), 7.10 (td, J = 7.8, 2.1 Hz, 1H), 4.34 (t, J = 6.1 Hz, 2H), 3.06 (t, J = 6.2 Hz, 2H). Example 4: Compounds 8-11

[0185] Compounds 8-11 were synthesized according to the general procedure I.

[0186] Compound 8 was obtained as an off-white solid in 68% yield. ¹H-NMR (400 MHz, DMSO-d₆): δ 12.05 (bs, 1H), 8.67 (s, 1H), 8.32 (dd, J = 4.1, 1.7 Hz, 1H), 8.23 (d, J = 5.1 Hz, 1H), 7.86 (d, J = 5.1 Hz, 1H), 7.36 (dd, J = 8.3, 1.7 Hz, 1H), 7.32 (dd, J = 8.3, 4.2 Hz, 1H), 4.34 (t, J = 6.2 Hz, 2H), 3.06 (t, J = 6.2 Hz, 2H).

[0187] Compound 9 was obtained as an off-white solid in 97% yield. ¹H-NMR (400 MHz, DMSO-d₆): δ 11.97 (bs, 1H), 8.33 (dd, J = 4.0, 1.5 Hz, 1H), 8.18 (d, J = 3.6 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.36-7.29 (m, 3H), 4.33 (t, J = 6.1 Hz, 2H), 3.08 (t, J = 6.1 Hz, 2H).

[0188] Compound 10 was obtained as a yellow solid in 67% yield as a mixture of E/Z- isomers (95:5).¹H-NMR (400 MHz, DMSO-d₆): δ 12.31 (bs, 1H), 8.72 (s, 1H), 8.31 (dd, J = 4.1, 1.7 Hz, 1H), 8.27 (d, J = 5.6 Hz, 1H), 7.35 (dd, J = 8.3, 1.7 Hz, 1H), 7.31 (dd, J = 8.3, 4.1 Hz, 1H), 7.23 (d, J = 5.5 Hz, 1H), 4.33 (t, J = 6.2 Hz, 2H), 3.10 (t, J = 6.2 Hz, 2H).

[0189] Compound 11 was obtained as a light yellow solid in 71% yield as a mixture of E/Z-isomers (85:15). Major isomer: ¹H-NMR (400 MHz, DMSO-d₆): δ 12.31 (bs, 1H), 8.31 (dd, J = 4.1, 1.7 Hz, 1H), 8.23 (d, J = 4.1 Hz, 1H), 8.09 (d, J = 7.0 Hz, 1H), 7.35 (dd, J = 8.3, 1.7 Hz, 1H), 7.32 (dd, J = 8.3, 4.1 Hz, 1H), 7.06 (dd, J = 7.7, 4.9 Hz, 1H), 4.33 (t, J = 6.1 Hz, 2H), 3.10 (t, J = 6.2 Hz, 2H). Minor isomer: ¹H-NMR (400 MHz, DMSO-d₆): δ 15.01 (bs, 1H), 8.49 (dd, J = 4.4, 1.5 Hz, 1H), 8.39 (dd, J = 4.8, 1.7 Hz, 1H), 8.29 (dd, J = 7.8, 1.7 Hz, 1H), 7.62 (dd, J = 8.5, 1.5 Hz, 1H), 7.57 (dd, J = 8.5, 4.4 Hz, 1H), 7.15 (dd, J = 7.8, 4.8 Hz, 1H), 4.48 (t, J = 5.9 Hz, 2H), 2.97 (t, J = 5.8 Hz, 2H). Example 5: Compound 12

[0190] Compound 12 was synthesized according to the general procedure II. The product was obtained as an orange solid in 42% yield as a mixture of E/Z-isomers (75:25). Major isomer: 1H-NMR (500 MHz, DMSO-d₆): δ 13.87 (s, 1H), 8.44 (dd, J = 4.5, 1.4 Hz, 1H), 7.71 (t, J = 7.9 Hz, 1H), 7.54 (dd, J = 8.4, 1.4 Hz, 1H), 7.47 (dd, J = 8.4, 4.5 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H), 6.88 (d, J = 7.5 Hz, 1H), 4.42 (t, J = 5.8 Hz, 2H), 2.91 (t, J = 5.8 Hz, 2H). Minor isomer: ¹H-NMR (500 MHz, DMSO-d₆): δ 10.43 (s, 1H), 8.27 (dd, J = 4.3, 1.5 Hz, 1H), 7.73 (t, J = 7.9 Hz, 1H), 7.55-7.53 (m, 1H), 7.32 (dd, J = 8.3, 1.5 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 7.27 (dd, J = 8.2, 4.3 Hz, 1H), 4.30 (t, J = 6.2 Hz, 2H), 3.01 (t, J = 6.2 Hz, 2H). Example 6: Compound 13

[0191] Compound 13 was synthesized according to the general procedure I. The product was obtained as a yellow solid in 67% yield.¹H-NMR (400 MHz, DMSO-d₆): δ 11.95 (bs, 1H), 8.32 (dd, J = 4.2, 1.7 Hz, 1H), 7.89 (s, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.35 (dd, J = 8.3, 1.7 Hz, 1H), 7.31 (dd, J = 8.4, 4.2 Hz, 1H), 7.30-7.25 (m, J = 0.8 Hz, 1H), 4.33 (t, J = 6.2 Hz, 2H), 3.06 (t, J = 6.2 Hz, 2H). Example 7: Compounds 14-19

[0192] Compounds 14-19 were synthesized according to the general procedure II.

[0193] Compound 14 was obtained as a brown solid in 44% yield. ¹H-NMR (500 MHz, DMSO-d₆): δ 8.71 (d, J = 4.8 Hz, 1H), 7.98 (d, J = 2.1 Hz, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.56-7.50 (m, 2H), 7.35 (dd, J = 8.6, 2.2 Hz, 1H), 2.94 (t, J = 5.9 Hz, 2H), 2.83-2.74 (m, 2H), 1.97 (dt, J = 12.3, 6.2 Hz, 2H).

[0194] Compound 15 was obtained as an orange solid in 50% yield as a mixture of E/Z- isomers (58:42). ¹H-NMR (500 MHz, DMSO-d₆): δ 14.88 (s, 0.9H), 11.84 (bs, 1.7H), 8.46 (dd, J = 4.5, 1.4 Hz, 1H), 8.32 (dd, J = 4.2, 1.5 Hz, 1.0H), 8.00 (d, J = 2.2 Hz, 1.5H), 7.98-7.90 (bs, 1.5H), 7.61 (dd, J = 8.4, 1.4 Hz, 1.3H), 7.56-7.51 (m, 2.9H), 7.38-7.26 (m, 4.2H), 4.46 (t, J = 5.9 Hz, 1.8H), 4.33 (t, J = 6.1 Hz, 2.7H), 3.06 (bs, 2.4H), 2.95 (t, J = 5.9 Hz, 1.8H).

[0195] Compound 16 was obtained as a dark yellow solid in 47% yield. ¹H-NMR (500 MHz, DMSO-d₆): δ 10.55 (d, J = 4.9 Hz, 1H), 8.42 (d, J = 8.0 Hz, 1H), 8.30 (dd, J = 4.2, 1.6 Hz, 1H), 7.61-7.58 (m, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.43-7.40 (m, 1H), 7.36 (dd, J = 8.3, 1.5 Hz, 1H), 7.31 (dd, J = 8.3, 4.2 Hz, 1H), 7.22 (dd, J = 7.0, 5.8 Hz, 1H), 6.34 (d, J = 6.9 Hz, 1H), 4.35 (t, J = 6.2 Hz, 2H), 3.38-3.32 (m, 2H).

[0196] Compound 17 was obtained as an orange solid in 22% yield as a mixture of E/Z- isomers (64:36). Major isomer: ¹H-NMR (500 MHz, DMSO-d₆): δ 11.79 (bs, 1H), 8.31 (dd, J = 4.3, 1.5 Hz, 1H), 7.71 (bs, 1H), 7.43 (bs, 1H), 7.35 (dd, J = 8.3, 1.5 Hz, 1H), 7.31 (dd, J = 8.3, 4.2 Hz, 1H), 7.16-7.12 (m, 1H), 4.33 (t, J = 6.0 Hz, 2H), 3.05 (t, J = 5.7 Hz, 2H). Minor isomer: ¹H-NMR (500 MHz, DMSO-d₆): δ 14.82 (bs, 1H), 8.46 (dd, J = 4.4, 1.3 Hz, 1H), 7.80 (dd, J = 8.7, 2.7 Hz, 1H), 7.60 (dd, J = 8.4, 1.3 Hz, 1H), 7.57-7.52 (m, 2H), 7.19 (td, J = 9.0, 2.7 Hz, 1H), 4.46 (t, J = 5.8 Hz, 2H), 2.94 (t, J = 5.6 Hz, 2H).

[0197] The purification of Compound 18 was performed as follows: After cooling down to rt, the mixture was evaporated to dryness, and the residue was purified via column chromatography on silica gel using a mixture of hexanes and EtOAc as an eluent (gradient: 100:0 to 0:100). Compound 18 was obtained as an orange solid in 39% yield. ¹H-NMR (500 MHz, DMSO- d6): δ 14.46 (s, 1H), 8.71 (dd, J = 4.7, 1.5 Hz, 1H), 8.21 (d, J = 9.0 Hz, 1H), 7.84 (d, J = 7.7 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.71-7.65 (m, 2H), 7.59 (t, J = 8.3 Hz, 1H), 7.45 (dd, J = 7.7, 4.8 Hz, 1H), 7.31 (t, J = 7.9 Hz, 1H), 2.93 (t, J = 6.1 Hz, 2H), 2.79 (t, J = 6.2 Hz, 2H), 1.96 (dt, J = 12.1, 6.0 Hz, 2H).

[0198] The purification of Compound 19 was performed as follows: After cooling down to rt, the mixture was evaporated to dryness, and the residue was purified via column chromatography on silica gel using a mixture of hexanes and EtOAc as eluent (gradient: 100:0 to 0:100). Compound 19 was obtained as a yellow solid in 18% yield. ¹H-NMR (500 MHz, CD3OD): δ 14.06 (s, 1H), 8.48 (d, J = 5.6 Hz, 1H), 8.24 (d, J = 9.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.72-7.68 (m, 2H), 7.61 (t, J = 7.7 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.48 (dd, J = 8.4, 4.5 Hz, 1H), 7.32 (t, J = 7.4 Hz, 1H), 4.45 (t, J = 5.8 Hz, 2H), 2.95 (t, J = 5.7 Hz, 2H). Example 8: Compound 20

[0199] Compound 20 was synthesized according to the general procedure I. The product was obtained as a yellow solid in 91% yield. ¹H NMR (400 MHz; DMSO-d6): δ 11.96 (bs, 1H), 8.31 (dd, J = 4.1, 1.7 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.43 (s, 1H), 7.36-7.29 (m, 2H), 7.14 (dd, J = 8.4, 2.1 Hz, 1H), 4.33 (t, J = 6.2 Hz, 2H), 3.06 (t, J = 6.2 Hz, 2H). Example 9: Compounds 21-25

[0200] Compounds 21-25 were synthesized according to the general procedure II.

[0201] Compound 21 was obtained as a black solid in 58% yield as mixture of E/Z- isomers (1:1).¹H-NMR (500 MHz, DMSO-d6): δ 11.25 (bs, 1H), 8.71 (d, J = 4.9 Hz, 1H), 8.52 (dd, J = 4.6, 1.6 Hz, 1H), 7.91-7.77 (m, 4H), 7.61-7.20 (m, 12H), 2.93 (t, J = 6.1 Hz, 1H), 2.78 (t, J = 6.2 Hz, 2H), 2.74 (t, J = 6.2 Hz, 1H), 1.95 (dt, J = 12.2, 6.2 Hz, 2H), 1.86 (dt, J = 12.2, 6.1 Hz, 2H).

[0202] Compound 22 was obtained as a brown solid in 20% yield as a mixture of E/Z- isomers (66:34). Major isomer: ¹H-NMR (500 MHz, DMSO-d6): δ 11.70 (bs, 1H), 8.54 (d, J = 5.9 Hz, 1H), 7.96 (bs, 1H), 7.65-7.54 (m, 2H), 7.32-7.21 (m, 3H), 2.80 (t, J = 5.7 Hz, 2H), 1.87 (t, J = 5.2 Hz, 2H). Minor isomer: ¹H-NMR (500 MHz, DMSO-d₆): δ 11.50 (s, 1H), 8.72-8.70 (m, 1H), 8.02 (bs, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.58-7.49 (m, 2H), 7.35-7.33 (m, 1H), 2.94 (t, J = 5.9 Hz, 2H), 1.98-1.96 (m, 2H).

[0203] Compound 23 was obtained as a brown solid in 20% yield. ¹H-NMR (500 MHz, DMSO-d6): δ 11.25 (bs, 1H), 8.52 (dd, J = 4.6, 1.6 Hz, 1H), 7.88 (d, J = 7.3 Hz, 2H), 7.60 (d, J = 7.6 Hz, 1H), 7.41 (t, J = 7.7 Hz, 2H), 7.34 (s, 1H), 7.32-7.27 (m, 1H), 7.26 (dd, J = 7.6, 4.6 Hz, 1H), 2.84-2.74 (m, 4H), 1.86 (dt, J = 12.3, 6.3 Hz, 2H).

[0204] Compound 24 was obtained as yellow oil in 58% yield. ¹H-NMR (500 MHz, CD₃OD): δ 8.37 (dd, J = 4.5, 1.1 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.41 (dd, J = 8.4, 1.1 Hz, 1H), 7.34 (dd, J = 8.4, 4.5 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 6.69 (d, J = 7.3 Hz, 1H), 4.41 (t, J = 5.8 Hz, 2H), 2.94 (t, J = 5.8 Hz, 2H), 2.40 (s, 3H).

[0205] Compound 25 was obtained as a yellow solid in 30% yield. ¹H-NMR (500 MHz, CDCl₃): δ 9.10 (d, J = 3.0 Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.39-7.36 (m, 1H), 6.59 (s, 1H), 3.01- 2.93 (m, 2H), 2.82 (s, 3H), 2.72 (s, 3H), 2.07 (dt, J = 12.0, 6.2 Hz, 2H). Example 10: Compound 26

[0206] Compound 26 was synthesized according to the general procedure I. The purification was performed as follows: After cooling down to rt, the mixture was evaporated to about 1/3 of the volume of the original mixture. Then it was cooled to -18 °C for 16 h. The precipitate was isolated by centrifugation, washed with diethyl ether and dried in vacuo. The product was obtained as a red solid in 25% yield as a mixture of E/Z-isomers (88:12). Major isomer: ¹H-NMR (400 MHz, DMSO-d6): δ 10.46 (bs, 1H), 8.89 (dd, J = 5.6, 0.7 Hz, 1H), 8.34 (dd, J = 4.3, 1.5 Hz, 1H), 8.00 (d, J = 5.5 Hz, 1H), 7.72 (d, J = 5.6 Hz, 1H), 7.51 (d, J = 5.5 Hz, 1H), 7.34 (dd, J = 8.3, 1.5 Hz, 1H), 7.27 (dd, J = 8.3, 4.4 Hz, 1H), 4.34 (t, J = 6.1 Hz, 2H), 3.10 (t, J = 6.1 Hz, 2H). Minor isomer: ¹H-NMR (400 MHz, DMSO-d₆): δ 10.83 (s, 1H), 8.28 (dd, J = 4.3, 1.6 Hz, 1H), 7.76-7.73 (m, 1H), 7.62 (d, J = 5.4 Hz, 1H), 7.57 (d, J = 5.3 Hz, 1H), 7.35-7.31 (m, 1H), 7.30-7.27 (m, 1H), 6.68 (d, J = 6.6 Hz, 1H), 4.32-4.30 (m, 2H), 3.28 (t, J = 6.2 Hz, 2H). Example 11: Compound 27

[0207] Compound 27 was synthesized according to the general procedure II. The product was obtained as a brown solid in 18% yield as a mixture of E/Z-isomers (50:50). ¹H-NMR (500 MHz, CD₃OD): δ 8.67 (d, J = 4.6 Hz, 1H), 8.53 (d, J = 4.6 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 6.5 Hz, 1H), 7.58 (bs, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.47 (dd, J = 7.8, 4.8 Hz, 1H), 7.38 (app. dd, J = 7.5, 5.3 Hz, 2H), 7.19 (dd, J = 8.3, 2.1 Hz, 1H), 7.15 (bs, 1H), 3.02 (t, J = 6.1 Hz, 2H), 2.96-2.90 (m, 4H), 2.87-2.85 (m, 2H), 2.11-2.01 (m, 4H). Example 12: Compound 28

[0208] Compound 28 was synthesized according to general procedure I. The product was obtained as a yellow solid in 53% yield as a mixture of E/Z-isomers (73:27). Major isomer: ¹H- NMR (400 MHz, DMSO-d₆): δ 14.27 (bs, 1H), 8.36 (dd, J = 4.5, 1.5 Hz, 1H), 8.03 (d, J = 4.8 Hz, 1H), 7.59 (ddd, J = 11.9, 8.0, 1.4 Hz, 1H), 7.55 (dd, J = 8.4, 1.5 Hz, 1H), 7.46 (dd, J = 8.4, 4.5 Hz, 1H), 6.86 (ddd, J = 8.1, 4.7, 3.5 Hz, 1H), 4.43 (t, J = 5.8 Hz, 2H), 2.93 (t, J = 5.8 Hz, 2H). Minor isomer: ¹H-NMR (400 MHz, DMSO-d₆): δ 9.50 (bs, 1H), 8.26 (dd, J = 4.3, 1.6 Hz, 1H), 8.05 (d, J = 4.8 Hz, 1H), 7.62-7.54 (m, 1H), 7.33 (dd, J = 8.3, 1.6 Hz, 1H), 7.27 (dd, J = 8.3, 4.3 Hz, 1H), 6.92 (ddd, J = 8.0, 4.7, 3.3 Hz, 1H), 4.31 (t, J = 6.1 Hz, 2H), 3.04 (t, J = 6.2 Hz, 2H). Example 13: Compounds 29-34

[0209] Compounds 29-34 were synthesized according to the general procedure II.

[0210] For Compound 29, after cooling the mixture to 5 °C, no precipitate was formed, and therefore the mixture was evaporated to dryness. The residue was purified on silica gel using a mixture of DCM and MeOH as eluent (gradient: 100:0 to 80:20). Compound 29 was obtained as a yellow solid in 6% yield. ¹H-NMR (500 MHz; CD₃OD): δ 8.70-8.64 (m, 1H), 8.06 (d, J = 5.5 Hz, 1H), 7.94 (d, J = 5.7 Hz, 1H), 7.77-7.75 (m, 1H), 7.61 (d, J = 5.5 Hz, 1H), 7.39-7.35 (m, 2H), 2.97 (t, J = 6.1 Hz, 2H), 2.91-2.88 (m, 2H), 2.08-2.03 (m, 2H).

[0211] Compound 30 was obtained as a yellow solid in 46% yield as a mixture of E/Z- isomers (60:40). Minor isomer: ¹H NMR (500 MHz; DMSO-d6): δ 12.03 (s, 1H), 8.48 (dd, J = 4.4, 1.3 Hz, 1H), 8.11 (d, J = 8.3 Hz, 1H), 7.84 (s, 1H), 7.62 (dd, J = 8.5, 1.4 Hz, 1H), 7.56 (dd, J = 8.4, 4.5 Hz, 1H), 7.48 (dd, J = 8.1, 1.1 Hz, 1H), 4.47 (t, J = 5.9 Hz, 2H), 2.96 (t, J = 5.9 Hz, 2H). Major isomer: ¹H NMR (500 MHz; DMSO): δ 12.03 (s, 1H), 8.32 (dd, J = 4.1, 1.4 Hz, 1H), 8.06 (bs, 1H), 7.79 (bs, 1H), 7.45-7.43 (m, 1H), 7.36 (dd, J = 8.3, 1.4 Hz, 1H), 7.33 (dd, J = 8.3, 4.2 Hz, 1H), 4.34 (t, J = 6.1 Hz, 2H), 3.07 (d, J = 0.6 Hz, 2H).

[0212] Crude Compound 31 was purified by column chromatography on silica gel using a mixture of hexanes and EtOAc as eluent (gradient: 100:0 to 0:100). 31 was obtained as yellow oil in 32% yield. ¹H-NMR (500 MHz, CD₃OD): δ 8.59 (d, J = 4.0 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.29 (dd, J = 7.8, 4.8 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 6.65 (d, J = 7.3 Hz, 1H), 2.91 (t, J = 6.1 Hz, 2H), 2.77 (t, J = 6.2 Hz, 2H), 2.39 (s, 3H), 1.99 (dt, J = 12.4, 6.2 Hz, 2H).

[0213] The purification of Compound 32 was performed as follows: After cooling down to rt, the mixture was evaporated to dryness, and the residue was purified via column chromatography on silica gel using a mixture of hexanes and EtOAc as eluent (gradient: 100:0 to 0:100). The dark powder was recrystallized from a mixture of hot EtOH and MeOH. Compound 32 was obtained as orange oil in 13% yield as a mixture of E/Z-isomers (62: 38). Major isomer: ¹H- NMR (500 MHz, CD3OD): δ 8.49 (d, J = 4.4 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.51-7.44 (m, 2H), 7.33 (dd, J = 7.5, 4.9 Hz, 1H), 7.07 (t, J = 8.8 Hz, 1H), 2.94-2.85 (m, 4H), 2.06-1.98 (m, 2H). Minor isomer: ¹H-NMR (500 MHz, CD₃OD): δ 8.62 (d, J = 4.6 Hz, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.53 (dd, J = 8.5, 2.7 Hz, 1H), 7.50-7.49 (m, 1H), 7.41 (dd, J = 7.5, 4.8 Hz, 1H), 7.15-7.11 (m, 1H), 2.97 (t, J = 6.2 Hz, 1H), 2.95-2.87 (m, 2H), 2.82-2.80 (m, 1H), 2.01-1.96 (m, 2H).

[0214] The purification of Compound 33 was performed as follows: After cooling down to rt, the mixture was evaporated to dryness, and the residue was purified via column chromatography on silica gel using a mixture of hexanes and EtOAc as eluent (gradient: 100:0 to 0:100). The brown powder was recrystallized from a mixture of hot EtOH and water. Compound 33 was obtained as a brown solid in 19% yield. ¹H-NMR (500 MHz, CD₃OD): δ 8.22 (dd, J = 4.5, 1.4 Hz, 1H), 7.34 (dd, J = 8.3, 1.4 Hz, 1H), 7.26 (dd, J = 8.3, 4.5 Hz, 1H), 7.16-7.11 (m, 2H), 7.10-7.07 (m, 2H), 4.33 (t, J = 6.1 Hz, 2H), 3.53 (s, 3H), 3.19 (t, J = 6.1 Hz, 2H).

[0215] The purification of Compound 34 was performed as follows: After cooling down to rt, the mixture was evaporated to dryness, and the residue was purified via column chromatography on silica gel using a mixture of hexanes and EtOAc as eluent (gradient: 100:0 to 0:100). Compound 34 was obtained as orange oil in 40% yield as a mixture of E/Z-isomers (54:46). ¹H-NMR (500 MHz, CD₃OD): δ 8.80 (d, J = 4.2 Hz, 1H), 8.51-8.48 (m, 1H), 8.17 (d, J = 8.3 Hz, 1H), 8.01 (d, J = 5.9 Hz, 1H), 7.84-7.82 (m, 2H), 7.75-7.72 (m, 1H), 7.71-7.68 (m, 1H), 7.59 (t, J = 7.5 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.46-7.40 (m, 2H), 7.33 (dd, J = 7.7, 4.7 Hz, 1H), 7.19 (d, J = 5.9 Hz, 1H), 7.13 (d, J = 7.0 Hz, 1H), 6.90 (s, 1H), 6.79 (s, 1H), 6.41 (d, J = 7.1 Hz, 1H), 3.23 (t, J = 6.6 Hz, 2H), 3.01-2.93 (m, 5H), 2.10-1.97 (m, 5H). Example 14: Compounds 35-45

[0216] Compounds 35-45 were synthesized according to the general procedure II.35 was obtained as a red solid in 41% yield as a mixture of E/Z-isomers (62:38). ¹H-NMR (500 MHz, CD3OD): δ 8.64 (d, J = 4.2 Hz, 0.6H), 8.50 (d, J = 3.8 Hz, 1H), 7.93 (d, J = 6.7 Hz, 1H), 7.91-7.88 (m, 0.6H), 7.83 (d, J = 7.6 Hz, 0.6H), 7.81-7.76 (m, 1H), 7.75 (bs, 0.6H), 7.69 (d, J = 7.9 Hz, 1H), 7.45-7.38 (m, 1.6H), 7.38-7.31 (m, 1.6H), 3.05-2.80 (m, 6H), 2.06-1.99 (m, 3.2H).

[0217] Compound 36 was obtained as a yellow solid in 33% yield. ¹H-NMR (500 MHz, CD₃OD): δ 8.62 (d, J = 4.6 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.37 (dd, J = 7.8, 4.7 Hz, 1H), 6.67 (s, 1H), 2.96 (t, J = 6.1 Hz, 2H), 2.87 (t, J = 6.2 Hz, 2H), 2.40 (s, 3H), 2.03 (dt, J = 12.4, 6.2 Hz, 2H).

[0218] Compound 37 was obtained as an off-white solid in 76% yield. ¹H-NMR (500 MHz, CD3OD): δ 8.42-8.32 (m, 2H), 7.91 (dd, J = 9.0, 2.1 Hz, 1H), 7.51 (d, J = 9.4 Hz, 1H), 7.46 (dd, J = 8.5, 1.5 Hz, 1H), 7.39 (dd, J = 8.4, 4.5 Hz, 1H), 4.43 (t, J = 5.8 Hz, 2H), 2.97 (t, J = 5.8 Hz, 2H).

[0219] Compound 38 was obtained as a brown solid in 47% yield. ¹H-NMR (500 MHz, CD₃OD): δ 8.70 (d, J = 1.4 Hz, 1H), 8.36 (dd, J = 4.5, 1.5 Hz, 1H), 8.12 (dd, J = 2.7, 1.5 Hz, 1H), 7.99 (d, J = 2.8 Hz, 1H), 7.45 (dd, J = 8.5, 1.5 Hz, 1H), 7.39 (dd, J = 8.4, 4.5 Hz, 1H), 4.44 (t, J = 5.8 Hz, 2H), 2.98 (t, J = 5.8 Hz, 2H).

[0220] Compound 39 was obtained as a yellow solid in 38% yield. ¹H NMR (500 MHz; CD₃OD): δ 8.56 (d, J = 4.6 Hz, 1H), 7.99 (d, J = 4.9 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.45 (ddd, J = 11.4, 7.9, 1.3 Hz, 1H), 7.35 (dd, J = 7.8, 4.8 Hz, 1H), 6.81 (ddd, J = 8.1, 4.7, 3.6 Hz, 1H), 2.96 (t, J = 6.1 Hz, 2H), 2.88-2.86 (m, 2H), 2.05-2.00 (m, 2H). [0221] Compound 40 was obtained as a yellow solid in 57% yield. ¹H-NMR (500 MHz; CD₃OD): δ 8.35 (dd, J = 4.5, 1.5 Hz, 1H), 8.06-8.05 (d, J = 2.5 Hz, 1H), 7.67 (dd, J = 9.0, 2.5 Hz, 1H), 7.42 (dd, J = 8.4, 1.5 Hz, 1H), 7.39 (d, J = 9.0 Hz, 1H), 7.36 (dd, J = 8.4, 4.5 Hz, 1H), 4.41 (t, J = 5.8 Hz, 2H), 2.94 (t, J = 5.8 Hz, 2H).

[0222] The purification of 41 was performed as follows: After cooling down to rt, the mixture was evaporated to dryness, and the residue was purified via column chromatography on silica gel using a mixture of hexanes and EtOAc as eluent (gradient: 100:0 to 0:100). Compound 41was obtained as an orange solid in 39% yield.¹H-NMR (500 MHz, CDCl₃): δ 8.59 (d, J = 4.7 Hz, 1H), 7.90 (d, J = 5.2 Hz, 1H), 7.72 (d, J = 7.1 Hz, 1H), 7.31 (dd, J = 7.7, 4.8 Hz, 1H), 7.26 (s, 1H), 6.66 (d, J = 5.3 Hz, 1H), 2.94 (t, J = 6.1 Hz, 2H), 2.80 (t, J = 6.2 Hz, 2H), 2.34 (s, 3H), 2.01 (dt, J = 12.4, 6.2 Hz, 2H).

[0223] Compound 42 was obtained as an orange solid in 53% yield as a mixture of E/Z- isomers (60:40).¹H-NMR (500 MHz, CD₃OD): δ 8.39 (dd, J = 4.5, 1.4 Hz, 1H), 8.29 (d, J = 3.5 Hz, 0.6H), 8.27 (d, J = 3.7 Hz, 0.9H), 7.74 (d, J = 7.8 Hz, 0.9H), 7.53 (d, J = 7.8 Hz, 1.1H), 7.49 (dd, J = 8.5, 1.4 Hz, 0.9H), 7.45 (d, J = 4.5 Hz, 0.6H), 7.43 (d, J = 4.4Hz, 0.4H), 7.40-7.27 (m, 4.4H), 7.17 (t, J = 8.1 Hz,1H), 7.14-7.08 (m, 1.6H), 4.45 (t, J = 5.9 Hz, 1.8H), 4.37 (t, J = 6.4 Hz, 2.2H), 3.17 (t, J = 6.4 Hz, 1.3H), 2.98 (t, J = 5.9 Hz, 2H).

[0224] Compound 43 was obtained as a yellow solid in 44% yield. ¹H-NMR (500 MHz, CD3OD): δ 8.69 (d, J = 1.3 Hz, 1H), 8.59 (d, J = 4.8 Hz, 1H), 8.09 (dd, J = 2.6, 1.5 Hz, 1H), 7.95 (d, J = 2.7 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.36 (dd, J = 7.8, 4.8 Hz, 1H), 2.96 (t, J = 6.2 Hz, 2H), 2.82 (t, J = 6.2 Hz, 2H), 2.03 (dt, J = 12.4, 6.2 Hz, 2H).

[0225] Compound 44 was obtained as a yellow solid in 48% yield. ¹H-NMR (500 MHz, CD₃OD): δ 8.36 (dd, J = 4.5, 1.5 Hz, 1H), 8.06 (d, J = 4.3 Hz, 1H), 7.68 (td, J = 7.8, 1.7 Hz, 1H), 7.42-7.40 (m, 1H), 7.35 (dd, J = 8.4, 4.5 Hz, 1H), 6.82 (ddd, J = 7.1, 5.1, 1.0 Hz, 1H), 4.41 (t, J = 5.8 Hz, 2H), 2.95 (t, J = 5.8 Hz, 2H).

[0226] Compound 45 was obtained as an off-white solid in 55% yield. ¹H-NMR (500 MHz, CD₃OD): δ 8.61 (d, J = 4.7 Hz, 1H), 8.35 (s, 1H), 7.88 (dd, J = 8.9, 2.3 Hz, 1H), 7.76 (d, J = 7.0 Hz, 1H), 7.51 (d, J = 8.9 Hz, 1H), 7.36 (dd, J = 7.8, 4.8 Hz, 1H), 2.95 (t, J = 6.1 Hz, 2H), 2.82 (t, J = 6.3 Hz, 2H), 2.03 (dt, J = 12.4, 6.2 Hz, 2H). Example 15: Compound 46

[0227] Compound 46 was synthesized according to the general procedure I. The product was obtained as a yellow solid in 67% yield. ¹H-NMR (500 MHz, CD₃OD): δ 8.58 (d, J = 3.9 Hz, 1H), 8.03 (d, J = 2.1 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.65 (dd, J = 9.0, 2.6 Hz, 1H), 7.40 (d, J = 9.0 Hz, 1H), 7.32 (dd, J = 7.8, 4.8 Hz, 1H), 2.94 (t, J = 6.1 Hz, 2H), 2.80-2.78 (m, 2H), 2.01 (t, J = 6.2 Hz, 2H). Example 16: Compound 47, 49-51, and AR

[0228] Compounds 47-51 were synthesized according to the general procedure II.

[0229] Compound 47 was obtained as an off-white solid in 33% yield as a mixture of E/Z-isomers (77:23). Major isomer: ¹H-NMR (500 MHz, CD₃OD): δ 8.44 (dd, J = 4.7, 1.5 Hz, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.65-7.64 (m, 2H), 7.28 (dd, J = 7.7, 4.8 Hz, 1H), 6.83 (d, J = 7.4 Hz, 1H), 2.85 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 6.6 Hz, 2H), 2.00 (dt, J = 12.3, 6.3 Hz, 2H). Minor isomer: ¹H- NMR (500 MHz, CD₃OD): δ 8.60 (d, J = 4.8 Hz, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.62-7.59 (m, 2H), 7.32 (dd, J = 7.8, 4.8 Hz, 1H), 6.77 (d, J = 7.5 Hz, 1H), 2.93 (t, J = 6.1 Hz, 2H), 2.79-2.74 (m, 2H), 2.04-1.94 (m, 2H).

[0230] Compound AR was obtained as an orange solid in 24% yield. ¹H-NMR (500 MHz, CDCl₃): δ 8.61 (dd, J = 4.6, 1.3 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.39 (dd, J = 7.8, 4.8 Hz, 1H), 7.34-7.31 (m, 1H), 7.16-7.13 (m, 1H), 2.95 (t, J = 6.1 Hz, 2H), 2.82-2.79 (m, 2H), 2.03 (dt, J = 12.4, 6.2 Hz, 2H).

[0231] The purification of Compound 49 was performed as follows: After cooling down to rt, the mixture was evaporated to dryness, and the residue was purified via column chromatography on silica gel using a mixture of hexanes and EtOAc as eluent (gradient: 100:0 to 0:100). The product was obtained as a yellow solid as a mixture of E/Z-isomers. Major isomer (11%): ¹H-NMR (500 MHz, CD₃OD): δ 8.52 (dd, J = 4.8, 1.6 Hz, 1H), 8.02 (d, J = 4.1 Hz, 1H), 7.64-7.60 (m, 2H), 7.35 (d, J = 8.5 Hz, 1H), 7.23 (dd, J = 7.8, 4.8 Hz, 1H), 6.76 (ddd, J = 7.1, 5.2, 0.9 Hz, 1H), 2.83 (t, J = 6.2 Hz, 2H), 2.73-2.71 (m, 2H), 1.93 (dt, J = 12.4, 6.2 Hz, 2H). Minor isomer (9%): ¹H-NMR (500 MHz, CD₃OD): δ 8.43 (dd, J = 4.7, 1.4 Hz, 1H), 8.08 (d, J = 5.0 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.69 (td, J = 7.8, 1.7 Hz, 1H), 7.61 (d, J = 7.0 Hz, 1H), 7.25 (dd, J = 7.7, 4.7 Hz, 1H), 6.85 (dd, J = 6.6, 5.5 Hz, 1H), 2.83 (t, J = 6.1 Hz, 2H), 2.77 (t, J = 6.6 Hz, 2H), 1.98 (dt, J = 12.2, 6.0 Hz, 2H).

[0232] Compound 50 was obtained as a dark brown solid in 30% yield. MS (ESI): m/z 269 [M+H]⁺.

[0233] The purification of Compound 51 was performed as follows: After cooling down to rt, the mixture was evaporated to dryness, and the residue was purified via column chromatography on silica gel using a mixture of DCM and MeOH as eluent (gradient: 100:0 to 80:20). The product was obtained as red oil in 38% yield as a mixture of E/Z-isomers (76:24). Major isomer: ¹H-NMR (400 MHz, CDCl₃): δ 8.72-8.70 (m, 1H), 7.69-7.64 (m, 1H), 7.39 (dd, J = 7.8, 3.9 Hz, 1H), 7.17-7.14 (m, 2H), 7.12-7.09 (m, 2H), 3.63 (s, 3H), 3.06-3.01 (m, 2H), 2.84-2.78 (m, 2H), 2.24-2.17 (m, 2H). Minor isomer: ¹H-NMR (400 MHz, CDCl₃): δ 8.57 (dd, J = 5.4, 1.5 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.29 (dd, J = 7.6, 5.5 Hz, 1H), 7.19-7.17 (m, 2H), 7.07-7.04 (m, 2H), 3.61 (s, 3H), 3.06-3.01 (m, J = 3.2 Hz, 2H), 2.92 (t, J = 6.1 Hz, 2H), 2.00 (dt, J = 12.4, 6.3 Hz, 2H). Example 17: Synthesis of 5,6,7,8-tetrahydro-9H-cyclohepta[b]pyridin-9-one (int-6)

[0234] To a solution of cycloheptanone (int-1) (5.0 g, 44.7 mmol) and 1,3- propanediamine (6.6 g, 89.3 mmol) in EtOH (100 mL) was added p-toluenesulfonic acid (5.0 g, 26.8 mmol) followed by copper(II) triflate (1.61 g, 4.5 mmol) at rt. The reaction vessel was pressurized with oxygen to 30 psi, and then heated to 110 °C for 24 h. The mixture was cooled to rt and cold water was added. The solution was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (2 x 60 mL), brine (60 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (100-200 µm silica) using 30% EtOAc in hexane as eluent to afford 1.5 g (23%) of 6,7,8,9-Tetrahydro-5H- cyclohepta[b]pyridine (int-2) as a pale brown semi-solid. MS (ESI) m/z 148.1[M+H]⁺.

[0235] Int-2 (1.5 g, 1.0 eq.) was dissolved in acetic acid (7.5 mL) and hydrogen peroxide (33%-solution in water, 1.5 mL) was added at rt. Then the mixture was heated to 70 °C for 12 h. After cooling down to rt, the mixture was concentrated under reduced pressure and the residue was dissolved in chloroform (30 mL). Sodium carbonate (Na₂CO₃, 500 mg) was added at 0 °C, and the mixture was stirred at rt for 2 h. The suspension was filtered, and the filtrate was concentrated in vacuo to afford 1.1 g (crude yield 84%) of 6,7,8,9-Tetrahydro-5H-cyclohepta[b]pyridine 1-oxide (int-3). The crude product was used in the next step without further purification.

[0236] Int-3 (1.1 g, 6.7 mmol) was dissolved in acetic anhydride (6 mL) and heated at 90 °C for 36 h. After cooling down to rt, the mixture was concentrated under reduced pressure to afford 1.0 g (crude yield 76%) of 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl acetate (int-4). The crude product was used without further purification in the next step. MS (ESI) m/z 206.17 [M+H]⁺.

[0237] A solution of Int-4 (1.0 g, 4.9 mmol) in MeOH/water (1:3, 15 mL) was cooled to 0 °C and K₂CO₃ (2.0 g, 14.6 mmol) was added. The mixture was heated to 70 °C for 24 h. After cooling down to rt, the mixture was extracted with EtOAc (2 x 50 mL) and the combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crude compound was purified by column chromatography (100-200 µm silica) using 30% EtOAc in hexane as eluent to afford 500 mg (62%) of 6,7,8,9-tetrahydro-5H- cyclohepta[b]pyridin-9-ol (int-5) as a pale brown semi-solid. MS (ESI) m/z 164 [M+H]⁺.

[0238] Int-5 (500 mg, 3.1 mmol) was dissolved in dry DCM (20 mL) and manganese dioxide (1.33 g, 15.3 mmol) was added. The mixture was stirred at rt for 16 h. A second portion of manganese dioxide (1.33 g, 15.3 mmol) was added, and the mixture was heated to 40 °C for 60 h. The suspension was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to afford the crude product. The product was purified via column chromatography on reversed phase silica gel using water/acetonitrile acidified with 0.1% formic acid as eluent to afford 250 mg (51%) of 5,6,7,8-tetrahydro-9H-cyclohepta[b]pyridin-9-one (int-6) as an off-white solid.¹H- NMR (400 MHz, CDCl₃): δ 8.64 (dd, J = 4.4, 1.6 Hz, 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.33 (dd, J = 8.0, 5.2 Hz, 1H), 2.92 (t, J = 5.6 Hz, 2H), 2.84-2.77 (m, 2H), 1.98-1.84 (m, 4H); MS (ESI) m/z 161.99 [M+H]⁺. Example 18: Compounds 52-58

[0239] Compounds 52-58 were synthesized according to the general procedure I.

[0240] In the synthesis of Compound 52, as no precipitate formed during the work-up, the mixture was evaporated to dryness and purified on silica gel with a mixture of DCM and MeOH as eluent (gradient 100:0 to 80:20). Compound 52 was obtained as a yellow-green solid in 92% yield.¹H-NMR (400 MHz, DMSO-d₆): δ 11.91 (bs, 1H), 8.71 (s, 1H), 8.49 (dd, J = 4.7, 1.5 Hz, 1H), 8.22 (d, J = 5.2 Hz, 1H), 7.84 (d, J = 5.1 Hz, 1H), 7.64 (d, J = 6.2 Hz, 1H), 7.34 (dd, J = 7.5, 4.8 Hz, 1H), 2.81-2.69 (m, 4H), 1.74 (dt, J = 12.6, 6.0 Hz, 2H), 1.61 (dt, J = 11.7, 5.9 Hz, 2H).

[0241] Compound 53 was obtained as a pale brown solid in 60% yield as a mixture of E/Z-isomers (98:2). ¹H-NMR (400 MHz, DMSO-d6): δ 11.99 (bs, 1H), 8.49 (dd, J = 4.8, 1.6 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.64 (dd, J = 7.6, 1.4 Hz, 1H), 7.39 (dd, J = 7.8, 0.7 Hz, 1H), 7.34 (dd, J = 7.6, 4.8 Hz, 1H), 7.11 (t, J = 7.9 Hz, 1H), 2.75-2.69 (m, 4H), 1.74 (dt, J = 12.6, 6.3 Hz, 2H), 1.61 (dt, J = 11.5, 5.9 Hz, 2H).

[0242] Compound 54 was obtained as a yellow solid in 29% yield. ¹H-NMR (400 MHz, DMSO-d₆): δ 11.84 (bs, 1H), 8.50 (dd, J = 4.7, 1.2 Hz, 1H), 8.20 (bs, 1H), 7.82 (bs, 1H), 7.64 (dd, J = 7.6, 1.2 Hz, 1H), 7.40-7.28 (m, 2H), 2.73 (app. t, J = 6.0 Hz, 4H), 1.74 (dt, J = 12.4, 6.1 Hz, 2H), 1.61 (dt, J = 10.8, 5.7 Hz, 2H).

[0243] Compound 55 was found to be highly soluble in MeOH. A 1:1 mixture of MeOH and water was used to wash the crude product. 55 was obtained as a yellow solid in 85% yield as mixture of E/Z-isomers (85:15). Major isomer: ¹H-NMR (400 MHz, DMSO-d₆): δ 12.11 (bs, 1H), 8.50 (dd, J = 4.8, 1.6 Hz, 1H), 8.28 (bs, 1H), 8.12 (bs, 1H), 7.65 (dd, J = 7.6, 1.6 Hz, 1H), 7.35 (dd, J = 7.6, 4.8 Hz, 1H), 7.10-7.08 (m, 1H), 2.80-2.70 (m, 4H), 1.75 (dt, J = 12.8, 6.3 Hz, 2H), 1.63 (dt, J = 11.7, 6.0 Hz, 2H). Minor isomer: ¹H-NMR (400 MHz, DMSO-d₆): δ 13.04 (bs, 1H), 8.60 (bs, 1H), 8.35-8.05 (m, 2H), 7.88-7.77 (m, 1H), 7.44-7.37 (m, 1H), 7.13-7.03 (m, 1H), 2.90-2.81 (m, 2H), 2.68-2.65 (m, 2H), 1.88 (dt, J = 10.9, 5.4 Hz, 2H), 1.80-1.78 (m, 2H).

[0244] Compound 56 was found to be highly soluble in MeOH, a 1:1 mixture of MeOH and water was used to wash the crude product. 56 was obtained as a yellow solid in 54% yield as mixture of E/Z-isomers (90:10). ¹H-NMR (400 MHz, DMSO-d6): δ 11.72 (bs, 1H), 8.49 (d, J = 3.6 Hz, 1H), 7.92 (bs, 1H), 7.63 (dd, J = 7.6, 1.5 Hz, 1H), 7.58 (bs, 1H), 7.34 (dd, J = 7.4, 4.9 Hz, 1H), 7.29 (d, J = 7.1 Hz, 1H), 2.79-2.66 (m, 4H), 1.74 (dt, J = 12.8, 6.4 Hz, 2H), 1.61 (dt, J = 11.5, 6.1 Hz, 2H).

[0245] Compound 57 was obtained as beige solid in 54% yield. ¹H-NMR (400 MHz, DMSO-d₆): δ 11.69 (bs, 1H), 8.49 (d, J = 3.6 Hz, 1H), 7.92 (bs, 1H), 7.63 (dd, J = 7.6, 1.3 Hz, 1H), 7.52 (bs, 1H), 7.33 (app. dd, J = 7.2, 4.8 Hz, 2H), 2.72 (t, J = 6.4 Hz, 2H), 2.71-2.66 (m, 2H), 1.74 (dt, J = 12.7, 6.3 Hz, 2H), 1.61 (dt, J = 11.2, 5.8 Hz, 2H).

[0246] 58 was obtained as a yellow solid in 88% yield as a mixture of E/Z-isomers (85:15). Major isomer: ¹H-NMR (400 MHz, DMSO-d₆): δ 11.76 (bs, 1H), 8.49 (dd, J = 4.8, 1.6 Hz, 1H), 7.82 (bs, 1H), 7.63 (dd, J = 7.6, 1.6 Hz, 1H), 7.55 (bs, 1H), 7.37-7.30 (m, 1H), 7.15 (bs, 1H), 2.72 (t, J = 6.4 Hz, 2H), 2.71-2.68 (m, 2H), 1.74 (dt, J = 12.8, 6.4 Hz, 2H), 1.61 (dt, J = 11.7, 5.9 Hz, 2H). Minor isomer: ¹H-NMR (400 MHz, DMSO-d₆): δ 13.03 (bs, 1H), 9.25 (bs, 1H), 8.60 (bs, 1H), 7.82 (bs, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.42 (bs, 1H), 6.99 (dd, J = 8.3, 2.1 Hz, 1H), 2.91-2.83 (m, 2H), 2.68-2.66 (m, 2H), 1.85 (dt, J = 12.0, 6.1 Hz, 2H), 1.81-1.74 (m, 2H). Example 19: Synthesis of 5,6,7,8-tetrahydro-9H-cyclohepta[b]pyridin-9-one (int-11)

[0247] 5,6,7,8-Tetrahydroquinoxaline (int-7) (10.0 g, 1.0 eq.) was dissolved in DCM (25 mL) and cooled to 0 °C before meta-chloroperbenzoic acid (1.0 eq.) was added. The mixture was stirred at rt for 16 h, then it was quenched with a 10% aq. sodium sulfite at 0 °C and stirred at 0 °C for 20 min. The solution was diluted with saturated aq. sodium bicarbonate and stirred for an additional 30 min at rt. Afterwards, the mixture was extracted with DCM (2 x 50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford 7.0 g of crude 5,6,7,8- tetrahydroquinoxaline 1-oxide (int-8) as a pale brown semi-solid. MS (ESI) m/z 151.1 [M+H]⁺. The crude compound was used in the next step without further purification.

[0248] Int-8 (7.0 g, 1.0 eq.) was dissolved in acetic acid (21 mL) and hydrogen peroxide (33% solution in water, 7 mL) was added at rt. The mixture was heated at 70 °C for 12 h. After cooling to rt, the mixture was concentrated under reduced pressure and the residue was diluted with chloroform (30 mL). Na₂CO₃ (500 mg) was added at 0 °C, and the mixture was stirred at rt for 2 h. The suspension was filtered, and the filtrate was concentrated in vacuo to obtain 6.0 g of the crude product, which was purified by column chromatography on silica gel using 20% EtOAc in hexane as eluent to afford 3.0 g (33%) of 5,6,7,8-tetrahydroquinoxalin-5-yl acetate (int-9) as a pale brown semi-solid. MS (ESI) m/z 192.92 [M+H]⁺.

[0249] Int-9 (3.0 g, 67.7 mmol) was dissolved in a mixture of MeOH and water (1:3, 30 mL). This solution was cooled to 0 °C, then K₂CO₃ (2.6 g, 203.1 mmol) was added, and the mixture was heated at 70 °C for 24 h. After cooling to rt, the mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (100-200 µm silica gel) using 30% EtOAc in hexane as eluent to afford 1.1 g (48%) of 5,6,7,8- tetrahydroquinoxalin-5-ol (int-10) as a brown semi-solid. MS (ESI) m/z 150.83[M+H]⁺. [0250] A solution of dry DMSO (1.9 mL, 26.64 mmol) in DCM (30 mL) was cooled to - 78 °C. Then oxalyl chloride (1.1 ml, 13.33 mmol) was added, and the solution was stirred for 15 min. Then a solution of Int-10 (1.0 g, 6.67 mmol) in DCM (10 mL) was added, and the mixture was stirred for an additional 30 min. Then triethylamine (4.7 ml, 33.33 mmol) was added to the mixture, and then it was allowed to warm to 0 °C over a period of 3 h. After the work-up, the residue was purified via column chromatography on neutral alumina to give 510 mg (51%) of 5,6,7,8-tetrahydro- 9H-cyclohepta[b]pyridin-9-one int-11 as a pale-brown solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.73 (d, J = 2.4 Hz, 1H), 8.71 (d, J = 1.6 Hz, 1H), 3.15 (t, J = 6.0 Hz, 2H), 2.79-2.53 (m, 2H), 2.14 (dt, J = 12.8, 6.4 Hz, 2H); MS (ESI) m/z 149.13 [M+H]⁺. Example 20: Compounds 59-66

[0251] Compounds 59-66 were synthesized according to the general procedure I.

[0252] Compound 59 was obtained as an orange solid in 79% yield.¹H-NMR (400 MHz, DMSO-d₆): δ 12.18 (bs, 1H), 8.60 (d, J = 2.3 Hz, 1H), 8.49 (d, J = 2.4 Hz, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.13 (t, J = 7.9 Hz, 1H), 2.97 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.4 Hz, 2H), 1.97 (dt, J = 12.3, 6.2 Hz, 2H).

[0253] Compound 60 was obtained as a yellow solid in 33% yield. ¹H-NMR (400 MHz, DMSO-d₆): δ 12.35 (bs, 1H), 8.79 (s, 1H), 8.61 (d, J = 2.3 Hz, 1H), 8.50 (d, J = 2.4 Hz, 1H), 8.31 (d, J = 5.7 Hz, 1H), 7.30 (d, J = 5.5 Hz, 1H), 2.98 (t, J = 6.1 Hz, 2H), 2.91 (t, J = 6.5 Hz, 2H), 1.96 (dt, J = 12.3, 6.2 Hz, 2H).

[0254] Compound 61 was obtained as a pale yellow solid in 84% yield as a mixture of E/Z-isomers (98:2). ¹H-NMR (400 MHz, DMSO-d6): δ 12.04 (bs, 1H), 8.62 (d, J = 2.3 Hz, 1H), 8.49 (d, J = 2.4 Hz, 1H), 8.22 (dd, J = 4.8, 1.4 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.34 (dd, J = 8.1, 4.8 Hz, 1H), 2.98 (t, J = 6.1 Hz, 2H), 2.89 (t, J = 6.5 Hz, 2H), 1.96 (dt, J = 12.3, 6.2 Hz, 2H).

[0255] Compound 62 was obtained as an off-white solid in 66% yield. ¹H-NMR (400 MHz, DMSO-d₆): δ 12.09 (bs, 1H), 8.73 (s, 1H), 8.60 (d, J = 2.4 Hz, 1H), 8.50 (d, J = 2.4 Hz, 1H), 8.25 (d, J = 5.2 Hz, 1H), 7.88 (d, J = 5.1 Hz, 1H), 2.98 (t, J = 6.2 Hz, 2H), 2.87 (t, J = 6.5 Hz, 2H), 1.97 (dt, J = 12.2, 6.2 Hz, 2H).

[0256] Compound 63 was obtained as a pale yellow solid in 67% yield as a mixture of E/Z-isomers (90:10). ¹H-NMR (400 MHz, DMSO-d₆): δ 12.32 (bs, 1H), 8.60 (d, J = 2.4 Hz, 1H), 8.50 (d, J = 2.4 Hz, 1H), 8.27 (d, J = 3.9 Hz, 1H), 8.14 (d, J = 7.3 Hz, 1H), 7.09 (dd, J = 7.7, 4.9 Hz, 1H), 2.98 (t, J = 6.1 Hz, 2H), 2.91 (t, J = 6.4 Hz, 2H), 1.96 (dt, J = 12.2, 6.2 Hz, 2H).

[0257] Compound 64 was obtained as an orange solid in 32% yield.¹H-NMR (400 MHz, DMSO-d₆): δ 11.97 (bs, 1H), 8.60 (d, J = 2.4 Hz, 1H), 8.48 (d, J = 2.4 Hz, 1H), 7.90 (s, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.28 (dd, J = 8.3, 2.1 Hz, 1H), 2.97 (t, J = 6.1 Hz, 2H), 2.87 (t, J = 6.5 Hz, 2H), 1.96 (dt, J = 12.2, 6.2 Hz, 2H). [0258] Compound 65 was obtained as an orange solid in 66% yield.¹H-NMR (400 MHz, DMSO-d₆): δ 11.97 (bs, 1H), 8.60 (d, J = 2.4 Hz, 1H), 8.48 (d, J = 2.4 Hz, 1H), 7.91 (d, J = 1.9 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.32 (dd, J = 8.5, 2.2 Hz, 1H), 2.97 (t, J = 6.1 Hz, 2H), 2.86 (t, J = 6.5 Hz, 2H), 1.96 (dt, J = 12.1, 6.2 Hz, 2H).

[0259] Compound 66 was obtained as a yellow solid in 88% yield as a mixture of E/Z- isomers (99:1). ¹H-NMR (400 MHz, DMSO-d6): δ 12.01 (bs, 1H), 8.60 (d, J = 2.4 Hz, 1H), 8.49 (d, J = 2.4 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.49 (s, 1H), 7.16 (dd, J = 8.4, 2.1 Hz, 1H), 2.97 (t, J = 6.1 Hz, 2H), 2.86 (t, J = 6.5 Hz, 2H), 1.96 (dt, J = 12.1, 6.2 Hz, 2H). Example 21: Synthesis of 7,8-dihydrooxepino[3,2-b]pyridin-9(6H)-one (int-15)

[0260] 2-Bromo-3-hydroxy pyridine (int-12) (20.0 g, 114.9 mmol) was dissolved in DMF (10 mL). K₂CO₃ (47.6 g, 137.2 mmol) was added at rt, followed by 5-bromopent-1-ene 2 (16.4 g, 137.8 mmol). The mixture was heated at 80 °C for 16 h. After cooling down to rt, cold water was added, and the mixture was extracted with EtOAc (3 x 250 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (100-200 µm silica) using 10% EtOAc in hexane as eluent to afford 17.0 g (71%) of 2-bromo-3-(pent-4-enyloxy) pyridine (int-13) as a brown semi-solid. MS (ESI) m/z 241.94 [M+H]⁺.

[0261] Int-13 (2 g, 8.26 mmol) was dissolved in dry dimethylacetamide (30 mL), and triethylamine (6.9 mL, 49.58 mmol) was added. The solution was degassed with argon for 15 min, then tris-orthotoluyl phosphine (502 mg, 1.65 mmol) was added, followed by palladium(II) acetate (556 mg, 0.82 mmol). The mixture was degassed for another 5 min, then it was heated to 150 °C for 4 h. After cooling down to rt, the mixture was diluted with cold water and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with water (2 x 50 mL), brine (50 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (100-200 µm silica) using 10% EtOAc in hexane as eluent to afford 400 mg (30%) of 9-methylene-6,7,8,9-tetrahydrooxepino[3,2-b]pyridine (int-14) as a pale brown solid. MS (ESI) m/z 162.02 [M+H]⁺.

[0262] Int-14 (1.5 g, 9.31 mmol) was dissolved in DCM (30 mL) and the solution was purged with ozone gas at -78 °C for 25 min. Then the reaction was quenched with dimethylsulfide at -78 °C and stirred for an additional 1 h at the same temperature. Then it was allowed to slowly warm to rt, and then cold water was added. The mixture was extracted with DCM (3 x 100 mL) and the combined organic layers were washed with water (2 x 30 mL), brine (30 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified via column chromatography on reversed phase silica gel to afford 300 mg (20%) of 7,8-dihydrooxepino[3,2-b]pyridin-9(6H)-one (int-15) as an off-white solid.¹H-NMR (300 MHz, CDCl₃): δ 8.49 (dd, J = 4.2, 1.2 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.36 (dd, J = 9.6, 5.7 Hz, 1H), 4.30 (t, J = 6.3 Hz, 2H), 2.99 (t, J = 6.9 Hz, 2H), 2.29 (dt, J = 13.5, 6.0 Hz, 2H); MS (ESI) m/z 164.04 [M+H]⁺. Example 22: Compounds 67-74

[0263] Compounds 67-74 were synthesized according to the general procedure I.

[0264] Compound 67: Since no precipitate formed during the work-up, the mixture was evaporated to dryness and purified on silica gel with a mixture of DCM and MeOH as eluent (gradient: 100:0 to 80:20). Compound 67 was obtained as a yellow solid in 64% yield as a mixture of E/Z-isomers (95:5). ¹H-NMR (400 MHz, DMSO-d₆): δ 12.09 (bs, 1H), 8.70 (bs, 1H), 8.38 (dd, J = 4.5, 1.5 Hz, 1H), 8.23 (d, J = 5.2 Hz, 1H), 7.85 (d, J = 4.9 Hz, 1H), 7.46 (dd, J = 8.2, 1.5 Hz, 1H), 7.38 (dd, J = 8.2, 4.5 Hz, 1H), 4.17 (t, J = 6.1 Hz, 2H), 2.89 (t, J = 6.4 Hz, 2H), 2.02 (dt, J = 12.6, 6.2 Hz, 2H).

[0265] Compound 68 was obtained as an off-white solid in 69% yield. ¹H-NMR (400 MHz, DMSO-d₆): δ 12.19 (bs, 1H), 8.38 (dd, J = 4.5, 1.4 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.46 (dd, J = 8.2, 1.4 Hz, 1H), 7.41-7.36 (m, 2H), 7.11 (t, J = 7.9 Hz, 1H), 4.17 (t, J = 6.1 Hz, 2H), 2.89 (t, J = 6.4 Hz, 2H), 2.02 (dt, J = 12.7, 6.3 Hz, 2H).

[0266] Compound 69 was obtained as an off-white solid in 26% yield as a mixture of E/Z-isomers (98:2). ¹H-NMR (400 MHz, DMSO-d₆): δ 12.01 (bs, 1H), 8.38 (dd, J = 4.4, 1.4 Hz, 1H), 7.87 (s, 1H), 7.48 (s, 1H), 7.45 (dd, J = 8.1, 1.4 Hz, 1H), 7.37 (dd, J = 8.2, 4.5 Hz, 1H), 7.28 (d, J = 8.6 Hz, 1H), 4.16 (t, J = 6.1 Hz, 2H), 2.89 (t, J = 6.4 Hz, 2H), 2.01 (dt, J = 12.5, 6.2 Hz, 2H).

[0267] Compound 70 was obtained as a yellow solid in 66% yield. ¹H-NMR (400 MHz, DMSO-d₆): δ 12.01 (bs, 1H), 8.37 (dd, J = 4.5, 1.5 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.45 (dd, J = 8.2, 1.5 Hz, 1H), 7.44 (s, 1H), 7.36 (dd, J = 8.2, 4.5 Hz, 1H), 7.14 (dd, J = 8.4, 2.1 Hz, 1H), 4.16 (t, J = 6.1 Hz, 2H), 2.89 (t, J = 6.5 Hz, 2H), 2.01 (dt, J = 12.8, 6.3 Hz, 2H).

[0268] Compound 71 was obtained as an off-white solid in 72% yield. ¹H-NMR (400 MHz, DMSO-d₆): δ 12.03 (bs, 1H), 8.39 (d, J = 3.5 Hz, 1H), 8.19 (d, J = 4.1 Hz, 1H), 7.71 (bs, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.37 (dd, J = 8.1, 4.5 Hz, 1H), 7.32 (dd, J = 7.9, 4.8 Hz, 1H), 4.17 (t, J = 6.0 Hz, 2H), 2.91 (t, J = 6.3 Hz, 2H), 2.01 (dt, J = 12.4, 6.1 Hz, 2H).

[0269] Compound 72 was obtained as a yellow solid in 31% yield. ¹H-NMR 400 MHz, DMSO-d₆): δ 12.32 (bs, 1H), 8.77 (bs, 1H), 8.38 (dd, J = 4.5, 1.4 Hz, 1H), 8.32 (bs, 1H), 7.46 (dd, J = 8.2, 1.4 Hz, 1H), 7.37 (dd, J = 8.2, 4.5 Hz, 1H), 7.28 (bs, 1H), 4.17 (t, J = 6.1 Hz, 2H), 2.93 (t, J = 6.5 Hz, 2H), 2.02 (dt, J = 12.6, 6.3 Hz, 2H).

[0270] Compound 73 was obtained as an orange solid in 19% yield as a mixture of E/Z- isomers (73:27).¹H-NMR (400 MHz, DMSO-d₆): δ 14.19 (bs, 2.9H), 12.26 (bs, 1.2H), 8.52 (dd, J = 4.5, 1.4 Hz, 3.2H), 8.38-8.36 (m, 3.3H), 8.28 (d, J = 7.6 Hz, 3.2H), 7.65 (dd, J = 8.4, 1.4 Hz, 2.4H), 7.53 (dd, J = 8.3, 4.5 Hz, 2.6H), 7.47 (dd, J = 8.2, 1.4 Hz, 1.0H), 7.38 (dd, J = 8.2, 4.5 Hz, 1.2H), 7.15 (dd, J = 7.8, 4.9 Hz, 2.5H), 7.09 (bs, 1.0H), 4.31 (t, J = 6.3 Hz, 5.0H), 4.17 (t, J = 6.1 Hz, 2.0H), 2.94 (bs, 2.3H), 2.81 (t, J = 6.8 Hz, 4.9H), 2.17 (dt, J = 13.2, 6.6 Hz, 5.4H), 2.02 (dt, J = 12.4, 6.1 Hz, 2.2H).

[0271] Compound 74 was obtained as an off-white solid in 84% yield. ¹H-NMR (400 MHz, DMSO-d₆): δ 11.95 (bs, 1H), 8.37 (dd, J = 4.5, 1.5 Hz, 1H), 7.87 (s, 1H), 7.45 (dd, J = 8.2, 1.5 Hz, 1H), 7.38 (bs, 1H), 7.36 (dd, J = 8.2, 4.5 Hz, 1H), 7.31 (dd, J = 8.5, 2.2 Hz, 1H), 4.16 (t, J = 6.1 Hz, 2H), 2.89 (t, J = 6.4 Hz, 2H), 2.01 (dt, J = 12.7, 6.3 Hz, 2H). Example 23: Synthesis of 7,8-dihydrooxepino[3,2-d]pyrimidin-9(6H)-one (int-22)

[0272] 2,4-Dichloro-5-methoxypyrimidine (int-16) (35.0 g, 195 mmol) was dissolved in 350 mL dichloroethane. Boron tribromide (92 mL 977 mmol) was added at 0 °C, and the mixture was heated at 80 ^°C for 12 h. Thereafter, the mixture was poured into ice-cold water and basified with 2 N NaOH solution. The pH was adjusted to 4-5 with saturated aq. ammonium chloride and acetic acid. The mixture was extracted with EtOAc (3 x 500 mL) and the combined organic layers were washed with water (150 mL), brine (150 mL), dried over Na₂SO₄ and concentrated under reduced pressure to afford 30.0 g (crude yield: 93%) of 2,4-dichloropyrimidin-5-ol (int-17) as an off-white solid. MS (ESI) m/z 164.85 [M+H]⁺.

[0273] Int-17 (30.0 g, 181.8 mmol) and 4-pentenol (22.0 mL 218 mmol) were dissolved in tetrahydrofuran (300 mL), and the mixture was cooled to 0 °C. Triphenyl phosphine (71.0 g 272 mmol) was added, followed by diisopropyl azodicarboxylate (55.0 mL 272 mmol). The mixture was stirred at rt for 12 h. Then, the mixture was diluted with water and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with water (150 mL), brine (150 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 10% EtOAc in hexane as eluent to afford 28.0 g (66%) of 2,4- dichloro-5-(pent-4-enyloxy)pyrimidine (int-18) as a pale yellow liquid. MS (ESI) m/z 232.96 [M+H]⁺. [0274] Int-18 (20.0 g, 85.83 mmol) was dissolved in dioxane (400 mL) and potassium acetate (28.2 g, 257.5 mmol) was added. The solution was degassed with argon gas for 15 min. Then triphenyl phosphine (9.0 g, 34.33 mmol) was added, followed by palladium(II) acetate (5.7 g, 8.583 mmol). The mixture was degassed for another 5 min, and then heated at 100 °C for 24 h. After cooling to rt, the mixture was diluted with water and extracted with EtOAc (3 x 400 mL). The combined organic layers were washed with water (240 mL), brine (240 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 10% EtOAc in hexane as eluent to afford 5.0 g (30%) of 2- chloro-9-methylene-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidine (int-19) as a pale yellow gummy solid. MS (ESI) m/z 196.96 [M+H]⁺.

[0275] Int-19 (3.0 g, 15.3 mmol) was dissolved in DCM (60 mL). N-methylmorpholine N-oxide (10.5 mL, 45.9 mmol) was added, followed by 2.5 wt% solution of osmium tetraoxide (3 mL) in tert-butanol at rt. After stirring at rt for 16 h, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 30% EtOAc in hexane as eluent to afford 2.7 g (77%) of 2-chloro-9-(hydroxymethyl)-6,7,8,9- tetrahydrooxepino[3,2-d]pyrimidin-9-ol (int-20) as an off-white solid. MS (ESI) m/z 231.11 [M+H]⁺.

[0276] Int-20 (2.7 g, 11.73 mmol) was dissolved in EtOH (100 mL). 10% Pd/C catalyst (0.7 g 20%, by wt) was added, followed by magnesium oxide (2.7g, 65.73 mmol). The mixture was stirred under hydrogen atmosphere at rt for 3 h. Then it was filtered through a celite pad and washed with EtOH. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using 2% MeOH in DCM as eluent to afford 1.0 g (45%) of 9- (hydroxymethyl)-6,7,8,9-tetrahydrooxepino[3,2-d]pyrimidin-9-ol int-21 as an off-white solid. MS (ESI) m/z 197.16 [M+H]⁺.

[0277] Int-21 (1.0 g, 5.10 mmol) was dissolved in tetrahydrofuran (25 mL), and a solution of sodium periodate (4.36 g, 20.40 mmol) in water (25 mL) was added at 0 °C. The mixture was stirred at rt for 3 h. Then it was diluted with saturated aq. sodium bicarbonate and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (60 mL), brine (60 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was washed with diethyl ether to afford 0.6 g (71%) of 7,8-dihydrooxepino[3,2-d]pyrimidin-9(6H)-one (int-22) as an off-white solid.¹H-NMR (400 MHz, DMSO-d₆): δ 8.99 (s, 1H), 8.81 (s, 1H), 4.36 (t, J = 5.6 Hz, 2H), 2.91 (t, J = 6.8 Hz, 2 H), 2.21 (dt, J = 12.4, 6.4 Hz, 2H). MS (ESI) m/z 164.98 [M+H]⁺. Example 24: Compounds 75-76

[0278] Compounds 75-76 were synthesized according to the general procedure I.

[0279] Compound 75 was obtained as a yellow solid in 74% yield. ¹H-NMR (400 MHz, DMSO-d₆): δ 12.25 (s, 1H), 8.93 (s, 1H), 8.56 (s, 1H), 7.80 (bs, 1H), 7.51 (bs, 1H), 7.17 (d, J = 8.1 Hz, 1H), 4.25 (t, J = 6.1 Hz, 2H), 2.95 (t, J = 6.2 Hz, 2H), 2.08 (dt, J = 12.6, 6.3 Hz, 2H).

[0280] Compound 76 was obtained as a yellow solid in 34% yield. ¹H-NMR (400 MHz, DMSO-d₆): δ 12.21 (s, 1H), 8.93 (s, 1H), 8.56 (s, 1H), 7.91 (bs, 1H), 7.47 (bs, 1H), 7.34 (d, J = 7.9 Hz, 1H), 4.25 (t, J = 6.1 Hz, 2H), 2.95 (t, J = 5.5 Hz, 2H), 2.08 (dt, J = 12.4, 6.2 Hz, 2H).

Example 25: Synthesis of 5,6,7,8-Tetrahydro-9H-cyclohepta[d]pyrimidin-9-one (int-27)

[0281] Int-1 (40 g, 1.0 eq.) and formamidine acetate (186.0 g, 1.0 eq.) were dissolved in n-butanol (400 mL) and the mixture was stirred at 120 °C for 18 h. After cooling to rt, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on neutral alumina using 50% EtOAc in hexane as eluent to afford 29.0 g (53%) of 6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine (int-23) as a pale brown semi-solid. MS (ESI) m/z 149.1 [M+H]⁺.

[0282] Int-23 (29.0 g, 195.94 mmol) was dissolved in acetic acid (90 mL). and hydrogen peroxide (33% solution in water, 40.3 mL, 391.89 mmol) was added at rt. The mixture was heated at 70 °C for 12 h. Then it was concentrated under reduced pressure, and the residue was diluted with chloroform (500 mL). Na₂CO₃ (15.0 g) was added at 0 °C to this solution, and it was stirred at rt for 2 h. Then the suspension was filtered and the filtrate was concentrated in vacuo to afford 24.0 g of crude 6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine 1-oxide (int-24). MS (ESI) m/z 165.1 [M+H]⁺. The product was used in the next step without further purification.

[0283] Int-24 (24.0 g, 145.45 mmol) was dissolved in acetic anhydride (120 mL) and the solution was heated at 90 °C for 36 h. After cooling to rt, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on neutral alumina using 30% EtOAc in hexane as eluent to afford 6.0 g (20%) of 6,7,8,9-tetrahydro-5H- cyclohepta[d]pyrimidin-9-yl acetate (int-25) as a pale yellow semi-solid. MS (ESI) m/z 207.1 [M+H]⁺.

[0284] Int-25 (6.0 g, 28.98 mmol) was dissolved in MeOH/water (1:9, 60 mL) and K2CO3 (12.0 g, 86.95 mmol) was added at 0 °C. The mixture was heated at 70 °C for 18 h. Then it was concentrated under reduced pressure, diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography on neutral alumina using 70% EtOAc in hexane as eluent to afford 3.1 g (65%) of 6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-9-ol (int-26) as a pale brown semi-solid. MS (ESI) m/z 165.08 [M+H]+.

[0285] Oxalyl chloride (0.52 ml, 6.06 mmol) was added dropwise to a solution of DMSO (0.85 ml, 12.12 mmol) in DCM (15 ml) at -78 °C. The mixture was stirred at -78 °C for 15 min, then a solution of Int-26 (500 mg, 3.03 mmol) in DCM (5 ml) was added dropwise over a period of 5 min. The mixture was stirred for 30 min at -78 °C. Triethylamine (2.2 ml, 15.15 mmol) was added at -78 °C, and the mixture was slowly warmed to 0 °C. The reaction was quenched with water (20 ml) and the aq. phase was extracted with DCM (3 x 50 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography on neutral alumina using 50% DCM in hexane as eluent to afford 200 mg (40%) of 7,8-dihydro-5H-cyclohepta[d]pyrimidin-9(6H)-one (int-27) as a pale yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 9.18 (s, 1H), 8.88 (s, 1H), 2.94-2.87 (m, 2H), 2.79 (m, 2H), 1.87-1.76 (m, 4H); MS (ESI) m/z 162.97 [M+H]⁺. Example 26: Compounds 77-82

[0286] Compounds 77-82 were synthesized according to the general procedure I.

[0287] Compound 77 was obtained as a yellow solid in 32% yield as a mixture of E/Z- isomers (89:11). ¹H-NMR (400 MHz, DMSO-d₆): δ 12.14 (bs, 1H), 9.12 (s, 1H), 8.67 (s, 1H), 8.21 (d, J = 3.9 Hz, 1H), 7.74 (bs, 1H), 7.34 (dd, J = 7.8, 4.9 Hz, 1H), 2.78-2.75 (m, 4H), 1.81-1.71 (m, 2H), 1.71-1.63 (m, 2H).

[0288] Compound 78 was obtained as a yellow solid in 7% yield as a mixture of E/Z- isomers (97:3).¹H-NMR (400 MHz, DMSO-d₆): δ 12.43 (bs, 1H), 9.10 (s, 1H), 8.74 (s, 1H), 8.67 (s, 1H), 8.30 (d, J = 5.6 Hz, 1H), 7.28 (d, J = 4.8 Hz, 1H), 2.80 (t, J = 6.2 Hz, 2H), 2.77 (t, J = 6.4 Hz, 2H), 1.77 (dt, J = 12.4, 6.2 Hz, 2H), 1.67 (dt, J = 11.7, 6.1 Hz, 2H).

[0289] Compound 79 was obtained as a pale yellow solid in 26% yield. ¹H-NMR (400 MHz, DMSO-d₆): δ 12.16 (bs, 1H), 9.11 (s, 1H), 8.72 (s, 1H), 8.67 (s, 1H), 8.24 (d, J = 5.2 Hz, 1H), 7.85 (d, J = 5.1 Hz, 1H), 2.77 (app. t, J = 5.9 Hz, 4H), 1.78 (dt, J = 12.5, 6.3 Hz, 2H), 1.67 (dt, J = 11.6, 5.9 Hz, 2H).

[0290] Compound 80 was obtained as a pale yellow solid in 44% yield. ¹H-NMR (400 MHz, DMSO-d6): δ 12.38 (bs, 1H), 9.10 (s, 1H), 8.67 (s, 1H), 8.25 (d, J = 4.1 Hz, 1H), 8.09 (d, J = 7.3 Hz, 1H), 7.07 (dd, J = 7.7, 4.9 Hz, 1H), 2.80 (t, J = 5.9 Hz, 2 H), 2.77 (t, J = 6.5 Hz, 2H), 1.77 (dt, J = 12.4, 6.2 Hz, 2H), 1.68 (dt, J = 11.6, 5.8 Hz, 2H).

[0291] Compound 81 was obtained as a yellow solid in 63% yield as a mixture of E/Z- isomers (92:8). ¹H-NMR 400 MHz, DMSO-d₆): δ 12.04 (bs, 1H), 9.10 (s, 1H), 8.66 (s, 1H), 7.88 (s, 1H), 7.41 (bs, 1H), 7.33 (dd, J = 8.5, 2.2 Hz, 1H), 2.76 (app. t, J = 6.0 Hz, 4H), 1.77 (dt, J = 12.6, 6.3 Hz, 2H), 1.66 (dt, J = 11.6, 5.9 Hz, 2H).

[0292] Compound 82 was obtained as a yellow solid in 68% yield. ¹H-NMR (400 MHz, DMSO-d₆): δ 12.10 (bs, 1H), 9.10 (s, 1H), 8.66 (s, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.48 (s, 1H), 7.16 (dd, J = 8.4, 2.0 Hz, 1H), 2.76 (app. t, J = 6.0 Hz, 4H), 1.77 (dt, J = 12.3, 6.2 Hz, 2H), 1.66 (dt, J = 11.5, 5.8 Hz, 2H).

Example 27: Synthesis of 6,7-dihydroquinazolin-8(5H)-one (int-33)

[0293] Cyclohexanone (int-28) (110.0 g, 1.0 eq.) was dissolved in n-butanol (1100 mL) and formamidine acetate (584.0 g, 1.0 eq.) was added at rt. The mixture was stirred at 120 °C for 18 h, then it was cooled to rt and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on neutral alumina using 50% EtOAc in hexane as eluent to afford 20.0 g (15%) of 5,6,7,8-tetrahydroquinazoline (int-29) as a pale brown semi-solid. MS (ESI) m/z 134.92 [M+H]⁺.

[0294] Int-29 (20.0 g, 1.0 eq.) was dissolved in acetic acid (60 mL) and hydrogen peroxide (33% solution in water, 6.0 mL) was added at rt. After heating at 70 °C for 12 h, the mixture was concentrated under reduced pressure and the residue was diluted with chloroform (300 mL). Na₂CO₃ (10.0 g) was added at 0 °C, and the suspension was stirred at rt for 2 h. The mixture was filtered and washed with chloroform (100 mL). The filtrate was concentrated under reduced pressure to afford 16.0 g of crude 5,6,7,8-tetrahydroquinazoline 1-oxide (int-30). The product was used without further purification in the next step. MS (ESI) m/z 151.07 [M+H]+.

[0295] Crude Int-30 (16.0 g, 1.0 eq.) was dissolved in acetic anhydride (65 mL) and the mixture was heated at 90 °C for 36 h. After cooling down to rt the mixture was concentrated under reduced pressure to afford the crude product, which was purified by column chromatography on neutral alumina using 30% EtOAc in hexane as eluent to afford 7.0 g of crude 5,6,7,8- tetrahydroquinazolin-8-yl acetate (int-31) as a pale brown semi-solid. The product was used in the next step without further purification. MS (ESI) m/z 193.03 [M+H]⁺.

[0296] Int-31 (7.0 g, 1.0 eq.) was dissolved in MeOH/water (1:9, 70 mL) and K₂CO₃ (15.0 g, 3.0 eq.) was added at 0 °C. The mixture was heated at 70 °C for 18 h. After cooling to rt, the mixture was concentrated under reduced pressure, diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography on neutral alumina using 60% EtOAc in hexane as eluent to afford 2.2 g (41%) of 5,6,7,8-tetrahydroquinazolin-8-ol (int-32) as a pale yellow semi-solid. MS (ESI) m/z 151.06 [M+H]⁺.

[0297] Oxalyl chloride (0.79 ml, 9.33 mmol) was added dropwise to a solution of DMSO (1.32 ml, 18.64 mmol, 4.0 eq.) in DCM (20 ml) at -78 °C. The mixture was stirred at this temperature for 15 min, then a solution of Int-32 (700 mg, 4.66 mmol, 1.0 eq.) in DCM (7 ml) was added dropwise to the mixture. The mixture was stirred for 30 min at -78° C. Then triethylamine (3.2 ml, 23.33 mmol, 5.0 eq.) was added at -78° C, and the mixture was allowed to warm up to 0 °C. Then the reaction was quenched with water (20 ml) and the aq. phase was extracted with DCM (3 x 50 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford the crude product, which was purified by column chromatography on neutral alumina using 40% DCM in hexane as eluent to afford 300 mg (43%) of 6,7-dihydroquinazolin-8(5H)-one (int-33) as a pale yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 9.23 (s, 1H), 9.02 (s, 1H), 2.98 (t, J = 6.0 Hz, 2H), 2.75 (app. t, J = 6.0 Hz, 2H), 2.11 (dt, J = 12.8, 6.4 Hz, 2H); MS (ESI) m/z 148.98 [M+H]⁺.

Example 28: Compounds 83-84

[0298] Compounds 83-84 were synthesized according to the general procedure I.

[0299] Compound 83 was obtained as a pale yellow solid in 54% yield. ¹H-NMR (400 MHz, DMSO-d₆): δ 12.10 (bs, 1H), 9.08 (s, 1H), 8.68 (s, 1H), 7.95 (s, 1H), 7.53 (bs, 1H), 7.31 (d, J = 8.7 Hz, 1H), 2.83 (t, J = 6.2 Hz, 2H), 2.79 (t, J = 5.9 Hz, 2H), 1.89 (dt, J = 11.8, 6.5 Hz, 2H).

[0300] Compound 84 was obtained as a pale yellow solid in 71% yield. ¹H-NMR (400 MHz, DMSO-d6): δ 12.11 (bs, 1H), 9.08 (s, 1H), 8.67 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.52 (s, 1H), 7.19 (dd, J = 8.4, 2.0 Hz, 1H), 2.83 (t, J = 6.4 Hz, 2H), 2.80 (t, J = 6.0 Hz. 2H), 1.89 (dt, J = 12.1, 6.1 Hz, 2H).

Example 29: Synthesis of 6,7-dihydrobenzo[d]thiazol-4(5H)-one (int-37)

[0301] Cyclohexane-1,2-dione (int-34) (5.0 g, 44.62 mmol) was dissolved in diethyl ether (40 mL) and a bromine solution (2.3 mL, 44.62 mmol) in diethyl ether (10 mL) was added at 0 °C. The mixture was stirred at 0 °C for 30 min, then it was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (100-200 µm silica) using 5% EtOAc in hexane as eluent to afford the semi-pure product, which was recrystallized from cold ether (100 mL) affording 3.7 g (43%) of 3-bromocyclohexane-1,2-dione (int-35). MS (ESI) m/z 192.87 [M-H]⁺. [0302] Int-35 (5.0 g, 26.17 mmol) was dissolved in EtOH (50 mL) and thiourea (1.99 g, 26.17 mmol) was added at rt. Then the mixture was heated at 90 °C for 16 h. After cooling down to rt, the mixture was concentrated under reduced pressure and the residue was diluted with water (50 mL) and extracted with EtOAc (2 x 150 mL). Combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by column chromatography on reversed phase silica gel using water/acetonitrile with 0.01% formic acid as eluent.2-Amino-6,7-dihydrobenzo[d]thiazol-4(5H)-one (int-36) was obtained as an off-white solid in 47% (2.1 g) yield. MS (ESI) m/z 169.01 [M-H]⁺.

[0303] Int-36 (1.0 g, 5.95 mmol) was dissolved in tetrahydrofuran (20 mL) and isoamyl nitrite (0.95 mL, 7.14 mmol) was added at 0 °C. Then the mixture was heated at 45 °C for 3 h. After cooling to rt, the mixture was quenched with aq. ammonium chloride and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by column chromatography on neutral alumina using 5% EtOAc in hexane as eluent. 6,7- Dihydrobenzo[d]thiazol-4(5H)-one (int-37) was obtained as an off-white solid in 52% (480 mg) yield. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.95 (s, 1H), 3.13 (t, J = 6.0 Hz, 2H), 2.60-2.53 (m, 2H), 2.13 (dt, J = 12.4, 6.4 Hz, 2H); MS (ESI) m/z 154.13 [M+H]⁺. Example 30: Compounds 85-87

[0304] Compounds 85-87 were synthesized according to the general procedure I. [0305] Compound 85 was obtained as a light purple solid in 61% yield. ¹H-NMR (400 MHz, DMSO-d₆): δ 11.66 (bs, 1H), 8.96 (s, 1H), 7.88 (s, 1H), 7.35 (bs, 1H), 7.30 (dd, J = 8.5, 2.2 Hz, 1H), 2.96 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 6.3 Hz, 2H), 1.97 (dt, J = 12.2, 6.1 Hz, 2H).

[0306] Compound 86 was obtained as an off-white solid in 39% yield as a mixture of E/Z-isomers (95:5). ¹H-NMR (400 MHz, DMSO-d6): δ 11.71 (bs, 1H), 8.97 (s, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.42 (s, 1H), 7.12 (dd, J = 8.3, 2.0 Hz, 1H), 2.96 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 6.4 Hz, 2H), 1.97 (dt, J = 12.3, 6.2 Hz, 2H).

[0307] 87 was obtained as an off-white solid in 43% yield.¹H-NMR (400 MHz, DMSO- d₆): δ 11.71 (bs, 1H), 8.97 (s, 1H), 7.88 (s, 1H), 7.44 (d, J = 8.9 Hz, 1H), 7.26 (d, J = 8.7 Hz, 1H), 2.96 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 6.3 Hz, 2H), 1.97 (dt, J = 12.0, 6.0 Hz, 2H). Example 31: S nthesis of 6H- rano 32-d rimidin-8 7H -one int-44

[0308] 2,4-Dichloro-5-methoxypyrimidine (int-38) (20.0 g, 111.0 mmol) was dissolved in 250 mL of dichloroethane and boron tribromide (52.7 mL, 555.0 mmol) was added at 0 °C. The mixture was heated at 80 ^oC for 16 h. Then the mixture was poured into ice-cold water and basified with 2 N NaOH solution. The pH was adjusted to 4-5 with saturated aq. ammonium chloride and acetic acid. The mixture was extracted with EtOAc (3 x 300 mL), and the combined organic layers were washed with water (180 mL), brine (180 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. 2,4-Dichloropyrimidin-5-ol (int-39) was obtained as an off-white solid in 82% (15.0 g) crude yield. The product was used without further purification in the next step. MS (ESI) m/z 164.88 [M+H]⁺.

[0309] Int-39 (15.0 g, 91.46 mmol) and but-3-en-1-ol (10.0 mL 109.0 mmol) were dissolved in tetrahydrofuran (150 mL). Triphenyl phosphine (47.6 g 181.8 mmol) was added at 0 °C, followed by diisopropyl azodicarboxylate (36.0 mL 181.8 mmol). After stirring at rt for 12 h, the mixture was diluted with water and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with water (120 mL), brine (120 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 10% EtOAc in hexane as eluent. 5-(But-3-enyloxy)-2,4-dichloropyrimidine (int-40) was obtained as a pale yellow liquid in 50% (10.0 g) yield. MS (ESI) m/z 218.94 [M+H]⁺.

[0310] Int-40 (20.0 g, 91.32 mmol) was dissolved in dioxane (400 mL) and potassium acetate (26.8 g, 273.9 mmol) was added. The mixture was degassed with argon gas for 25 min. Then triphenyl phosphine (9.5 g, 36.52 mmol) was added, followed by palladium(II) acetate (3.0 g, 13.69 mmol). The mixture was degassed for an additional 5 min before it was heated to 100 °C for 24 h. After cooling down to rt, the mixture was diluted with water and extracted with EtOAc (3 x 400 mL). The combined organic layers were washed with water (240 mL), brine (240 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 10% EtOAc in hexane as eluent. 2-Chloro-8-methylene-7,8- dihydro-6H-pyrano[3,2-d]pyrimidine (int-41) was obtained as a pale yellow gummy solid in 30% (8.0 g) yield. MS (ESI) m/z 182.96 [M+H]⁺.

[0311] Int-41 (3.0 g, 16.39 mmol) was dissolved in DCM (50 mL) and the solution was purged with ozone gas for 3 h at -78 °C. Then dimethylsulfide (12.0 mL, 13.9 mmol) was added at the same temperature. The mixture was allowed to slowly warm to rt over 16 h before it was diluted with water and extracted with DCM (3 x 100 mL). The combined organic layers were washed with water (60 mL), brine (60 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 40% EtOAc in hexane as eluent. 2-Chloro-6H-pyrano[3,2-d]pyrimidin-8(7H)-one (int-42) was obtained as a pale yellow liquid in 50% (1.5 g) yield.¹H-NMR (400 MHz, CDCl₃): δ 8.65 (s, 1H), 4.71 (t, J = 6.4 Hz, 2H), 3.04 (t, J = 6.0 Hz, 2H); MS (ESI) m/z 185.25 [M+H]⁺.

[0312] Int-42 (4.0 g, 21.73 mmol) was dissolved in EtOH (100 mL) and 10% Pd/C- catalyst (1.2 g, 30% by wt) followed by magnesium oxide (4.0 g 130.4 mmol) was added. The mixture was stirred under hydrogen atmosphere at rt for 3 h before it was filtered through a celite pad and washed with EtOH. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using 2% MeOH in DCM as eluent. 7,8- Dihydro-6H-pyrano[3,2-d]pyrimidin-8-ol (int-43) was obtained as an off-white solid in 30% (1.0 g) yield.

[0313] Oxalyl chloride (0.69 ml, 7.89 mmol) was added dropwise to a DMSO solution (1.12 ml, 15.78 mmol) in DCM (20 ml) at -78 °C. The mixture was stirred at this temperature for 15 min, before a solution of Int-43 (600 mg, 3.94 mmol) in DCM (7 ml) was added dropwise. The mixture was stirred for 30 min at -78 °C before triethylamine (2.7 ml, 19.73 mmol) was added at -78 °C. Subsequently, it was allowed to warm to 0 °C over a period of 1 h, then it was quenched with water (20 ml) and the aq. phase was extracted with DCM (3 x 50 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography on reversed phase silica gel using 40% acetonitrile with 0.1% formic acid in water. 6H-Pyrano[3,2-d]pyrimidin-8(7H)-one (int-44) was obtained as a pale yellow solid in 38% (200 mg) yield. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.96 (s, 1H), 8.87 (s, 1H), 4.71 (t, J = 6.0 Hz, 2H), 2.99 (t, J = 6.4 Hz, 2H); MS (ESI) m/z 150.95 [M+H]⁺. Example 32: Compound 88

[0314] Compound 88 was synthesized according to the general procedure I. The product was obtained as an orange solid in 62% yield. ¹H-NMR (400 MHz, DMSO-d₆): δ 12.24 (bs, 1H), 8.84 (s, 1H), 8.53 (s, 1H), 7.92 (s, 1H), 7.39 (bs, 1H), 7.34 (dd, J = 8.4, 2.0 Hz, 1H), 4.40 (t, J = 6.0 Hz, 2H), 3.09 (t, J = 6.0 Hz, 2H). Example 33: Synthesis of 2-hydrazinyl-5-(trifluoromethoxy)benzo[d]thiazole (int-47)

[0315] 5-(Trifluoromethoxy)benzo[d]thiazole-2-thiol (int-45) (1.0 g, 4.0 mmol) was dissolved in dry tetrahydrofuran (16 mL) and cooled to 0 °C. Then sodium hydride (60% dispersion in mineral oil, 176 mg, 4.4 mmol) was added in portions. The mixture was stirred at 0 °C for 30 minutes before methyl iodide (300 µL, 4.8 mmol) was added dropwise. The mixture was allowed to reach rt over 16 hours, then the reaction was quenched with saturated aq. ammonium chloride (15 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo to yield 2-(methylthio)-5- (trifluoromethoxy)benzo[d]thiazole (int-46) as a red oil. The product was used in the next step without further purification. ¹H-NMR (400 MHz, CDCl3): δ 7.75-7.73 (m, 2H), 7.20-7.15 (m, 1H), 2.80 (s, 3H).

[0316] Int-46 (1.1 g, 5.0 mmol) was dissolved in EtOH (1.1 mL) and hydrazine hydrate (2.4 mL, 50 mmol) was added. The mixture was heated at 100 °C for 3 h. After cooling to rt, water was added and the off-white precipitate was isolated by centrifugation. The crude product was washed with water (2 x 10 mL) and dried in vacuo to give 2-hydrazinyl-5- (trifluoromethoxy)benzo[d]thiazole (int-47) as an off-white solid in 65% (652 mg) yield. ¹H-NMR (400 MHz, DMSO-d6): δ 9.32 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.26 (m, 1H), 6.98 (m, 1H), 5.14 (s, 2H). Example 34: Compounds 89-95

[0317] Compounds 89-95 were synthesized according to the general procedure I.

[0318] Compound 89 was obtained as a white solid in 25% yield. ¹H-NMR (400 MHz, DMSO-d6): δ 11.76 (bs, 1H), 8.97 (s, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.35 (s, 1H), 7.08 (d, J = 8.5 Hz, 1H), 2.96 (t, J = 5.9 Hz, 2H), 2.78 (t, J = 6.1 Hz, 2H), 1.97 (dt, J = 12.0, 6.0 Hz, 2H).

[0319] Compound 90 was obtained as an off-white solid in 59% yield. ¹H-NMR (400 MHz, DMSO-d₆): δ 12.16 (bs, 1H), 9.08 (s, 1H), 8.68 (s, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.44 (s, 1H), 7.15 (d, J = 8.6 Hz, 1H), 2.84 (t, J = 6.2 Hz, 2H), 2.79 (t, J = 6.1 Hz, 2H), 1.89 (dt, J = 12.1, 6.1 Hz, 2H).

[0320] Compound 91 was obtained as a pale yellow solid in 66% yield. ¹H-NMR (400 MHz, DMSO-d6): δ 12.05 (bs, 1H), 8.38 (dd, J = 4.5, 1.5 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.46 (dd, J = 8.2, 1.5 Hz, 1H), 7.37 (dd, J = 8.2, 4.5 Hz, 2H), 7.10 (d, J = 8.5 Hz, 1H), 4.17 (t, J = 6.1 Hz, 2H), 2.89 (t, J = 6.4 Hz, 2H), 2.01 (dt, J = 12.7, 6.3 Hz, 2H).

[0321] Compound 92 was obtained as an orange solid in 61% yield.¹H-NMR (400 MHz, DMSO-d₆): δ 12.05 (bs, 1H), 8.60 (d, J = 2.4 Hz, 1H), 8.49 (d, J = 2.4 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.42 (s, 1H), 7.13 (dd, J = 8.6, 1.2 Hz, 1H), 2.97 (t, J = 6.1 Hz, 2H), 2.87 (t, J = 6.5 Hz, 2H), 1.96 (dt, J = 12.4, 6.3 Hz, 2H).

[0322] Compound 93 was obtained as a pale yellow solid in 37% yield. ¹H-NMR (400 MHz, DMSO-d₆): δ 12.13 (bs, 1H), 9.10 (s, 1H), 8.67 (s, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.40 (s, 1H), 7.12 (d, J = 8.5 Hz, 1H), 2.77 (app. t, J = 5.9 Hz, 4H), 1.77 (dt, J = 12.4, 6.7 Hz, 2H), 1.67 (dt, J = 11.8, 6.0 Hz, 2H).

[0323] Compound 94 was obtained as an off-white solid in 57% yield. ¹H-NMR (400 MHz, DMSO-d₆): δ 11.80 (bs, 1H), 8.49 (dd, J = 4.7, 1.4 Hz, 1H), 7.89 (bs, 1H), 7.64 (dd, J = 7.6, 1.5 Hz, 1H), 7.48 (bs, 1H), 7.34 (dd, J = 7.5, 4.8 Hz, 1H), 7.11 (bs, 1H), 2.79-2.65 (m, 4H), 1.74 (dt, J = 12.7, 6.4 Hz, 2H), 1.61 (dt, J = 11.4, 5.8 Hz, 2H).

[0324] Compound 95 was obtained as a yellow solid in 56% yield. ¹H-NMR (400 MHz, DMSO-d₆): δ 11.97 (bs, 1H), 8.32 (dd, J = 4.1, 1.7 Hz, 1H), 7.93 (bs, 1H), 7.48 (bs, 1H), 7.36 (dd, J = 8.3, 1.7 Hz, 1H), 7.32 (dd, J = 8.3, 4.1 Hz, 1H), 7.12 (bs, 1H), 4.34 (t, J = 6.1 Hz, 2H), 3.12-3.01 (m, 2H). Example 35: Synthesis of (E)-9-(2-(6-(trifluoromethyl)thiazolo[4,5-b]pyridin-2-yl)hydrazono)-

[0325] To a solution of 3-chloro-5-(trifluoromethyl)pyridin-2-amine (int-48) (3.0 g, 15.3 mmol) in tetrahydrofuran (50 mL) was added benzoyl isothiocyanato (int-49) (5.0 g, 30.6 mmol). The solution was stirred at 60 ^°C for 15 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel with a mixture of petroleum ether and EtOAc (100:1) as eluent to give N-((3-chloro-5-(trifluoromethyl)pyridin-2- yl)carbamothioyl)benzamide (int-50) (1.2 g, 21%) as a light yellow solid. MS (ESI): m/z 359.7 [M+H]⁺. [0326] To a solution of Int-50 (1.2 g, 3.3 mmol) in N-methyl-2-pyrrolidone (20 mL) was added sodium methoxide (0.9 g, 16.7 mmol) under nitrogen atmosphere. The mixture was stirred at 120 ^°C for 5 h. The mixture was diluted with water (50 mL) and extracted with DCM (3 x 50 mL). The combined organic phases were concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with a mixture of petroleum ether and EtOAc (5:1) as eluent to give N-(6-(trifluoromethyl)thiazolo[4,5-b]pyridin-2-yl)benzamide (int-51) (800 mg, 75% yield) as a yellow solid. MS (ESI): m/z 323.7 [M+H]⁺.

[0327] A solution of Int-51 (800 mg, 2.48 mmol) in sulfuric acid (10 mL) was stirred at 120 ^°C for 15 h. The mixture was added dropwise into ice water and the pH was adjusted to 9-10 with 1 N aq. NaOH solution. The precipitate was isolated by filtration and washed with ice water (30 mL) to give 6-(trifluoromethyl)thiazolo[4,5-b]pyridin-2-amine (int-52) (500 mg, 92% yield) as a grey solid. MS (ESI): 219.9 [M+H]⁺.

[0328] Int-52 (500 mg, 2.28 mmol) was dissolved in ethane-1,2-diol (5 mL) with concentrated HCl (aq.) (1.4 mL) and cooled to 0 °C. Then hydrazine hydrate (1 mL) was added dropwise. The mixture was stirred at 130 ^°C for 3 h. The mixture was cooled to rt and water (20 mL) was added. The precipitate was isolated by filtration and washed with water (20 mL) to give 2- hydrazinyl-6-(trifluoromethyl)thiazolo[4,5-b]pyridine (int-53) (200 mg, 37%) as a yellow solid. MS (ESI): m/z 234.9 [M+H]⁺.

[0329] Acetic acid (2 drops) was added to a solution of Int-53 (70.0 mg, 0.30 mmol) and Int-15 (49.0 mg, 0.30 mmol) in EtOH (10 mL) and the solution was stirred at rt for 15 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of DCM and MeOH (40:1) as eluent to give (E)-9-(2-(6- (trifluoromethyl)thiazolo[4,5-b]pyridin-2-yl)hydrazono)-6,7,8,9-tetrahydrooxepino[3,2-b]pyridine (96) (30 mg, 26%) as a light yellow solid.¹H-NMR (400 MHz, DMSO-d₆) δ 12.61 (s, 1H), 8.64 (bs, 2H), 8.40 (d, J = 4.2 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.41 (dd, J = 8.1, 4.4 Hz, 1H), 4.19 (t, J = 6.0 Hz, 2H), 2.96 (t, J = 5.7 Hz, 2H), 2.14– 1.95 (m, 2H); MS (ESI): m/z 379.07 [M+H]⁺. Example 36: Synthesis of (E)-9-(2-(5-chlorothiazolo[5,4-b]pyridin-2-yl)hydrazono)-6,7,8,9- tetrahydrooxepino[3,2-b]pyridine (97)

[0330] 6-Chloropyridin-3-amine (int-54) (5.0 g, 39 mmol) and potassium thiocyanate (7.5 g, 78 mmol) were dissolved in acetic acid (50 mL), then bromine (12.2 g, 78 mmol) was added dropwise. The solution was stirred at 50 ^°C for 15 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of petroleum ether and EtOAc (1:1) as eluent to give 5-chlorothiazolo[5,4-b]pyridin-2-amine (int-55) (800 mg, 11% yield) as a yellow solid. MS (ESI) m/z 185.9 [M+H]⁺.

[0331] Int-55 (400 mg, 2.2 mmol) was dissolved in ethane-1,2-diol (10 mL). Concentrated aq. HCl (2 mL) was added to this solution, followed by dropwise addition of hydrazine hydrate (1 mL) at 0 ^°C. The mixture was stirred at 130 ^°C for 3 h. The mixture was cooled to rt and water (20 mL) was added. The precipitate was isolated by filtration and washed with water (20 mL) to give 5-chloro-2-hydrazinylthiazolo[5,4-b]pyridine (int-56) (300 mg, 70% yield) as a light yellow solid. MS (ESI) m/z 201.0 [M+H]⁺.

[0332] Int-56 (150 mg, 0.75 mmol) and 7,8-dihydrooxepino[3,2-b]pyridin-9(6H)-one and Int-15 (122 mg, 0.75 mmol ) were dissolved in EtOH (10 mL) and acetic acid (2 drops) was added. The mixture was stirred at rt for 15 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of DCM and MeOH (40:1) as eluent to give (E)-9-(2-(5-chlorothiazolo[5,4-b]pyridin-2-yl)hydrazono)-6,7,8,9- tetrahydrooxepino[3,2-b]pyridine (97) (100 mg^38%) as an off-white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 12.15 (s, 1H), 8.40 (d, J = 3.5 Hz, 1H), 7.84 (bs, 1H), 7.54– 7.34 (m, 3H), 4.18 (t, J = 6.0 Hz, 2H), 2.91 (t, J = 5.9 Hz, 2H), 2.13– 1.94 (m, 2H); MS (ESI) m/z 345.8 [M+H]⁺. Example 37: Synthesis of (E)-9-(2-(6-chlorothiazolo[4,5-c]pyridin-2-yl)hydrazono)-6,7,8,9-

[0333] 4,6-Dichloropyridin-3-amine (int-57) (1.5 g, 9.3 mmol) and potassium thiocyanate (2.69 g, 27.8 mmol) were dissolved in dioxane (30 mL) and concentrated aq. HCl (0.1 mL) was added. The solution was stirred at 110 ^°C for 2 days. Then, the solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel using a mixture of petroleum ether and EtOAc (1:1) as eluent to give 6-chlorothiazolo[4,5-c]pyridin-2-amine (int-58) (1.3 g, 76% yield) as a yellow solid. MS (ESI): m/z 185.9 [M+H]⁺.

[0334] Int-58 (400 mg, 2.2 mmol) was dissolved in ethane-1,2-diol (10 mL) and concentrated aq. HCl (2 mL) was added. Then hydrazine hydrate (1 mL) was added dropwise at 0 ^°C. The mixture was stirred at 130 ^°C for 3 h. Then, the mixture was cooled to rt and water (20 mL) was added. The precipitate was isolated by filtration and washed with water (20 mL) to give 6- chloro-2-hydrazinylthiazolo [4,5-c]pyridine (int-59) (300 mg, 70%) as a light yellow solid. MS (ESI): m/z 201.0 [M+H]⁺.

[0335] Int-59 (100 mg, 0.5 mmol) and 7,8-dihydrooxepino[3,2-b]105yridine-9(6H)-one and Int-15 (81 mg, 0.5 mmol ) were dissolved in EtOH (10 mL) and acetic acid (2 drops) was added. The solution was stirred at rt for 15 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of DCM and MeOH (200:1) to give (E)-9-(2-(6-chlorothiazolo[4,5-c]pyridin-2-yl)hydrazono)-6,7,8,9- tetrahydrooxepino[3,2-b]pyridine 98 (30 mg, 17% yield) as a light yellow solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 12.21 (s, 1H), 8.55 (bs, 1H), 8.39 (d, J = 4.4 Hz, 1H), 8.03 (bs, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.39 (dd, J = 8.1, 4.5 Hz, 1H), 4.18 (t, J = 6.0 Hz, 2H), 2.90 (t, J = 6.2 Hz, 2H), 2.09– 1.99 (m, 2H); MS (ESI): m/z 345.8 [M+H]⁺. Example 38: Synthesis of (E)-9-(2-(6-chlorothiazolo[4,5-b]pyridin-2-yl)hydrazono)-6,7,8,9- tetrahydrooxepino[3,2-b]pyridine (99)

[0336] To a solution of 3,5-dichloropyridin-2-amine (int-60) (1.0 g, 6.1 mmol) in tetrahydrofuran (15 mL) was added Int-49 (1.99 g, 12.2 mmol) in one charge under nitrogen atmosphere. The solution was stirred at 60 ^°C for 16 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of petroleum ether and EtOAc (5:1) as eluent to give N-((3,5-dichloropyridin-2- yl)carbamothioyl)benzamide (int-61) (1.49 g, 75% yield) as a yellow solid. MS (ESI): m/z 325.9 [M+H]⁺.

[0337] Sodium methoxide (502 mg, 9.3 mmol) was added to a solution of Int-61 (1.0 g, 3.1 mmol) in N-methyl-2-pyrrolidone (10 mL) at rt under nitrogen atmosphere. The mixture was stirred at 120 ^°C for 4 h. The mixture was diluted with EtOAc (30 mL) and the organic layer was washed with water (2 x 30 mL), brine (30 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of petroleum ether and EtOAc (5:1) as eluent to give N-(6-chlorothiazolo[4,5-b]pyridin-2-yl)benzamide (int-62) (0.7 g, 78%) as a light yellow solid. MS (ESI): m/z 290.0 [M+H]⁺.

[0338] Int-62 (500 mg, 1.72 mmol) was dissolved in concentrated sulfuric acid (10 mL). The mixture was stirred at 110 ^°C for 2 h. The solution was cooled to rt and poured into iced water (20 mL). Then, the suspension was neutralized with 10% aq. NaOH solution (pH 7) and a precipitate formed. The precipitate was isolated by filtration and washed with water. Then the precipitate was dried under reduced pressure to give 6-chlorothiazolo[4,5-b]pyridin-2-amine (int-63) (300 mg, 93% yield) as an off-white solid. MS (ESI): m/z 185.9 [M+H]⁺.

[0339] Concentrated aq. HCl (0.4 mL, 4.85 mmol) was added dropwise over 5 min to a solution of hydrazine hydrate (485 mg, 9.70 mmol) in ethylene glycol (5mL) at 0 ^°C. Then Int-63 (300 mg, 1.61 mmol) was added and the mixture was heated at 190 °C for 2 h. The mixture was poured into iced water (20 mL) and stirred at 3 °C for 2 h. A formed precipitate was isolated by filtration and dried under reduced pressure to give 6-chloro-2-hydrazinylthiazolo[4,5-b]pyridine (int- 64) (140 mg, 43% yield) as an off-white solid. MS (ESI): m/z 200.9 [M+H]⁺.

[0340] Int-64 (140 mg, 0.70 mmol) and 7,8-dihydrooxepino[3,2-b]pyridin-9(6H)-one and Int-15 (114 mg, 0.70 mmol) were dissolved in MeOH and acetic acid (5 drops) was added. Then the solution was stirred at rt for 16 h. The solvent was removed under reduced pressure (27 ^°C, in the dark) and the residue was purified by column chromatography on silica gel using DCM and MeOH (40:1) to give (E)-9-(2-(6-chlorothiazolo[4,5-b]107yridine-2-yl)hydrazono)-6,7,8,9- tetrahydrooxepino [3,2-b]pyridine (99) (50 mg, 21% yield) as a light yellow solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 12.38 (bs, 1H), 8.38 (d, J = 4.2 Hz, 1H), 8.29 (bs, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.38 (dd, J = 8.1, 4.5 Hz, 1H), 4.18 (t, J = 6.1 Hz, 2H), 2.93 (t, J = 6.4 Hz, 2H), 2.11– 1.97 (m, 2H); MS (ESI): m/z 345.9 [M+H]⁺. Example 39: Synthesis of (E)-9-(2-(6-(trifluoromethyl)thiazolo[5,4-c]107yridine-2-yl)hydrazono)- 6,7,8,9-tetrahydrooxepino[3,2-b]pyridine (100)

[0341] 2-(Trifluoromethyl)pyridin-4-amine (int-65) (1.0 g, 6.17 mmol) was dissolved in DCM (15 mL) and a solution of N-bromosuccinimide (1.09 g, 6.17 mmol) in DCM (10 mL) was added. The mixture was stirred at rt for 16 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of petroleum ether and EtOAc (3:1) as eluent to give 5-bromo-2-(trifluoromethyl)pyridin-4-amine (int-66) (1.2 g, 80%) as a yellow solid. MS (ESI): m/z 240.9 [M+H]⁺.

[0342] Int-66 (1.0 g, 4.1 mmol) was dissolved in N-methyl-2-pyrrolidone (15 mL) and potassium ethyl xanthate (int-67) (1.31 g, 8.2 mmol) was added in one portion under nitrogen atmosphere. The mixture was stirred at 210 ^°C for 4 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of petroleum ether and EtOAc (2:1) as eluent to give 6-(trifluoromethyl)thiazolo[5,4-c]pyridine-2(1H)- thione (int-68) (800 mg, 80% yield) as a yellow solid. MS (ESI): m/z 202.8 [M+H]⁺.

[0343] Int-68 (400 mg, 1.69 mmol) was dissolved in DMF (10 mL). K₂CO₃ (351 mg, 2.54 mmol) was added at rt, followed by addition of methyl iodide (286 mg, 2.03 mmol). The mixture was stirred at rt for 1 h. The mixture was diluted with EtOAc (30 mL) and the organic layer was washed with water (2 x 30 mL), brine (30 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of petroleum ether and EtOAc (5:1) to give 2-(methylthio)-6-(trifluoromethyl)thiazolo[5,4-c]pyridine (int-69) (400 mg, 94% yield) as a light yellow solid. MS (ESI): m/z 250.9 [M+H]⁺.

[0344] Int-69 (400 mg, 1.60 mmol) was dissolved in EtOH (10 mL) and hydrazine hydrate (2 mL) was added under nitrogen atmosphere. The mixture was heated to reflux for 1 h. The solution was poured into iced water. The formed precipitate was isolated by filtration, washed with water and dried under reduced pressure to give 2-hydrazinyl-6-(trifluoromethyl)thiazolo[5,4- c]pyridine (int-70) (300 mg, 80% yield) as a yellow solid. MS (ESI): m/z 234.9 [M+H]⁺.

[0345] Int-70 (200 mg, 0.85 mmol) was dissolved in MeOH and 7,8- dihydrooxepino[3,2-b]pyridin-9(6H)-one int-15 (139 mg, 0.85 mmol) was added, followed by acetic acid (5 drops). Then, the mixture was stirred at rt for 16 h. The solvent was removed under reduced pressure (at 27 ^°C in the dark) and the residue was purified by column chromatography on silica gel using a mixture of DCM and MeOH (40:1) as eluent to give (E)-9-(2-(6- (trifluoromethyl)thiazolo[5,4-c]pyridin-2-yl)hydrazono)-6,7,8,9-tetrahydrooxepino[3,2-b]pyridine (100) (140 mg, 43% yield) as a light yellow solid.¹H-NMR (400 MHz, DMSO-d₆) δ 12.50 (bs, 1H), 9.03 (s, 1H), 8.40 (d, J = 4.4 Hz, 1H), 7.80 (bs, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.40 (dd, J = 8.2, 4.5 Hz, 1H), 4.19 (t, J = 6.1 Hz, 2H), 2.94 (t, J = 6.4 Hz, 2H), 2.05 (dt, J = 12.4, 6.4 Hz, 2H); MS (ESI): m/z 379.9 [M+H]⁺. Example 40: Synthesis of (E)-9-(2-(6-chlorothiazolo[5,4-c]pyridin-2-yl)hydrazono)-6,7,8,9- tetrahydrooxepino[3,2-b]pyridine (101)

[0346] 2,5-Dichloropyridin-4-amine (int-71) (1.0 g, 6.1 mmol) was dissolved in N- methyl-2-pyrrolidone (15 mL) under nitrogen atmosphere. Int-67 (1.97 g, 12.2 mmol) was added in one portion and the mixture was stirred at 200 ^°C for 4 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of petroleum ether and EtOAc (1:2) as eluent to give 6-chlorothiazolo[5,4-c]pyridine-2(1H)-thione (int-72) (700 mg, 72% yield) as a yellow solid. MS (ESI): m/z 236.9 [M+H]⁺.

[0347] Int-72 (1.0 g, 4.8 mmol) was dissolved in DMF (10 mL) and K₂CO₃ (995 mg, 7.2 mmol) was added at rt, followed by addition of methyl iodide (0.45 mL, 7.2 mmol). The mixture was stirred at rt for 1 h. The mixture was diluted with EtOAc (30 mL) and washed with water (2 x 30 mL), brine (30 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of petroleum ether and EtOAc (5:1) as eluent to give 6-chloro-2-(methylthio)thiazolo[5,4-c]pyridine (int-73) (0.83 g, 80%) as a light yellow solid. MS (ESI): m/z 216.8 [M+H]⁺.

[0348] Int-73 (400 mg, 1.85 mmol) was dissolved in EtOH (10 mL) and hydrazine hydrate (2 mL) was added under nitrogen atmosphere. The mixture was heated to reflux for 1 h. The solution was poured into iced water. The formed precipitate was isolated by filtration, washed with water and dried under reduced pressure to give 6-chloro-2-hydrazinylthiazolo[5,4-c]pyridine (int-74) (300 mg, 80% yield) as an off-white solid. MS (ESI): m/z 200.9 [M+H]⁺.

[0349] Int-74 (300 mg, 1.49 mmol) was dissolved in MeOH and Int-15 (243 mg, 1.49 mmol) was added, followed by acetic acid (10 drops). The mixture was stirred at rt for 16 h. The solvent was removed under reduced pressure (at 27 ^°C in the dark) and the residue was purified by column chromatography on silica gel using a mixture of DCM and MeOH (40:1) as eluent to give (E)-9-(2-(6-chlorothiazolo[5,4-c]pyridin-2-yl)hydrazono)-6,7,8,9-tetrahydrooxepino[3,2-b]pyridine (101) (250 mg, 48% yield) as an off-white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 12.48 (bs, 1H), 8.69 (bs, 1H), 8.39 (d, J = 4.0 Hz, 1H), 7.48 (d, J = 7.8 Hz, 2H), 7.40 (dd, J = 8.1, 4.4 Hz, 1H), 4.18 (t, J = 6.0 Hz, 2H), 2.93 (t, J = 6.0 Hz, 2H), 2.11-1.98 (m, 2H); MS (ESI): m/z 345.9 [M+H]⁺. Example 41: Synthesis of (E)-9-(2-(6-(trifluoromethyl)thiazolo[4,5-c]pyridin-2-yl)hydrazono)- 6,7,8,9-tetrahydrooxepino[3,2-b]pyridine (102)

[0350] 6-(Trifluoromethyl)pyridin-3-amine (int-75) (1.3 g, 8.0 mmol) was dissolved in dichloroethane (50 mL), and N-bromosuccinimide (1.4 g, 8.0 mmol) was added. The mixture was stirred at rt for 15 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of petroleum ether and EtOAc (20:1) as eluent to give 4-bromo-6-(trifluoromethyl)pyridin-3-amine (int-76) (1.5 g, 78% yield) as a white solid. MS (ESI): m/z 240.7 [M+H]⁺.

[0351] Int-76 (600 mg, 2.5 mmol) and Int-67 (402 mg, 2.5 mmol) were dissolved in N- methyl-2-pyrrolidone (20 mL) under nitrogen. Then copper(I) chloride (48 mg, 0.25 mmol) was added. The mixture was stirred at 180 ^°C for 5 h. The residue was washed with petroleum ether (100 mL) to give 6-(trifluoromethyl)thiazolo[4,5-c]pyridine-2(3H)-thione (int-77) (300 mg, 51%) as a gray solid. MS (ESI): m/z 236.8 [M+H]⁺.

[0352] Int-77 (300 mg, 1.27 mmol) and K₂CO₃ (530 mg, 2.54 mmol) were dissolved in DMF (20 mL) and methyl iodide (2.9 mg, 1.9 mmol) was added. The mixture was stirred at rt for 3 h. The mixture was diluted with water (50 mL) and extracted with DCM (3 x 50 mL). The combined organic extracts were concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of DCM and MeOH (20:1) as eluent to give 2- (methylthio)-6-(trifluoromethyl)thiazolo[4,5-c]pyridine (int-78) (250 mg, 79%) as a light yellow solid. MS (ESI): m/z 250.8 [M+H]⁺.

[0353] Int-78 (200 mg, 0.8 mmol) and concentrated aq. HCl (1.4 mL) were dissolved in ethane-1,2-diol (5 mL). Then hydrazine hydrate (1 mL) was added dropwise at 0 ^°C. The mixture was stirred at 130 ^°C for 3 h. After cooling down to rt, DI water (20 mL) was added. The formed precipitate was isolated by filtration and washed with water (20 mL) to give 2-hydrazinyl-6- (trifluoromethyl)thiazolo[4,5-c]pyridine (int-79) (170 mg, 91%) as a light yellow solid. MS (ESI): m/z 234.8 [M+H]⁺.

[0354] Int-79 (200 mg, 0.85 mmol) and 7,8-dihydrooxepino[3,2-b]pyridin-9(6H)-one and Int-15 (139 mg, 0.85 mmol) were dissolved in EtOH (5 mL) and acetic acid (2 drops) was added. The mixture was stirred at rt for 15 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of DCM and MeOH (200:1) as eluent to give (E)-9-(2-(6-(trifluoromethyl)thiazolo[4,5-c]pyridin-2- yl)hydrazono)-6,7,8,9-tetrahydrooxepino[3,2-b]pyridine (102) (130 mg, 78%) as a white solid. ¹H- NMR (400 MHz, DMSO-d₆): δ 12.59 (bs, 1H), 9.06 (s, 1H), 8.40 (dd, J = 4.4, 1.2 Hz, 1H), 7.83 (s, 1H), 7.48 (dd, J = 8.3, 1.3 Hz, 1H), 7.41 (dd, J = 8.2, 4.6 Hz, 1H), 4.18 (t, J = 6.1 Hz, 2H), 2.93 (t, J = 6.6 Hz, 2H), 2.05 (dt, J = 12.5, 6.3 Hz, 2H); MS (ESI): m/z 379.8 [M+H]⁺. Example 42: Synthesis of (Z)-9-(2-(6-(trifluoromethoxy)thiazolo[4,5-b]pyridin-2-yl) hydrazono)- 6,7,8,9-tetrahydrooxepino[3,2-b]pyridine (103)

[0355] 2-Chloro-5-(trifluoromethoxy)pyridine (int-80) (1.0 g, 5.06 mmol), sodium tert- butoxide (0.97 g, 10.12 mmol) and benzophenone imine (int-81) (1.10 g, 6.07 mmol) were dissolved in toluene (15 mL). Then Pd₂(dba)₃ (92.60 mg, 0.10 mmol) and DPEPhos (109.0 mg, 0.20 mmol) were added under nitrogen atmosphere. The mixture was heated at 80 °C for 2 h. Then it was filtered and washed with EtOAc (20 mL). The filtrate was treated with 3 M HCl (50 mL) at 50 °C for 4 h. The phases were separated and the aq. phase was basified with 10% NaOH to pH 10. The aq. phase was extracted with EtOAc (3 x 50 mL). The combined organic layers was dried over anhydrous Na₂SO₄ and concentrated in vacuo. Crude 5-(trifluoromethoxy)pyridin-2-amine (int-82) (400 mg, 44%) was used directly in the next step without further purification. MS (ESI): m/z 178.9 [M+H]⁺.

[0356] Int-82 (200 mg, 1.12 mmol) was dissolved in DCM (10 mL) and a solution of N- bromosuccinimide (200 mg, 1.12 mmol) in DCM (5 mL) was added dropwise. The mixture was stirred at rt for 16 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of petroleum ether and EtOAc (2:1) as eluent to give 3-bromo-5-(trifluoromethoxy)pyridin-2-amine (int-83) (200 mg, 69%) as a yellow solid. MS (ESI): m/z 257.9 [M+H]⁺.

[0357] Int-83 (200 mg, 0.78 mmol) was dissolved in N-methyl-2-pyrrolidone (5 mL) and Int-67 (252 mg, 1.56 mmol) was added in one portion under nitrogen atmosphere. The solution was stirred at 200 °C for 4 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of petroleum ether and EtOAc (2:1) as eluent to give 6-(trifluoromethyl)thiazolo[5,4-c]pyridine-2(1H)-thione (int-84) (100 mg, 51%) as a yellow solid. MS (ESI): m/z 252.8 [M+H]⁺.

[0358] Int-84 (100 mg, 0.39 mmol) was dissolved in DMF (3 mL). K₂CO₃ (81 mg, 0.58 mmol) was added at rt, followed by methyl iodide (82 mg, 0.58 mmol). The mixture was stirred at rt for 1 hr, and then diluted with EtOAc (20 mL). The organic layer was washed with water (2 x 15 mL), brine (15 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of petroleum ether and EtOAc (5:1) as eluent to give 2-(methylthio)-6-(trifluoromethoxy)thiazolo[4,5-b]pyridine (int-85) (70 mg, 67%) as a light yellow solid. MS (ESI): m/z found 266.9 [M+H]⁺.

[0359] Int-85 (70 mg, 0.26 mmol) was dissolved in EtOH (5 mL) and hydrazine hydrate (2 mL) was added under nitrogen atmosphere. The mixture was refluxed for 1 h. The solution was poured into ice water. The formed precipitate was isolated by filtration, washed with water and dried under reduced pressure to give 2-hydrazinyl-6-(trifluoromethoxy)thiazolo[4,5-b]pyridine (int-86) (50 mg, 76%) as a yellow solid. MS (ESI): m/z 250.9 [M+H]⁺.

[0360] Int-86 (50 mg, 0.20 mmol) was dissolved in MeOH. Int-15 (33 mg, 0.20 mmol) was added, followed by acetic acid (2 drops). The mixture was stirred at rt for 16 h. The solvent was removed under reduced pressure (27 °C in the dark) and the residue was purified by column chromatography on silica gel using a mixture of DCM and MeOH (40:1) as eluent to give (E)-9-(2- (6-(trifluoromethoxy)thiazolo[4,5-b]pyridin-2-yl)hydrazono)-6,7,8,9-tetrahydrooxepino [3,2- b]pyridine (103) (9 mg, 11%) as a light yellow solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 12.44 (s, 1H), 8.37 (d, J = 4.4 Hz, 1H), 8.26 (s, 1H), 8.23 (s, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.36 (dd, J = 8.1, 4.5 Hz, 1H), 4.18 (t, J = 6.0 Hz, 2H), 2.93 (t, J = 6.0 Hz, 2H), 2.11-1.97 (dt, J = 12.8, 6.0 Hz, 2H); MS (ESI): m/z 395.9 [M+H]⁺. Example 43: Compounds 104-105

[0361] Compound 104: Compound 20 (31.5 mg, 0.095 mmol) was dissolved in MeOH (1.0 mL) and a solution of zinc(II) chloride (11.9 mg, 0.087 mmol) in MeOH (0.9 mL) was added dropwise at rt whereupon the mixture turned orange and a precipitate was formed. After the addition was complete, the mixture was heated in a sealed vial at 80 °C for 2 h to yield an orange suspension. Then it was cooled to rt and stored at -20 °C overnight. The orange precipitate was isolated by centrifugation, washed with diethyl ether and dried in vacuo. The product was obtained as an orange solid in 92% yield. The structural composition of compound 104 was confirmed by SEM-EDX analysis: C 34.55%, N 6.28%, O 2.47%, S 9.48%, Cl 27.19%, Zn 20.03%.

[0362] Compound 105: (E)-2-(2-(Phenyl(pyridin-2- yl)methylene)hydrazinyl)benzo[d]thiazole (Compound A) (33 mg, 0.1 mmol) was dissolved in MeOH (1 mL) and a solution of copper(II) acetate dihydrate (20 mg, 0.1 mmol) in MeOH (1 mL) was added dropwise at rt whereupon the mixture turned deep-red in color. After completion of addition, the mixture was refluxed for 2 h to yield a dark-red solution. The mixture was slowly evaporated at rt to produce dark-green crystals, which were suitable for X-ray analysis in 52% yield. The structural composition of compound 105 was further confirmed by SEM-EDX analysis: C 49.16%, N 7.12%, O 4.77%, S 10.65%, Cu 28.30%. (Figure 7). Example 44: Compounds 106-110

[0363] Compound 106: (E)-2-(2-(1-(Pyridin-2-yl)ethylidene)hydrazinyl)benzo[d]thiazole (Compound C) (26.8 mg, 0.1 mmol) was dissolved in MeOH (1 mL) and a solution of copper(II) acetate dihydrate (20 mg, 0.1 mmol) in MeOH (1 mL) was added dropwise at rt whereupon the mixture turned deep red in color. After addition was complete, the mixture was refluxed for 2 h to yield a deep-red solution. The mixture was slowly evaporated at rt to produce dark-red crystals in 77% yield. The structural composition of compound 106 was confirmed by SEM-EDX analysis: C 43.09%, N 8.11%, O 5.94%, S 13.44%, Cu 29.48%.

[0364] Compound 107: Compound 20 (47.3 mg, 0.143 mmol) was dissolved in MeOH (1.5 mL) and a solution of copper(II) acetate dihydrate (26 mg, 0.13 mmol) in MeOH (1.3 mL) was added dropwise at rt whereupon the mixture turned deep-red in color. After complete addition the mixture was heated in a sealed vial to 80 °C for 2 h to yield a deep-red solution. The mixture was concentrated to about half the initial volume and stored at -20 °C overnight. Formed red solid was isolated by centrifugation, washed with diethyl ether and dried in vacuo. The product was obtained as a red solid in 92% yield. The structural composition of compound 107 was confirmed by SEM- EDX analysis: C 42.09%, N 9.09%, O 6.84%, S 10.96%, Cl 11.69%, Cu 19.32%.

[0365] Compound 108: Compound 20 (31.5 mg, 0.095 mmol) was dissolved in MeOH (0.9 mL) and a solution of iron(III) chloride (14.1 mg, 0.087 mmol) in MeOH (1.0 mL) was added dropwise at rt whereupon the mixture turned deep red in color. After the addition was complete, the mixture was heated in a sealed vial at 80 °C for 2 h to yield a deep-red solution. The mixture was concentrated to about half the initial volume and stored at -20 °C overnight. Formed orange solid was isolated by centrifugation, washed with diethyl ether and dried in vacuo. The product was obtained as an orange solid in 91% yield. The structural composition of compound 108 was confirmed by SEM-EDX analysis: C 31.34%, N 7.12%, O 3.31%, Ni 2.40%, S 10.65%, Cl 30.47%, Fe 14.71%.

[0366] Compound 109: Compound 20 (31.5 mg, 0.095 mmol) was dissolved in MeOH (0.9 mL) and a solution of cobalt(II) chloride hexahydrate (20.7 mg, 0.087 mmol) in MeOH (1.0 mL) was added dropwise at rt whereupon the mixture turned deep red in color. After complete addition the mixture was heated in a sealed vial at 80 °C for 2 h to yield a deep-red solution with a significant amount of orange precipitate. The mixture was concentrated to about half the initial volume and stored at -20 °C overnight. The precipitate was isolated by centrifugation, washed with diethyl ether and dried in vacuo. The product was obtained as a red solid in 98% yield. The structural composition of compound 109 was confirmed by SEM-EDX analysis: C 28.78%, N 6.16%, O 1.79%, S 10.33%, Cl 30.29%, Co 22.65%.

[0367] Compound 110: Compound 20 (31.5 mg, 0.095 mmol) was dissolved in MeOH (0.9 mL) and a solution of nickel(II) chloride hexahydrate (20.7 mg, 0.087 mmol) in MeOH (1.0 mL) was added dropwise at rt whereupon the mixture turned deep red in color. After completion of addition, the mixture was heated in a sealed vial at 80 °C for 2 h to yield a deep-red solution. Then it was cooled to rt, concentrated to about half the initial volume and stored at -20 °C overnight. The formed precipitate was isolated by centrifugation, washed with diethyl ether and dried in vacuo. The product was obtained as an orange solid in 99% yield. The structural composition of compound 110 was confirmed by SEM-EDX analysis: C 35.22%, N 6.81%, O 2.65%, S 9.85%, Cl 27.98%, Ni 17.49%. Example 45: Synthesis of (E)-9-(2-(5-chlorobenzo[d]thiazol-2-yl)hydrazono)-8,8-dimethyl-6,7,8,9- tetrahydrooxepino[3,2-b]pyridine (111)

[0368] To a solution of 7,8-dihydrooxepino[3,2-b]pyridin-9(6H)-one (int-15, 200 mg, 1.2 mmol) in THF (20 mL), NaH (147 mg, 3.6 mmol) was added in portions at 0 °C. The solution was stirred for 1 hr, then iodomethane (522 mg, 3.66 mmol) was added. The mixture was stirred at RT for 2 hrs, quenched with water (20 mL) and extracted with DCM (3 x 30 mL). Combined organic phases were concentrated under reduced pressure and the residue was purified by chromatography on silica gel with a mixture of petroleum ether and EtOAc (5:1) as eluent to give 8,8-dimethyl-7,8- dihydrooxepino[3,2-b]pyridin-9(6H)-one (int-87, 120 mg, 51% yield) as a light yellow oil. MS (ESI): m/z 191.9 [M+H]⁺.

[0369] To a solution of 5-chlorobenzo[d]thiazol-2-amine (int-88, 4 g, 21.7 mmol) and concentrated aq. HCl (7 mL) in ethane-1,2-diol (5 mL) hydrazine hydrate (9 g) was added dropwise at 0 °C. The mixture was stirred at 180 °C for 3 hrs, cooled to RT and water (20 mL) was added. The precipitate was filtered and washed with water (20 mL) to give 5-chloro-2- hydrazinylbenzo[d]thiazole int-89 (int-89, 4 g, 74%) as a yellow solid. MS (ESI): m/z 199.8 [M+H]⁺.

[0370] To a solution of 8,8-dimethyl-7,8-dihydrooxepino[3,2-b]pyridin-9(6H)-one (int- 87, 57 mg, 0.30 mmol) and 5-chloro-2-hydrazinylbenzo[d]thiazole (int-89, 60 mg, 0.3 mmol) in EtOH (10 mL), and acetic acid (2 drops) was added and the solution was stirred at 50 ^°C for 15 hrs. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel with a mixture of 0-3% MeOH in DCM as eluent to give (E)-9-(2-(5- chlorobenzo[d]thiazol-2-yl)hydrazono)-8,8-dimethyl-6,7,8,9-tetrahydrooxepino[3,2-b]pyridine (111) (36 mg, 32% yield) as a light yellow solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 12.14 (s, 1H), 8.45 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.48 (m, 3H), 7.17 (d, J = 8.0 Hz, 1H), 4.25 (s, 2H), 1.96 (s, 2H), 1.24 (s, 6H); MS (ESI): m/z 372.7 [M+H]⁺. Example 46: Synthesis of (E)-8,8-dimethyl-9-(2-(6-morpholinothiazolo[5,4-c]pyridin-2- yl)hydrazono)-6,7,8,9-tetrahydrooxepino[3,2-b]pyridine (112)

[0371] A microwave vial was charged with 6-chloro-2-(methylthio)-1,2- dihydrothiazolo[5,4-c]pyridine (int-73, 200 mg, 0.91 mmol) and morpholine (2 mL). The mixture was heated to 170 °C for 4 h in a microwave reactor, concentrated in vacuo, and the residue was purified by column chromatography on silica gel with a mixture of petroleum ether and EtOAc (2:1) to give 4,4'-(thiazolo[5,4-c]pyridine-2,6-diyl)dimorpholine (int-90, 200 mg, 71%) as a white solid. MS (ESI): m/z 306.9 [M+H]⁺.

[0372] To a solution of hydrazine hydrate (200 mg, 3.92 mmol) in ethylene glycol (5 mL), concentrated aq. HCl (0.16 mL, 1.96 mmol) was added dropwise within 5 minutes at 0 ^°C. Then, int-90 (200 mg, 0.65 mmol) was added and the mixture was heated to 190 °C and for 4 h. The mixture was poured into ice water (20 mL) and stirred at 3 °C for 2 h. The precipitate was isolated by filtration and dried under reduced pressure to give 4-(2-hydrazinylthiazolo[5,4-c]pyridin-6- yl)morpholine (int-91, 60 mg, 37%) as a pale yellow solid. MS (ESI): m/z 251.9 [M+H]⁺. [0373] To a solution of int-91 (60 mg, 0.24 mmol) in MeOH (2 mL) 8,8-dimethyl-7,8- dihydrooxepino[3,2-b]pyridin-9(6H)-one (int-87, 46 mg, 0.24 mmol) was added, followed by AcOH (2 drops). The solution was stirred at 70 °C for 36 h, the solvent was removed under reduced pressure (at 27 °C, in the dark), and the residue was purified by column chromatography on silica gel using a mixture of DCM and MeOH (40:1). A second purification via prep-TLC (with petroleum ether/EtOAc (1:1) was performed to give (E)-8,8-dimethyl-9-(2-(6-morpholinothiazolo[5,4- c]pyridin-2-yl)hydrazono)-6,7,8,9-tetrahydrooxepino[3,2-b]pyridine (112, 26 mg, 25%) as a yellow solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 12.18 (bs, 1H), 8.42 (bs, 2H), 7.52-7.46 (m, 2H), 6.80 (bs, 1H), 4.24 (s, 2H), 3.71 (s, 4H), 3.39 (s, 4H), 1.94 (s, 2H), 1.23 (s, 6H); MS (ESI): m/z 424.9 [M+H]⁺. Example 47: Synthesis of (E)-9-(2-(6-morpholinothiazolo[5,4-c]pyridin-2-yl)hydrazono)-6,7,8,9- tetrahydrooxepino[3,2-b]pyridine (113)

[0374] To a solution of int-91 (60 mg, 0.24 mmol) in methanol (2 mL), 7,8- dihydrooxepino[3,2-b]pyridin-9(6H)-one (int-15, 39 mg, 0.24 mmol) followed by AcOH (2 drops) was added. The mixture was stirred at RT for 16 h, thesolvent was removed under reduced pressure (at 27 °C, in the dark), and the residue was treated with DCM (1mL) and Et₂O (5 mL). The resulting precipitate was filtered and dried under reduced pressure to give (E)-9-(2-(6- morpholinothiazolo[5,4-c]pyridin-2-yl)hydrazono)-6,7,8,9-tetrahydrooxepino[3,2-b]pyridine (113, 30 mg, 31%) as a light yellow solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 12.08 (bs, 1H), 8.38 (d, J = 4.4 Hz, 1H), 8.29 (bs, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.38 (dd, J = 8.1, 4.5 Hz, 1H), 6.60 (bs, 1H), 4.17 (t, J = 6.0 Hz, 2H), 3.73– 3.71 (m, 4H), 3.41– 3.40 (m, 4H), 2.94 (t, J = 6.0 Hz, 2H), 2.04– 1.99 (m, 2H); MS (ESI): m/z 396.9 [M+H]⁺. Example 48: Synthesis of (E)-9-(2-(6-chlorothiazolo[5,4-c]pyridin-2-yl)hydrazono)-8,8-dimethyl- 6,7,8,9-tetrahydrooxepino[3,2-b]pyridine (114)

[0375] To a solution of 6-chloro-2-hydrazinylthiazolo[5,4-c]pyridine (int-74, 60 mg, 0.30 mmol) in methanol (2 mL), 8,8-dimethyl-7,8-dihydrooxepino[3,2-b]pyridin-9(6H)-one (int-87, 57 mg, 0.30 mmol) followed by AcOH (2 drops) was added. The mixture was stirred at 70 °C for 36 h. The solvent was removed under reduced pressure (at 27 °C, in the dark) and the residue was purified by prep-TLC with petroleum ether/EtOAc (2:1) to give (E)-9-(2-(6-chlorothiazolo[5,4- c]pyridin-2-yl)hydrazono)-8,8-dimethyl-6,7,8,9-tetrahydrooxepino[3,2-b]pyridine (114, 30 mg, 27%) as a light yellow solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 12.39 (bs, 1H), 8.78 (bs, 1H), 8.43 (d, J = 3.3 Hz, 1H), 7.62– 7.40 (m, 3H), 4.30– 4.21 (m, 2H), 2.00– 1.92 (m, 2H), 1.24 (s, 6H); MS (ESI): m/z 373.9 [M+H]⁺. Example 49: Synthesis of (E)-8,8-dimethyl-9-(2-(6-(trifluoromethyl)thiazolo[5,4-c]pyridin-2- yl)hydrazono)-6,7,8,9-tetrahydrooxepino[3,2-b]pyridine (115)

[0376] To a solution of 2-hydrazinyl-6-(trifluoromethyl)thiazolo[5,4-c]pyridine (int-70, 100 mg, 0.42 mmol) in ethanol (5 mL), 8,8-dimethyl-7,8-dihydrooxepino[3,2-b]pyridin-9(6H)-one (int-87, 81 mg, 0.42 mmol) followed by AcOH (2 drops) was added. The r mixture was stirred at 150 °C for 15 h, the solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture DCM and MeOH (200:1) as eluent to give (E)- 8,8-dimethyl-9-(2-(6-(trifluoromethyl)thiazolo[5,4-c]pyridin-2-yl)hydrazono)-6,7,8,9- tetrahydrooxepino[3,2-b]pyridine (115, 95 mg, 46 %) as a white solid.¹H-NMR (400 MHz, DMSO- d₆) δ 12.44 (bs, 1H), 9.14 (bs, 1H), 8.44 (d, J = 3.2 Hz, 1H), 7.86 (bs, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.52– 7.42 (m, 1H), 4.26 (s, 2H), 1.97 (s, 2H), 1.25 (s, 6H); MS (ESI): m/z 407.7 [M+H]⁺. Example 50: Synthesis of (E)-8,8-dimethyl-9-(2-(6-(trifluoromethyl)thiazolo[4,5-c]pyridin-2- yl)hydrazono)-6,7,8,9-tetrahydrooxepino[3,2-b]pyridine (116)

[0377] To a solution of 2-hydrazinyl-6-(trifluoromethyl)thiazolo[4,5-c]pyridine (int-79. 70 mg, 0.29 mmol) in ethanol (10 mL), 8,8-dimethyl-7,8-dihydrooxepino[3,2-b]pyridin-9(6H)-one (int-87. 57 mg, 0.29 mmol ) followed by AcOH (2 drops) was added. The mixture was stirred at 80 °C for 15 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of DCM and MeOH (100:1) as eluent to give (E)-8,8-dimethyl-9-(2-(6-(trifluoromethyl)thiazolo[4,5-c]pyridin-2-yl)hydrazono)-6,7,8,9- tetrahydrooxepino[3,2-b]pyridine (116, 21 mg, 17%) as a white solid. ¹H-NMR (400 MHz, DMSO- d₆) δ 12.45 (bs, 1H), 9.13 (bs, 1H), 8.44 (d, J = 4.0 Hz, 1H), 7.85 (bs, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.52– 7.44 (m, 1H), 4.27 (s, 2H), 1.97 (s, 2H), 1.26 (s, 6H); MS (ESI): m/z 407.7 [M+H]⁺. Example 51: Synthesis of (E)-9-(2-(6-chlorothiazolo[4,5-c]pyridin-2-yl)hydrazono)-8,8-dimethyl- 6,7,8,9-tetrahydrooxepino[3,2-b]pyridine (117)

[0378] Compound 117 was synthesized in a similar fashion as compound 114, but using 6-chloro-2-hydrazineylthiazolo[4,5-c]pyridine. ¹H-NMR (400 MHz, DMSO-d₆): δ 12.23 (s, 1H), 8.46 (s, 1H), 8.43 (dd, J = 4.5, 1.3 Hz, 1H), 8.05 (s, 1H), 7.53 (dd, J = 8.4, 1.2 Hz, 1H), 7.46 (dd, J = 8.3, 4.4 Hz, 1H), 4.24 (app. t, J = 5.4 Hz, 2H), 1.95 (app. t, J = 5.5 Hz, 2H), 1.22 (s, 6H). Example 52. Cell Proliferation Assays

[0379] The general protocol for the cellular proliferation assays is provided below.

[0380] Materials: The tissue culture was prepared in T25 culture flasks, 15 mL and 50 mL conical tubes. RPMI-10 complete media: RPMI 1640 media containing 2 mM L-Glutamine and supplemented with 10% heat-inactivated FBS, 100 U/mL Penicillin G and 100 µg/mL Streptomycin.

[0381] DMEM-10 complete media: DMEM containing 4 mM L-Glutamine and supplemented with 10% heat-inactivated FBS, 100 U/mL Penicillin G and 100 µg/mL Streptomycin.

[0382] Assay Conditions: Cells were maintained in logarithmic phase growth prior to testing. Desired density prior to harvesting was approximately 75% confluent. Cells were harvested with the preferred dissociating reagent and washed once with complete media, then re-suspended to a density of 4 x 10⁵ cells/mL in complete growth media. Cells were plated at 50µL/well (20,000 cells/well) in a 384-well plate. Compounds were arrayed into appropriate wells of a 384-well plate (100 µL/well) with the starting concentration of 1,000-fold above the desired test concentration. Compounds were diluted using serial half-log dilutions in 100% DMSO using an automated liquid handler. Compounds were distributed using a pin tool array or similar device. A 50 nL pin results in final DMSO concentrations of 0.1% in a 384-well plate. Cell lines, once distributed into microplates with appropriate test and control compounds, were incubated at 37°C/5% CO₂ for 48 h. DMSO was used as control. CellTiter Glo reagent (Promega, Inc.,#G7572) was added at rt at a volume of 15 µL/well for 384-well plates. The plates were incubated for 5 minutes at rt and luminescence was measured in luminescence plate reader.

[0383] The following six cancer cell lines were used: TOV-112D ovarian cancer cell line; Au565 breast cancer cell line; MDA-MB-468 breast cancer cell line; NCI-H1299 non-small cell lung carcinoma cell line; LS174T colon cancer cell line; and A549 lung cancer cell line. Assay Data for Compounds

[0384] Compounds of some embodiments were prepared according to synthetic methods described herein and assay data obtained for IC₅₀ of the various cancer cell lines. The following cell lines were used: TOV-112D, Au565, NCI-H1975, NCI-H1993, NCI-H1299, A549, LS1034, PANC- 1, LS174T, WI-38, and MCF7 [0385] The cells were plated on 96-well BD Falcon culture plates (Corning Life Sciences) in 100 µL media (RPMI supplemented with 10% FBS for each cell line except PANC-1 (DMEM supplemented with 10% FBS)) at 5,000 cells/well (TOV-112D, Au565, PANC-1, WI-38, MCF7) or 3,000 cells/well (NCI-H1975, NCI-H1993, NCI-H1299, A549, LS1034, LS174T) and allowed to attach for 24 hrs. Cells were treated with varying concentration of compounds in a dose response manner for 72 hrs. Cytotoxicity was determined using 100 µL CellTiter-Glo and 10 minutes of incubation at RT. Luminescence was visualized with an Alpha Innotech Multi-Image Light Cabinet CCD camera (30 sec exposure at medium sensitivity). The IC₅₀ values were determined using Prism software. The assay data obtained is presented in Tables 3-5, in which A= less than 1 µM, B = greater than or equal to 1 µM and less than or equal to 10 µM; and C = greater than 10 µM. Several comparative compounds 1A, 1B, 1C and 1D were also tested.

[0386] While the disclosure has been illustrated and described in detail in the foregoing description, such illustration and description are to be coµnsidered illustrative or exemplary and not restrictive. The disclosure is not limited to the disclosed embodiments. Variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed disclosure, from a study of the drawings, the disclosure and the appended claims.

[0387] All references cited herein are incorporated herein by reference in their entirety. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material.

[0388] Unless otherwise defined, all terms (including technical and scientific terms) are to be given their ordinary and customary meaning to a person of ordinary skill in the art, and are not to be limited to a special or customized meaning unless expressly so defined herein. It should be noted that the use of particular terminology when describing certain features or aspects of the disclosure should not be taken to imply that the terminology is being re-defined herein to be restricted to include any specific characteristics of the features or aspects of the disclosure with which that terminology is associated.

[0389] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments.

[0390] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term‘including’ should be read to mean ‘including, without limitation,’‘including but not limited to,’ or the like; the term‘comprising’ as used herein is synonymous with‘including,’‘containing,’ or‘characterized by,’ and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term‘having’ should be interpreted as‘having at least;’ the term‘includes’ should be interpreted as‘includes but is not limited to;’ the term‘example’ is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; adjectives such as‘known’,‘normal’,‘standard’, and terms of similar meaning should not be construed as limiting the item described to a given time period or to an item available as of a given time, but instead should be read to encompass known, normal, or standard technologies that may be available or known now or at any time in the future; and use of terms like‘preferably,’‘preferred,’‘desired,’ or‘desirable,’ and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function of the invention, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the invention. Likewise, except for the claims, a group of items linked with the conjunction‘and’ should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as‘and/or’ unless the context indicates otherwise. Similarly, except for the claims, a group of items linked with the conjunction‘or’ should not be read as requiring mutual exclusivity among that group, but rather should be read as‘and/or’ unless the context indicates otherwise. [0391] With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. The indefinite article“a” or“an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

[0392] It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases“at least one” and“one or more” to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles“a” or“an” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases“one or more” or“at least one” and indefinite articles such as“a” or“an” (e.g.,“a” and/or“an” should typically be interpreted to mean“at least one” or“one or more”); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should typically be interpreted to mean at least the recited number (e.g., the bare recitation of “two recitations,” without other modifiers, typically means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to“at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g.,“a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). In those instances where a convention analogous to“at least one of A, B, or C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g.,“a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and/or phrase presenting two or more alternative terms, except in the claims, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms, unless the context indicates otherwise. For example, the phrase“A or B” will be understood to include the possibilities of“A” or“B” or“A and B,” unless the context indicates otherwise.

[0393] All numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification are to be understood as being modified in all instances by the term‘about.’ Accordingly, unless indicated to the contrary, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claims in any application claiming priority to the present application, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.

[0394] Furthermore, although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it is apparent to those skilled in the art that certain changes and modifications may be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention to the specific embodiments and examples described herein, but rather to also cover all modification and alternatives coming with the true scope and spirit of the invention.

Claims

WHAT IS CLAIMED IS:

1. A compound having the structure of formula (A):

or a pharmaceutically acceptable salt thereof, wherein

ring B is selected from

; wherein

Y¹ is selected from N and CR¹;

Y² is selected from N and CR²;

Y³ is selected from N and CR³;

Y^2a is CR^2a;

Y^3a is selected from NR^A, O, and S; and

each R^6a, R^6b, R¹⁰, R¹¹ and R¹² is independently selected from the group consisting of H, optionally substituted C_1-6 alkyl, optionally substituted C_6-10 aryl, optionally substituted C_7-14 aralkyl, and optionally substituted C_3-7 cycloalkyl; or R^6a and R^6b together with the nitrogen atom to which they are attached forms an optionally substituted 4 to 6 membered heterocyclyl; each R⁷, R⁸, R⁹, R¹³ and R¹⁴ is independently selected from the group consisting of H, optionally substituted C_1-6 alkyl, optionally substituted C_2-6 alkenyl, optionally substituted C_2- ₆ alkynyl, optionally substituted C_6-10 aryl, optionally substituted C_7-14 aralkyl, and optionally substituted C_3-7 cycloalkyl;

substituted with at least one R¹⁵; and

is selected from

.

2. Th m n f laim 1, having the structure of formula (I):

or a pharmaceutically acceptable salt thereof, wherein

Y¹ is selected from N and CR¹; Y² is selected from N and CR²;

Y³ is selected from N and CR³;

substituted with at least one R¹⁵; and

when Y¹ is CR¹, R¹ is H or CH₃, Y² is CR², R² is H or -C(O)OR⁹, Y³ is CH, R⁵ is H,

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Y¹ is CR¹.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Y² is CR² and Y³ is CR³.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y¹ is N.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein Y² is CR² and Y³ is CR³.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y² is N.

8. The compound of claim 1 or 7, or a pharmaceutically acceptable salt thereof, wherein Y¹ is CR¹ and Y³ is CR³.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y³ is N.

10. The compound of claim 1 or 9, or a pharmaceutically acceptable salt thereof, wherein Y¹ is CR¹ and Y² is CR².

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R⁵ is selected from H and C_1-6 alkyl. 12 Th m n f n n f lim 1 11 r hrm i ll ptable salt

thereof,

wherein each X is independently selected from CH₂, NR¹⁸, O or S;

each m i in n ntly selected from 0 to 3; and

wherein

is optionally substituted with one or more R¹⁶.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein X is CH₂.

14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, whereinh m n f f rml I i l r r n f rml I1 I1 I1 r I1

15. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is also represented by formula (Ia2), (Ib2), (Ic2) or (Id2):

16. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein X is O.

17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein th

18. The compound of claim 16, or a pharmaceutically acceptable salt thereof, whereinh m n f f rml I i l r r n f rml I4 I4 I4 r I4

19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein each R¹, R² and R³ is H.

20. The compound of any one of claims 1 to 19, wherein R⁴ is 5 or 6 membered heteroaryl or 9 or 10 membered heteroaryl, each optionally substituted with one or more R¹⁵.

21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein the 6 membered heteroaryl is selected from the group consisting of pyridyl, pyrimidyl, and pyridazinyl.

22. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein the 5 membered heteroaryl is selected from the group consisting of oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, and thienyl.

23. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein the 9 membered heteroaryl is selected from the group consisting of benzothiazolyl, benzimidazolyl, benzoxazolyl, benzothienyl, indolyl, isoindolyl and indazolyl.

24. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein the 10 membered heteroaryl is selected from quinolinyl, isoquinolinyl, and quinazolinyl.

2 Th m n f n n f l im 1 2 r h rm i ll l l

optionally substituted with one or more R¹⁵, and wherein R¹⁹ is selected from the group consisting of H, optionally substituted C_1-6 alkyl, and optionally substituted C_3-7 cycloalkyl.

26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein R¹⁵ is selected from halo, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, 4 to 6 membered heterocyclyl, or phenyl optionally substituted with one to four R¹⁷.

27. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein two adjacent R¹⁵ together with the atoms to which they are attached form a 6 membered heterocyclyl optionally substituted with one to four R¹⁷.

28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein

.

29. The com ound of claim 1 having the structure of formula (II):

or a pharmaceutically acceptable salt thereof, wherein

Y^2a is CR^2a;

Y^3a is selected from NR^A, O, and S; and

30. The compound of claim 1 or 29, or a pharmaceutically acceptable salt thereof, wherein Y^3a is S.

31. The compound of claim 1 or 29, or a pharmaceutically acceptable salt thereof, wherein Y^3a is O.

32. The compound of claim 1 or 29, or a pharmaceutically acceptable salt thereof, wherein Y^3a is NR^A.

33. The compound of any one of claims 1, 29 or 32, or a pharmaceutically acceptable salt thereof, wherein R^A is H or C_1-6 alkyl.

34. The compound of claim 1 or 29, or a pharmaceutically acceptable salt thereof, wherein Y^3a is is NH.

35. The compound of any one of claims 1 or 29-34, or a pharmaceutically acceptable salt thereof, wherein R^2a is selected from H and C_1-6 alkyl.

36. The compound of claim 1 or 29, or a pharmaceutically acceptable salt thereof, wherein Y^3a is S and R^2a is H.

37. The compound of any one of claims 29 to 36, or a pharmaceutically acceptable salt thereof, wherein R⁵ is selected from H and C_1-6 alkyl.

38. The compound of any one of claims 29 to 37, or a pharmaceutically acceptable salt thereof, wherein R⁵ is selected from H.

Th m n f n n f laims 29 to 38, or a pharmaceutically acceptable salt

thereo

from the group consisting of:

wherein each X is independently selected from CH₂, NR^18a, O or S;

R^18a is independently selected from the group consisting of H, optionally substituted C_1-6 alkyl, and optionally substituted C_3-7 cycloalkyl; and

each n is independently selected from 0 to 3.

40. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein X¹ is CH₂.

41. The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein the com n f f rml II i l r r n f rml II1 II 1 r II1

(IIc1).

42. The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein the comound of formula II is also reresented b formula IIa2 IIb2 or IIc2:

(IIc2).

43. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein X¹ is O.

44. The compound of claim 43, or a pharmaceutically acceptable salt thereof, wherein the com n f f rml II i l r r n f rml II II r I

(Ic3).

45. The compound of claim 43, or a pharmaceutically acceptable salt thereof, wherein the com ound of formula II is also re resented b formula IIa4 IIb4 or IIc4 :

(IIc4).

46. The compound of any one of claims 29 to 45, or a pharmaceutically acceptable salt thereof, wherein R^2a is H.

47. The compound of any one of claims 29 to 46, wherein R⁴ is 5 or 6 membered heteroaryl or 9 or 10 membered heteroaryl, each optionally substituted with one or more R¹⁵.

48. The compound of claim 47, or a pharmaceutically acceptable salt thereof, wherein the 6 membered heteroaryl is selected from the group consisting of pyridyl, pyrimidyl, and pyridazinyl.

49. The compound of claim 47, or a pharmaceutically acceptable salt thereof, wherein the 5 membered heteroaryl is selected from the group consisting of oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, and thienyl.

50. The compound of claim 47, or a pharmaceutically acceptable salt thereof, wherein the 9 membered heteroaryl is selected from the group consisting of benzothiazolyl, benzimidazolyl, benzoxazolyl, benzothienyl, indolyl, isoindolyl and indazolyl.

51. The compound of claim 47, or a pharmaceutically acceptable salt thereof, wherein the 10 membered heteroaryl is selected from quinolinyl, isoquinolinyl, and quinazolinyl.

52. The com ound of an one of claims 29 to 47 or a harmaceuticall acce table salt

53. The compound of any one of claims 29 to 52, or a pharmaceutically acceptable salt thereof, wherein R¹⁵ is selected from halo, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, 4 to 6 membered heterocyclyl, or phenyl optionally substituted with one to four R¹⁷.

54. The compound of any one of claims 29 to 52, or a pharmaceutically acceptable salt thereof, wherein two adjacent R¹⁵ together with the atoms to which they are attached form a 6 membered heterocyclyl optionally substituted with one to four R¹⁷.

55. The compound of claim 54, or a pharmaceutically acceptable salt thereof, wherein

.

56. The compound of any one of claims 1, 2 or 29, selected from Compounds 1 to 104, 107-110 and 112 to 117 of Table 1, or pharmaceutically acceptable salts thereof.

57. A pharmaceutical composition comprising a compound of any one of claims 1 to 56, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

58. A metal complex comprising a metal cation selected from the group consisting of copper (I), copper (II), zinc (II), iron (III), gallium (III), nickel (II), cobalt (II), cobalt (III), gold (I), gold (III), platinum (II), platinum (IV), manganese (II), palladium (II), titanium (IV), vanadium (IV) and vanadium (V); and a compound of formula (A) selected from any one of claims 1 to 56, or an anion or solvate thereof.

59. A metal complex comprising a metal cation selected from the group consisting of copper (I), copper (II), zinc (II), iron (III), gallium (III), nickel (II), cobalt (II), cobalt (III), gold (I), gold (III), platinum (II), platinum (IV), manganese (II), palladium (II), titanium (IV), vanadium (IV) and vanadium (V); and a compound of formula (I) selected from any one of claims 2 to 28, or an anion or solvate thereof.

60. A metal complex comprising a metal cation selected from the group consisting of copper (I), copper (II), zinc (II), iron (III), gallium (III), nickel (II), cobalt (II), cobalt (III), gold (I), gold (III), platinum (II), platinum (IV), manganese (II), palladium (II), titanium (IV), vanadium (IV) and vanadium (V); and a compound of formula (II) selected from any one of claims 29 to 55, or an anion or solvate thereof.

61. The metal complex of any one of claims 58-60, wherein the metal cation is Cu²⁺.

62. The metal complex of claim 61, wherein the metal cation forms a complex with the compound of formula (I) or (II) in a molar ratio of 1:1 or 2:1.

63. A method of treating cancer, comprising:

selecting a subject having a p53 mutation in the DNA-binding domain; and administering an therapeutically effective amount of a compound of any one of claims 1 to 56, a pharmaceutically acceptable salt thereof, a pharmaceutical composition of claim 57, or a metal complex of any one of claims 58-62 to the subject.

64. The method of claim 63 wherein the p53 mutation is selected from R273H, R273C, R175H, R175L, G245S, G245D, R249S, R282W, C242W, R248Q, R248W, Y220C, and R280K.

65. A method of modulating or activating a p53 signaling pathway in a subject, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 56, a pharmaceutically acceptable salt thereof, a pharmaceutical composition of claim 57, or a metal complex of any one of claims 58 to 62 to the subject in need thereof.

66. The method of claim 65, wherein the subject has been identified as possessing low levels of wild-type p53.

67. The method of claim 65, wherein the subject has been identified as possessing a p53 mutation.

68. The method of claim 67, wherein the subject has been identified as possessing high levels of p53 protein having the p53 mutation.

69. The method of claim 67 or 68, wherein the p53 mutation is selected from R273H, R273C, R175H, R175L, G245S, G245D, R249S, R282W, C242W, R248Q, R248W, Y220C, and R280K.

70. The method of claim 67 or 68, wherein the p53 mutation affects an amino acid involved in binding Zn²⁺ ion.

71. The method of claim 70, wherein the p53 mutation is in an amino acid residue selected from 175, 176, 179, 238, 242 and 245.

72. A method of inhibiting cancer cell growth, comprising contacting a cancer cell with an effective amount of a compound of any one of claims 1 to 56, a pharmaceutically acceptable salt thereof, a pharmaceutical composition of claim 57, or a metal complex of any one of claims 58 to 62.

73. The method of claim 72, wherein the cancer cell is selected from a breast cancer cell, a lung cancer cell, a colon cancer cell, a prostate cancer cell, a liver cancer cell, a cervical cancer cell, an ovarian cancer cell, a bladder cancer cell, a brain cancer cell, an esophageal cancer cell, a kidney cancer cell, a leukemia cell, a melanoma cell, a non-hodgkin lymphoma cell, a pancreatic cancer cell, a skin cancer cell, a thyroid cancer cell, and an endometrial cancer cell.

74. The method of claim 72 or 73, wherein the cancer cell has been identified as possessing wild-type p53.

75. The method of claim 72 or 73, wherein the cancer cell has been identified as underexpressing p53.

76. The method of claim 72 or 73, wherein the cancer cell has been identified as possessing a p53 mutation.

77. The method of claim 76, wherein the p53 mutation is selected from R273H, R273C, R175H, R175L, G245S, G245D, R249S, R282W, C242W, R248Q, R248W, Y220C, and R280K.

78. A compound selected from compounds D, I, L, M, N, O, R, S, V, W, Y, Z, AA, AB, AD, AE, AG, AH, AI, AJ, AK, AL, AM, AN, AO, AP of Table 2, or pharmaceutically acceptable salts thereof.

79. A metal complex comprising a metal cation selected from the group consisting of copper (I), copper (II), zinc (II), iron (III), gallium (III), nickel (II), cobalt (II), cobalt (III), gold (I), gold (III), platinum (II), platinum (IV), manganese (II), palladium (II), titanium (IV), vanadium (IV) and vanadium (V); and a compound selected from Compounds A; C through I and L through AP in Table 2, or an anion or solvate thereof.

80. The metal complex of claim 79, wherein the metal cation is Cu²⁺.

81. The metal complex of claim 80, wherein the metal cation forms a complex with the compound in a molar ratio of 1:1 or 1:2.

82. A method of treating cancer, comprising:

selecting a subject having a p53 mutation in the DNA-binding domain; and administering an therapeutically effective amount of a compound of any one of claims 1 to 56, a pharmaceutically acceptable salt thereof, a pharmaceutical composition of claim 57, or a metal complex of any one of claims 58 to 62 to the subject.

83. The method of claim 82, wherein the cancer is selected from breast cancer, lung cancer, colon cancer, prostate cancer, liver cancer, cervical cancer, ovarian cancer, bladder cancer, brain cancer, esophageal cancer, kidney cancer, leukemia, melanoma, non-hodgkin lymphoma, pancreatic cancer, skin cancer, thyroid cancer, and endometrial cancer.

84. The method of claim 83, wherein the p53 mutation is selected from R273H, R273C, R175H, R175L, G245S, G245D, R249S, R282W, C242W, R248Q, R248W, Y220C, and R280K.

85. A method of modulating or activating a p53 signaling pathway in a subject, comprising administering a therapeutically effective amount of a compound selected from Compounds A; C through I; and L through AP in Table 2, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, or a metal complex of claim 79 to the subject.

86. The method of claim 85, wherein the subject has been identified as possessing low levels of wild-type p53.

87. The method of claim 85, wherein the subject has been identified as possessing a p53 mutation.

88. The method of claim 87, wherein the subject has been identified as possessing high levels of p53 protein having the p53 mutation.

89. The method of claim 87 or 88, wherein the p53 mutation is selected from R273H, R273C, R175H, R175L, G245S, G245D, R249S, R282W, C242W, R248Q, R248W, Y220C, and R280K.

90. A method of inhibiting cancer cell growth, comprising contacting a cancer cell with an effective amount of a compound selected from Compounds A; C through I; and L through AP in Table 2, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, or a metal complex of claim 79.

91. The method of claim 90, wherein the cancer cell is selected from a breast cancer cell, a lung cancer cell, a colon cancer cell, a prostate cancer cell, a liver cancer cell, a cervical cancer cell, an ovarian cancer cell, a bladder cancer cell, a brain cancer cell, an esophageal cancer cell, a kidney cancer cell, a leukemia cell, a melanoma cell, a non-hodgkin lymphoma cell, a pancreatic cancer cell, a skin cancer cell, a thyroid cancer cell, and an endometrial cancer cell.

92. The method of claim 90, wherein the cancer cell has been identified as possessing low levels of wild-type p53.

93. The method of claim 90, wherein the subject has been identified as possessing a p53 mutation.

94. The method of claim 93, wherein the subject has been identified as possessing high levels of p53 protein having the p53 mutation.

95. The method of claim 93 or 94, wherein the p53 mutation is selected from R273H, R273C, R175H, R175L, G245S, G245D, R249S, R282W, C242W, R248Q, R248W, Y220C, and R280K.