Copper complexes, pharmaceutical composition comprising the same and use for treatment of neurodegenerative disorders

Abstract

This invention relates to copper complexes, pharmaceutical compositions comprising such complexes, chemical methods for preparing such complexes, and their use in the treatment of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS).

Description

Prior Technology

[0001] Neurodegenerative diseases are age-dependent disorders that are becoming increasingly prevalent due in part to the increasing geriatric population (Heemels, Nature (2016) 539:179).

[0002] For example, amyotrophic lateral sclerosis (ALS) (also known as motor neuron disease, Lou Gehrig's disease, or Charcot's disease) is estimated to occur in any At any given time, 30,000 Americans and more than 400,000 people worldwide are affected. About 5,000 Americans are diagnosed with ALS each year. The disease causes progressive death of motor neurons, leading to progressive paralysis that kills patients within one to five years on average. Most people diagnosed with ALS survive 3 to 5 years after they first show signs of the disease. About 10% of people with ALS survive at least 10 years. The variable rate of disease progression makes prognosis unpredictable and therapy development difficult.

[0003] Only two agents (riluzole and edaravone) have been approved by the FDA for the treatment of ALS, and although both agents slow disease progression and prolong life in some patients months at most, but neither treats nor cures the disease.

[0004] Some inherited forms of ALS are caused by genetic mutations. This genetic change alters an enzyme in the cell called copper-zinc superoxide dismutase (Cu-Zn superoxide dismutase, now commonly known as SOD1). This enzyme serves to protect cells from metabolic waste, which can cause damage if not rendered harmless.

[0005] By rigorous methods established in the art, the compound CuATSM has been shown to be protective in a transgenic mouse model of ALS engineered to express SOD1 familial ALS It was found to contain mutated human SOD1.

[0006] However, there is a need in the art for improved therapeutics that can treat neurological diseases and / or copper deficiency related conditions.

Content of invention

[0007] Provided herein are compounds useful in a method of treating or preventing a neurodegenerative disease in a subject in need thereof.

[0008] In one aspect, the present invention provides a compound of formula (I): , or a pharmaceutically acceptable salt thereof, wherein L, R1, R2, R3 and R4 are as defined herein.

[0009] In one embodiment, the compound of formula (I) is selected from the group consisting of compounds 1 to 22 or pharmaceutically acceptable salts thereof.

[0010] In another aspect, the present invention provides a compound of formula (II): , or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3 and R4 are as defined herein.

[0011] In one embodiment, the compound of formula (II) is selected from the group consisting of compounds 23-46.

[0012] In another aspect, the present invention provides a compound of formula (III):, or a pharmaceutically acceptable salt thereof, wherein L, R1, R2 and R3 are as defined herein.

[0013] In one embodiment, the compound of formula (III) is selected from the group consisting of compounds 47-53.

[0014] In another aspect, the present invention provides a compound of formula (IV): , or a pharmaceutically acceptable salt thereof, wherein L, R1, R2, R3 and R4 are as defined herein.

[0015] In one embodiment, the compound of formula (IV) is selected from the group consisting of compounds 1-22, 57, 59-61 and 66-78.

[0016] In another aspect, the present invention provides a compound of formula (V): , or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3 and R4 are as defined herein.

[0017] In one embodiment, the compound of formula (V) is selected from the group consisting of compounds 23-46 and 79-127.

[0018] In another aspect, the present invention provides a compound selected from the group consisting of compounds 56-65.

[0019] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, diluent or carrier.

[0020] In another aspect, the invention provides a method of treating or preventing a neurodegenerative disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the invention.

[0021] In one embodiment, the neurodegenerative disease is amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson's disease (Parkinson's disease), Huntington's disease (Huntington's disease) and Alzheimer's disease. In another embodiment, the neurodegenerative disease is ALS. In another embodiment, ALS is familial or sporadic.

[0022] In another aspect, the invention provides a method of making a compound of the invention.

Implementation

[0055] Cross Reference to Related Applications

[0056] This application claims the benefit of US Serial No. 63 / 070,792 filed August 26, 2020, the disclosure of which is incorporated herein by reference in its entirety.

[0057] Provided herein are compounds of formula (I): and pharmaceutically acceptable salts thereof, compounds of formula (II): and pharmaceutically acceptable salts thereof, compounds of formula (III): and pharmaceutically acceptable salts thereof Salts, compounds of formula (IV): and pharmaceutically acceptable salts thereof, and compounds of formula (V): and pharmaceutically acceptable salts thereof, which are all applicable to the treatment of neurological diseases and / or copper-deficiency related diseases . definition

[0058] Listed below are definitions of various terms used herein. These definitions apply to terms as they are used throughout this specification and claims, individually or as part of a larger group, unless otherwise limited in a specific instance.

[0059] Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature and laboratory procedures in cell culture, molecular genetics, organic chemistry and peptide chemistry used herein are those well known and commonly employed in the art.

[0060] As used herein, the article "a (a / an)" refers to one or more than one (ie, at least one) grammatical object of the article. By way of example, "an element" means One element or more than one element. Furthermore, the use of the term "including" and other forms such as "include", "includes" and "included" is not limiting.

[0061] As used herein, the term "about" will be understood by those of ordinary skill in the art and will vary somewhat depending on the context in which it is used. As used herein, when referring to measurable values, such as amounts, durations, and the like, the term "about" is meant to encompass ±20% or ±10% (including ±5%, ± 1% and ±0.1%) variations, so variations are suitable for performing the disclosed methods.

[0062] As used in this specification and claims, the term "comprising" may include the embodiments "consisting of" and "consisting essentially of". As used herein, the terms "comprising", "comprising", "having / has", "may", "comprising" and variations thereof are intended to require the presence of the named components / steps and to permit other components / An open-ended transitional phrase, term or word for the existence of a step. However, this description should be read as also describing a composition or process such as "consisting of" and "consisting essentially of the enumerated compounds", which only allows for the named compound and any pharmaceutically acceptable The presence of the carrier and the exclusion of other compounds.

[0063] As used herein, unless otherwise stated, the term "alkyl" by itself or as part of another substituent means a straight or branched chain hydrocarbon having the indicated number of carbon atoms (ie, C1-C6 alkyl means an alkyl group having one to six carbon atoms), and includes straight and branched chains. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl and 1-hexyl.

[0064] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halo substituents, wherein alkyl and halo are as defined herein. Haloalkyl includes, for example, chloromethyl, trifluoromethyl, bromoethyl, chlorofluoroethyl, and the like.

[0065] As used herein, the term "alkoxy" refers to the group -O-alkyl, wherein alkyl is as defined herein. Alkoxy includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, secondary butoxy, tertiary butoxy, and the like.

[0066] As used herein, unless otherwise stated, the term "halo" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.

[0067] As used herein, the term "cycloalkyl" means a partially or fully saturated non-aromatic carbocyclic ring system having the indicated number of carbon atoms. Cycloalkyl groups can be monocyclic, fused polycyclic, bridged polycyclic or spiro polycyclic carbocyclic rings. The term "cycloalkyl" includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl, spiro[3.3]heptyl, and bicyclo[1.1.1]pentyl.

[0068] As used herein, the term "heterocyclyl" or "heterocycloalkyl" means a non-aromatic saturated or partially saturated monocyclic, fused polycyclic, bridged polycyclic or spiropolycyclic ring system containing the specified number of ring atoms, and wherein the ring atoms are carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. The term "heterocyclyl" includes cyclic esters (ie, lactones) and cyclic amides (ie, lactamides), and also includes, but is not limited to, epoxy, oxetanyl, tetrahydrofuranyl, tetrahydrofuranyl, Hydropyranyl (also known as oxanyl), pyranyl, dioxanyl, aziridinyl, azetidinyl, pyrrolidinyl, 2,5-dihydro-1H -Pyrrolyl, oxazolidinyl, thiazolidinyl, piperidinyl, thiolinyl, piperyl, thiothiolinyl, 1,3-oxazepinyl, 1,3-thiazolinyl Base, 2-azabicyclo[2.1.1]hexyl, 5-azabicyclo[2.1.1]hexyl, 6-azabicyclo[3.1.1]heptanyl, 2-azabicyclo[ 2.2.1] Heptyl, 3-azabicyclo[3.1.1]heptanyl, 2-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.0]hexyl, 2-Azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 3-oxa-7-aza Heterobicyclo[3.3.1]nonyl, 3-oxa-9-azabicyclo[3.3.1]nonyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 6 -Oxa-3-azabicyclo[3.1.1]heptanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxaspiro[ 3.3] Heptyl, 2-oxaspiro[3.5]nonyl, 3-oxaspiro[5.3]nonyl and 8-oxabicyclo[3.2.1]octanyl. Unless otherwise indicated, a heterocycle or heterocycloalkyl is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.

[0069] As used herein, the term "aromatic" means having one or more polyunsaturated rings and having an aromatic character, that is, having (4n + 2) delocalized π (pi) electrons (where n is integer) carbocycle or heterocycle.

[0070] As used herein, the term "aryl" means an aromatic carbocyclic ring system containing the indicated number of ring atoms. The aryl group can be a single ring or multiple rings (up to three rings) fused together or linked covalently. If rings are fused, one of the rings must be fully unsaturated and the fused ring may be fully saturated, partially unsaturated, or fully unsaturated. The term "aryl" includes, but is not limited to, phenyl, naphthyl, indenyl and 1,2,3,4-tetrahydronaphthyl.

[0071] As used herein, the term "heteroaryl" means an aromatic carbocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S. A heteroaryl group can be a single ring or multiple rings (up to three rings) fused together or covalently linked. If rings are fused, one of the rings must be fully unsaturated and the fused ring may be fully saturated, partially unsaturated, or fully unsaturated. The term "heteroaryl" includes, but is not limited to, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxazolyl, Diazolyl, thiadiazolyl, pyridyl, pyridyl, pyrimidyl, pyridyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, benzo [d][1,3]Dioxolyl, 5,6,7,8-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 6,7- Dihydro-5H-cyclopenta[b]pyridyl, 6,7-dihydro-5H-cyclopenta[c]pyridyl, 1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 2,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 6,7-dihydro-5H -pyrrolo[1,2-b][1,2,4]triazolyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine Base, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridyl, 4,5,6,7-tetrahydro-1H-indazolyl and 4,5,6,7- Tetrahydro-2H-indazolyl. Unless otherwise indicated, a heterocycle or heterocycloalkyl is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.

[0072] As used herein, the term "substituted" means that an atom or group of atoms has replaced a hydrogen as a substituent attached to another group.

[0073] "Pharmaceutically acceptable salt" is intended to mean a salt of a free acid or base of a compound of the invention that is non-toxic, biotolerable, or otherwise biologically suitable for administration to a subject. It should possess the desired pharmacological activity of the parent compound. See generally G.S. Paulekuhn et al., "Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database", J. Med. Chem., 2007, 50:6665-72, S.M. Berge et al., "Pharmaceutical Salts", J. Pharm Sci., 1977, 66:1-19 and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, edited by Stahl and Wermuth, Wiley-VCH and VHCA, Zurich, 2002.

[0074] The term "treatment" refers to an application to ameliorate one or more specific procedures of a disease. In certain embodiments, the specific procedure is the administration of one or more pharmaceutical agents. "Treatment" of an individual (eg, a mammal such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. Treatment includes, but is not limited to, administration of pharmaceutical compositions and can be performed prophylactically or after the onset of a pathological event or exposure to a pathogen. Treatment includes any desired effect on a symptom or lesion of a disease or condition, and may include, for example, minimal change or improvement in one or more measurable markers of the disease or condition being treated.

[0075] As used herein, the term "prevent / prevention" means the absence of a condition or disease from developing in the absence of a condition or disease, or the development of a further condition or disease in the absence of an existing condition or disease . Also considered is our ability to prevent some or all of the symptoms associated with a disorder or disease.

[0076] As used herein, if not otherwise specified, the term "use" includes any one or more of the following embodiments of the present invention: for the treatment of pain; for the manufacture of medicines for the treatment of these diseases Compositions, for example for use in the manufacture of a medicament; methods of use of the compounds of the invention in the treatment of these diseases; pharmaceutical preparations having the compounds of the invention for use in the treatment of these diseases; and compounds of the invention, if they are optionally Determination and benefit are used to treat these diseases.

[0077] As used herein, the term "patient", "individual" or "subject" is intended to include an organism that suffers from or suffers from a disease, disorder or condition associated with protein kinase activity, such as Prokaryotes and eukaryotes. Examples of subjects include mammals such as humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In certain embodiments, the subject is a human, eg, a human having, at risk of, or at risk of developing ALS. In another embodiment, the subject is a cell. The terms "patient", "individual" or "subject" do not denote a particular age or gender.

[0078] As used in reference to methods of treatment / prevention and use of the compounds described herein and pharmaceutical compositions thereof, a subject "in need thereof" is one who has been diagnosed with or was previously treated for the condition to be treated. With regard to prophylaxis, a subject in need thereof can also be one who is at risk of developing a condition (eg, family history of the condition, lifestyle factors indicative of risk of developing the condition, etc.). In general, when a step of administering a compound of the invention is disclosed herein, the invention further encompasses the step of identifying an individual or subject in need of administration of a particular treatment or suffering from a particular condition to be treated.

[0079] As used herein, the terms "effective amount", "pharmaceutically effective amount" and "therapeutically effective amount" refer to a non-toxic amount of an agent which is sufficient to provide a desired biological result. The result may be a reduction and / or alleviation of the signs, symptoms or causes of a disease or any other desired change in a biological system. The appropriate therapeutic amount in any particular case can be determined by one of ordinary skill in the art using routine experimentation.

[0080] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound useful in the present invention and a pharmaceutically acceptable diluent, excipient or carrier. Pharmaceutical compositions facilitate administration of a compound to a patient or subject. A variety of compound administration techniques exist in the art, including but not limited to intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0081] The term "combination", "therapeutic combination" or "pharmaceutical combination" as used herein refers to a fixed or non-fixed combination in one unit dosage form or a set of divided parts for combined administration, wherein two The or more therapeutic agents may be administered simultaneously or separately at time intervals, especially where such time intervals are such that the combined partners exhibit a cooperative (eg, synergistic) effect.

[0082] The term "sporadic" refers to non-hereditary neurodegenerative diseases, such as ALS. Sporadic ALS accounts for about 90% of cases, in which affected individuals have the only member of the family with the disease. The etiology of sporadic ALS is not well understood but may result from a combination of environmental and genetic risk factors.

[0083] The term "familial" refers to an inherited neurodegenerative disease, such as ALS. Familial ALS accounts for about 10% of cases, in which more than one person in the family has ALS and sometimes family members also have frontotemporal dementia. People with familial ALS usually start showing symptoms at an earlier age than sporadic ALS. The most common form of familial ALS is systemic chromosomal dominant. Compounds of the invention

[0084] In one aspect, the compound of formula (I) is provided herein:, or a pharmaceutically acceptable salt thereof, wherein: L is C3-C7 cycloalkyl, C1-C6 alkyl, or is absent R1 is C1-C6 alkyl optionally substituted by 5-10 membered heteroaryl, NH2, NH(C1-C6 alkyl) or N(C1-C6 alkyl)2; R2 is optionally 5- to 10-membered 10-membered heteroaryl, NH2, NH(C1-C6 alkyl) or N(C1-C6 alkyl) substituted C1-C6 alkyl; R3 is C6-C10 aryl, 5-10 membered heteroaryl , C(O)NH-(C1-C6 alkyl)-PPh3, hydroxyl, C1-C6 alkoxy or O-(C1-C6 alkyl)-O-(C1-C6 alkyl), where C6-C10 Aryl is substituted once, twice or three times by a group R3a, and wherein a 5- to 10-membered heteroaryl is optionally substituted once, twice or three times by a group R3b; R3a is independently C3-C7 at each occurrence Cycloalkyl or 4- to 8-membered heterocyclic ring, wherein the 4- to 8-membered heterocyclic ring is optionally further substituted once, twice or three times by C1-C3 alkyl; R3b is independently C1-C3 alkane at each occurrence Oxygen, C3-C7 cycloalkyl or 4-membered to 8-membered heterocyclic ring, wherein the heterocyclic ring is optionally further substituted once, twice or three times by C1-C3 alkyl; and R4 is hydrogen, C1-C3 alkyl or C6 -C10 aryl; The restriction is that when L does not exist, R3 is a C6-C10 aryl substituted once, twice or three times by the group R3a; or when L does not exist, R3 is the group A 6- to 10-membered heteroaryl group substituted once, twice or three times by R3b.

[0085] In one embodiment, L is C3-C7 cycloalkyl or C1-C6 alkyl. In one embodiment, L is C3-C7 cycloalkyl. In one embodiment, L is C1-C6 alkyl. In one embodiment, L is C3-C5 cycloalkyl or C1-C3 alkyl. In one embodiment, L is C3-C5 cycloalkyl. In one embodiment, L is C1-C3 alkyl.

[0086] In one embodiment, L is -CH2-. In one embodiment, L is -CH2CH2-. In one embodiment, L is -CH2CH2CH2-. In one embodiment, L is -CH2CH2CH2CH2-. In one embodiment, L is -CH(CH3)-. In one embodiment, L is -CH(CH2CH3)-. In one embodiment, L is -C(CH3)2-.

[0087] In one embodiment, L is C3-C7 cycloalkyl or C3-C5 cycloalkyl, wherein the cycloalkyl comprises a quaternary carbon that forms the point of attachment to the group R3 and the rest of the structure. Therefore, in one embodiment, L is represented by one of the following groups: .

[0088] In one embodiment, R1 is C1-6 alkyl. In one embodiment, R1 is C1-3 alkyl. In one embodiment, R1 is methyl or ethyl. In one embodiment, R1 is methyl. In one embodiment, R1 is ethyl.

[0089] In one embodiment, R2 is C1-6 alkyl. In one embodiment, R2 is C1-3 alkyl. In one embodiment, R2 is methyl or ethyl. In one embodiment, R2 is methyl. In one embodiment, R2 is ethyl.

[0090] In one embodiment, R1 is the same as R2.

[0091] In one embodiment, R3 is C6-C10 aryl, 6-membered to 10-membered heteroaryl, C(O)NH-(C1-C6 alkyl)-PPh3, hydroxyl, C1-C6 alkoxy Or O-(C1-C6 alkyl)-O-(C1-C6 alkyl), wherein the C6-C10 aryl is substituted once, twice or three times by the group R3a, and wherein the 5-membered to 10-membered heteroaryl The radicals are optionally substituted one, two or three times by the group R3b.

[0092] In one embodiment, R3 is phenyl, pyridyl, C(O)NH-(C1-C6 alkyl)-PPh3, hydroxyl, C1-C6 alkoxy or O-(C1-C6 alkyl )-O-(C1-C6 alkyl), wherein the phenyl is substituted once, twice or three times by the group R3a, and wherein the pyridyl is optionally substituted once, twice or three times by the group R3b.

[0093] In one embodiment, R3 is phenyl, pyridyl, C(O)NH-(C1-C6 alkyl)-PPh3, hydroxyl, C1-C6 alkoxy or O-(C1-C6 alkyl )-O-(C1-C6 alkyl), wherein the phenyl is substituted once by the group R3a, and wherein the pyridyl is optionally substituted once by the group R3b.

[0094] In one embodiment, each occurrence of R3a is independently a 4- to 8-membered heterocyclic ring optionally further substituted once, twice or three times with C1-C3 alkyl. In one embodiment, each occurrence of R3a is independently a 4-8 membered heterocyclic ring optionally further substituted once with methyl.

[0095] In one embodiment, each occurrence of R3a is independently pyrrolidinyl, pyrrolidinonyl, tetrahydrofuryl, thiol, thiol, piperidinyl, or piperolinyl, each of which Optionally further substituted once, twice or three times with C1-C3 alkyl. In one embodiment, each occurrence of R3a is independently pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, thiolinyl, thiothiolinyl, piperidinyl, or piperidinyl, each of which is optionally further Substituted once with methyl. In one embodiment, each occurrence of R3a is independently pyrrolidinyl, pyrrolidinonyl or oxalinyl. In one embodiment, each occurrence of R3a is independently represented by a group selected from: .

[0096] In one embodiment, each occurrence of R3b is independently a C1-C3 alkoxy group or a 4- to 8-membered heterocycle, wherein the heterocycle is further substituted once or twice by a C1-C3 alkyl as the case may be or three times. In one embodiment, each occurrence of R3b is independently C1-C3 alkoxy or a 4- to 8-membered heterocycle, wherein the heterocycle is optionally further substituted once with methyl.

[0097] In one embodiment, each occurrence of R3b is independently a C1-C3 alkoxy group or a heterocycle selected from the group consisting of: pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, thiolyl , Thio-alkonyl, piperidinyl and piper-inyl, wherein the heterocycle is further substituted once, twice or three times by C1-C3 alkyl as appropriate. In one embodiment, each occurrence of R3b is independently C1-C3 alkoxy or a heterocycle selected from the group consisting of pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, thiolinyl, thio ??? Linyl, piperidinyl and piper???, wherein the heterocycle is optionally further substituted once with a methyl group. In one embodiment, each occurrence of R3b is independently methoxy or a heterocycle selected from the group consisting of pyrrolidinyl and oxalinyl. In one embodiment, each occurrence of R3b is independently represented by a group selected from: .

[0098] In one embodiment, R4 is hydrogen, C1-C3 alkyl or phenyl. In one embodiment, R4 is hydrogen, methyl or phenyl. In one embodiment, R4 is hydrogen or C1-C3 alkyl. In one embodiment, R4 is hydrogen or methyl. In one embodiment, R4 is hydrogen. In one embodiment, R4 is methyl. In one embodiment, R4 is phenyl.

[0099] In one embodiment, the group represented by R3-L has one of the following structures:.

[0100] In one embodiment, R3 is pyridyl substituted once, twice or three times by a C1-C3 alkoxy group or a 4- to 8-membered heterocycle, wherein the 4- to 8-membered heterocycle is optionally C1-C3 alkyl is substituted once.

[0101] In one embodiment, L is absent and R3 is pyridyl substituted once, twice or thrice by C1-C3 alkoxy.

[0102] In one embodiment, L is absent and R3 is phenyl substituted with a 4-8 membered heterocycle.

[0103] In one embodiment, L is C3-C5 cycloalkyl or C1-C3 alkyl; R3 is pyridyl substituted once, twice or three times by 4-membered to 8-membered heterocycle as appropriate; and R4 is methyl.

[0104] In one embodiment, the compound of formula (I) has the structure of compound 9:.

[0105] Exemplary compounds of formula (I) include the compounds described below or pharmaceutically acceptable salts thereof:.

[0106] In another aspect, provided herein is a compound of formula (II): , or a pharmaceutically acceptable salt thereof, wherein: R1 is optionally 5- to 10-membered heteroaryl, NH2, NH(C1 -C6 alkyl) or C1-C6 alkyl substituted by N(C1-C6 alkyl)2; R2 is optionally 5 to 10 membered heteroaryl, NH2, NH (C1-C6 alkyl) or N( C1-C6 alkyl) 2 substituted C1-C6 alkyl; R3 is a 4-membered to 8-membered heterocyclic ring or a 5-membered heteroaryl group, wherein the 4-membered to 8-membered heterocyclic ring is optionally substituted once or twice by the group R3a or three times, and wherein the 5-membered heteroaryl is optionally substituted once, twice or three times by the group R3b; R3a is independently C1-C6 alkyl, C1-C6 alkyl-(C6-C10 Aryl), S(O)2H, S(O)2-(C1-C6 alkyl), S(O)2-(C3-C7 cycloalkyl) or S(O)2-(C6-C10 aryl group); R3b is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, halo, nitro, cyano, C(O)-(4 to 8-membered heterocycle) or C1-C6 alkyl-(4-8 membered heterocycle), wherein each 4-8 membered heterocycle is further substituted once, twice or three times by C1-C3 alkyl as appropriate; and R4 is hydrogen or C1-3 alkyl.

[0107] In one embodiment, R1 is C1-6 alkyl. In one embodiment, R1 is C1-3 alkyl. In one embodiment, R1 is methyl or ethyl. In one embodiment, R1 is methyl. In one embodiment, R1 is ethyl.

[0108] In one embodiment, R2 is C1-6 alkyl. In one embodiment, R2 is C1-3 alkyl. In one embodiment, R2 is methyl or ethyl. In one embodiment, R2 is methyl. In one embodiment, R2 is ethyl.

[0109] In one embodiment, R1 and R2 are the same.

[0110] In one embodiment, R3 is a 6-membered heterocycle or a 5-membered heteroaryl, wherein the 6-membered heterocycle is optionally substituted once, twice or three times by the group R3a, and wherein the 5-membered heteroaryl is optionally The cases are substituted one, two or three times by the group R3b.

[0111] In one embodiment, R3 is ? three times, and wherein the furyl, thienyl and pyrazolyl are optionally substituted once, twice or three times by the group R3b.

[0112] In one embodiment, R3 is furyl, thienyl or pyrazolyl optionally substituted once, twice or three times with the group R3b. In one embodiment, R3 is furyl, thienyl or pyrazolyl substituted once, twice or three times by the group R3b.

[0113] In one embodiment, R3 is furyl optionally substituted once, twice or three times with the group R3b. In one embodiment, R3 is furyl substituted one, two or three times with the group R3b.

[0114] In one embodiment, R3 is thiolinyl or piperidinyl optionally substituted once, twice or three times with the group R3a.

[0115] In one embodiment, each occurrence of R3a is independently C1-C6 alkyl, C1-C6 alkyl-(C6-C10 aryl), S(O)2-(C1-C6 alkyl ) or S(O)2-(C6-C10 aryl).

[0116] In one embodiment, each occurrence of R3a is independently C1-C6 alkyl, C1-C6 alkyl-(phenyl), S(O)2-(C1-C6 alkyl) or S (O)2-(phenyl).

[0117] In one embodiment, each occurrence of R3a is independently represented by a group selected from: .

[0118] In one embodiment, each occurrence of R3b is independently C1-C6 alkyl, halo, nitro, C(O)-(4- to 8-membered heterocycle) or C1-C6 alkyl -(4- to 8-membered heterocyclic ring), wherein each 4- to 8-membered heterocyclic ring is further substituted once, twice or three times by C1-C3 alkyl as appropriate.

[0119] In one embodiment, each occurrence of R3b is independently C1-C6 alkyl, halo, nitro, C(O)-(4- to 8-membered heterocycle) or C1-C6 alkyl -(4-membered to 8-membered heterocyclic ring), wherein each 4-membered to 8-membered heterocyclic ring is independently selected from the group consisting of pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, thiol, thiol , piperidinyl and piperyl, and each of the 4- to 8-membered heterocyclic rings is further substituted once, twice or three times by C1-C3 alkyl as appropriate.

[0120] In one embodiment, each occurrence of R3b is independently C1-C6 alkyl, halo, nitro, C(O)-(4- to 8-membered heterocycle) or C1-C6 alkyl -(4-membered to 8-membered heterocycle), wherein each 4- to 8-membered heterocycle is independently selected from the group consisting of ? The rings are further substituted once, twice or three times with methyl groups as appropriate.

[0121] In one embodiment, each occurrence of R3b is independently represented by a group selected from: .

[0122] In one embodiment, R4 is hydrogen or methyl. In one embodiment, R4 is hydrogen. In one embodiment, R4 is methyl.

[0123] In one embodiment, R3 is C(O)-(4-membered to 8-membered heterocyclic ring) or C1-C6 alkyl-(4-membered to 8-membered heterocyclic ring) substituted once, twice or three times Furanyl, wherein each 4- to 8-membered heterocyclic ring is further substituted once, twice or three times by C1-C3 alkyl as appropriate.

[0124] In one embodiment, R3 is C(O)-(4-membered to 8-membered heterocyclic ring) or C1-C6 alkyl-(4-membered to 8-membered heterocyclic ring) substituted once, twice or three times Furanyl, wherein each 4- to 8-membered heterocyclic ring is independently selected from the group consisting of pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, thiolinyl, thiothiolinyl, piperidinyl and piperoneyl , and wherein each 4- to 8-membered heterocyclic ring is further substituted once, twice or three times by a C1-C3 alkyl group as appropriate.

[0125] In one embodiment, R3 is C(O)-(4-membered to 8-membered heterocyclic ring) or C1-C6 alkyl-(4-membered to 8-membered heterocyclic ring) substituted once, twice or three times Furanyl, wherein each 4- to 8-membered heterocyclic ring is independently selected from the group consisting of ? The group is substituted once, twice or three times.

[0126] In one embodiment, R3 is furanyl substituted once, twice or three times by C(O)-(𠰌linyl) or C1-C6 alkyl-(𠰌linyl).

[0127] In one embodiment, R3 is represented by a group selected from: .

[0128] In one embodiment, the compound of formula (II) has the structure of compound 24:.

[0129] In one embodiment, the compound of formula (II) has the structure of compound 25:.

[0130] In one embodiment, the compound of formula (II) has the structure of compound 37:.

[0131] Exemplary compounds of formula (II) include the compounds described below or pharmaceutically acceptable salts thereof:.

[0132] In yet another aspect, provided herein is a compound of formula (III): , or a pharmaceutically acceptable salt thereof, wherein: L is C1-C6 alkyl or absent R1 is optionally 5 members C1-C6 alkyl substituted with 10-membered heteroaryl, NH2, NH(C1-C6 alkyl) or N(C1-C6 alkyl)2; R2 is optionally 5-10 membered heteroaryl, NH2 , NH (C1-C6 alkyl) or N (C1-C6 alkyl) substituted C1-C6 alkyl; R3 is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, halogen radical, hydroxyl, C(O)NH2, C(O)NH(C1-C6 alkyl), C(O)N(C1-C6 alkyl)2 or C(O)-(4- to 8-membered heterocycle ), wherein the C1-C6 alkyl group and the C1-C6 alkoxy group are optionally substituted by C6-C10 aryl once, twice or three times, and wherein the C(O)-(4-membered to 8-membered heterocycle) Optionally substituted once, twice or three times with C1-C3 alkyl.

[0133] In one embodiment, L is C1-C3 alkyl or is absent. In one embodiment, L is C1-C3 alkyl. In one embodiment, L is absent.

[0134] In one embodiment, R1 is C1-C6 alkyl optionally substituted with NH2, NH(C1-C6 alkyl) or N(C1-C6 alkyl)2. In one embodiment, R1 is C1-C6 alkyl optionally substituted with N(C1-C6 alkyl)2. In one embodiment, R1 is C1-C3 alkyl optionally substituted with N(C1-C3 alkyl)2. In one embodiment, R1 is methyl or ethyl, wherein the ethyl is optionally substituted with N(CH2CH3)2.

[0135] In one embodiment, R2 is C1-C6 alkyl optionally substituted with NH2, NH(C1-C6 alkyl) or N(C1-C6 alkyl)2. In one embodiment, R2 is C1-C6 alkyl optionally substituted with N(C1-C6 alkyl)2. In one embodiment, R2 is C1-C3 alkyl optionally substituted with N(C1-C3 alkyl)2. In one embodiment, R2 is methyl or ethyl, wherein the ethyl is optionally substituted with N(CH2CH3)2.

[0136] In one embodiment, R1 and R2 are the same.

[0137] In one embodiment, R3 is C1-C6 alkyl, C1-C6 alkoxyl, hydroxyl or C(O)-(4 to 8 member heterocycle), wherein the C1-C6 alkyl and the C1-C6 alkoxy is optionally substituted once by C6-C10 aryl, and wherein the C(O)-(4-membered to 8-membered heterocycle) is optionally substituted once by C1-C3 alkyl.

[0138] In one embodiment, R3 is C1-C3 alkyl, C1-C3 alkoxyl, hydroxyl or C(O)-(6-membered heterocycle), wherein the C1-C3 alkyl and the C1-C3 Alkoxy is optionally substituted once with phenyl.

[0139] In one embodiment, R3 is C1-C3 alkyl, C1-C3 alkoxyl, hydroxyl or C(O)-(𠰌linyl), wherein the C1-C3 alkyl and the C1-C3 alkane Oxygen is optionally substituted once with phenyl.

[0140] In one embodiment, the group represented by R3-L has one of the following structures: .

[0141] In one embodiment, L is absent and R3 is C1-C6 alkyl.

[0142] Exemplary compounds of formula (III) include the compounds described below or pharmaceutically acceptable salts thereof:.

[0143] In another aspect, the compound of formula (IV) is provided herein:, or a pharmaceutically acceptable salt thereof, wherein: L is C3-C7 cycloalkyl, C1-C6 alkyl, or does not exist R1 is C1-C6 alkyl optionally substituted by 5 to 10 membered heteroaryl, NH2, NH (C1-C6 alkyl) or N (C1-C6 alkyl) 2; R2 is optionally substituted by 5 C1-C6 alkyl substituted by NH2, NH2, NH(C1-C6 alkyl) or N(C1-C6 alkyl)2; R3 is C6-C10 aryl, 5-10 membered heteroaryl Aryl, C3-C10 cycloalkyl, C(O)NH-(C1-C6 alkyl)-PPh3, hydroxyl, C1-C6 alkoxy or O-(C1-C6 alkyl)-O-(C1- C6 alkyl), wherein the C6-C10 aryl is substituted once, twice or three times by the group R3a, and wherein the 5- to 10-membered heteroaryl is optionally substituted once, twice or three times by the group R3b; R3a is in Each occurrence is independently a C3-C7 cycloalkyl group or a 4- to 8-membered heterocyclic ring, wherein the 4- to 8-membered heterocyclic ring is further substituted once, twice or three times by a C1-C3 alkyl group as appropriate; R3b in each The second occurrence is independently C1-C3 alkyl, C1-C3 alkoxy, C3-C7 cycloalkyl or 4 to 8 membered heterocycle, wherein the heterocycle is further substituted by C1-C3 alkyl once, twice times or three times; and R4 is hydrogen, C1-C3 alkyl or C6-C10 aryl; with the proviso that, when L is absent, R3 is C6-C10 substituted once, twice or three times by the group R3a Aryl; or when L is absent, R3 is a 6- to 10-membered heteroaryl group substituted once, twice or three times by a group R3b; or when L is absent, R3 is optionally a group R3b A 6- to 10-membered heteroaryl group substituted once, twice or three times, and R4 is H.

[0144] In one embodiment, L is C3-C7 cycloalkyl or C1-C6 alkyl. In one embodiment, L is C3-C7 cycloalkyl. In one embodiment, L is C1-C6 alkyl. In one embodiment, L is C3-C5 cycloalkyl or C1-C3 alkyl. In one embodiment, L is C3-C5 cycloalkyl. In one embodiment, L is C1-C3 alkyl.

[0145] In one embodiment, L is -CH2-. In one embodiment, L is -CH2CH2-. In one embodiment, L is -CH2CH2CH2-. In one embodiment, L is -CH2CH2CH2CH2-. In one embodiment, L is -CH(CH3)-. In one embodiment, L is -CH(CH2CH3)-. In one embodiment, L is -C(CH3)2-.

[0146] In one embodiment, L is C3-C7 cycloalkyl or C3-C5 cycloalkyl, wherein the cycloalkyl comprises a quaternary carbon that forms the point of attachment to the group R3 and the rest of the structure. Therefore, in one embodiment, L is represented by one of the following groups: .

[0147] In one embodiment, R1 is C1-6 alkyl. In one embodiment, R1 is C1-3 alkyl. In one embodiment, R1 is methyl or ethyl. In one embodiment, R1 is methyl. In one embodiment, R1 is ethyl.

[0148] In one embodiment, R1 is C1-C6 alkyl optionally substituted with a 5-membered heteroaryl. In one embodiment, R1 is C1-C6 alkyl optionally substituted with furyl. In one embodiment, R1 is CH2-furyl.

[0149] In one embodiment, R2 is C1-6 alkyl. In one embodiment, R2 is C1-3 alkyl. In one embodiment, R2 is methyl or ethyl. In one embodiment, R2 is methyl. In one embodiment, R2 is ethyl.

[0150] In one embodiment, R2 is C1-C6 alkyl optionally substituted with a 5-membered heteroaryl. In one embodiment, R2 is C1-C6 alkyl optionally substituted with furyl. In one embodiment, R2 is CH2-furyl.

[0151] In one embodiment, R1 and R2 are the same.

[0152] In one embodiment, R3 is a C6-C10 aryl group, a 5- to 10-membered heteroaryl group, a C3-C10 cycloalkyl group or a C1-C6 alkoxy group, wherein the C6-C10 aryl group is R3a is substituted once, twice or three times, and wherein the 5- to 10-membered heteroaryl is optionally substituted once, twice or three times by the group R3b.

[0153] In one embodiment, R3 is a 5-membered to 10-membered heteroaryl group or a C3-C10 cycloalkyl group, wherein the 5-membered to 10-membered heteroaryl group is optionally substituted once, twice or three times by the group R3b .

[0154] In one embodiment, R3 is phenyl, pyrazolyl, pyridyl, benzofuryl, benzothiazolyl, benzodioxolyl, C3-C6 cycloalkyl, adamantane C(O)NH-(C1-C6 alkyl)-PPh3, hydroxyl, C1-C6 alkoxy or O-(C1-C6 alkyl)-O-(C1-C6 alkyl), where the benzene The radical is substituted once, twice or three times by the group R3a; and wherein the pyrazolyl, pyridyl, benzofuryl, benzothiazolyl and benzodioxolyl are optionally substituted once by the group R3b, two or three times.

[0155] In one embodiment, R3 is phenyl, pyrazolyl, pyridyl, benzofuryl, benzothiazolyl, benzodioxolyl or C1-C6 alkoxyl, wherein pyrazolyl Azolyl, pyridyl, benzofuryl, benzothiazolyl and benzodioxolyl are optionally substituted once or twice by the group R3b.

[0156] In one embodiment, R3 is pyridyl, benzofuryl or benzodioxolyl, wherein pyridyl, benzofuryl and benzodioxolyl are optionally selected from The group R3b is substituted once or twice.

[0157] In one embodiment, R3 is benzofuranyl or benzodioxolyl, wherein benzofuryl and benzodioxolyl are optionally substituted once by the group R3b or twice.

[0158] In one embodiment, each occurrence of R3a is independently a 4- to 8-membered heterocyclic ring optionally further substituted once, twice or three times with C1-C3 alkyl. In one embodiment, each occurrence of R3a is independently a 4-8 membered heterocyclic ring optionally further substituted once with methyl.

[0159] In one embodiment, each occurrence of R3a is independently pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, thiolinyl, thiothiolinyl, piperidinyl or piperhexyl, each of which Optionally further substituted once, twice or three times with C1-C3 alkyl. In one embodiment, each occurrence of R3a is independently pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, thiolinyl, thiothiolinyl, piperidinyl, or piperidinyl, each of which is optionally further Substituted once with methyl. In one embodiment, each occurrence of R3a is independently pyrrolidinyl, pyrrolidinonyl or oxalinyl. In one embodiment, each occurrence of R3a is independently represented by a group selected from: .

[0160] In one embodiment, each occurrence of R3b is independently C1-C3 alkyl, C1-C3 alkoxy or 4-8 membered heterocycle, wherein the heterocycle is optionally further modified by C1-C3 alkane The group is substituted once, twice or three times. In one embodiment, each occurrence of R3b is independently C1-C3 alkoxy or a 4- to 8-membered heterocycle, wherein the heterocycle is optionally further substituted once with methyl.

[0161] In one embodiment, each occurrence of R3b is independently C1-C3 alkyl, C1-C3 alkoxy or selected from pyrrolidinyl, pyrrolidinonyl, tetrahydrofuryl, thiol, thio A heterocyclic ring formed from the group consisting of thiolinyl, piperidinyl and piperazyl, wherein the heterocyclic ring is further substituted once, twice or three times by C1-C3 alkyl as appropriate. In one embodiment, each occurrence of R3b is independently C1-C3 alkyl, C1-C3 alkoxy or selected from pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, thiol, thiol A heterocyclic ring of the group consisting of yl, piperidinyl and piperidinyl, wherein the heterocyclic ring is optionally further substituted once with methyl. In one embodiment, each occurrence of R3b is independently methyl, methoxy, or a heterocycle selected from the group consisting of pyrrolidinyl and oxalinyl. In one embodiment, each occurrence of R3b is independently represented by a group selected from: .

[0162] In one embodiment, R4 is hydrogen, C1-C3 alkyl or phenyl. In one embodiment, R4 is hydrogen, methyl or phenyl. In one embodiment, R4 is hydrogen or C1-C3 alkyl. In one embodiment, R4 is hydrogen or methyl. In one embodiment, R4 is hydrogen. In one embodiment, R4 is methyl. In one embodiment, R4 is phenyl.

[0163] In one embodiment, L is C1-C6 alkyl, and R3 is C1-C6 alkoxy.

[0164] In one embodiment, the group represented by R3-L is represented by one of the following: .

[0165] In one embodiment, the group represented by R3-L is represented by one of the following: .

[0166] In one embodiment, R3 is pyridyl substituted once, twice or three times by C1-C3 alkoxy or 4-8 membered heterocycle, wherein the 4-8 membered heterocycle is optionally C1-C3 alkyl is substituted once.

[0167] In one embodiment, when L is absent, R3 is a C6-C10 aryl group substituted once, twice or three times by group R3a; or when L is absent, R3 is via group R3b A 6- to 10-membered heteroaryl group substituted once, twice or three times. In another embodiment, when L is absent, R3 is a C6-C10 aryl substituted once, twice or three times by the group R3a; or when L is absent, R3 is optionally the group R3b A 6- to 10-membered heteroaryl group substituted once, twice or three times, and R4 is H.

[0168] In one embodiment, when L is absent, R3 is pyridyl substituted once, twice or thrice by C1-C3 alkoxy.

[0169] In one embodiment, when L is absent, R3 is phenyl substituted with a 4-8 membered heterocycle.

[0170] In one embodiment, when L is absent, R3 is a C6-C10 aryl group substituted once, twice or three times by group R3a; or when L is absent, R3 is via group R3b A 6- to 10-membered heteroaryl group substituted once, twice or three times.

[0171] In one embodiment, L is a C3-C5 cycloalkyl group or a C1-C3 alkyl group; R3 is a pyridyl group substituted once, twice or three times by a 4- to 8-membered heterocyclic ring as appropriate; and R4 is methyl.

[0172] Exemplary compounds of formula (IV) include the following compounds or pharmaceutically acceptable salts thereof: .

[0173] In one embodiment, the compound of formula (IV) is one of the following compounds or a pharmaceutically acceptable salt thereof:.

[0174] In one embodiment, the compound of formula (IV) has the structure of compound 2:.

[0175] In one embodiment, the compound of formula (IV) has the structure of compound 59:.

[0176] In one embodiment, the compound of formula (IV) has the structure of compound 60:.

[0177] In one embodiment, the compound of formula (IV) has the structure of compound 61:.

[0178] In one embodiment, the compound of formula (IV) has the structure of compound 74:.

[0179] In one embodiment, the compound of formula (IV) has the structure of compound 74:.

[0180] In another aspect, provided herein is a compound of formula (V): , or a pharmaceutically acceptable salt thereof, wherein: R1 is optionally 5- to 10-membered heteroaryl, NH2, NH(C1 -C6 alkyl) or C1-C6 alkyl substituted by N(C1-C6 alkyl)2; R2 is optionally 5 to 10 membered heteroaryl, NH2, NH (C1-C6 alkyl) or N( C1-C6 alkyl) 2 substituted C1-C6 alkyl; R3 is a 4-membered to 8-membered heterocyclic ring or a 5-membered heteroaryl group, wherein the 4-membered to 8-membered heterocyclic ring is optionally substituted once or twice by the group R3a or three times, and wherein the 5-membered heteroaryl is optionally substituted once, twice or three times by the group R3b; R3a is independently C1-C6 alkyl, C1-C6 alkyl-(C6-C10 Aryl), C1-C6 alkyl-(5-membered to 10-membered heteroaryl), S(O)2H, S(O)2-(C1-C6 alkyl), S(O)2-(C3- C7 cycloalkyl) or S (O) 2- (C6-C10 aryl); wherein each heteroaryl is further substituted by C1-C6 alkyl or C6-C10 aryl as appropriate one to four times; and wherein each C6- C10 aryl is optionally further substituted by C1-C6 alkyl one to four times; R3b is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkane at each occurrence Base-N(R5)2, (C1-C6 alkyl)-O-(C1-C6 alkyl), halo, nitro, cyano, C6-C10 aryl, C(O)-(4 to 8-membered heterocycle), C1-C6 alkyl-(C6-C10 aryl), C1-C6 alkyl-(5-10 membered heteroaryl) or C1-C6 alkyl-(4-8 membered heteroaryl Ring), wherein each 4- to 8-membered heterocycle, C6-C10 aryl and 5- to 10-membered heteroaryl are further modified by C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl or halo substituted one to four times; R4 is hydrogen or C1-3 alkyl; and R5 is independently hydrogen, C1-C6 alkyl, C1-C3 alkyl-(C6-C10 aryl) at each occurrence.

[0181] In one embodiment, R1 is C1-6 alkyl. In one embodiment, R1 is C1-3 alkyl. In one embodiment, R1 is methyl or ethyl. In one embodiment, R1 is methyl. In one embodiment, R1 is ethyl.

[0182] In one embodiment, R1 is C1-C6 alkyl optionally substituted with a 5-membered heteroaryl. In one embodiment, R1 is C1-C6 alkyl optionally substituted with furyl. In one embodiment, R1 is CH2-furyl.

[0183] In one embodiment, R2 is C1-6 alkyl. In one embodiment, R2 is C1-3 alkyl. In one embodiment, R2 is methyl or ethyl. In one embodiment, R2 is methyl. In one embodiment, R2 is ethyl.

[0184] In one embodiment, R2 is C1-C6 alkyl optionally substituted with 5-membered heteroaryl. In one embodiment, R2 is C1-C6 alkyl optionally substituted with furyl. In one embodiment, R2 is CH2-furyl.

[0185] In one embodiment, R1 and R2 are the same.

[0186] In one embodiment, R3 is a 5-6 membered heterocycle or a 5-membered heteroaryl, wherein the 5-6 membered heterocycle is optionally substituted once, twice or three times by the group R3a, and wherein the The 5-membered heteroaryl is optionally substituted once, twice or three times by the group R3b.

[0187] In one embodiment, R3 is tetrahydrofuranyl, thiolyl, piperidinyl, furyl, thienyl, pyrrolyl, oxazolyl, pyrazolyl or imidazolyl, wherein the tetrahydrofuranyl, thiolyl and piperidinyl are optionally substituted once, twice or three times by group R3a, and wherein the furyl, thienyl, pyrrolyl, oxazolyl, pyrazolyl and imidazolyl are optionally substituted by group R3b once, twice times or three times.

[0188] In one embodiment, R3 is furyl, thienyl, oxazolyl, pyrazolyl or imidazolyl optionally substituted once, twice or thrice by group R3b. In another embodiment, R3 is furyl, thienyl, oxazolyl, pyrazolyl or imidazolyl substituted once, twice or thrice by the group R3b.

[0189] In one embodiment, R3 is furyl optionally substituted one, two or three times with the group R3b. In another embodiment, R3 is furyl substituted one, two or three times with the group R3b.

[0190] In one embodiment, R3 is thienyl optionally substituted one, two or three times with the group R3b. In another embodiment, R3 is thienyl substituted one, two or three times with the group R3b.

[0191] In one embodiment, R3 is oxazolyl optionally substituted one, two or three times with the group R3b. In another embodiment, R3 is oxazolyl substituted one, two or three times with the group R3b.

[0192] In one embodiment, R3 is pyrazolyl optionally substituted one, two or three times with the group R3b. In another embodiment, R3 is pyrazolyl substituted one, two or three times with the group R3b.

[0193] In one embodiment, R3 is imidazolyl optionally substituted one, two or three times with the group R3b. In another embodiment, R3 is imidazolyl substituted one, two or three times with the group R3b.

[0194] In one embodiment, R3 is tetrahydrofuranyl, metholinyl or piperidinyl, each of which is optionally substituted once, twice or three times with the group R3a.

[0195] In one embodiment, each occurrence of R3a is independently C1-C6 alkyl, C1-C6 alkyl-(C6-C10 aryl), C1-C6 alkyl-(5 to 10 members Heteroaryl), S(O)2-(C1-C6 alkyl) or S(O)2-(C6-C10 aryl), wherein each heteroaryl is further modified by C1-C6 alkyl or C6- C10 aryl is substituted one to four times; and wherein each C6-C10 aryl is optionally further substituted by C1-C6 alkyl one to four times.

[0196] In one embodiment, each occurrence of R3a is independently C1-C6 alkyl, C1-C6 alkyl-(phenyl), C1-C6 alkyl-(5 to 6 membered heteroaryl ), S(O)2-(C1-C6 alkyl) or S(O)2-(phenyl), wherein each heteroaryl is optionally further substituted one to four times by C1-C3 alkyl or phenyl; and Wherein each phenyl group is further substituted by a C1-C3 alkyl group for one to four times as appropriate.

[0197] In one embodiment, each occurrence of R3a is independently: .

[0198] In one embodiment, each occurrence of R3b is independently C1-C6 alkyl, C1-C6 alkyl-N(R5)2, (C1-C6 alkyl)-O-(C1-C6 alkane base), halo, nitro, C6-C10 aryl, C(O)-(4 to 8-membered heterocycle), C1-C6 alkyl-(C6-C10 aryl), C1-C6 alkyl- (5-membered to 10-membered heteroaryl) or C1-C6 alkyl-(4-membered to 8-membered heterocycle), wherein each 4-membered to 8-membered heterocycle, C6-C10 aryl and 5-10 membered heteroaryl The group is optionally further substituted one to four times by C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl or halo.

[0199] In one embodiment, each occurrence of R3b is independently C1-C6 alkyl, C1-C6 alkyl-N(R5)2, halo, C6-C10 aryl, C1-C6 alkyl- (4-membered to 8-membered heterocyclic ring) or C1-C6 alkyl-(C6-C10 aryl), wherein each 4-membered to 8-membered heterocyclic ring and C6-C10 aryl group are further modified by C1-C3 alkyl, C1 -C3 alkoxy, C1-C3 haloalkyl or halo are substituted one to four times.

[0200] In one embodiment, each occurrence of R3b is independently C1-C6 alkyl, C1-C3 alkyl-N(R5)2, halo, phenyl, C1-C3 alkyl-(5 member to 6-membered heterocycle) or C1-C6 alkyl-phenyl, wherein each of 5-6 membered heterocycle and phenyl is further substituted by C1-C3 alkyl or halo one to four times as appropriate.

[0201] In one embodiment, each occurrence of R3b is independently C1-C6 alkyl, C1-C6 alkyl-N(R5)2, (C1-C6 alkyl)-O-(C1-C6 alkane base), halo, nitro, C6-C10 aryl, C(O)-(4 to 8-membered heterocycle), C1-C6 alkyl-(C6-C10 aryl), C1-C6 alkyl- (5-membered to 10-membered heteroaryl) or C1-C6 alkyl-(4-membered to 8-membered heterocycle), wherein each 4-membered to 8-membered heterocycle, C6-C10 aryl and 5-10 membered heteroaryl The group is optionally further substituted one to four times with -CH3, -CH2CH3, -OCH3, -CH2F, CHF2, -CF3, -F or -Cl.

[0202] In one embodiment, each occurrence of R3b is independently C1-C6 alkyl, C1-C6 alkyl-N(R5)2, (C1-C6 alkyl)-O-(C1-C6 alkane base), halo, nitro, phenyl, C(O)-(4 to 8 membered heterocycle), C1-C6 alkyl-phenyl, C1-C6 alkyl-(5 to 10 membered heteroaryl base) or C1-C6 alkyl-(4- to 8-membered heterocyclic ring); wherein each 4- to 8-membered heterocyclic ring is independently selected from the group consisting of pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, 𠰌 Linyl, thiol-thiolinyl, piperidinyl and piperyl; each of which has 5 to 10 membered heteroaryls selected from the group consisting of furyl and tetrahydroisoquinolinyl; and each of which has 4 to 8 members Heterocycle, phenyl and 5- to 10-membered heteroaryl are optionally substituted one to four times by -CH3, -CH2CH3, -OCH3, -CH2F, CHF2, -CF3, -F or -Cl.

[0203] In one embodiment, each occurrence of R3b is independently C1-C6 alkyl, C1-C6 alkyl-N(R5)2, (C1-C6 alkyl)-O-(C1-C6 alkane base), halo, nitro, phenyl, C(O)-(4 to 8 membered heterocycle), C1-C6 alkyl-phenyl, C1-C6 alkyl-(5 to 10 membered heteroaryl base) or C1-C6 alkyl-(4 to 8 membered heterocyclic ring); wherein each 4 to 8 membered heterocyclic ring is independently selected from the group consisting of pyrrolidinyl, 𠰌linyl, piperidinyl and piperidinyl 𠯤 group; wherein each 5- to 10-membered heteroaryl is selected from the group consisting of furyl and tetrahydroisoquinolinyl; and wherein each of 4-8-membered heterocycle, phenyl, and 5- to 10-membered heteroaryl Optionally further substituted with -CH3, -OCH3, -CF3 or -F one to four times.

[0204] In one embodiment, each occurrence of R3b is independently: .

[0205] In one embodiment, each occurrence of R3b is independently: .

[0206] In one embodiment, each occurrence of R3b is independently: .

[0207] In one embodiment, each occurrence of R3b is independently: .

[0208] In one embodiment, each occurrence of R3b is independently: .

[0209] In one embodiment, R3 is a furyl group optionally substituted once, twice or three times by: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkane Base-N(R5)2, (C1-C6 alkyl)-O-(C1-C6 alkyl), halo, nitro, cyano, C6-C10 aryl, C(O)-(4 to 8-membered heterocycle), C1-C6 alkyl-(C6-C10 aryl), C1-C6 alkyl-(5-10 membered heteroaryl) or C1-C6 alkyl-(4-8 membered heteroaryl Ring), wherein each 4- to 8-membered heterocycle, C6-C10 aryl and 5- to 10-membered heteroaryl are further modified by C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl Or halo is substituted one to four times.

[0210] In one embodiment, R3 is a furyl group optionally substituted once, twice or three times by: C1-C6 alkyl, C1-C6 alkyl-N(R5)2, halo, C(O )-(4-membered to 8-membered heterocyclic ring) or C1-C6 alkyl-(4-membered to 8-membered heterocyclic ring), wherein each 4-membered to 8-membered heterocyclic ring is further modified by C1-C3 alkyl, C1-C3 alkane Oxygen, C1-C3 haloalkyl or halo are substituted one to four times.

[0211] In one embodiment, R3 is a furyl group optionally substituted once, twice or three times by: C1-C6 alkyl-N(R5)2 or C1-C6 alkyl-(4 to 8 members Heterocycle), wherein each 4- to 8-membered heterocycle is further substituted one to four times by C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl or halo as appropriate.

[0212] In one embodiment, R3 is a furyl group optionally substituted once by: C1-C3 alkyl-N(C1-C4 alkyl)2 or C1-C3 alkyl-(5-6 membered hetero ring), wherein each 5- to 6-membered heterocyclic ring is optionally further substituted one to four times by a C1-C3 alkyl group.

[0213] In one embodiment, R3 is a furyl group substituted once by the following: C1-C3 alkyl-N(C1-C4 alkyl)2 or C1-C3 alkyl-(5 to 6 membered heterocycle) , wherein each 5- to 6-membered heterocycle is further substituted by C1-C3 alkyl one to four times as appropriate.

[0214] In one embodiment, R3 is thienyl, oxazolyl, pyrazolyl or imidazolyl, optionally through C1-C6 alkyl, halo, C6-C10 aryl or C1-C6 alkyl- (C6-C10 aryl) is substituted once, twice or three times, wherein each C6-C10 aryl is further substituted by C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl or halo as the case may be. four times.

[0215] In one embodiment, R3 is thienyl, oxazolyl, pyrazolyl or imidazolyl, optionally substituted by methyl, ethyl, halo, phenyl or C1-C3 alkyl-phenyl Once, twice or three times, wherein each phenyl group is optionally further substituted by C1-C3 alkyl or halo one to four times.

[0216] In one embodiment, R3 is: .

[0217] In one embodiment, R3 is: .

[0218] In one embodiment, R3 is: .

[0219] In one embodiment, R3 is: .

[0220] In one embodiment, R3 is: .

[0221] In one embodiment, R4 is hydrogen or methyl. In one embodiment, R4 is hydrogen. In one embodiment, R4 is methyl.

[0222] In one embodiment, R5 is C1-C6 alkyl or C1-C3 alkyl-(C6-C10 aryl). In another embodiment, R5 is C1-C4 alkyl or C1-C3 alkyl-phenyl. In another embodiment, R5 is C1-C4 alkyl or benzyl.

[0223] In one embodiment, when R1 is not methyl, R2 is not methyl and R4 is not hydrogen, then R3b is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkyl-N(R5)2, (C1-C6 alkyl)-O-(C1-C6 alkyl), halo, nitro, cyano, C6-C10 aromatic C(O)-(4 to 8 member heterocycle), C1-C6 alkyl-(C6-C10 aryl), C1-C6 alkyl-(5 to 10 member heteroaryl) or C1- C6 alkyl-(4-membered to 8-membered heterocyclic ring), wherein each 4-membered to 8-membered heterocyclic ring, C6-C10 aryl group and 5-membered to 10-membered heteroaryl group are further modified by C1-C3 alkyl, C1- C3 alkoxy, C1-C3 haloalkyl or halo are substituted once or twice.

[0224] In one embodiment, when R4 is not hydrogen, then R3b is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkyl in each occurrence -N(R5)2, (C1-C6 alkyl)-O-(C1-C6 alkyl), halo, nitro, cyano, C6-C10 aryl, C(O)-(4 to 8 member heterocycle), C1-C6 alkyl-(C6-C10 aryl), C1-C6 alkyl-(5-10 member heteroaryl) or C1-C6 alkyl-(4-8 member heterocycle ), wherein each of the 4-membered to 8-membered heterocyclic ring, C6-C10 aryl group and 5-membered to 10-membered heteroaryl group is further modified by C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl or Halo is substituted once or twice.

[0225] In one embodiment, when R3 is oxazolyl, R3 does not have the following structure: .

[0226] In one specific embodiment of the compound of formula (V) or a pharmaceutically acceptable salt thereof: R1 is C1-C3 alkyl; R2 is C1-C3 alkyl; R3 is optionally substituted by group R3b One, two or three 5-membered heteroaryl groups; R3b is independently C1-C6 alkyl, C1-C6 alkyl-N(R5)2, (C1-C6 alkyl)-O-( C1-C6 alkyl), halo, C6-C10 aryl, C(O)-(4 to 8-membered heterocycle), C1-C6 alkyl-(C6-C10 aryl), C1-C6 alkyl -(5-membered to 10-membered heteroaryl) or C1-C6 alkyl-(4-membered to 8-membered heterocycle), wherein each 4-membered to 8-membered heterocycle, C6-C10 aryl and 5- to 10-membered heterocycle Aryl is optionally further substituted one to four times with C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl or halo; R4 is hydrogen or methyl; and R5 is independently C1 at each occurrence -C4 alkyl or benzyl.

[0227] In another embodiment of the compound of formula (V) or a pharmaceutically acceptable salt thereof: R1 is C1-C3 alkyl; R2 is C1-C3 alkyl; R3 is optionally substituted by group R3b Furanyl once, twice or three times; R3b is independently C1-C6 alkyl-N(R5)2 or C1-C6 alkyl-(4-membered to 8-membered heterocycle) at each occurrence, wherein each 4 1 to 8 membered heterocycles are optionally further substituted one to four times by C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl or halo; R4 is hydrogen or methyl; and R5 at each occurrence are independently C1-C4 alkyl or benzyl.

[0228] In another embodiment of the compound of formula (V) or a pharmaceutically acceptable salt thereof: R1 is C1-C3 alkyl; R2 is C1-C3 alkyl; R3 is optionally substituted by group R3b Furanyl once, twice or three times; R3b is independently C1-C6 alkyl-N(R5)2 or C1-C6 alkyl-(4-membered to 8-membered heterocycle) at each occurrence, wherein each 4 1 to 8 membered heterocycles are optionally further substituted one to four times by C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl or halo; R4 is hydrogen or methyl; and R5 at each occurrence are independently C1-C4 alkyl or benzyl; the proviso is that when R1 is C2-C3 alkyl, R2 is C2-C3 alkyl and R4 is methyl, then R3b is independently at each occurrence C1-C6 alkyl-N(R5)2 or C1-C6 alkyl-(4-membered to 8-membered heterocycle), wherein each 4-membered to 8-membered heterocycle is further modified by C1-C3 alkyl, C1-C3 alkane Oxygen, C1-C3 haloalkyl or halo is substituted once or twice.

[0229] In another embodiment of the compound of formula (V) or a pharmaceutically acceptable salt thereof: R1 is C1-C3 alkyl; R2 is C1-C3 alkyl; R3 is optionally substituted by group R3b Furanyl once, twice or three times; R3b is independently C1-C6 alkyl-N(R5)2 or C1-C6 alkyl-(4-membered to 8-membered heterocycle) at each occurrence, wherein each 4 1 to 8 membered heterocycles are optionally further substituted one to four times by C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl or halo; R4 is hydrogen or methyl; and R5 at each occurrence independently C1-C4 alkyl or benzyl; with the proviso that when R4 is methyl, then R3b is independently C1-C6 alkyl-N(R5)2 or C1-C6 alkane in each occurrence Base-(4-membered to 8-membered heterocyclic ring), wherein each 4-membered to 8-membered heterocyclic ring is further substituted once or twice by C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl or halo Second-rate.

[0230] Exemplary compounds of formula (V) include the following compounds or pharmaceutically acceptable salts thereof: .

[0231] In one embodiment, the compound of formula (V) is one of the following compounds or a pharmaceutically acceptable salt thereof:.

[0232] In one embodiment, the compound of formula (V) has the structure of compound 25:.

[0233] In one embodiment, the compound of formula (V) has the structure of compound 32:.

[0234] In one embodiment, the compound of formula (V) has the structure of compound 34:.

[0235] In one embodiment, the compound of formula (V) has the structure of compound 35:.

[0236] In one embodiment, the compound of formula (V) has the structure of compound 37:.

[0237] In one embodiment, the compound of formula (V) has the structure of compound 80:.

[0238] In one embodiment, the compound of formula (V) has the structure of compound 81:.

[0239] In one embodiment, the compound of formula (V) has the structure of compound 82:.

[0240] In one embodiment, the compound of formula (V) has the structure of compound 84:.

[0241] In one embodiment, the compound of formula (V) has the structure of compound 85:.

[0242] In one embodiment, the compound of formula (V) has the structure of compound 86:.

[0243] In one embodiment, the compound of formula (V) has the structure of compound 87:.

[0244] In one embodiment, the compound of formula (V) has the structure of compound 88:.

[0245] In one embodiment, the compound of formula (V) has the structure of compound 90:.

[0246] In one embodiment, the compound of formula (V) has the structure of compound 94:.

[0247] In one embodiment, the compound of formula (V) has the structure of compound 95:.

[0248] In one embodiment, the compound of formula (V) has the structure of compound 96:.

[0249] In one embodiment, the compound of formula (V) has the structure of compound 98:.

[0250] In one embodiment, the compound of formula (V) has the structure of compound 100:.

[0251] In one embodiment, the compound of formula (V) has the structure of compound 105:.

[0252] In one embodiment, the compound of formula (V) has the structure of compound 106:.

[0253] In one embodiment, the compound of formula (V) has the structure of compound 120:.

[0254] In one embodiment, the compound of formula (V) has the structure of compound 123:.

[0255] Another aspect of the present invention is a compound selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof:.

[0256] In one embodiment, the present invention provides a compound having the structure of compound 54:.

[0257] In another aspect, the present invention provides a compound having the structure of Compound 20:.

[0258] Another aspect of the present invention is a compound selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof:.

[0259] Another aspect of the present invention is a compound selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof:. synthetic intermediate

[0260] In another aspect, the invention also relates to synthetic intermediates of the copper complexes described herein. In some embodiments, a synthetic intermediate has a structure represented by Formula (I-A): wherein the variables L, R1, R2, R3, and R4 correspond to variables of the same name as defined in Formula (I).

[0261] Exemplary synthetic intermediates represented by formula (I-A) include the following: .

[0262] In some embodiments, the synthetic intermediate has a structure represented by formula (II-A): wherein the variables R1, R2, R3 and R4 correspond to the variables of the same name as defined in formula (II).

[0263] Exemplary synthetic intermediates represented by formula (II-A) include the following: .

[0264] In some embodiments, the synthetic intermediate has a structure represented by Formula (III-A): wherein the variables L, R1, R2 and R3 correspond to the variables of the same name as defined in Formula (III).

[0265] Exemplary synthetic intermediates represented by formula (III-A) include the following: .

[0266] In another aspect, the invention also relates to synthetic intermediates of the copper complexes described herein. In some embodiments, a synthetic intermediate has a structure represented by Formula (IV-A): wherein the variables L, R1, R2, R3, and R4 correspond to variables of the same name as defined in Formula (IV).

[0267] Exemplary synthetic intermediates represented by formula (IV-A) include the following:

[0268] In some embodiments, a synthetic intermediate has a structure represented by Formula (V-A): wherein the variables R1, R2, R3, and R4 correspond to variables of the same name as defined in Formula (V).

[0269] Exemplary synthetic intermediates represented by formula (V-A) include the following: .

[0270] Other exemplary synthetic intermediates of the invention include the following compounds: . pharmaceutical composition

[0271] In another aspect, provided herein are pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0272] The formulation of therapeutic compositions and their subsequent administration (administration) are within the skill of those skilled in the art. Dosing depends on the severity and response of the disease condition to be treated, with the course of treatment continuing for days to months or until sufficient attenuation of the disease condition is achieved. Optimal dosing schedules can be calculated from measurements of drug accumulation in the patient.

[0273] Optimum dosages, method of administration and repetition rates can be readily determined by one of ordinary skill in the art. Optimum dosages may vary depending on the relative potencies of the compounds of the invention and can generally be estimated based on EC50 values ​​believed to be effective in in vitro and in vivo animal models. In general, dosages are 0.01 μg / kg body weight to 100 g / kg body weight, and may be given one or more times daily, weekly, monthly or yearly or even once every 2 to 20 years. One of ordinary skill in the art can readily assess repetition rates for dosing based on measured residence times and concentrations of the drug in body fluids or tissues. Following successful treatment, it may be desirable to subject the patient to maintenance therapy to prevent recurrence of the disease condition, wherein the compound of the invention is administered at a maintenance dose in the range of 0.01 μg / kg body weight to 100 g / kg body weight, administered one or more times daily Up to one investment every 20 years.

[0274] Various dosage regimens are available for the treatment of neurodegenerative diseases (eg, ALS). In some embodiments, a daily dose, such as any of the exemplary doses described above, is administered once, twice, three, or four times a day for three, four, five, six days. days, seven days, eight days, nine days or ten days. Depending on the stage and severity of the disease being treated, shorter treatment periods (for example, up to five days) may be used with higher doses, or longer treatment periods (for example, ten or more days or more) may be used with lower doses. weeks or a month or more). In some embodiments, the once-daily or twice-daily doses are administered every other day.

[0275] In one aspect, the compounds of the invention may be administered alone or in combination with at least one pharmaceutically acceptable excipient. The expression "pharmaceutically acceptable" means acceptable for use in the fields of medicine and veterinary medicine, ie without unacceptable toxicity or otherwise unsuitable. Examples of pharmaceutically acceptable adjuvants, diluents, excipients and the like can be found in "Remington's: The Science and Practice of Pharmacy", 21st Edition, Lippincott Williams and Wilkins, 2005, the contents of which are incorporated by reference way incorporated into this article.

[0276] The compounds of the invention, in pure form or in suitable pharmaceutical compositions, may be administered by any of the recognized modes of administration or agents known in the art. The compounds of the invention can be administered, for example, orally, nasally, parenterally (intravenously, intramuscularly or subcutaneously), topically, transdermally, intravaginally, intravesically, intracistemally or rectally. Dosage forms can be, for example, solid, semi-solid, lyophilized powder or liquid dosage forms, such as lozenges, pills, soft elastic or hard gelatin capsules, powders, solutions, suspensions, suppositories, sprays or the like, for example in a form suitable for Unit dosage form for simple administration of precise doses. Some examples of suitable pharmaceutical carriers (including pharmaceutical diluents) are gelatin capsules; sugars, such as lactose and sucrose; starches, such as corn starch and potato starch; cellulose derivatives, such as sodium carboxymethylcellulose, ethylcellulose , methylcellulose and cellulose acetate phthalate; gelatin; talc; stearic acid; magnesium stearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and cocoa butter; propylene glycol, glycerin, Sorbitol; polyethylene glycol; water; agar; alginic acid; isotonic saline and phosphate buffered saline; and other compatible substances commonly used in pharmaceutical formulations. A particular route of administration is oral, especially one in which a convenient daily dosage regimen can be adjusted according to the severity of the condition to be treated.

[0277] Adjuvants and adjuvants may include, for example, preservatives, wetting agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, emulsifying agents and dispensing agents. Emulsifiers may include polysorbates such as TWEEN, for example TWEEN-20 and TWEEN-80. Prevention of the action of microorganisms is commonly afforded by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. Isotonic agents, such as sugars, sodium chloride, and the like, may also be included. Prolonged absorption of the injectable pharmaceutical form is brought about by the use of agents which delay absorption, for example, aluminum monostearate and gelatin. Adjuvants may also include wetting agents, emulsifiers, pH buffering agents, and antioxidants such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, and the like .

[0278] Solid dosage forms can be prepared with coatings and shells, such as enteric coatings and others well known in the art. It may contain a soothing agent and may be of a composition so that it releases the compound of the invention in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The compounds of the invention can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0279] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. Such dosage forms are prepared by dissolving, dispersing, etc., a compound of the invention and, optionally, a pharmaceutical adjuvant, in a carrier such as water, saline, aqueous dextrose, glycerol, to thereby form a solution or suspension. , ethanol and the like; solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethyl Phenamides; oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil; fatty acid esters of glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan; or these substances mixtures and the like.

[0280] In general, depending on the intended mode of administration, a pharmaceutically acceptable composition will contain about 1% to 99% by weight of a compound disclosed herein and 99% to 1% by weight of the pharmaceutically acceptable composition. acceptable excipients. In one example, the composition will be between about 5% and about 75% by weight of the compound of the invention, with the remainder being suitable pharmaceutical excipients.

[0281] Actual methods for preparing such dosage forms are known, or will be apparent, to those skilled in the art. See, eg, Remington's Pharmaceutical Sciences, 18th Edition (Mack Publishing Company, Easton, Pa., 1990). treatment method

[0282] The methods described herein comprise administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein. A "therapeutically effective amount" is an amount of a compound of the invention effective to treat a neurodegenerative disease when administered alone to a patient. An amount that has been demonstrated to be a "therapeutically effective amount" in a given individual subject may not be 100% effective in subjects similarly being treated for the disease or condition under investigation, although such doses are considered by skilled practitioners to be "therapeutically effective amount". The amount of a compound of the invention corresponding to a therapeutically effective amount will depend largely on the type of disease, the stage of the disease, the age of the patient being treated, and other facts.

[0283] Accordingly, in one aspect, the invention provides a method of treating or preventing a neurodegenerative disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the invention. In particular, the method comprises administering to the subject a therapeutically effective amount of a compound of formula (I), (II), (III), (IV) or (V). Non-limiting examples of neurodegenerative diseases that can be treated or prevented with the compounds disclosed herein include amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson's disease, Huntington's disease, and Alzheimer's disease Haimer's disease. In a preferred embodiment, the neurodegenerative disease to be treated or prevented by the disclosed compounds is ALS. In one embodiment, the ALS is familial ALS. In one embodiment, the ALS is sporadic ALS.

[0284] Although the amounts of the compounds disclosed herein should be effective in treating or preventing neurodegenerative diseases, such amounts are preferably not harmful to the patient (i.e., such amounts are preferably within the limits of toxicity as established by medical guidelines). within limits). In some embodiments, limitations on the total administered dose are provided to prevent excessive toxicity or to provide more effective treatment of neurodegenerative diseases, or both. Typically, amounts contemplated herein are daily; however, half-day and two- or three-day periods are also contemplated herein.

[0285] In certain embodiments, the subject in need thereof is treatment naïve. In certain embodiments, the subject in need thereof has received prior treatment for ALS, wherein the prior treatment was not administered with a compound of the invention, and wherein the prior treatment has been inappropriate (e.g., as assessed by the subject and / or a physician). ), are ineffective and / or do not produce a detectable improvement in one or more parameters or symptoms associated with ALS, and / or have not elicited biological effects related to the underlying pathology leading to ALS symptoms.

[0286] In certain embodiments, the subject in need thereof is a human, and the human has a genetic mutation associated with ALS. In other embodiments, the genetic mutation associated with ALS comprises a mutation of the SOD1 gene.

[0287] In certain embodiments, a compound of the invention is administered to a subject in combination with another ALS treatment therapy. Current ALS treatments include the administration of riluzole and edaravone, which have been shown to be moderately effective. Other treatments for ALS include drugs to treat specific symptoms associated with the disease, for example muscle relaxants such as baclofen or diazepam may be prescribed for muscle cramps, spasm and Spasticity. Gabapentin may be prescribed to help manage pain. Drugs such as amitriptyline, trihexyphenidyl, scopolamine, and glycopyrrolate may be administered to treat excessive salivation in the mouth due to dysphagia. Medications are also needed to treat constipation, fatigue, depression, difficulty falling asleep, and pseudobulbar mood associated with ALS.

[0288] In certain embodiments, compounds of the invention are administered at a dose that achieves a plasma Cmax of about 50 to 650 ng / mL in a subject. The term "Cmax" is defined as the maximum concentration of active compound achieved in the plasma or spinal cord following administration of a drug.

[0289] In another aspect, the invention provides a method of treating, preventing or diagnosing cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the invention. In particular, isotopes of the compounds disclosed herein (eg 64Cu) can be used in PET imaging to detect the presence or absence of cancer cells in a subject in need thereof. Accordingly, in another aspect, the invention provides a method of positron emission tomography (PET) imaging in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the invention And then a PET scan was performed on the subject.

[0290] In yet another aspect, the invention provides a method of treating or preventing an infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the invention.

[0291] In another aspect, the present invention provides a method for treating a disease or condition associated with abnormal copper metabolism (such as Menkes disease or Wilson's disease) in a subject in need thereof. disease )), the method comprising administering to the subject a therapeutically effective amount of a compound of the invention. In some embodiments, the subject has congenital SOD1 deficiency or mutation. In some embodiments, the subject does not have a congenital SOD1 deficiency or mutation. Preparation

[0292] One aspect of the present invention pertains to a process for the preparation of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0293] In one embodiment, the process at least comprises the following steps: the compound of formula (I-A): mixed with copper (II) salt to form the compound of formula (I) or a pharmaceutically acceptable salt thereof; wherein: L is C3-C7 cycloalkyl, C1-C6 alkyl, or is absent R1 is optional 5-membered to 10-membered heteroaryl, NH2, NH(C1-C6 alkyl) or N(C1-C6 Alkyl) 2 substituted C1-C6 alkyl; R2 is optionally 5 to 10 membered heteroaryl, NH2, NH (C1-C6 alkyl) or N (C1-C6 alkyl) 2 substituted C1- C6 alkyl; R3 is C6-C10 aryl, 5- to 10-membered heteroaryl, C(O)NH-(C1-C6 alkyl)-PPh3, hydroxyl, C1-C6 alkoxy or O-(C1 -C6 alkyl)-O-(C1-C6 alkyl), wherein the C6-C10 aryl is substituted once, twice or three times by the group R3a, and wherein the 5- to 10-membered heteroaryl is optionally substituted by the group The group R3b is substituted once, twice or three times; R3a is independently a C3-C7 cycloalkyl or a 4- to 8-membered heterocycle at each occurrence, wherein the 4- to 8-membered heterocycle is optionally further modified by a C1-C3 alkane substituted once, twice or three times; R3b is independently C1-C3 alkoxy, C3-C7 cycloalkyl or 4 to 8 membered heterocycle at each occurrence, wherein the heterocycle is further modified by C1-C3 Alkyl is substituted once, twice or three times; and R4 is hydrogen, C1-C3 alkyl or C6-C10 aryl; with the proviso that when L is absent, R3 is substituted once or twice by the group R3a Or three C6-C10 aryl groups; or when L is absent, R3 is a 6- to 10-membered heteroaryl group substituted once, twice or three times by the group R3b.

[0294] In one embodiment, the copper(II) salt is CuCl2 or Cu(OAc)2 or a hydrate thereof.

[0295] Another aspect of the present invention pertains to a process for the preparation of a compound of formula (II) as described herein, or a pharmaceutically acceptable salt thereof.

[0296] In one embodiment, the process comprises at least the following steps: Formula (II-A) compound: mixed with copper (II) salt to form formula (II) compound; wherein: R1 is optionally through 5 members to 10-membered heteroaryl, NH2, NH(C1-C6 alkyl) or N(C1-C6 alkyl) substituted C1-C6 alkyl; R2 is optionally 5-10 membered heteroaryl, NH2, C1-C6 alkyl substituted by NH(C1-C6 alkyl) or N(C1-C6 alkyl)2; R3 is 4-membered to 8-membered heterocycle or 5-membered heteroaryl, wherein The ring is optionally substituted once, twice or three times by the group R3a, and wherein the 5-membered heteroaryl is optionally substituted once, twice or three times by the group R3b; R3a is independently C1-C6 alkyl at each occurrence , C1-C6 alkyl-(C6-C10 aryl), S(O)2H, S(O)2-(C1-C6 alkyl), S(O)2-(C3-C7 cycloalkyl) or S(O)2-(C6-C10 aryl); R3b independently at each occurrence is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, halo, nitro, cyano C(O)-(4-membered to 8-membered heterocyclic ring) or C1-C6 alkyl-(4-membered to 8-membered heterocyclic ring), wherein each 4-membered to 8-membered heterocyclic ring is further modified by C1-C3 alkyl Substituted once, twice or three times; and R4 is hydrogen or C1-3 alkyl.

[0297] In one embodiment, the copper(II) salt is CuCl2 or Cu(OAc)2 or a hydrate thereof.

[0298] In another embodiment, the process comprises at least the steps of: mixing a compound of formula (II-A) with a zinc salt to form a compound of formula (II-B): , and mixing a compound of formula (II-B) with The copper(II) salts are mixed to form the compound of formula (II).

[0299] In one embodiment, the zinc salt is Zn(OAc)2 or a hydrate thereof.

[0300] In one embodiment, the copper(II) salt is CuCl2 or Cu(OAc)2 or a hydrate thereof.

[0301] Another aspect of the present invention pertains to a process for the preparation of a compound of formula (III) as described herein, or a pharmaceutically acceptable salt thereof.

[0302] In one embodiment, the process at least comprises the following steps: compound of formula (III-A): mixed with copper (II) salt to form compound of formula (III); wherein: L is C1-C6 alkyl or R that is absent is C1-C6 alkyl optionally substituted by 5-10 membered heteroaryl, NH2, NH(C1-C6 alkyl) or N(C1-C6 alkyl)2; R2 is optionally C1-C6 alkyl substituted by 5- to 10-membered heteroaryl, NH2, NH(C1-C6 alkyl) or N(C1-C6 alkyl)2; R3 is C1-C6 alkyl, C1-C6 alkane Oxygen, C1-C6 haloalkyl, halo, hydroxyl, C(O)NH2, C(O)NH(C1-C6 alkyl), C(O)N(C1-C6 alkyl)2 or C( O)-(4-membered to 8-membered heterocyclic ring), wherein the C1-C6 alkyl and the C1-C6 alkoxy are optionally substituted once, twice or three times by C6-C10 aryl, and wherein C(O) -(4- to 8-membered heterocyclic ring) is optionally substituted once, twice or three times by C1-C3 alkyl.

[0303] In one embodiment, the copper(II) salt is CuCl2 or Cu(OAc)2 or a hydrate thereof.

[0304] In another embodiment, the process comprises at least the steps of: mixing a compound of formula (III-A) with a zinc salt to form a compound of formula (III-B): , and mixing a compound of formula (III-B) with The copper (II) salts are mixed to form the compound of formula (III).

[0305] In one embodiment, the zinc salt is Zn(OAc)2 or a hydrate thereof.

[0306] In one embodiment, the copper(II) salt is CuCl2 or Cu(OAc)2 or a hydrate thereof.

[0307] Another aspect of the present invention pertains to a process for the preparation of a compound of formula (IV) as described herein, or a pharmaceutically acceptable salt thereof.

[0308] In one embodiment, the process at least comprises the following steps: mixing the compound of formula (IV-A) with copper (II) salt to form the compound of formula (IV) or a pharmaceutically acceptable salt thereof; wherein The variables L, R1, R2, R3 and R4 correspond to the variables of the same name as defined in formula (IV).

[0309] In one embodiment, the copper(II) salt is CuCl2 or Cu(OAc)2 or a hydrate thereof.

[0310] In yet another aspect of the present invention, it relates to a process for the preparation of a compound of formula (V) as described herein, or a pharmaceutically acceptable salt thereof.

[0311] In one embodiment, the process comprises at least the following steps: compound of formula (V-A): mixed with copper (II) salt to form compound of formula (V) or a pharmaceutically acceptable salt thereof; wherein variable R1 , R2, R3 and R4 correspond to variables of the same name as defined in formula (V).

[0312] In one embodiment, the copper(II) salt is CuCl2 or Cu(OAc)2 or a hydrate thereof.

[0313] In another embodiment, the process comprises at least the steps of: mixing a compound of formula (V-A) with a zinc salt to form a compound of formula (V-B): and mixing a compound of formula (V-B) with a salt of copper (II) to form a compound of formula (V).

[0314] In one embodiment, the zinc salt is Zn(OAc)2 or a hydrate thereof.

[0315] In one embodiment, the copper(II) salt is CuCl2 or Cu(OAc)2 or a hydrate thereof. example

[0316] The present invention is further related to the following experimental examples. These examples are included merely for the purpose of illustrating certain aspects and embodiments of the invention, and are not intended to limit the invention. Accordingly, the invention should in no way be construed as limited to the following examples, but rather should be construed to cover any and all variations which become apparent as a result of the teachings provided herein.

[0317] Example 1: Preparation of Compound 1-22 Flowchart 1: Synthesis of Compound 1 Acetic acid (4.2 g, 24.2 mmol), N,O-dimethylhydroxylamine (2.8 g, 29.1 mmol), HOBt (3.9 g, 29.1 mmol) and TEA (12 ml, 84.7 mmol) in DCM (100 ml) EDCI (5.6 g, 29.1 mmol) was added to the stirred mixture. The reaction was stirred overnight at ambient temperature. The mixture was washed with water (100 ml) and brine (100 ml). The organic layer was dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent 100% DCM to 5% MeOH). Yield 2.9 g (66%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.14 min). MS (ESI) m / z 232.3 [MH]+. 1H-NMR (400MHz, CDCl3): δ (ppm) 3.21 (s, 3H), 3.66 (s, 3H), 3.78 (s, 2H), 7.24 (d, 2H), 8.55 (d, 2H).

[0318] Synthesis of 3-ethoxy-1-(pyridin-4-yl)but-3-en-2-one: solution of ethyl vinyl ether (3.1 g, 42.9 mmol) in tetrahydrofuran (100 ml) Cool to -78 °C and add tert-butyllithium (1.7 M, 23.0 ml, 38.8 mmol) in pentane. The mixture was warmed to 0 °C over a period of 1 h, stirred for 45 min and cooled to -30 °C. A solution of N-methoxy-N-methyl-2-(pyridin-4-yl)acetamide (0.7 g, 3.8 mmol) in tetrahydrofuran (20 mL) was added and the reaction was stirred at 0 °C for 2 h. The progress of the reaction was monitored by TLC. The mixture was poured into aqueous NH4Cl (100 ml) and extracted with Et2O (3x50 ml). The combined extracts were dried over Na2SO4, the solution was decanted and the solvent was removed under reduced pressure. The title compound was used in the next step without further purification. Yield 0.2 g (27%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.72 min). MS (ESI) m / z 192.4 [MH]+. 1H-NMR (400MHz, CDCl3): δ (ppm) 1.40 (t, 3H), 3.83 (q, 2H), 3.99 (s, 2H), 4.41 (d, 1H), 5.25 (d, 1H), 7.18 ( dd, 1H), 8.55 (dd, 1H), 8.54 (dd, 2H).

[0319] Synthesis of INT-1 ((2Z,2'E)-2,2'-(1-(pyridin-4-yl)butane-2,3-diylidene)bis(N-methylhydrazine- 1-thioformamide)) 3-ethoxy-1-(pyridin-4-yl)but-3-en-2-one (0.2 g, 1.04 mmol) was dissolved in EtOH (5 ml), Methionamide (0.22 g, 2.08 mmol) and 3 drops of H2SO4 were added, and the reaction mixture was stirred at reflux for 4 h and at ambient temperature overnight. The progress of the reaction was monitored by TLC. The precipitate was filtered, washed with EtOH, Et2O and dried. Yield 0.21 g (60%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.98 min). MS (ESI) m / z 338.9 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 2.28 (s, 3H), 2.98 (d, 3H), 3.02 (d, 3H), 4.76 (s, 2H), 7.72 (d, 2H), 8.36 (dd, 1H), 8.50 (dd, 1H), 8.78 (d, 2H), 10.35 (s, 1H), 10.85 (s, 1H).

[0320] Synthesis of INT-5 ((2Z,2'E)-2,2'-(5-(pyridin-4-yl)pentane-2,3-diylidene)bis(N-methylhydrazine- 1-thioformamide)): INT-5 was made using a procedure similar to that for the preparation of INT-1. Yield 1.54 g (85%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.94 min). MS (ESI) m / z 352.5 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 2.15 (s, 3H), 2.66 (t, 2H), 3.01 (d, 6H), 3.28 (t, 2H), 7.32 (d, 2H), 8.21 (dd, 1H), 8.33 (dd, 1H), 8.45 (d, 2H), 10.21 (s, 1H), 10.67 (s, 1H).

[0321] Synthesis of INT-6 ((2Z,2'E)-2,2'-(5-(pyridin-3-yl)pentane-2,3-diylidene)bis(N-methylhydrazine- 1-thioformamide)): INT-6 was made using a procedure similar to that for the preparation of INT-1. Yield 0.42 g (49%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.94 min). MS (ESI) m / z 352.4 [MH]+.

[0322] Synthesis of INT-9 ((2E, 2'E)-2,2'-(1-(pyridin-3-yl) butane-2,3-diylidene) bis(N-methylhydrazine- 1-thioformamide)): INT-9 was made using a procedure similar to that for the preparation of INT-1. Yield 8.6 g (76%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.91 min). MS (ESI) m / z 338.4 [MH]+.

[0323] Synthesis of INT-10 ((2E, 2'E)-2,2'-(1-(6-methoxypyridin-3-yl) propane-1,2-diylidene) bis(N- Ethylhydrazine-1-thioformamide)): INT-10 was made using a procedure similar to that for the preparation of INT-1. Yield 1.2 g (46.2%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.52 min, MS (ESI) m / z 382.0 [MH] +.1H-NMR (400MHz, CDCl3): δ (ppm) 0.94 (t, 3H), 1.15 (t, 3H), 2.35 (s, 3H), 3.34 (q, 2H), 3.60 (q, 2H), 3.91 (s, 3H), 6.44 (d, 1H), 7.62 (d, 1H), 8.05 (s, 1H), 8.68 (br.s, 1H), 9.54 (s, 1H), 10.71 (s, 1H) .

[0324] Synthesis of INT-11 ((2E, 2'E)-2,2'-(1-(6-methoxypyridin-3-yl) propane-1,2-diylidene) bis(N- Methylhydrazine-1-thioformamide)): INT-11 was made using a procedure similar to that for the preparation of INT-1. Yield 0.7 g (56.6%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.41 min, MS (ESI) m / z 354.5 [MH] +.1H-NMR (400MHz, CDCl3): δ (ppm) 2.36 (s, 3H), 2.87 (s, 3H), 3.03 (s, 3H), 3.92 (s, 3H), 6.95 (d, 1H), 7.15 (br.s, 1H), 7.61 (d, 1H), 8.04 (s, 1H), 8.62 (br.s, 1H), 9.54 (s, 1H), 10.56 (s, 1H).

[0325] Synthesis of Compound 1: CuCl2.2H2O (0.08 g, 0.48 mmol) was added to INT-1 (0.15 g, 0.44 mmol) in ethanol (6 mL). The mixture was stirred overnight at ambient temperature. The complex was isolated as a reddish-brown powder. The formed precipitate was collected by filtration after cooling, washed with water (2x50 ml), ethanol (2x50 ml) and copious amounts of diethyl ether (5x50 ml), and then dried in vacuo. Yield 0.075 g (42%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.29). MS (ESI) m / z 399.1 [MH]+.

[0326] Synthesis of compound 5: According to the method for preparing compound 1, the title compound was prepared from INT-5. The complex was isolated as a reddish-brown powder. The formed precipitate was collected by filtration after cooling, washed with water (2x50 ml), ethanol (2x50 ml) and copious amounts of diethyl ether (5x50 ml), and then dried in vacuo. Yield 0.5 g (78%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.26). MS (ESI) m / z 413.4 [MH]+.

[0327] Synthesis of compound 6: According to the method for preparing compound 1, the title compound was prepared from INT-6. The complex was isolated as a reddish-brown powder. The formed precipitate was collected by filtration after cooling, washed with water (2x50 ml), ethanol (2x50 ml) and copious amounts of diethyl ether (5x50 ml), and then dried in vacuo. Yield 0.18 g (95%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.25). MS (ESI) m / z 412.9 [MH]+.

[0328] Synthesis of compound 9: According to the method for preparing compound 1, the title compound was prepared from INT-9. The complex was isolated as a reddish-brown powder. The formed precipitate was collected by filtration after cooling, washed with water (2x50 ml), ethanol (2x50 ml) and copious amounts of diethyl ether (5x50 ml), and then dried in vacuo. Yield 2.3 g (97%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.30). MS (ESI) m / z 399.1 [MH]+.

[0329] Synthesis of compound 10: According to the method for preparing compound 1, the title compound was prepared from INT-10. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.13 g (37.3%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 2.31). MS (ESI) m / z 443.5 [MH]+.

[0330] Synthesis of compound 11: According to the method for preparing compound 1, the title compound was prepared from INT-11. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.12 g (34.5%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.97). MS (ESI) m / z 415.3 [MH]+. Scheme 2: Synthesis of Compound 2 Synthesis of ethyl 2-(pyridin-3-yl)acetate: Add 3-pyridineacetic acid (25.0 g, 145 mmol) in EtOH ( To the stirred solution in 250 ml) was added SOCl2 (11.6 ml, 160 mmol). The reaction was then heated to reflux for an additional 16 h. EtOH was evaporated under reduced pressure. To the residue was added 2M aqueous Na2CO3 (30 ml), and the resulting mixture was extracted with EtOAc (3 x 400 ml). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the title compound as a colorless liquid. Yield 22.3 g (93%). 1H-NMR (400MHz, CDCl3): δ (ppm): 1.26 (t, 3 H), 3.62 (s, 2 H), 4.17 (q, 2 H), 7.27-7.28 (m, 1 H), 7.64- 7.65 (m, 1H), 8.53 (m, 2H).

[0332] Synthesis of ethyl 1-(pyridin-3-yl)cyclopentane-1-carboxylate: Dissolve sodium hydride (7.3 g, 181 mmol, 60% in oil) in anhydrous THF (160 ml) at 0°C A solution of ethyl 2-(pyridin-3-yl)acetate (10.0 g, 60.5 mmol) in anhydrous THF (35 ml) was added dropwise to the stirred suspension in . The reaction mixture was stirred at 0 °C for 30 min (until gas formation was complete). Dibromobutane (19.6 g, 90.5 mmol) was then added at 0 °C and the reaction mixture was stirred at ambient temperature for 14 h. Subsequently, the reaction mixture was quenched with saturated aqueous ammonium chloride (60 ml). The reaction mixture was extracted with EtOAc (3 x 40 ml). The organic phase was washed with brine (100 ml), dried over anhydrous Na2SO4, filtered and concentrated. The resulting dark solid was purified by flash chromatography (silica gel, eluting with hexane-ethyl acetate, 4:1 to 1:1). Yield 9.8 g (74%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.01 min). MS (ESI) m / z 220.6 [MH]+. 1H-NMR (400MHz, CDCl3): δ (ppm) 1.16 (t, 3H), 1.74-1.78 (m, 4H), 1.88-1.98 (m, 2H), 2.67-2.73 (m, 2H), 4.09 (q , 2H), 7.23-7.27 (m, 1H), 7.67-7.71 (m, 1H), 8.49 (dd, 1H), 8.65 (dd, 1H).

[0333] Synthesis of 1-(pyridin-3-yl)cyclopentane-1-carboxylic acid: 1-(pyridin-3-yl)cyclopentane-1-carboxylic acid ethyl ester (8.4 g, 38.5 mmol) in MeOH To a solution in (60 ml) was added a 20% aqueous solution of LiOH (2.5 g, 96.2 mmol). The reaction mixture was stirred at 60 °C for 8 h. The solvent was then removed by lyophilization and the corresponding crude product was used in the next step without further purification. Yield 7 g (80%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.82 min). MS (ESI) m / z 192.1 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.66-1.70 (m, 4H), 1.85-1.92 (m, 2H), 2.52-2.58 (m, 2H), 7.56 (dd, 1H), 7.98 -8.02 (m, 1H), 8.58 (dd, 1H), 8.66 (d, 1H), 12.66 (br.s, 1H).

[0334] Synthesis of N-methoxy-N-methyl-1-(pyridin-3-yl)cyclopentane-1-formamide: to 1-(pyridin-3-yl)cyclopentane at 4°C -1-carboxylic acid (5.0 g, 22.0 mmol), N,O-dimethylhydroxylamine (2.6 g, 26.4 mmol), HOBt (3.6 g, 26.4 mmol) and TEA (10.8 ml, 77 mmol) in DCM (150 ml) was added EDCI (5.1 g, 26.4 mmol). The reaction was stirred overnight at ambient temperature. The mixture was washed with water (100 ml) and brine (100 ml). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent 100% DCM to 5% MeOH) to afford the title compound. Yield 2.5 g (49%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.84 min). MS (ESI) m / z 235.3 [MH]+. 1H-NMR (400MHz, CDCl3): δ (ppm) 1.66-1.81 (m, 4H), 2.05-2.11 (m, 2H), 2.42-2.48 (m, 2H), 2.89 (s, 3H), 3.13 (s , 3H), 7.34 (q, 1H), 7.65 (d, 1H), 8.49 (d, 1H), 8.59 (d, 1H).

[0335] Synthesis of 2-ethoxy-1-(1-(pyridin-3-yl)cyclopentyl)prop-2-en-1-one: ethyl vinyl ether (1.69 g, 23.6 mmol) in tetrahydrofuran The solution in (40 ml) was cooled to -78°C and tert-butyllithium (1.7 M, 13.0 ml, 21.5 mmol) in pentane was added. The mixture was warmed to 0 °C over a period of 1 h, stirred for 45 min and cooled to -30 °C. A solution of N-methoxy-N-methyl-1-(pyridin-3-yl)cyclopentane-1-carboxamide (1.0 g, 4.3 mmol) in THF (15 ml) was added and dissolved at 0 The reaction was stirred at °C for 4 h. The progress of the reaction was monitored by TLC. The mixture was poured into aqueous NH4Cl (100 ml) and extracted with Et2O (3x50 ml). The combined extracts were dried over Na2SO4. The solution was decanted, and the solvent was removed under reduced pressure. The title compound was used without further purification. Yield 0.85 g (81%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.11 min). MS (ESI) m / z 246.4 [MH]+. 1H-NMR (400MHz, CDCl3): δ (ppm) 1.05 (t, 3H), 1.69-1.73 (m, 4H), 2.06-2.08 (m, 2H), 2.46-2.52 (m, 2H), 3.50 (q , 2H), 4.30 (d, 1H), 5.18 (d, 1H), 7.21-7.25 (m, 1H), 7.51-7.54 (m, 1H), 8.45 (dd, 1H), 8.52 (d, 1H).

[0336] Synthesis of INT-2 ((2Z, 2'E)-2,2'-(1-(1-(pyridin-3-yl) cyclopentyl) propane-1,2-diylidene) bis( N-methylhydrazine-1-thioformamide)): 2-ethoxy-1-(1-(pyridin-3-yl)cyclopentyl)prop-2-en-1-one (0.85 g, 3.5 mmol) was dissolved in EtOH (5 ml), methionamide (0.80 g, 7.7 mmol) and 3 drops of H2SO4 were added, and the reaction mixture was stirred at reflux for 4 h and at ambient temperature overnight. The progress of the reaction was monitored by TLC. The precipitate was filtered, washed with EtOH, Et2O and dried. Yield 0.21 g (15%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.00 min). MS (ESI) m / z 392.3 [MH]+.

[0337] Synthesis of INT-3 ((2Z, 2'E)-2,2'-(1-(1-(pyridin-3-yl) cyclobutyl) propane-1,2-diylidene) bis( N-Methylhydrazine-1-thioformamide)): INT-3 was made using a procedure similar to that for the preparation of INT-2. Yield 0.08 g (10%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.01 min). MS (ESI) m / z 378.5 [MH]+.

[0338] Synthesis of INT-4 ((2Z,2'E)-2,2'-(4-(pyridin-3-yl)pentane-2,3-diylidene)bis(N-methylhydrazine- 1-thioformamide)): INT-4 was made using a procedure similar to that for the preparation of INT-2. Yield 0.58 g (42%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.96 min). MS (ESI) m / z 352.3 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.52 (d, 3H), 2.24 (s, 3H), 2.90 (d, 3H), 3.00 (d, 3H), 5.23 (q, 1H), 7.32-7.34 (m, 1H), 7.39-7.42 (m, 1H), 7.62 (d, 1H), 8.40 (s, 1H), 8.46 (d, 2H), 9.84 (s, 1H), 10.30 (s, 1H).

[0339] Synthesis of Compound 2: CuCl2.2H2O (0.08 g, 0.5 mmol) was added to INT-2 (0.18 g, 0.46 mmol) in ethanol (6 mL). The mixture was stirred overnight at ambient temperature. The complex was isolated as a reddish-brown powder. The formed precipitate was collected by filtration after cooling, washed with water (2x50 ml), ethanol (2x50 ml) and copious amounts of diethyl ether (5x50 ml), and then dried in vacuo. Yield 0.08 g (39%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 2.01). MS (ESI) m / z 453.4 [MH]+.

[0340] Synthesis of compound 3: According to the method of preparing compound 2, the title compound was prepared from INT-3. The complex formed was isolated as a reddish-brown powder. The formed precipitate was collected by filtration after cooling, washed with water (2x50 ml), ethanol (2x50 ml) and copious amounts of diethyl ether (5x50 ml), and then dried in vacuo. Yield 0.05 g (61%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.49). MS (ESI) m / z 439.0 [MH]+.

[0341] Synthesis of compound 4: According to the method for preparing compound 2, the title compound was prepared from INT-4. The complex was isolated as a reddish-brown powder. The formed precipitate was collected by filtration after cooling, washed with water (2x50 ml), ethanol (2x50 ml) and copious amounts of diethyl ether (5x50 ml), and then dried in vacuo. Yield 0.61 g (89%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.30). MS (ESI) m / z 413.5 [MH]+.

[0342] Process 3: Synthesis of Compound 7

[0343] Synthesis of 2-(6-𠰌linylpyridin-3-yl)acetonitrile: heating 2-(6-𠰌linylpyridin-3-yl)acetonitrile (1.8 g, 11.8 mmol), triethylamine at 150°C (3.3 ml, 23.5 mmol) and a solution of phylloline (1.13 g, 13.1 mmol) in n-butanol (15 ml) for 2 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, CCl4-ethyl acetate 8:2). Yield 0.7 g (29%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.91 min). MS (ESI) m / z 204.1 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 2.42 (d, 4H), 3.69 (d, 4H), 3.86-3.88 (m, 2H), 6.83-6.87 (m, 1H), 7.52-7.55 (m, 1H), 8.08 (s, 1H).

[0344] Synthesis of 2-(6-𠰌linylpyridin-3-yl)acetic acid: 2-(6-𠰌linylpyridin-3-yl)acetonitrile (1.0 g, 5.2 mmol) was dissolved in concentrated hydrochloric acid (15 mL) The mixture was refluxed for 3 h. The liquid was stripped in vacuo to give the crude product (1.40 g, 86.8%) as a white solid. LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.51 min). MS (ESI) m / z 223.6 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 3.66 (s, 2H), 3.73 (s, 8H), 7.36 (d, 1H), 7.94 (dd, 1H), 7.97 (d, 1H), 13.94 (br.s, 1H).

[0345] Synthesis of N-methoxy-N-methyl-2-(6-𠰌linylpyridin-3-yl) acetamide: 2-(6-𠰌linylpyridin-3-yl) at 4°C ) acetic acid (1.4 g, 4.5 mmol), N,O-dimethylhydroxylamine (0.53 g, 5.4 mmol), HOBt (0.73 g, 5.4 mmol) and TEA (2.2 ml, 15.7 mmol) in DCM (25 ml) To the mixture was added EDCI (1.03 g, 5.4 mmol). The reaction was stirred overnight at ambient temperature. The mixture was washed with water (100 ml), brine (100 ml). The organic layer was dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent 100% DCM to 5% MeOH) to afford the crude title product. Yield 1.0 g (84%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.91 min). MS (ESI) m / z 266.5 [MH]+. 1H-NMR (400MHz, CDCl3): δ (ppm) 3.20 (s, 3H), 3.48 (t, 4H), 3.65 (s, 2H), 3.68 (s, 3H),3.82 (t, 4H), 6.63 ( d, 1H), 7.52 (dd, 1H), 8.09 (d, 1H).

[0346] Synthesis of 3-ethoxyl-1-(6-𠰌linylpyridin-3-yl)but-3-en-2-one: ethyl vinyl ether (3.0 g, 41.8 mmol) in tetrahydrofuran (50 ml) was cooled to -78°C and tert-butyllithium (1.7 M, 20.2 ml, 34.6 mmol) in pentane was added. The mixture was warmed to 0 °C over a period of 1 h, stirred for 45 min, cooled to -30 °C, and magnesium bromide etherate (8.9 g, 34.6 mmol) was added. The mixture was allowed to warm to 0 °C over a period of 15 min, and N-methoxy-N-methyl-2-(6-alcholinylpyridin-3-yl)acetamide (1.0 g, 3.8 mmol) was added in Solution in tetrahydrofuran (20 mL). The mixture was allowed to come to room temperature independently and stirred overnight. The progress of the reaction was monitored by TLC. The mixture was poured into aqueous NH4Cl (100 ml) and extracted with Et2O (3x50 ml). The combined extracts were dried over Na2SO4. The solution was decanted, and the solvent was removed under reduced pressure. The title compound was used in the next step without further purification. Yield 0.26 g (25%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.96 min). MS (ESI) m / z 277.5 [MH]+. 1H-NMR (400MHz, CDCl3): δ (ppm) 1.43 (t, 3H), 2.01-2.04 (m, 4H), 3.46-3.51 (m, 4H), 3.82 (q, 2H), 3.84 (s, 2H) ), 4.41 (d, 1H), 5.22 (d, 1H), 6.39 (dd, 1H), 7.38 (dd, 1H), 8.01 (dd, 1H).

[0347] Synthesis of INT-7 ((2E, 2'E)-2,2'-(1-(6-?-olinylpyridin-3-yl) butane-2,3-diylidene) bis(N -Ethylhydrazine-1-thioformamide)): 3-Ethoxy-1-(6-?olinylpyridin-3-yl)but-3-en-2-one (0.26 g, mmol) was dissolved in EtOH (5 ml), ethionamide (0.22 g, 1.88 mmol) and 3 drops of H2SO4 were added, and the reaction mixture was stirred at reflux for 4 h and at ambient temperature overnight. The progress of the reaction was monitored by TLC. The precipitate was filtered, washed with EtOH, Et2O and dried. Yield 0.41 g (97%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.14 min). MS (ESI) m / z 451.5 [MH]+.

[0348] Synthesis of INT-8 ((2E,2'E)-2,2'-(1-(6-(pyrrolidin-1-yl)pyridin-3-yl)butane-2,3-diylidene yl)bis(N-ethylhydrazine-1-thioformamide)): INT-8 was made using a procedure similar to that for the preparation of INT-7. Yield 0.25 g (99%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.17 min). MS (ESI) m / z 435.5 [MH]+.

[0349] Synthesis of Compound 7: CuCl2.2H2O (0.07 g, 0.4 mmol) was added to INT-7 (0.18 g, 0.4 mmol) in ethanol (6 mL). The mixture was stirred overnight at ambient temperature. The complex was isolated as a reddish-brown powder. The formed precipitate was collected by filtration after cooling, washed with water (2x50 ml), ethanol (2x50 ml) and copious amounts of diethyl ether (5x50 ml), and then dried in vacuo. Yield 0.03g (14%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.55). MS (ESI) m / z 512.7 [MH]+.

[0350] Synthesis of compound 8: According to the method for preparing compound 7, the title compound was prepared from INT-8. The complex was isolated as a reddish-brown powder. The formed precipitate was collected by filtration after cooling, washed with water (2x50 ml), ethanol (2x50 ml) and copious amounts of diethyl ether (5x50 ml), and then dried in vacuo. Yield 0.05g (16%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.57). MS (ESI) m / z 496.5 [MH]+.

[0351] Scheme 4: Synthesis of Compound 12 Synthesis of 1-(4-acetylphenyl)pyrrolidin-2-one: pyrrolidin-2-one (1.7 g, 20.0 mmol), 1-(4-iodo To a mixture of phenyl)ethanone (4.1 g, 16.7 mmol), CuI (0.32 g, 1.67 mmol), glycine (0.25 g, 3.34 mmol) was added potassium phosphate (2.1 g, 40.0 mmol). The glass tube was evacuated, filled with argon at room temperature, and sealed. DMF (0.5 mL) was added via syringe under argon. The mixture was then stirred at 100 °C for 24 h. The cooled mixture was partitioned between water and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluting with 1:8 to 1:2 ethyl acetate-hexanes) to afford the title compound. Yield 3.2 g (94%). 1H-NMR (400MHz, CDCl3): δ (ppm) 2.22 (m, 2H), 2.60 (s, 3H), 2.66 (t, 2H), 3.92 (t, 2H), 7.77 (dd, 2H), 7.99 ( dd, 2H).

[0352] Synthesis of 2-oxo-2-(4-(2-oxopyrrolidin-1-yl) phenyl) acetaldehyde: SeO2 (0.16 g, 1.5 mmol), 1, 4-Dioxane (3 ml) and water (0.5 ml). The mixture was heated to 50 °C and stirred until most of the SeO2 was dissolved. 1-(4-Acetylphenyl)pyrrolidin-2-one (0.3 g, 1.47 mmol) was added and the reaction was heated at gentle reflux overnight. The progress of the reaction was monitored by TLC (CCl4-EtOAc 7:3). Selenium solids precipitated during the course of the reaction. The mixture was cooled on an ice bath and filtered through celite to remove selenium. The filter cake was washed with a portion of 1,4-dioxane. The filtrate was concentrated in vacuo until most of the 1,4-dioxane was removed. The crude product was used in the next step without purification. Yield 0.25 g (83%).

[0353] Synthesis of INT-12 (2Z,2'E)-2,2'-(1-(4-(2-oxopyrrolidin-1-yl)phenyl)ethane-1,2-di Subunit) bis(N-ethylhydrazine-1-thioformamide): 2-oxo-2-(4-(2-oxopyrrolidin-1-yl)phenyl)acetaldehyde (0.25 g, 1.2 mmol) was dissolved in EtOH (5 ml), ethionamide (0.35 g, 2.4 mmol) and 3 drops of H2SO4 were added, and the reaction mixture was stirred at reflux for 4h and at ambient temperature for 15h. The progress of the reaction was monitored by TLC (CCl4-EtOAc 7:3). The formed precipitate was filtered, washed with EtOH, water, Et2O and dried. Yield 0.45 g (73%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.49 min). MS (ESI) m / z 420.5 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.15 (t, 3H), 1.19 (t, 3H), 2.94-2.11 (m, 2H), 2.28 (s, 1H0, 3.36-3.47 (m, 1H), 3.57-3.65 (m, 4H), 3.82 (t, 2H), 7.69-7.82 (m, 4H), 7.94 (d, 1H), 8.23 ​​(s, 1H), 8.91 (t, 1H), 11.77 (s, 1H), 12.31 (s, 1H).

[0354] Synthesis of INT-14 ((2Z, 2'E)-2,2'-(1-(4-(pyrrolidin-1-yl) phenyl) ethane-1,2-diylidene) bis (N-Ethylhydrazine-1-thioformamide)): INT-14 was made using a procedure similar to that for the preparation of INT-12. Yield 0.3 g (15.5%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.92 min, MS (ESI) m / z 406.3 [MH] +.1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.12-1.24 (m, 6H), 1.91-2.06 (m, 4H), 3.19-3.29 (m,4H), 3.53-3.66 (m, 4H), 6.58 (d, 2H), 7.65 (d, 2H), 7.93 (br.s, 1H), 8.22 (s, 1H), 8.74 (br.s, 1H), 11.73 (s, 1H), 12.16 (s, 1H).

[0355] Synthesis of INT-15 ((2Z, 2'E)-2,2'-(1-(4-alcolinylphenyl) ethane-1,2-diylidene) bis(N-ethyl Hydrazine-1-thioformamide)): INT-15 was made using a procedure similar to that for the preparation of INT-12. Yield 1.1 g (53.5%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.66 min, MS (ESI) m / z 422.4 [MH] +.1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.16 (t, 3H), 1.20 (t, 3H), 3.16-3.24 (m, 4H), 3.54-3.66 (m, 4H), 3.71 -3.79 (m, 4H), 7.00 (d, 2H), 7.23 (br.s, 1H), 7.70 (d, 2H), 7.95 (br.s, 1H), 8.83 (br.s, 1H), 11.74 (s, 1H), 12.23 (s, 1H).

[0356] Synthesis of Compound 12: CuCl2.2H2O (0.16 g, 0.9 mmol) was added to ethanol containing INT-12 (0.4 g, 0.9 mmol). The mixture was stirred at ambient temperature for 15 h. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.016 g (4%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.84). MS (ESI) m / z 481.3 [MH]+.

[0357] Synthesis of compound 14: According to the method of preparing compound 12, the title compound was prepared from INT-14. The formed complex was precipitated as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.057 g (49.6%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 2.34). MS (ESI) m / z 467.0 [MH]+.

[0358] Synthesis of compound 15: According to the method for preparing compound 12, the title compound was prepared from INT-15. The formed complex was precipitated as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo to afford the title product. Yield 0.17 g (85%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.97). MS (ESI) m / z 483.5 [MH]+.

[0359] Scheme 5: Synthesis of Compound 13 Synthesis of 4-? Stir the solution, 𠰌line (1.44 g, 16.5 mmol) and K2CO3 (2.85 g, 20.6 mmol) and heat at 110° C. for 18 h. Water was added and the precipitate formed was filtered, washed with water and hexanes. Yield 2.6 g (83%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.24 min). MS (ESI) m / z 189.1 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 3.27 (t, 4H), 3.72 (t, 4H), 7.02 (d, 2H), 7.60 (d, 2H).

[0360] Synthesis of 4-𠰌line-4-yl-benzonitrile (2.6 g, 14.7 mmol) and sodium hydroxide (2.2 g, 58.8 mmol) in water (90 ml) and A stirred solution in a mixture of MeOH (5 ml) was heated to reflux in a water bath for 5 hours. The solution was then cooled to room temperature and acidified with aqueous HCl (10%). The precipitate was filtered, washed with water, dried under vacuum at 60 °C and crystallized from EtOH to give compound 2. Yield 2.0 g (70%). 1H-NMR (400MHz, DMSO-d6): δ (ppm) 3.12 (t, 2H), 3.24 (t, 2H), 3.73 (t, 4H), 6.96 (t, 2H), 7.77 (t, 2H), 12.31 (br.s, 1H).

[0361] Synthesis of N-methoxyl-N-methyl-4-𠰌linylbenzamide: 4-𠰌linylbenzoic acid (1.4 g, 6.7 mmol), N, O-dimethyl To a mixture of hydroxylamine (1.3 g, 8.7 mmol), HOBT (1.0 g, 7.7 mmol) and TEA (0.9 ml, 9 mmol) in DCM (25 ml) was added EDCI (1.4 g, 9 mmol). The reaction was stirred overnight at ambient temperature. The mixture was washed with water (15 ml), 1N aqueous HCl (20 ml), water (50 ml), brine (100 ml). The organic layer was dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent 100% DCM to 5% MeOH) to afford the crude title product. Yield 0.97g (58%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.12 min). MS (ESI) m / z 251.6 [MH]+. 1H-NMR (400MHz, CDCl3): δ (ppm) 3.26 (t, 4H), 3.36 (s, 3H), 3.59 (s, 3H), 3.89 (t, 4H), 6.89 (d, 2H), 7.74 ( d, 2H).

[0362] Synthesis of 2-ethoxy-1-(4-𠰌linylphenyl)prop-2-en-1-one: ethyl vinyl ether (0.9 g, 12.2 mmol) was dissolved in anhydrous tetrahydrofuran (25 ml ) was cooled to -78°C, and tert-butyllithium (1.7 M, 6.6 ml, 11.1 mmol) in pentane was added. The mixture was warmed to 0 °C over a period of 1 h, stirred for 45 min and cooled to -30 °C. Then a solution of N-methoxy-N-methyl-4-?olinylbenzamide (0.93 g, 3.7 mmol) in THF (10 ml) was added, and the mixture was stirred at 0 °C for 4 h. The progress of the reaction was monitored by TLC. The mixture was poured into aqueous NH4Cl (100 ml) and extracted with Et2O (3x100 ml). The combined extracts were dried over Na2SO4, filtered and evaporated. The product was used in the next step without additional purification. Yield 0.6 g (62%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.40 min). MS (ESI) m / z 262.0 [MH]+. 1H-NMR (400MHz, CDCl3): δ (ppm) 1.42 (t, 3H), 3.33 (t, 4H), 3.87 (t, 4H), 3.94 (q, 2H), 4.65 (d, 1H), 4.91 ( d, 1H), 6.87 (d, 2H), 7.92 (d, 2H).

[0363] Synthesis of INT-13 ((2Z, 2'E)-2,2'-(1-(4-𠰌linylphenyl)propane-1,2-diylidene)bis(N-ethylhydrazine -1-thioformamide)): Dissolve 2-ethoxy-1-(4-?olinylphenyl)prop-2-en-1-one (0.6 g, 2.3 mmol) in EtOH (5 ml), thiocarbamide (0.6 g, 5.1 mmol) and 3 drops of H2SO4 were added, and the reaction mixture was stirred at reflux for 4 h and at ambient temperature for 15 h. The formed precipitate was filtered, washed with EtOH, water, Et2O and dried. Yield 0.3 g (30%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.49 min). MS (ESI) m / z 436.4 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 0.93 (t, 3H), 1.15 (t, 3H), 2.33 (s, 3H), 3.19 (t, 4H), 3.34-3.38 (m, 2H ), 3.56-3.63 (m, 2H), 3.75 (t, 4H), 6.97 (t, 1H), 7.12 (q, 4H), 8.70 (s, 1H), 8.74 (t, 1H), 10.75 (s, 1H).

[0364] Synthesis of compound 13: CuCl22H2O (0.07 g, 0.4 mmol) was added to ethanol containing INT-13 (0.17 g, 0.4 mmol). The mixture was stirred at ambient temperature for 15 h. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.2 g (99%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.87). MS (ESI) m / z 497.4 [MH]+.

[0365] Process 6: Synthesis of Compound 16 Synthesis of 1-(4-Phenolylphenyl)-2-phenylethane-1,2-dione: To 4-Phenylformaldehyde (24.0 g, 125 mmol ) and benzaldehyde (13.3 g, 125 mmol) in EtOH (50 mL) was added a solution of potassium cyanide (0.43 g, 66 mmol) in water (35 ml). The mixture was stirred at reflux for 5 h, cooled to ambient temperature. The solution was placed in a refrigerator for fractional crystallization at about 8°C. The formed precipitate consisting mainly of α-hydroxyketone was removed by filtration and discarded, the filtrate was evaporated to dryness in vacuo. The residue was purified by column chromatography (silica gel, eluent EtOAc-hexane). Yield 2.2 g (6%). 1H-NMR (400MHz, CDCl3): δ (ppm) 3.36-3.40 (m, 4H), 3.84-3.89 (m, 4H), 6.87 (d, 2H), 7.50 (dd, 2H), 7.64 (dd, 1H ), 7.88 (d, 2H), 7.99 (d, 2H).

[0366] Synthesis of INT-16 ((2E, 2'E)-2,2'-(1-(4-? olinophenyl)-2-phenylethane-1,2-diylidene) bis (N-Ethylhydrazine-1-thioformamide)): 1-(4-𠰌linylphenyl)-2-phenylethane-1,2-dione (0.61 g, 2.06 mmol, 1 eq) was dissolved in EtOH (15 ml), methionamide (0.45 g, 2 eq) and 3 drops of H2SO4 were added, and the reaction mixture was stirred at reflux for 4 h and at ambient temperature for 15 h. The formed precipitate was filtered, washed with EtOH, water, Et2O and dried. Yield 0.45 g (44%). 1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.13-1.19 (m, 6H), 3.17-3.20 (m, 4H), 3.55 (q, 4H), 3.70-3.75 (m, 4H), 6.94 (d, 2H), 7.42-7.47 (m, 3H), 7.55 (d, 2H), 7.70-7.74 (m, 2H), 8.88 (ddd, 2H), 9.49 (d, 2H).

[0367] Synthesis of INT-17 ((2E, 2'E)-2,2'-(1-(4-? olinophenyl)-2-phenylethane-1,2-diylidene) bis (N-Methylhydrazine-1-thioformamide)): INT-17 was made using a procedure similar to that for the preparation of INT-16. Yield 0.31 g (36%). 1H-NMR (400MHz, DMSO-d6): δ (ppm) 2.99-3.06 (m, 6H), 3.17-3.20 (m, 4H), 3.70-3.74 (m, 4H), 6.94 (d, 2H), 7.42 -7.47 (m, 3H), 7.55 (d, 2H), 7.70-7.74 (m, 2H), 8.84 (ddd, 2H), 9.49 (d, 2H).

[0368] Synthesis of Compound 16: Cu(OAc)22H2O (0.06 g, 1.1 equiv) was added to ethanol containing INT-16 (0.12 g, 0.26 mmol, 1 equiv). The mixture was stirred at ambient temperature for 15 h. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.03 g (22%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 2.21 min). MS (ESI) m / z 559.0 [MH]+.

[0369] Synthesis of compound 17: According to the method of preparing compound 16, the title compound was prepared from INT-17. The formed complex precipitated from the reaction mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.03 g (22%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 2.24 min). MS (ESI) m / z 531.2 [MH]+.

[0370] Scheme 7: Synthesis of Compound 18 Synthesis of 5-hydroxy-N-methoxy-N-methylpentanamide: at -20°C, over a period of 30 minutes to lactone (4 g, 40 mmol, 1 equivalent) and N,O-dimethylhydroxylamine hydrochloride (6.04 g, 1.55 equivalent) in THF (150 ml) suspension was added dropwise 2.9 Mi-PrMgBr in 2-methyltetrahydrofuran (50 ml, 3.6 Equivalent) in the solution. The mixture was stirred at -20 °C for 3 hours and quenched with 50 mL of saturated NH4Cl solution. The layers were separated and the aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (eluent 80 / 20 EtOAc / hexanes to 100% EtOAc). Yield 2.0 g (31%). NMR (400MHz, CDCl3): 1.57-1.63 (m, 2H), 1.70-1.76 (m, 2H), 2.44-2.50 (m, 2H), 3.18 (s, 3H), 3.62 (t, 2H), 3.68 ( s, 2H). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.90 min), MS (ESI) m / z 162.4 [MH ]+.

[0371] Synthesis of 5-((tertiary butyldiphenylsilyl)oxy)-N-methoxy-N-methylpentanamide: Stirring 5-hydroxy-N-methoxy at ambient temperature -N-methylpentanamide (2.1 g, 13 mmol, 1 equivalent), tertiary butyldiphenylsilane chloride (5.4 g, 5 ml, 1.5 equivalents), imidazole (1.6 g, 1.8 equivalents) and DMAP ( 0.16 g, 0.1 eq) in DMF (25 ml) for 15 h. The reaction mixture was diluted with water (200 ml) and extracted with EtOAc (3 x 60 ml). The combined organic layers were dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by column chromatography (SiO2 / hexane, hexane:EtOAc 5:1). Yield 3g (58.6%). NMR (400MHz, CDCl3): 1.20 (s, 9H), 1.60-1.66 (m, 2H), 1.70-1.78 (m, 2H), 2.41-2.47 (m, 2H), 3.19 (s, 3H), 3.65 ( s, 3H), 3.70 (t, 2H), 7.38-7.44 (m, 6H), 7.66-7.71 (m, 4H). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 2.20 min), MS (ESI) m / z 400.5 [MH ]+.

[0372] Synthesis of 7-((tertiary butyldiphenylsilyl)oxy)-2-ethoxyhept-1-en-3-one: ethyl vinyl ether (1.8 g, 2.4 ml, 3.3 eq) in anhydrous tetrahydrofuran (50 mL) was cooled to -78°C, and tert-butyllithium (1.7 M, 13 ml, 3 eq) in pentane was added. The mixture was warmed to 0 °C over a period of 1 h, stirred for 45 min and then cooled to -30 °C. Add 5-((tertiary butyldiphenylsilyl)oxy)-N-methoxy-N-methylpentanamide (3.0 g, 7.5 mmol, 1 equivalent) in THF, and The mixture was stirred for 4 h. The progress of the reaction was monitored by TLC. The mixture was poured into aqueous NH4Cl and extracted with Et2O. The combined extracts were dried over Na2SO4, filtered and the solvent was evaporated. The product was used in the next step without further purification. Yield 2.5 g (81%). NMR (400MHz, CDCl3): 1.02 (s, 9H), 1.35 (t, 3H), 1.58-1.62 (m, 2H), 1.70-1.76 (m, 2H), 2.69 (t, 2H), 3.68 (t, 2H), 3.81 (q, 2H), 4.40 (d, 1H), 5.18 (d, 1H), 7.38-7.43 (m, 6H), 7.64-7.68 (m, 4H).

[0373] Synthesis of (2Z, 2'E)-2,2'-(7-((tertiary butyldiphenylsilyl)oxy)heptane-2,3-diylidene)bis(N- Ethylhydrazine-1-thioformamide): 7-((tertiary butyldiphenylsilyl)oxy)-2-ethoxyhept-1-en-3-one (2.0 g, 4.9 mmol, 1 equiv) was dissolved in EtOH (50 ml), and ethionamide (1.16 g, 2 equiv) was added along with 3 drops of H2SO4. The reaction mixture was stirred and heated to reflux for 4h and then at ambient temperature for 15h. The formed precipitate was filtered, washed with EtOH, water, Et2O and dried. Yield 1.71 g (60%). NMR (400MHz, DMSO-d6): 0.88 (s, 9H), 6.72 (t, 6H), 1.40-1.60 (m, 4H), 2.18 (s, 3H), 3.38-3.43 (m, 4H), 3.56- 3.62 (m, 4H), 7.38-7.44 (m, 6H), 7.56-7.61 (m, 4H), 10.21-10.23 (m, 2H), 10.38-10.42 (m, 2H).

[0374] Synthesis of INT-18 ((2Z, 2'E)-2,2'-(7-hydroxyheptane-2,3-diylidene) bis(N-ethylhydrazine-1-thioformyl) Amine)): Stirring (2Z,2'E)-2,2'-(7-((tertiarybutyldiphenylsilyl)oxy)heptane-2,3-diylidene at ambient temperature ) a mixture of bis(N-ethylhydrazine-1-thioformamide) (1.3 g, 2.3 mmol) and n-tetrabutylammonium fluoride trihydrate (0.88 g, 1.2 equivalents) in THF (25 ml) for 15 h . The reaction mixture was diluted with water (150 ml) and extracted with EtOAc (3 x 60 ml). The organic layer was separated, dried over Na2SO4, filtered and the solvent was evaporated. Yield 0.53 g (65%). NMR (400MHz, DMSO-d6): 1.10-1.16 (m, 6H), 1.38-1.48 (m, 4H), 2.19 (s, 3H), 2.84-2.87 (m, 2H), 3.41-3.47 (m, 2H ), 3.58-3.62 (m, 4H), 4.50 (t, 1H), 8.26-8.38 (m, 2H), 10.20 (s, 1H), 10.41 (s, 1H).

[0375] Synthesis of Compound 18: Cu(OAc)2.2H2O (0.12 g, 1.1 equiv) was added to ethanol containing INT-18 (0.18 g, 0.5 mmol, 1 equiv). The mixture was stirred at ambient temperature for 15 h. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.06 g (25%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.74 min). MS (ESI) m / z 408.5 [MH]+.

[0376] Process 8: Synthesis of Compound 19 Synthesis of (2-aminoethyl) triphenylphosphonium bromide: triphenylphosphine (4.3 g, 16.6 mmol) and 2-bromoethylamine hydrobromide under nitrogen atmosphere A stirred solution of the acid salt (3.4 g, 16.6 mmol) in n-propanol (100 ml) was heated to reflux for 72 hours. The mixture was then cooled to room temperature, and the solid was filtered, washed with portions of anhydrous ether, and dried in vacuo. The product was dissolved in 50 ml of water, the insoluble solid was filtered, and the filtrate was concentrated to dryness in vacuo to afford the title compound (6.40 g, 100%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.25 min, MS (ESI) m / z 306.5 [MH] +.

[0377] Synthesis of (4Z,5E)-4,5-bis(2-(methylthiocarbamoyl)hydrazinylidene)pentanoic acid: To imidazole propionic acid (0.5 g, 3.6 mmol) in water (18 mL) was added a solution of NBS (0.63 g, 1 equiv) in acetonitrile (5.5 mL) in one portion. After stirring for 20 min, the acetonitrile was removed in vacuo. A solution of sodium acetate trihydrate (0.7 g) and methionamide (1.12 g, 3 equiv) in water (7.5 mL) was added to the reaction mixture. Crystals started to form within 5 min. Crystallization was continued for 14 h at ambient temperature, the precipitate was filtered and recrystallized from water. Yield 0.34 g (31.3%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.10 min, MS (ESI) m / z 305.0 [MH] +.1H-NMR (400MHz, DMSO-d6): δ (ppm) 2.41 (br.s, 2H), 2.91 (br.s, 2H), 2.99 (br.s, 6H), 7.60 (s, 1H) , 8.29 (br.s, 1H), 8.54 (br.s, 1H), 10.80 (s, 1H), 11.73 (s, 1H).

[0378] Synthesis of INT-19 ((2-((4Z,5E)-4,5-bis(2-(methylthioaminoformyl)hydrazine subgroup)pentylamino)ethyl)triphenyl phosphonium): (4Z,5E)-4,5-bis(2-(methylthioaminoformyl)hydrazinylidene)pentanoic acid (0.44 g, 1.4 mmol), bromide (2 A mixture of -aminoethyl)triphenylphosphonium (0.55 g, 1 eq), EDCI (0.3 g, 1.1 eq) and HOBT (0.21 g, 1.1 eq) in DMF (15 ml) was stirred overnight. The reaction mixture was diluted with water (50 ml), extracted with dichloromethane (3 x 20 ml), the extract was dried over Na2SO4, filtered and evaporated. Yield 0.2 g (23.3%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.17 min, MS (ESI) m / z 592.8 [MH] +.

[0379] Synthesis of INT-20 ((2-((4Z,5E)-4,5-bis(2-thioaminoformylhydrazinylidene)pentamido)ethyl)triphenylphosphonium): INT-20 was made using a procedure similar to that for INT-19. Yield 0.76 g (74.4%). 1H-NMR (400MHz, DMSO-d6): δ (ppm) 2.30-2.43 (m, 2H), 2.77-2.92 (m, 2H), 7.59 (s, 1H), 7.80 (br.s, 1H), 7.92 (br.s, 1H), 8.33 (br.s, 1H), 8.39 (br.s, 1H), 10.76 (s, 1H), 11.65 (s, 1H).

[0380] Synthesis of INT-21 ((2-((4Z,5E)-4,5-bis(2-(ethylthioaminoformyl) hydrazine subgroup) pentamylamino) ethyl) triphenyl phosphonium): INT-21 was made using a procedure similar to the procedure for making INT-19. Yield 0.76 g (74.4%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.33 min, MS (ESI) m / z 620.5 [MH] +.1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.00-1.21 (m, 6H), 2.29 (br.s, 2H), 2.87 (br.s, 2H), 3.34 (br.s, 2H), 3.49-3.55 (m, 4H), 3.65-3.77 (m, 2H), 7.58 (s, 1H), 7.77-7.96 (m, 15H), 8.41 (br.s, 1H), 8.53 (br. s, 1H), 8.60 (br.s, 1H), 10.74 (s, 1H), 11.74 (s, 1H).

[0381] Synthesis of Compound 19: Cu(OAc)2.2H2O (0.025 g, 1.1 equiv) was added to ethanol containing INT-19 (0.087 g, 0.1 mmol, 1 equiv). The mixture was stirred at ambient temperature for 15 h. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.018 g (19%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.56 min). MS (ESI) m / z 653.3 [MH]+.

[0382] Synthesis of compound 20: The title compound was prepared from INT-20 according to the method of compound 19. The product precipitated from the reaction mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.09 g (45%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.49 min). MS (ESI) m / z 625.3 [MH]+.

[0383] Synthesis of compound 21: According to the method of compound 19, the title compound was prepared from INT-21. The product precipitated from the reaction mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.09 g (45%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.79 min). MS (ESI) m / z 681.2 [MH]+.

[0384] Scheme 9: Synthesis of Compound 22 Synthesis of 2-(2-methoxyethoxy)acetyl chloride: To a solution of acid (1) (5.0 g, 37 mmol) in CH2Cl2 (100 mL) was added A few drops of DMF, followed by SOCl2 (13.3 g, 3 eq) were added, and the mixture was stirred at ambient temperature for 15 h. The solvent was evaporated to give compound (2) (4.4 g, 78%) which was used in the next step without further purification. NMR (400MHz, CDCl3): 3.37 (s, 3H), 3.57-3.60 (m, 2H), 3.74-3.78 (m, 2H), 4.50 (s, 2H).

[0385] Synthesis of N-methoxy-2-(2-methoxyethoxy)-N-methylacetamide: to 2-(2-methoxyethoxy) acetyl chloride (4.4 g , 29 mmol) in CH2Cl2 (100 mL) was added N,O-dimethylhydroxylamine hydrochloride (3.4 g, 1.2 eq) followed by Et3N (11.7 g, 4 eq). The mixture was stirred at ambient temperature for 15 h, quenched with 10% aqueous HCl, extracted with EtOAc. The combined org. extracts were dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by elution on silica gel with a gradient of 10% to 75% EtOAc / hexanes to afford compound (3) (2.7 g, 53%). NMR (400MHz, CDCl3): 3.18 (s, 3H), 3.39 (s, 3H), 3.57-3.64 (m, 2H), 3.68 (s, 3H), 3.73-3.77 (m, 2H), 4.34 (s, 2H).

[0386] Synthesis of 3-ethoxy-1-(2-methoxyethoxy)but-3-en-2-one: Ethyl vinyl ether (2.0 g, 2.7 ml, 3.3 equivalents) was dissolved in anhydrous The solution in tetrahydrofuran (75 mL) was cooled to -78 °C and tert-butyllithium (1.7 M, 15 ml, 3 equiv) in pentane was added. The mixture was warmed to 0 °C over a period of 1 h, stirred for 45 min and then cooled to -30 °C. N-Methoxy-2-(2-methoxyethoxy)-N-methylacetamide (1.53 g, 8.6 mmol, 1 equiv) was added in THF, and the mixture was stirred at 0 °C for 4 h. The progress of the reaction was monitored by TLC. The mixture was poured into aqueous NH4Cl and extracted with Et2O. The combined extracts were dried over Na2SO4, filtered and the solvent was evaporated. The product was used in the next step without additional purification. Yield 0.73g (45%) NMR (400MHz, DMSO-d6): 1.28 (t, 3H), 3.22 (s, 3H), 3.32 (s, 2H), 3.42-3.46 (m, 2H), 3.53-3.58 (m, 2H), 4.52 (s, 2H), 4.62 (d, 1H), 5.10 (d, 1H).

[0387] Synthesis of INT-22 ((2Z, 2'E)-2,2'-(1-(2-methoxyethoxy) butane-2,3-diylidene) bis(N-methyl hydrazine-1-thioformamide)): 3-ethoxy-1-(2-methoxyethoxy)but-3-en-2-one (0.73 g, 3.9 mmol, 1 equivalent ) was dissolved in EtOH (100 ml), methionamide (0.82 g, 2 equiv) and 3 drops of H2SO4 were added. The reaction mixture was stirred and heated to reflux for 4h and then at ambient temperature for 15h. The formed precipitate was filtered, washed with EtOH, water, Et2O and dried. Yield 0.2 g (15%). NMR (400MHz, DMSO-d6): 2.20 (s, 3H), 3.02, 3.04 (m, 6H), 3.28 (s, 3H), 3.48-3.60 (m, 4H), 4.84 (s, 2H), 8.38- 8.50 (m, 2H), 10.23 (s, 1H), 10.58 (s, 1H). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.34 min), MS (ESI) m / z 335.6 [MH ]+.

[0388] Synthesis of Compound 22 Cu(OAc)2.2H2O (0.16 g, 1.1 equiv) was added to sulfur semicarbazone 5 (0.2 g, 0.66 mmol, 1 equiv) in ethanol. The mixture was stirred at ambient temperature for 15 h. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.06 g (25%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.77 min). MS (ESI) m / z 396.3 [MH]+.

[0389] Example 2: Preparation of Compounds 23 to 46 Synthesis of INT-25 ((2Z,2'E)-2,2'-(1-(furan-2-yl)propane-1,2-diylidene) Bis(N-methylhydrazine-1-thioformamide): INT-25 was made using a procedure similar to that for the preparation of INT-1 of Example 1. Yield 6.78 g (78%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.34 min). MS (ESI) m / z 313.4 [MH]+. 1H-NMR (400MHz, CDCl3): δ (ppm) 2.25 (s, 3H), 3.20 (s, 3H), 3.28 (s, 3H), 6.62 (d, 1H), 6.84 (d, 1H), 7.31 ( s, 1H), 7.33 (s, 1H), 7.53 (s, 1H), 7.71 (s, 1H), 8.79 (s, 1H), 10.52 (s, 1H).

[0390] Synthesis of INT-33 ((2E, 2'E)-2,2'-(1-(2,5-dimethylfuran-3-yl) propane-1,2-diylidene) bis( N-Ethylhydrazine-1-thioformamide)): INT-33 was made using a procedure similar to that for the preparation of INT-1 of Example 1. Yield 1.8 g (48%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.60 min). MS (ESI) m / z 369.5 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.07 (t, 3H), 1.15 (t, 3H), 2.06 (s, 3H), 2.28 (s, 3H), 2.30 (s, 3H), 3.41-3.48 (m, 2H), 3.55-3.63 (m, 2H), 6.09 (s, 1H), 6.84 (d, 1H), 7.37 (t, 1H), 8.69 (t, 1H), 9.52-10.52 ( m, 1H).

[0391] Synthesis of INT-41 ((2E,2'E)-2,2'-(1-(1-ethyl-1H-pyrazol-5-yl) propane-1,2-diylidene) bis (N-Methylhydrazine-1-thioformamide)): INT-41 was made using a procedure similar to that for the preparation of INT-1 of Example 1. Yield 0.55 g (52.9%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.83 min, MS (ESI) m / z 341.3 [MH] +.

[0392] Synthesis of compound 25: The title compound was prepared from INT-25 according to the method for preparing compound 1 of Example 1. Yield 6.2 g (76%). ICP / MS sulfur: 17.36%, copper: 16.518%. LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 2.11 min). MS (ESI) m / z 374.1 [MH]+.

[0393] Synthesis of Compound 33: The title compound was prepared from INT-33 according to the method for preparing Compound 1 of Example 1. The product was isolated as a reddish brown powder. The formed precipitate was collected by filtration after cooling, washed with water (2x50 ml), ethanol (2x50 ml) and copious amounts of diethyl ether (5x50 ml), and then dried in vacuo. Yield 0.7 g (75%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 2.34 min). MS (ESI) m / z 430.5 [MH]+.

[0394] Synthesis of compound 41: The title compound was prepared from INT-41 according to the method for preparing compound 1 of Example 1. The product precipitated from the reaction mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.18 g (55.7%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.80 min). MS (ESI) m / z 401.8 [MH]+.

[0395] Process 10: Synthesis of compound 23 Synthesis of methyl 5-(3-oxopropyl)furan-2-carboxylate: under inert atmosphere, methyl 5-bromofurancarboxylate (5.7 g, 28 mmol, 1 eq) to a stirred solution in DMF (550 ml) was added allyl alcohol (2.28 g, 1.4 eq), Pd(OAc)2 (0.189 g, 0.03 eq), TEBAC (6.39 g, 1 eq) and Na2CO3 (6.85 g, 2 equiv). The mixture was then stirred at 80 °C for 2 h. Once the reaction had completed, the resulting mixture was filtered through celite, concentrated in vacuo at ≤40°C, diluted with ethyl acetate, washed with brine, concentrated in vacuo to dryness, and analyzed by column chromatography (ethyl acetate:hexane 1:3) to purify the residue. Yield 2.7 g (53%). 1H-NMR (400MHz, CDCl3): δ (ppm) 2.89(dd, 2H), 3.05(dd, 2H), 3.89(s, 3H), 6.19(s, 1H), 7.09(s, 1H), 9.83( s, 1H).

[0396] Synthesis of 5-(3-olylpropyl) methyl furan-2-carboxylate: 5-(3-oxopropyl) methyl furan-2-carboxylate (1.6 g, 9 mmol, 1 eq) was dissolved in MeOH (90 ml), and to this solution was added molecular sieve 3A (2.64 g). After stirring for 15 min, the mixture was cooled to 0 °C. To the stirred solution of the aldehyde was added a solution of phylloline (1.15 g, 1.5 equiv) and acetic acid (1.05 g, 2 equiv) in methanol (42 mL). After stirring for 2 min, NaBH3CN (1.66 g, 3 equiv) was added. The resulting mixture was stirred at 0 °C for 14 h and allowed to reach ambient temperature naturally. The reaction mixture was diluted with DCM, filtered through celite, and the filtrate was washed with aqueous NaHCO3. The aqueous phase was extracted twice with DCM. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by column chromatography (SiO2, eluting with 1:5 to 1:3 to 1:1 to 100% EtOAc, and then CH2Cl2-MeOH, 10:1). Yield 1.5 g (68%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.28 min. MS (ESI) m / z 254.4 [MH] +, retention time 0.8 min. MS (ESI) m / z 254.6 [MH]+. 1H-NMR (400MHz, CDCl3): δ (ppm) 1.86-1.94 (m, 2H), 2.39-2.44 (m, 2H) , 2.44-2.53(m, 4H), 2.66-2.86(m, 2H), 3.68-3.77(m, 4H), 3.88(s, 3H), 6.16(d, 1H), 7.11(d, 1H).

[0397] Synthesis of 5-(3-𠰌linylpropyl) furan-2-carboxylic acid: 5-(3-𠰌linylpropyl)furan-2-carboxylic acid methyl ester (1.5 g, 6.0 mmol) in methanol To a solution in (20 ml) was added a solution of NaOH (0.6 g, 2 equiv) in water (5 ml) and the reaction mixture was stirred at room temperature overnight. Methanol was removed in vacuo, the residue was diluted with water and acidified to pH 1. The acidified solution was evaporated to dryness in vacuo and treated with isopropanol. The solid salt was filtered, and the filtrate was evaporated to dryness in vacuo. Yield 1.4 g (73.5%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.28 min. MS (ESI) m / z 240.4 [MH] +, retention time 0.67 min. MS (ESI) m / z 240.1 [MH]+. 1H-NMR (400MHz, CDCl3): δ (ppm) 1.98-2,15 (m,2H), 2.68-2.80 (m, 2H), 2.91-3.17(m, 4H), 3.37-3.49(m, 2H), 3.75-3.99(m, 4H), 6.41(s, 1H), 7.14(s, 1H), 11.26(br.s, 1H), 12.91(br.s, 1H).

[0398] Synthesis of N-methoxy-N-methyl-5-(3-𠰌linyl propyl) furan-2-formamide: to 5-(3-𠰌linyl propyl) furan at 5°C -2-carboxylic acid (1.2 g, 4.0 mmol, 1 equivalent), N, O-dimethylhydroxylamine (0.55 g, 1.3 equivalents), HOBt (0.65 g, 1.1 equivalents) and DIPEA (3 ml, 4 equivalents) in To a stirred mixture in CH2Cl2 (25 ml) was added EDCI (0.83 g, 1 equiv). The reaction was stirred at ambient temperature for 15h. The mixture was washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered and the solvent was concentrated under reduced pressure. The product was used without further purification. Yield 0.9 g (73%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.34 min. MS (ESI) m / z 283.6 [MH] +, retention time 0.85 min. MS (ESI) m / z 283.5 [MH]+. 1H-NMR (400MHz, CDCl3): δ (ppm) 1.86-1.94 (m,2H), 2.40-2.53 (m, 6H) , 2.71-2.81(m, 2H), 3.34(s, 3H), 3.68-3.74(m, 4H), 3.76(s,3H), 6.15(d, 1H), 7.07(d, 1H).

[0399] Synthesis of 1-(5-(3-𠰌linyl propyl) furan-2-yl) ethyl-1-ketone: N-methoxy-N-methyl-5-(3-𠰌linyl A solution of propyl)furan-2-carboxamide (0.9 g, 3.0 M, 1 equiv) in THF (50 ml) was cooled to 5°C and methylmagnesium bromide in THF (3.4 M, 2.8 ml, 3 Equivalent) in the solution. The reaction mixture was stirred at 5 °C for 2 h, poured into aqueous NH4Cl and extracted with Et2O. The combined extracts were dried over Na2SO4 and evaporated. The title product was used in the next step without purification. Yield 0.6 g (79%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 minutes, retention time 0.3min, MS (ESI) m / z 238.4 [MH] +, retention time 0.8 min, MS (ESI) m / z 238.4 [MH]+. 1H-NMR (400MHz, CDCl3): δ (ppm) 1.88-1.96 (m, 2H), 2.35-2.64 (m, 9H) , 2.73-2.79 (m, 2H), 3.66-3.90 (m, 4H), 6.20 (s, 1H), 7.11 (s, 1H).

[0400] Synthesis of INT-23 ((2E,2'E)-2,2'-(1-(5-(3-𠰌linylpropyl)furan-2-yl)ethane-1,2-di Subunit) bis(N-ethylhydrazine-1-thioformamide)): 1-(5-(3-𠰌linylpropyl)furan-2-yl)ethan-1-one (0.5 g , 2.0 mmol, 1 equiv), NaBr (0.11 g, 0.5 equiv) and DMSO (1.1 ml) was heated to 85 °C, then H2SO4 (6 drops) was added (bubbling), and the reaction temperature started to rise. The reaction was heated to 110-115 °C until the formation of dimethyl sulfide ceased and the reaction mixture became viscous. The resulting viscous mass was dissolved in EtOH and ethionamide (0.5 g, 2 equiv) was added to the solution. The reaction mixture was refluxed for 2 hours, then cooled to room temperature, the solvent was evaporated in vacuo, the residue was dissolved in water (25 ml), neutralized with saturated aqueous Na2CO3 and extracted with EtOAc (3 x 50 mL). The organic layer was separated, dried over Na2SO4, filtered, and the solvent was evaporated. Treat the residue with water. The formed precipitate was filtered and washed with EtOH to afford the pure title compound. Yield 0.2 g (21%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.18 min, MS (ESI) m / z 454.4 [MH] +.

[0401] Synthesis of INT-27 ((2E, 2'E)-2,2'-(1-(5-(3-(3-alkinylpropyl)furan-2-yl)ethane-1,2-di Subunit) bis(N-methylhydrazine-1-thioformamide)): INT-21 was made using a procedure similar to that for the preparation of INT-19. Yield 0.16 g (15%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.02 min, MS (ESI) m / z 426.3 [MH] +.

[0402] Synthesis of compound 23: CuCl2.2H2O (0.034 g, 1 equiv) was added to ethanol containing sulfur semicarbazone 6 (0.09 g, 0.2 mmol, 1 equiv). The mixture was stirred at ambient temperature for 15 h. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.05 g (48%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.56 min). MS (ESI) m / z 515.4 [MH]+.

[0403] Synthesis of compound 27: According to the method of compound 23, the title compound was prepared from INT-27. The product precipitated from the reaction mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.095 g (87%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.46 min). MS (ESI) m / z 487.5 [MH]+.

[0404] Scheme 11: Synthesis of compound 31 Synthesis of ethyl 5-(1-chloroethyl)furan-2-carboxylate: Zinc chloride (3.9 g, 28.6 mmol) was added to paraldehyde (17.3 g, 131.1 mmol) and ethyl 2-furoate (16.9 g, 120.7 mmol) in chloroform (36 mL). Hydrogen chloride was passed through the mixture under vigorous stirring at 25°C to 30°C within 5 h. Then, 250 mL of chloroform was added; the reaction mixture was washed with water (2×30 mL), and then dried over calcium chloride. The solvent was removed under reduced pressure to afford the target product 1, which was used in the next step without further purification. Yield 35 g (31%). 1H-NMR (400MHz, CDCl3): δ (ppm) 1.18 (d, 3H), 1.33 (t, 3H), 4.32 (q, 2H), 5.09 (q, 1H), 6.41 (d,1H), 7.07 ( d, 1H).

[0405] Synthesis of 5-(1-(piperidin-1-yl) ethyl) ethyl furan-2-carboxylate: stirring 5-(1-chloroethyl) ethyl furan-2-carboxylate (5.0 g, 24.6 mmol), piperidine (4.2 g, 49.2 mmol) and potassium carbonate (6.8 g, 49.2 mmol) in CH3CN (100 ml) for 12 h. Allow the mixture to cool to room temperature. CH3CN was removed by evaporation, and the residue was diluted with 20 ml 2N aqueous sodium carbonate and extracted with dichloromethane. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography (silica gel, eluent 100% DCM to 5% MeOH) to afford the title product which was used in the next step without further purification. Yield 5.1 g (82%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.90 min). MS (ESI) m / z 252.1 [MH]+. 1H-NMR (400MHz, CDCl3): δ (ppm) 1.36 (d, 2H), 1.38 (d, 3H), 1.44 (d, 3H), 1.58 (q, 4H), 2.35-2.41 (m, 2H), 2.48-2.53 (m, 2H), 3.81 (q, 1H), 4.35 (q, 2H), 6.29 (d, 1H), 7.17 (d, 1H).

[0406] Synthesis of 5-(1-(piperidin-1-yl) ethyl)furan-2-carboxylic acid: 5-(1-(piperidin-1-yl)ethyl)furan-2-carboxylic acid ethyl To a solution of the ester (5.1 g, 20.3 mmol) in MeOH (50 ml) was added a 20% aqueous solution of LiOH (1.6 g, 60.9 mmol). The reaction mixture was stirred at 60 °C for 8 h. The solvent was then removed by lyophilization and the corresponding crude product was used in the next step without further purification. Yield 4.4 g (83%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.65 min). MS (ESI) m / z 224.4 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.33-1.38 (m, 2H), 1.43 (d, 3H), 1.57-1.61 (m, 4H), 2.07 (s, 1H), 2.60-2.63 (m, 2H), 4.07 (q, 2H), 4.32 (s, 1H), 6.52 (d, 1H), 7.04 (d, 1H).

[0407] Synthesis of N-methoxy-N-methyl-5-(1-(piperidin-1-yl) ethyl) furan-2-formamide: 5-(1-(piperidin) at 4°C Pyridin-1-yl)ethyl)furan-2-carboxylic acid (5.2 g, 20 mmol), N,O-dimethylhydroxylamine (2.3 g, 24 mmol), HOBt (3.2 g, 24 mmol) and TEA ( 12 ml, 90 mol) in DCM (80 ml) was added EDCI (4.6 g, 24 mmol) and then the mixture was stirred at room temperature overnight. The mixture was washed with water (15 ml), brine (100 ml). The organic layer was dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent 100% DCM to 5% MeOH) to afford the crude product. Yield 2.2 g (42%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.77 min). MS (ESI) m / z 267.5 [MH]+. 1H-NMR (400MHz, CDCl3): δ (ppm) 1.38 (t, 2H), 1.46 (d, 3H), 1.54-1.60 (m, 4H), 2.36-2.41 (m, 2H), 2.50-2.55 (m , 2H), 3.33 (s, 3H), 3.78 (s, 3H), 3.81-3.87 (m, 1H), 6.26 (dd, 1H), 7.23 (dd, 1H).

[0408] Synthesis of 2-ethoxy-1-(5-(1-(piperidin-1-yl) ethyl) furan-2-yl) prop-2-en-1-one: ethyl vinyl ether (1.8 g, 24.4 mmol) in tetrahydrofuran (50 ml) was cooled to -78°C and tert-butyllithium (1.7 M, 14.0 ml, 22.2 mmol) in pentane was added. The mixture was warmed to 0 °C over a period of 1 h, stirred for 45 min and cooled to -30 °C. To this mixture was added N-methoxy-N-methyl-5-(1-(piperidin-1-yl)ethyl)furan-2-carboxamide (1.0 g, 3.7 mmol) in THF (15 ml) and the mixture was stirred at 0°C for 4 h. The progress of the reaction was monitored by TLC. The mixture was poured into aqueous NH4Cl (100 ml) and extracted with Et2O (3x50 ml). The combined extracts were dried over Na2SO4. The product solution was then decanted, and the solvent was removed under reduced pressure to afford the title compound, which was used in the next step without further purification. Yield 1.1 g (87%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.97 min). MS (ESI) m / z 278.6 [MH]+. 1H-NMR (400MHz, CDCl3): δ (ppm) 1.38 (t, 2H), 1.46 (d, 3H), 1.47 (d, 3H), 1.55-1.63 (m, 4H), 2.38-2.44 (m, 2H ), 2.51-2.56 (m, 2H), 3.81-3.87 (m, 1H), 3.93 (q, 2H), 4.58 (d, 1H), 5.33 (d, 1H), 6.31 (d, 1H), 7.47 ( d, 1H).

[0409] Synthesis of INT-31 ((2Z, 2'E)-2,2'-(1-(5-(1-(piperidin-1-yl) ethyl) furan-2-yl) propane-1 ,2-diylidene)bis(N-ethylhydrazine-1-thioformamide)): 2-ethoxy-1-(5-(1-(piperidin-1-yl)ethyl )furan-2-yl)prop-2-en-1-one (1.1 g, 3.7 mmol) was dissolved in EtOH (30 ml), ethionamide (0.9 g, 7.4 mmol) and 3 drops of H2SO4 were added. The stirred reaction mixture was heated to reflux for 4 h and then kept at ambient temperature overnight. The progress of the reaction was monitored by TLC (CCl4 / EtOAc 7:3). The precipitate was filtered, washed with EtOH, water, Et2O and dried. Yield 0.5 g (33%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.17 min). MS (ESI) m / z 452.0 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.07 (t, 3H), 1.15 (t, 3H), 1.38-1.55 (m, 3H),1.60-1.66 (m, 4H), 1.70-1.79 (m, 4H), 2.33 (s, 3H), 3.41-3.48 (m, 2H), 3.55-3.63 (m, 2H), 4.72 (s, 1H), 6.91 (dd, 1H), 7.14 (dd, 1H ), 7.73 (t, 1H), 8.73 (t, 1H), 9.08-9.78 (m, 2H), 10.48 (s, 1H), 10.55 (s, 1H).

[0410] Synthesis of INT-24 ((2E,2'E)-2,2'-(1-(5-(𠰌linylmethyl)furan-2-yl)propane-1,2-diylidene) Bis(N-ethylhydrazine-1-thioformamide): INT-24 was made using a procedure similar to that for the preparation of INT-31. Yield 4.6 g (63%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.01 min). MS (ESI) m / z 440.5 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.10 (t, 3H), 1.16 (t, 3H), 1.39 , 2.32 (s, 3H), 2.35-2.47 (m, 4H), 3.42-3.58 (m, 2H), 3.58-3.76 (m, 8H), 6.61 (s, 1H), 7.01 (s, 1H), 7.78 (br.s, 1H), 8.70 (br.s, 1H), 10.40 (s , 1H), 10.51 (s, 1H).

[0411] Synthesis of INT-32 ((2E,2'E)-2,2'-(1-(5-(𠰌olylmethyl)furan-2-yl)propane-1,2-diylidene) Bis(N-methylhydrazine-1-thioformamide): INT-32 was made using a procedure similar to that for the preparation of INT-31. Yield 0.25 g (54%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.06 min. MS (ESI) m / z 412.4 [MH] +.1H-NMR (400MHz, DMSO-d6): δ (ppm) 2.33 (s, 3H), 2.92-3.00(m, 4H), 3.03-3.10(m, 4H), 3.12-3.45(m, 4H) , 3.70-3.82(m, 4H), 4.5(s, 3H), 6.9(s, 1H), 7.07(s, 1H), 7.71(s, 1H), 8.67(s, 1H), 10.39(s, 1H ), 10.54(s, 1H).

[0412] Synthesis of INT-37 ((2E,2'E)-2,2'-(1-(5-((4-methylpiper-1-yl)methyl)furan-2-yl)propane -1,2-diylidene)bis(N-ethylhydrazine-1-thioformamide)): INT-37 was made using a procedure similar to that for the preparation of INT-31. Yield 0.9 g (61.5%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.06 min). MS (ESI) m / z 453.5 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.10 (t, 3H), 1.16 (t, 3H), 1.39 , 2.32 (s, 3H), 2.55-2.74 (m, 2H), 2,79 -2.89 (M, 4H), 3.42-3.59 (m, 6H), 3.62 (q, 2H), 3.97 (s, 3H), 6.71 (s, 1H), 7.08 (s, 1H), 7.76 (s, 1H ), 8.74 (s, 1H), 10.44 (s, 1H), 10.54 (s, 1H).

[0413] Synthesis of INT-39 ((2Z, 2'E)-2,2'-(1-(5-(1-(1-alginyl ethyl)furan-2-yl)propane-1,2-diethylene yl)bis(N-ethylhydrazine-1-thioformamide)): INT-39 was made using a procedure similar to that for the preparation of INT-31. Yield 0.2 g (20%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.11 min). MS (ESI) m / z 454.3 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.10 (t, 3H), 1.16 (t, 3H), 1.39 (dd, 3H), 2.32 (s, 3H), 2.34-2.38 (m, 2H ), 2.47-2.49 (m, 2H), 3.48-3.53 (m, 2H), 3.56-3.65 (m, 4H),3.60-3.65 (m, 2H), 3.84-3.90 (m, 1H), 6.56 (dd , 1H), 7.06 (dd, 1H), 7.87 (t, 1H), 8.70 (t, 1H), 10.47 (d, 1H), 10.59 (d, 1H).

[0414] Synthesis of compound 31: CuCl2.2H2O (0.2 g, 2.4 mmol) was added to 30 ml of ethanol containing compound 6 (0.5 g, 1.2 mmol). The mixture was stirred at ambient temperature for 15 h. The formed precipitate was collected by filtration after cooling, washed with water (2x50 ml), ethanol (2x50 ml) and copious amounts of diethyl ether (5x50 ml), and then dried in vacuo. Yield 0.4 g (75%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.66 min). MS (ESI) m / z 513.3 [MH]+.

[0415] Synthesis of compound 24: The title compound was prepared from INT-24 according to the method of compound 31. The product precipitated from the reaction mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 4.7 g (92%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.48 min). MS (ESI) m / z 501.3 [MH]+.

[0416] Synthesis of compound 32: According to the method of preparing compound 31, the title compound was prepared from INT-32. The product precipitated from the reaction mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.14 g (97%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.38 min). MS (ESI) m / z 473.0 [MH]+.

[0417] Synthesis of compound 37: According to the method of preparing compound 31, the title compound was prepared from INT-37. The product precipitated from the reaction mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.8 g (96%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.52 min). MS (ESI) m / z 514.3 [MH]+.

[0418] Synthesis of compound 39: The title compound was prepared from INT-39 according to the method for preparing compound 31. The product precipitated from the reaction mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water (2x50 ml), ethanol (2x50 ml) and copious amounts of diethyl ether (5x50 ml), and then dried in vacuo. Yield 0.15 g (86%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.57 min). MS (ESI) m / z 515.2 [MH]+.

[0419] Process 12: Synthesis of Compound 26 Synthesis of 5-(3-oxopropyl) methyl furan-2-carboxylate: under an inert atmosphere, 5-bromo-methyl furancarboxylate (5.7 g, 28 mmol , 1 equivalent) was dissolved in 550 ml DMF. Allyl alcohol (2.28 g, 1.4 equiv), Pd(OAc)2 (0.189 g, 0.03 equiv), TEBAC (6.39 g, 1 equiv) and Na2CO3 (6.85 g, 2 equiv) were added. The mixture was then stirred at 80 °C for 2 h. Upon completion, the resulting mixture was filtered through celite, the filtrate was concentrated in vacuo at ≤40 °C, diluted with ethyl acetate, washed with brine, concentrated to dryness, and analyzed by column chromatography (silica gel, ethyl acetate-hexane Alkane 1:3) to purify the residue. Yield 2.7 g (53%). 1H-NMR (400MHz, CDCl3): δ (ppm) 2.89(dd, 2H), 3.05(dd, 2H), 3.89(s, 3H), 6.19(s, 1H), 7.09(s, 1H), 9.83( s, 1H).

[0420] Synthesis of 5-(3-(piperidin-1-yl) propyl) methyl furan-2-carboxylate: 5-(3-oxopropyl) methyl furan-2-carboxylate (2.7 g , 15 mmol, 1 equiv) was dissolved in MeOH (150 ml), and molecular sieves (4.4 g) were added to the solution. After stirring for 15 min, the mixture was cooled to 0 °C. To the stirred solution of aldehyde 1 was added a solution of piperidine (1.9 g, 1.5 equiv) and acetic acid (1.8 g, 2 equiv) in methanol (70 ml) at 0 °C. After stirring for 2 min, NaBH3CN (2.8 g, 3 equiv) was added. The resulting mixture was stirred for 14 h, allowing to warm naturally from 0 °C to room temperature. Then, the reaction mixture was diluted with DCM, filtered through celite, and the filtrate was washed with aqueous NaHCO3. The aqueous phase was extracted twice with DCM. The organic phase was dried over Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by column chromatography (SiO2, first eluted with EtOAc / Hexane, gradient 1:5 to 1:3 to 1:1 to 100% EtOAc, and then CH2Cl2 / MeOH, 10:1) thing. Yield 1.8 g (49%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.94 min. MS (ESI) m / z 252.4 [MH] +.1H-NMR (400MHz, CDCl3): δ (ppm) 1.45-1.66 (m,2H), 1.78-1.88 (m, 2H), 1.96-2.17(m, 4H), 2.57-2.88(m, 6H) , 3.41-3.56(m, 2H), 3.88(s, 3H), 6.23(s, 1H), 7.09(s, 1H).

[0421] Synthesis of 5-(3-(piperidin-1-yl) propyl) furan-2-carboxylic acid: to 5-(3-(piperidin-1-yl) propyl)furan-2-formic acid To a stirred solution of the ester (1.8 g, 7.0 mmol) in methanol (20 ml) was added a solution of NaOH (0.73 g, 2.6 equiv) in water (25 ml). The reaction mixture was stirred at ambient temperature for 15 h. Methanol was removed in vacuo, the residue was diluted with water and acidified to pH 1. The acidified solution was evaporated to dryness and the residue was treated with isopropanol. The solid salt was filtered, and the filtrate was evaporated to dryness. Yield 1.35 g (68%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.35 min. MS (ESI) m / z 238.3 [MH] +, retention time 0.86 min. MS (ESI) m / z 238.3 [MH]+.

[0422] Synthesis of N-methoxy-N-methyl-5-(3-(piperidin-1-yl) propyl) furan-2-formamide: 5-(3-(piperidin) at 5°C Pyridin-1-yl)propyl)furan-2-carboxylic acid methyl ester (1.35 g, 5.0 M, 1 equiv), N,O-dimethylhydroxylamine (0.72 g, 1.3 equiv), HOBt (0.83 g, 1.1 equiv ) and DIPEA (3.3 ml, 4 equiv) in CH2Cl2 (25 ml) was added EDCI (1.04 g, 1.1 equiv). The reaction was then stirred at ambient temperature for 15 h. The mixture was washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was used further without purification. Yield 0.4 g (29%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.35 min. MS (ESI) m / z 281.5 [MH] +, retention time 0.93 min. MS (ESI) m / z 281.3 [MH]+. 1H-NMR (400MHz, CDCl3): δ (ppm) 1.38-1.48 (m,2H), 1.55-1.64(m, 4H) , 1.86-1.97(m, 2H), 2.31-2.48(m, 6H), 2.69-2.81(m, 2H), 3.34(s, 3H), 3.76(s, 3H), 6.14(d, 1H), 7.07 (d, 1H).

[0423] Synthesis of 2-ethoxy-1-(5-(3-(piperidin-1-yl) propyl) furan-2-yl) prop-2-en-1-one: ethyl vinyl ether (0.72 g, 0.96 ml, 7 equiv) in anhydrous tetrahydrofuran (20 mL) was cooled to -78°C, and tert-butyllithium (1.7 M, 5 ml, 6 equiv) in pentane was added. The mixture was warmed to 0 °C over a period of 1 h, stirred for 45 min and cooled to -30 °C. A solution of N-methoxy-N-methyl-5-(3-(piperidin-1-yl)propyl)furan-2-carboxamide (0.4 g, 1.4 mmol, 1 equiv) in THF was added , and the mixture was stirred at 0 °C for 4 h. The progress of the reaction was monitored by TLC. The mixture was poured into aqueous NH4Cl and extracted with Et2O. The combined extracts were dried over Na2SO4, filtered and evaporated in vacuo. The product was used in the next step without further purification. Yield 0.39 g (93%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.04 min. MS (ESI) m / z 292.3 [MH] +.1H-NMR (400MHz, CDCl3): δ (ppm) 1.18-1.48(m, 5H), 1.50-1.64 (m,4H), 1.82-2.03(m,2H), 2.27-2.48 (m, 6H) , 2.62-2.78(m, 2H), 3.84-3.98(m, 2H), 3.92(q, 2H), 4.56(s, 1H), 5.31(s, 1H), 6.21(d, 1H), 7.44(d , 1H).

[0424] Synthesis of INT-26 ((2E, 2'E)-2,2'-(1-(5-(3-(piperidin-1-yl) propyl) furan-2-yl) propane-1 ,2-diylidene)bis(N-ethylhydrazine-1-thioformamide)): 2-ethoxy-1-(5-(3-(piperidin-1-yl)propyl )furan-2-yl)prop-2-en-1-one (0.41 g, 1.45 mmol, 1 equiv) was dissolved in EtOH (10 ml), added thiocarbamide (0.33 g, 2 equiv) and 1 drop H2SO4. The reaction mixture was stirred and heated to reflux for 4h and then at ambient temperature for 15h. The formed precipitate was filtered, washed with EtOH, water, Et2O and crystallized from EtOH. Yield 0.08 g (12%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.21 min. MS (ESI) m / z 466.5 [MH] +.1H-NMR (400MHz, CDCl3): δ (ppm) 1.11(t, 3H), 1.16(t, 1H), 1.53-1.91(m, 6H), 2.05-2.15(m, 2H), 2.32(s , 3H), 2.77-2.89(m, 2H), 3.05-3.19(m, 2H), 3.35-3.45(m, 4H), 3.53(q, 2H), 3.62(q, 2H), 6.49(s, 1H ), 7.05(s, 1H), 7.78(s, 1H), 8.72(s, 1H), 10.48(s, 1H), 10.52(s, 1H).

[0425] Synthesis of INT-28 ((2Z, 2'E)-2,2'-(1-(5-(3-(3-alginyl propyl) furan-2-yl) butane-2,3-di Subunit) bis(N-ethylhydrazine-1-thioformamide)): INT-28 was made using a procedure similar to that for the preparation of INT-26. Yield 0.18 g (50%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.15 min. MS (ESI) m / z 468.5 [MH] +.1H-NMR (400MHz, CDCl3): δ (ppm) 1.11(t, 3H), 1.16(t, 1H), 2.04-2.14(m, 2H), 2.32(s, 3H), 2.77-2.86(m , 2H), 3.17-3.26(m, 2H), 3.39-3.73(m, 10H), 3.91-4.04(m, 2H), 6.5(s, 1H), 7.06(s, 1H), 7.8(s, 1H ), 8.72(s, 1H), 10.47(s, 1H), 10.52(s, 1H).

[0426] Synthesis of compound 26: CuCl2.2H2O (0.026 g, 1 eq) was added to ethanol containing sulfur semicarbazone 6 (0.07 g, 0.15 mmol, 1 eq). The mixture was stirred at ambient temperature for 15 h. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.054 g (68%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.76 min). MS (ESI) m / z 527.5 [MH]+.

[0427] Synthesis of compound 28: According to the method of compound 26, the title compound was prepared from INT-28. The product precipitated from the reaction mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.14 g (85%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.65 min). MS (ESI) m / z 529.0 [MH]+.

[0428] Process 13: Synthesis of Compound 29 Synthesis of ethyl 5-(𠰌linylmethyl)furan-2-carboxylate: Add ethyl 2-chloromethyl-5-furancarboxylate (9.6 g, 50 mmol) in CH2Cl2 To the stirred solution in (200 ml) were added ? The reaction mixture was stirred at room temperature for 15 h, then washed with water (3 x 50 ml). The organic layer was separated, dried over Na2SO4, filtered, and the solvent was evaporated. Yield 8 g (66%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.82 min). MS (ESI) m / z 240.1 [MH]+. 1H-NMR (400MHz, CDCl3): δ (ppm) 1.38 (t, 3H), 2.50-2.55 (m, 4H), 3.62 (s, 3H), 3.70-3.75 (m, 4H), 4.37 (q, 2H ), 6.36 (d, 1H), 7.13 (d, 1H).

[0429] Synthesis of 5-(𠰌olinylmethyl)furan-2-carboxylate hydrochloride: 5-(𠰌olinylmethyl)furan-2-carboxylic acid ethyl ester (4.6 g, 20 mmol) in methanol To a solution in (100 ml) was added a solution of NaOH (2 g, 2 equiv) in water (10 ml) and the reaction mixture was stirred at ambient temperature for 15 h. Methanol was stripped in vacuo, the residue was diluted with water and acidified to pH 1. The acidified solution was evaporated to dryness and the residue was treated with isopropanol. The solid salt was filtered, and the filtrate was evaporated to dryness. Yield 4.4 g (86%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.29 min). MS (ESI) m / z 212.3 [MH]+.

[0430] Synthesis of N-methoxy-N-methyl-5-(𠰌linylmethyl)furan-2-formamide: Stir 5-(𠰌linylmethyl)furan-2-formamide at 60°C A mixture of ester hydrochloride (7.1 g, 29 mmol) and 1,1'-carbonyldiimidazole (5.57 g, 1.2 equiv) in DMF (47 mL) for 30 min. Then N,O-dimethylhydroxylamine (3.35 g, 1.2 equiv) and triethylamine (3.2 g, 4.4 ml, 1.1 equiv) were added. The mixture was stirred at 80 °C for 16 h, then the volatiles were evaporated in vacuo, and the residue was partitioned between EtOAc and H2O. The organic layer was separated, dried over Na2SO4, filtered, and the solvent was evaporated. Yield 7 g (96%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.28 min. MS (ESI) m / z 255.6 [MH] +, retention time 0.78 min. MS (ESI) m / z 255.6 [MH]+. 1H-NMR (400MHz, CDCl3): δ (ppm) 2.52-2.55 (m, 4H), 3.35 (s, 3H), 3.64 (s, 2H), 3.71-3.74 (m, 4H), 6.36 (d, 1H), 6.71 (d, 1H).

[0431] Synthesis of 1-(5-(𠰌linylmethyl)furan-2-yl)ethan-1-ketone: N-methoxy-N-methyl-5-(𠰌linylmethyl)furan - A solution of 2-formamide (3.4 g, 13 mmol, 1 eq) in THF (150 ml) was cooled to 5°C and a solution of methylmagnesium bromide in THF (1.4 M, 26 ml, 3 eq) was added solution. The reaction mixture was stirred at 5 °C for 2 h, poured into aqueous NH4Cl and extracted with Et2O. The combined extracts were dried over Na2SO4, filtered and the solvent was evaporated. Compound 3 was used in the next step without purification. Yield 2.6 g (93%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.31 min, MS (ESI) m / z 210.1 [MH] +, retention time 0.67 min, MS (ESI) m / z 210.3 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 2.34-2.45 (m, 7H), 3.49-3.63 (m, 6H), 6.54 (s, 1H), 7.46 (s, 1H).

[0432] Synthesis of INT-29 ((2E, 2'E)-2,2'-(1-(5-(𠰌linylmethyl) furan-2-yl) ethane-1,2-diylidene ) Bis(N-methylhydrazine-1-thioformamide)): 1-(5-(𠰌linylmethyl)furan-2-yl)ethan-1-one (1.4 g, 7.0 mmol, 1 equiv), NaBr (0.33 g, 0.5 equiv) and DMSO (3.45 ml) were heated to 85 °C, then H2SO4 (6 drops) was added (foaming), and the reaction temperature started to rise. The reaction was heated to 110-115 °C until the formation of dimethyl sulfide ceased and the reaction mixture became viscous. The resulting viscous mass was dissolved in EtOH and methionamide (1.41 g, 2 equiv) was added to the solution. The reaction mixture was refluxed for 2 hours, then cooled to room temperature, the solvent was evaporated in vacuo, the residue was dissolved in water (25 ml), neutralized with saturated aqueous Na2CO3 and extracted with EtOAc (3 x 50 mL). The organic layer was separated, dried over Na2SO4, filtered, and the solvent was evaporated. Treat the residue with water. The formed precipitate was filtered and washed with EtOH to afford the pure title compound. Yield 0.7 g (26%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.08 min, MS (ESI) m / z 398.3 [MH] +.

[0433] Synthesis of INT-38 ((2E,2'E)-2,2'-(1-(5-(𠰌linylmethyl)furan-2-yl)ethane-1,2-diylidene ) bis(N-ethylhydrazine-1-thioformamide)): INT-38 was made using a procedure similar to that for the preparation of INT-29. Yield 0.5 g (37%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.12 min, MS (ESI) m / z 426.0 [MH] +.

[0434] Synthesis of compound 29: CuCl2.2H2O (0.062 g, 1 equiv) was added to ethanol containing sulfur semicarbazone 6 (0.14 g, 0.4 mmol, 1 equiv). The mixture was stirred at ambient temperature for 15 h. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.055 g (32%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.29 min). MS (ESI) m / z 459.5 [MH]+.

[0435] Synthesis of compound 38: The title compound was prepared from INT-36 according to the method of compound 29. The product precipitated from the reaction mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.07 g (77%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.47 min). MS (ESI) m / z 487.4 [MH]+.

[0436] Process 14: Synthesis of Compound 30 Synthesis of 5-(𠰌line-4-carbonyl)furan-2-carboxylic acid: To furan 2,5-dicarboxylic acid (5 g, 32 mmol, 1 equivalent) in DMF ( To a stirred solution in 100 ml), DIPEA (14.5 g, 19.5 ml, 3.5 eq) was added, the reaction flask was flushed with argon, and TBTU (12.3 g, 1.2 eq) in DMF was added dropwise over 1 h at ambient temperature (75 ml) solution. The reaction mixture was stirred for an additional hour. The phenoline was then added in one portion and the mixture was stirred at ambient temperature for 2 h. The mixture was cooled in an ice bath, HCl (2N, 170 ml) was added and the product was extracted with EtOAc, the EtOAc was evaporated and the residue was washed with EtOH and diethyl ether. Yield 6.19 g (85%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.33 min). MS (ESI) m / z 226.3 [MH]+, retention time 0.84 min). MS (ESI) m / z 226.3 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 3.52-3.88(m, 8H), 7.09 (d, 1H), 7.29(d, 1H).

[0437] Synthesis of N-methoxy-N-methyl-5-(𠰌line-4-carbonyl)furan-2-formamide: at 4°C to 5-(𠰌line-4-carbonyl)furan-2 -Carboxylic acid (2.6 g, 11 mmol, 1 equiv), N,O-dimethylhydroxylamine (1.46 g, 1.3 equiv), HOBT (1.71, 1 equiv) and DIPEA (2 ml) in DCM (150 ml) To the mixture was added EDCI (2.21 g, 1 eq) and the mixture was stirred at room temperature overnight. The reaction mixture was treated with water. Solid material insoluble in water and DCM was removed by filtration. The organic layer was separated, dried over Na2SO4, filtered, and the solvent was evaporated. The residue was purified by column chromatography (SiO2, CH2Cl2 100%). Yield 2.1 g (68%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.95 min). MS (ESI) m / z 269.5 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 3.26 (s, 3H), 3.54-3.73 (m, 8H), 3.76 (s, 3H), 7.10 (d, 1H), 7.22 (d, 1H ).

[0438] Synthesis of 1-(5-(𠰌line-4-carbonyl)furan-2-yl)ethan-1-ketone: N-methoxy-N-methyl-5-(𠰌line-4-carbonyl ) furan-2-carboxamide (1.45 g, 5.4 mmol, 1 equiv) in THF (50 ml) was cooled to 5°C and methylmagnesium bromide in THF (1.4 M, 11 ml, 3 equiv) was added solution in. The reaction mixture was stirred at 5 °C for 2 h, poured into aqueous NH4Cl and extracted with Et2O. The combined extracts were dried over Na2SO4, filtered and the solvent was evaporated. The title product was used in the next step without purification. Yield 0.45 g (37%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.92 min). MS (ESI) m / z 224.4 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 2.46 (s, 3H), 3.57-3.79 (m, 8H), 3.76 (s, 3H), 7.14 (d, 1H), 7.50 (d, 1H ).

[0439] Synthesis of 2-(5-(𠰌line-4-carbonyl) furan-2-yl)-2-side oxyacetaldehyde: in a three-necked flask, SeO2 (0.42 g, 1.4 equivalents), 1, 4-Dioxane (6 mL) and water (0.36 mL). The mixture was heated to 50 °C and stirred until most of the SeO2 was dissolved. 1-(5-(𠰌line-4-carbonyl)furan-2-yl)ethan-1-one (0.6 g, 0.003 M, 1 equiv) was added, and the reaction was heated to gentle reflux overnight. Selenium solids precipitated during the course of the reaction. The mixture was cooled in an ice bath and filtered through celite to remove selenium. The filter cake was washed with a portion of 1,4-dioxane. The filtrate was concentrated to afford 0.5 g of crude title product which was used in the next step without purification. Yield 0.5 g (78%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.92 min, MS (ESI) m / z 238.1 [MH] +.

[0440] Synthesis of INT-30 ((2E,2'E)-2,2'-(1-(5-(𠰌line-4-carbonyl)furan-2-yl)ethane-1,2-diethylene base) bis(N-ethylhydrazine-1-thioformamide)): crude 2-(5-(𠰌line-4-carbonyl)furan-2-yl)-2-side oxyacetaldehyde ( 0.5 g, 2.0 mmol, 1 equiv) was dissolved in EtOH (25 ml), and ethionamide (0.5 g, 2 equiv) was added along with 2 drops of H2SO4. The reaction mixture was stirred and heated to reflux for 4h and then at ambient temperature for 15h. The formed precipitate was filtered, washed with EtOH, MeCN, water, Et2O and dried. Yield 0.25 g (27%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.37 min, MS (ESI) m / z 440.5 [MH] +.1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.00-1.26 (m, 6H), 3.43-4.09 (m, 13H), 7.19 (s, 1H), 7.24 (s, 1H), 6.06 (br.s, 1H), 8.92 (br.s, 1H), 11.98 (s, 1H), 12.29 (s, 1H).

[0441] Synthesis of intermediate ZN-30: Zn(OAc)22H2O (0.19 g, 1.5 equiv) was added to ethanol containing INT-30 (0.73 g, 2.0 mmol, 1 equiv). The mixture was refluxed for 4 h. The formed complex precipitated from the mixture as a yellow powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.175 g (61%). 1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.11(t, 3H), 1.19 (t, 3H), 3.36-3.85 (m, 13H), 7.11 (s, 1H), 7.15 (s, 1H ), 8.20 (s, 1H), 8.43 (s, 1H).

[0442] Synthesis of compound 30: ZN-30 (0.175 g, 0.3 mmol, 1 equiv) was dissolved in DMSO (4 ml) and a solution of CuCl22H2O (0.076 g, 1.1 equiv) in water (4 ml) was added. The mixture was stirred for 5 min, filtered and washed with water and Et2O. Yield 0.08 g (46%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.86 min). MS (ESI) m / z 501.3 [MH]+.

[0443] Process 15: Synthesis of Compound 34 Synthesis of 2-(furan-2-yl)-2-oxoacetaldehyde: Into a three-necked flask, SeO2 (3.2 g, 28.6 mmol), 1,4-di Gorane (37 ml) and water (2.5 ml). The mixture was heated to 50 °C and stirred until most of the SeO2 was dissolved. 1-(2-furyl)ethanone (3 g, 27.2 mmol) was added, and the reaction was heated to gentle reflux overnight. The progress of the reaction was monitored by TLC (CCl4 / EtOAc 7:3). Selenium solids precipitated during the course of the reaction. The mixture was cooled on an ice bath and filtered through celite to remove selenium. The filter cake was washed with a portion of 1,4-dioxane. The filtrate was concentrated to afford 3.0 g of crude compound 1, which was used in the next step without purification. Yield 3.0 g (88%).

[0444] Synthesis of INT-34 ((2Z,2'E)-2,2'-(1-(furan-2-yl)ethane-1,2-diylidene)bis(N-methylhydrazine- 1-thioformamide)): Dissolve 2-(furan-2-yl)-2-oxoacetaldehyde (0.7 g, 6 mmol) in EtOH (20 mL), add methionamide ( 1.3 g, 12 mmol) and 3 drops of H2SO4. The reaction mixture was stirred and heated to reflux for 4h and then at ambient temperature for 15h. The progress of the reaction was monitored by TLC (CCl4 / EtOAc 7:3). The formed precipitate was filtered, washed with EtOH, water, Et2O and dried. Yield 0.57 g (32%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.35 min). MS (ESI) m / z 299.5 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 3.02 (d, 3H), 3.01 (d, 3H), 6.78 (q, 1H), 7.52 (d, 1H), 7.84 (s, 1H), 7.99-8.04 (m, 1H), 8.13 (dd, 1H), 8.88-8.92 (m, 1H), 10.81 (s, 1H), 11.79 (s, 1H).

[0445] Synthesis of INT-35 ((2Z,2'E)-2,2'-(1-(furan-2-yl)ethane-1,2-diylidene)bis(N-ethylhydrazine- 1-Thioformamide)): INT-35 was made using a procedure similar to that of INT-34. Yield 0.47g (24%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 2.23 min). MS (ESI) m / z 327.5 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.07 (t, 3H), 1.15 (t, 3H), 3.41-3.48 (m, 2H), 3.55-3.63 (m, 2H), 6.78 (q , 1H), 7.52 (d, 1H), 7.84 (s, 1H), 7.99-8.04 (m, 1H), 8.13 (dd, 1H), 8.88-8.92 (m, 1H), 10.81 (s, 1H), 11.79 (s,1H).

[0446] Synthesis of INT-36 ((2Z, 2'E)-2,2'-(1-(5-nitrofuran-2-yl) ethane-1,2-diylidene) bis(N- Ethylhydrazine-1-thioformamide)): INT-36 was made using a procedure similar to that for the preparation of INT-34. Yield 0.02 g (24%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 10 min, retention time 8.11 min). MS (ESI) m / z 372.5 [MH]+.

[0447] Synthesis of INT-40 ((2Z,2'E)-2,2'-(1-(5-bromothiophen-2-yl)ethane-1,2-diylidene)bis(N-ethane Hydrazine-1-thioformamide)): INT-40 was made using a procedure similar to that for the preparation of INT-34. Yield 0.24 g (39%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.85 min). MS (ESI) m / z 422.4 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.15 (t, 3H), 1.18 (t, 3H), 3.41-3.49 (m, 4H), 7.25 (d, 1H), 7.33 (d, 1H ), 8.09 (t, 1H), 8.16 (s, 1H), 8.60 (t, 1H), 11.75 (s, 1H), 11.90 (s, 1H).

[0448] Synthesis of Compound 34: CuCl2.2H2O (0.33 g, 1.9 mmol) was added to 10 ml of ethanol containing INT-34 (0.57 g, 1.9 mmol). The mixture was stirred overnight. The complex was isolated as a reddish-brown powder. The formed precipitate was collected by filtration after cooling, washed with water (2x50 ml), ethanol (2x50 ml) and copious amounts of diethyl ether (5x50 ml), and then dried in vacuo. Yield 0.3 g (47%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.40 min). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.83 min). MS (ESI) m / z 360.3 [MH]+.

[0449] Synthesis of compound 35: According to the method of compound 34, the title compound was prepared from INT-35. After cooling the product was collected by filtration, washed with water (2x50 ml), ethanol (2x50 ml) and copious amounts of diethyl ether (5x50 ml), and then dried in vacuo. Yield 0.3 g (57%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 2.18 min). MS (ESI) m / z 388.5 [MH]+.

[0450] Synthesis of compound 36: The title compound was prepared from INT-36 according to the method for preparing compound 34. The product was isolated as a reddish brown powder. Yield 0.026 g (40%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.70 min). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.69 min). MS (ESI) m / z 433.2 [MH]+.

[0451] Synthesis of compound 40: The title compound was prepared from INT-40 according to the method of compound 34. The product was isolated as a reddish brown powder. The formed precipitate was collected by filtration after cooling, washed with water (2x50 ml), ethanol (2x50 ml) and copious amounts of diethyl ether (5x50 ml), and then dried in vacuo. Yield 0.01 g (6%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 2.72 min). MS (ESI) m / z 484.1 [MH]+.

[0452] Process 16: Synthesis of Compound 42 Synthesis of 1-(4-(phenylsulfonyl)-2-yl)ethan-1-one: to 1-2-yl-ethyl at 5°C To a solution of the ketone (0.3 g, 2.3 mmol) in DCM (50 ml) was added triethylamine (0.59 g, 2.5 equiv) followed by benzenesulfonyl chloride (0.51 g, 1.25 equiv). The mixture was stirred at ambient temperature for 15 h, acidified with 10% aqueous HCl and extracted with DCM. The combined organic extracts were dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography (silica gel, eluent 10% EtOAc / hexane). Yield 0.30 g (48%). NMR (400MHz, CDCl3): 2.20 (s, 3H), 2.22-2.28 (m, 1H), 2.46 (ddd, 1H), 3.58-3.61 (m, 1H), 3.76 (ddd, 1H), 3.90-3.95 ( m, 1H), 4.00-4.09 (m, 2H), 7.54-7.60 (m, 2H), 7.63-7.67 (m, 1H), 7.77-7.80 (m, 2H).

[0453] Synthesis of INT-42 ((2Z,2'Z)-2,2'-(1-(4-(phenylsulfonyl)-2-yl)ethane-1,2-diethylene Base) bis(N-ethylhydrazine-1-thioformamide)) SeO2 (0.14 g, 1.1 equivalent), 1,4-dioxane (3.5 mL) and water (0.1 mL) were charged into the flask . The mixture was warmed to 50 °C and stirred until most of the SeO2 was dissolved. 1-(4-(Phenylsulfonyl)?olin-2-yl)ethan-1-one was added and the reaction was heated at gentle reflux for 4 h. Selenium solids precipitated during the course of the reaction. The mixture was cooled on an ice bath and filtered through celite to remove selenium. The filter cake was washed with a portion of 1,4-dioxane. The filtrate was concentrated in vacuo until most of the 1,4-dioxane was removed. The residue was dissolved in EtOH and filtered. To the filtrate was added thiamide and 1 drop of H2SO4, and the reaction mixture was refluxed for 2 h. Filter the precipitate. Yield 0.08 g (15%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.62 min), MS (ESI) m / z 486.5 [MH ]+.

[0454] Synthesis of Compound 42: INT-42 (0.08 g, 0.17 mmol) was dissolved in DMSO (0.4 ml) and a solution of CuCl2.2H2O (28 mg, 1.0 equiv) in water (0.4 ml) was added. The mixture was stirred for 5 min, filtered, and the precipitate was washed with saturated potassium carbonate solution, water and Et2O. Yield 0.015 g (17%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 2.27 min). MS (ESI) m / z 547.5 [MH]+.

[0455] Process 17: Synthesis of Compound 43 Synthesis of phylloline-2-carboxylic acid methyl ester hydrochloride: 2 carboxylic acid (1.94 g, 15 mmol, 1 equivalent) in methanol (75 ml) at 0 to 10 ° C ) was added thionyl chloride (8.8 g, 5.4 ml, 5 equiv) dropwise. The reaction mixture was stirred at room temperature for 1 h and then heated to reflux for 4 h. The reaction mixture was evaporated. Yield 2.3 g (85.6%). NMR (400MHz, DMSO-d6): 2.78-3.15 (m, 3H), 3.25-3.35 (m, 1H), 3.69 (s, 3H), 3.69-3.81 (m, 1H), 3.95-4.05 (m, 1H) ), 4.60 (dd, 1H), 9.80-10.40 (m, 2H).

[0456] Synthesis of 4-(methylsulfonyl)methyl thioline-2-carboxylate: Stir methyl thioline-2-carboxylate hydrochloride (2.3 g, 12.7 mmol, 1 eq.), formazan at ambient temperature A mixture of sulfonyl chloride (1.74 g, 1.1 ml, 1.2 equiv) and triethylamine (3.2 g, 4.4 ml, 2.5 equiv) in dichloromethane (100 ml) 15h. The reaction mixture was washed with water, dried over Na2SO4, filtered and the solvent was evaporated. Yield 1.3 g (46%). NMR (400MHz, CDCl3): 2.83 (s, 3H), 2.95-3.04 (m, 2H), 3.50-3.58 (m, 1H), 3.74-3.80 (m, 1H), 3.82 (s, 3H), 3.83- 3.88 (m, 1H), 4.09 (ddd, 1H), 4.27 (dd, 1H).

[0457] Synthesis of 4-(methylsulfonyl)-2-carboxylic acid: 4-(methylsulfonyl)-2-carboxylic acid methyl ester (1.3 g, 5.8 mmol, 1 equivalent) was dissolved in methanol (50 ml) and a solution of NaOH (0.58 g, 2.5 equiv) in water (10 ml) was added. The reaction mixture was stirred overnight at room temperature. Methanol was removed in vacuo, the residue was diluted with water, acidified to pH 1 with concentrated HCl and extracted with EtOAc. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo. Yield 0.95 g (78%). NMR (400MHz, DMSO-d6): 2.32 (s, 3H), 2.87-2.95 (m, 1H), 3.20-3.25 (m, 2H), 3.51-3.59 (m, 2H), 3.83-3.99 (m, 2H ).

[0458] Synthesis of N-methoxy-N-methyl-4-(methylsulfonyl) 𠰌line-2-formamide: to 4-(methylsulfonyl) 𠰌line-2 at 0°C - To a stirred solution of carboxylic acid (0.97 g, 5 mmol, 1 equiv) in THF (25 ml) was added carbonyldiimidazole (0.69 g, 0.5 equiv). Then, N,O-dimethylhydroxylamine hydrochloride (0.45 g, 1 eq) and triethylamine (2.34 g, 3.2 ml, 5 eq) were added to the solution, and the ice bath was removed. The reaction mixture was stirred at room temperature until the acid disappeared as determined using TLC. Upon completion, triethylamine hydrochloride was removed by filtration. The filtrate was concentrated to dryness via rotary evaporation. The residue was purified by short path silica gel column chromatography eluting with 20% ethyl acetate / hexane. Yield 0.26 g (22%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.99 min), MS (ESI) m / z 253.1 [MH ]+.

[0459] Synthesis of 2-ethoxy-1-(4-(methylsulfonyl)-2-yl) prop-2-en-1-one: ethyl vinyl ether (0.82 g, 1 ml , 11 equiv) in anhydrous THF (20 mL) was cooled to -78°C, and tert-butyllithium (1.7 M, 6 ml, 9.9 equiv) in pentane was added. The mixture was allowed to warm to 0 °C over a period of 1 h, stirred for 45 min and then cooled to -30 °C. Magnesium bromide (2.5 g, 9.9 equiv) was added. The mixture was then allowed to warm to 0 °C over a period of 15 min and N-methoxy-N-methyl-4-(methylsulfonyl)oxoline-2-carboxamide (0.26 g, 1 mmol , 1 equivalent). The mixture was stirred at 0 °C for 4 h. The progress of the reaction was monitored by TLC. The mixture was poured into aqueous NH4Cl and extracted with Et2O. The combined extracts were dried over Na2SO4, filtered and the solvent was evaporated. The product was used in the next step without further purification. Yield 0.17 g (62%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.36 min), MS (ESI) m / z 527.3 [2MH ]+

[0460] Synthesis of INT-43 ((2Z,2'Z)-2,2'-(1-(4-(methylsulfonyl)-2-yl)propane-1,2-diylidene ) Bis(N-ethylhydrazine-1-thioformamide)): 2-ethoxy-1-(4-(methylsulfonyl) 𠰌line-2-yl) prop-2-ene -1-One (0.16 g, 0.6 mmol, 1 equiv) was dissolved in EtOH (20 ml), and ethionamide (0.14 g, 2 equiv) and 1 drop of H2SO4 were added. The reaction mixture was stirred and heated to reflux for 4h and then at ambient temperature for 15h. The formed precipitate was filtered, washed with EtOH, water, Et2O and dried. Yield 0.15 g (55%). NMR (400MHz, DMSO-d6): 1.10-1.21 (m, 6H), 1.47-1.53 ​​(m, 1H), 2.16-2.21 (m, 1H), 2.47-2.55 (m, 4H), 2.78-2.84 (m , 1H), 2.95 (br.d, 1H), 3.08-3.16 (m, 1H), 3.30 (s, 3H), 3.42-3.50 (m, 4H), 7.78 (br.s, 1H), 8.69 (br .s, 1H), 10.75 (s, 1H), 12.18 (s, 1H). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.47 min), MS (ESI) m / z 438.4 [MH ]+.

[0461] Synthesis of compound 43: CuCl2.2H2O (0.058 g, 1 equiv) was added to ethanol containing sulfur semicarbazone 6 (0.15 g, 0.3 mmol, 1 equiv). The mixture was stirred at ambient temperature for 15 h. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.07g (41%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 2.06 min). MS (ESI) m / z 499.5 [MH]+.

[0462] Process 18: Synthesis of Compound 44 Synthesis of 4-(tertiary butoxycarbonyl) phylloline-2-carboxylic acid: Dissolve 𠰌line-2-carboxylic acid (2 g, 15.6 mmol) in dioxane- To a mixture of water (8 ml / 4 ml), potassium carbonate (4.3 g, 2 equiv) was then added and the mixture was stirred for 30 min. Tert-butyldi-dicarbonate (3.7 g, 1.1 equiv) was added and the reaction mixture was stirred overnight, the solvent was evaporated, the residue was dissolved in water and the solution was acidified with 10% H2SO4, the product was extracted with EtOAc. The organic layer was separated, dried over Na2SO4, filtered and the solvent was evaporated. Yield 1.7 g (47%). NMR (400MHz, DMSO-d6): 1.40 (s, 9H), 3.04-3.10 (m, 2H), 3.42-3.56 (m, 2H), 3.78-3.84 (m, 2H), 4.01-4.07 (m, 1H) ), 12.95 (br.s, 1H).

[0463] Synthesis of tertiary-butyl 2-(methoxy(methyl)aminoformyl)metholine-4-carboxylate: a solution of CDI in THF (7 ml) was added to 4-(tris Butoxycarbonyl)-2-carboxylic acid in THF (7 ml). The mixture was stirred at room temperature for 1 h. The mixture was then cooled to 0°C and a suspension of triethylamine (0.7 ml) and N,O-dimethylhydroxylamine in MeCN (10 ml) was added at 0°C and the reaction was stirred at room temperature for 16 h. The solvent was evaporated, the residue was dissolved in DCM and the solution was washed with water, acetic acid (20% solution) and saturated NaHCO3. The organic layer was separated and dried. The organic layer was washed with water, separated, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by column chromatography (SiO2 / hexane:EtOAc 2:1). Yield 0.78 g (73%). NMR (400MHz, CDCl3): 1.49 (s, 9H), 3.02 (br.s, 1H), 3.24 (s, 3H), 3.60 (dd, 1H), 3.75 (s, 3H), 3.90 (br.s, 1H), 4.00-4.30 (m, 2H), 4.85 (br.s, 1H).

[0464] Synthesis of tertiary butyl 2-(2-ethoxyacryloyl)-4-carboxylate: Ethyl vinyl ether (2 g, 2.6 ml, 11 equivalents) in anhydrous tetrahydrofuran (75 mL) The solution in was cooled to -78°C, and tert-butyllithium (1.7 M, 13 ml, 8.9 equiv) in pentane was added. The mixture was allowed to warm to 0 °C over a period of 1 h, stirred for 45 min and then cooled to -30 °C. Magnesium bromide etherate (5.2 g, 8.9 equiv) was added. The mixture was then allowed to warm to 0 °C over a period of 15 min and tert-butyl 2-(methoxy(methyl)carbamoyl)metholine-4-carboxylate (0.7 g, 2.6 mmol, 1 eq. ). The mixture was stirred at 0 °C for 4 h. The progress of the reaction was monitored by TLC. The mixture was poured into aqueous NH4Cl and extracted with Et2O. The combined extracts were dried over Na2SO4 and evaporated. The product was used in the next step without further purification. Yield 0.6 g (82%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.33 min), MS (ESI) m / z 286.1 [MH ]+.

[0465] Synthesis of 2-((6E,8E)-8-methyl-4,11-dithiol-3,5,6,9,10,12-hexaazatetradecyl-6,8- Dien-7-yl) thioline-4-carboxylic acid tertiary butyl ester: 2-(2-ethoxyacryloyl) thioline-4-carboxylic acid tertiary butyl ester (0.39 g, 1.4 mmol, 1 equivalent ) was dissolved in EtOH (150 ml), thiocarbamide (0.33 g, 2 equiv) and 3 drops of H2SO4 were added. The reaction mixture was stirred and heated to reflux for 4h and then at ambient temperature for 15h. The formed precipitate was filtered, washed with EtOH, water, Et2O and dried. Yield 0.23 g (37.2%). NMR (400MHz, DMSO-d6): 1.10-1.18 (m, 6H), 1.40 (br.d, 9H), 2.20 (s, 3H), 2.90-2.06 (m, 1H), 3.18 (br.s, 1H) ), 3.52-3.80 (m, 6H), 3.82-3.87 (m, 1H), 4.02-4.07 (m, 2H), 5.12 (br.s, 1H), 8.28 (br.s, 1H), 8.51 (t , 1H), 10.24 (s, 1H), 11.20 (br.s, 1H).

[0466] Synthesis of INT-44 (2E,2'E)-2,2'-(1-(𠰌line-2-yl)propane-1,2-diylidene)bis(N-ethylhydrazine-1 -thioformamide) hydrochloride: to 2-((6E,8E)-8-methyl-4,11-dithiol-3,5,6,9,10,12-hexaaza Tetradec-6,8-dien-7-yl) tert-butyl thioline-4-carboxylate (0.23 g, 0.5 mmol) in dioxane was added with HCl / dioxane (3M, 6 ml). The reaction mixture was stirred overnight at room temperature. The formed precipitate was filtered. Yield 0.15 g (76%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.13 min), MS (ESI) m / z 360.4 [MH ]+.

[0467] Synthesis of compound 44: CuCl2.2H2O (0.036 g, 1 equiv) was added to ethanol containing INT-44 (0.1 g, 0.2 mmol, 1 equiv). The mixture was stirred at ambient temperature for 15 h. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.03 g (33%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.47 min). MS (ESI) m / z 421.0 [MH]+.

[0468] Scheme 19: Synthesis of compound 45. Synthesis of 4-benzyl phenoline-2-carbonitrile: 2-chloroacetonitrile (6 g, 1.03 eq.) was dissolved in toluene (16 ml). A solution of N-benzyl alcohol ethanolamine (10 g, 66 mmol) in toluene (5 ml) was added and the reaction mixture was stirred at ambient temperature for 15 h. Toluene (30 ml) was then added and the solution was cooled to -5°C. A suspension of t-BuOK (7.6 g, 1.03 equiv) in THF (128 ml) was added slowly and the mixture was stirred at -5°C for 50 min. The mixture was washed with brine, dried and evaporated. The residue was purified by column chromatography (silica gel, hexane:EtOAc gradient 3:1 to 1:1). Yield 8.4 g (62.8%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.22 min), MS (ESI) m / z 203.4 [MH ]+.

[0469] Synthesis of 4-benzyl phenoline-2-carboxylic acid: Dissolve 4-benzyl phenoline-2-carbonitrile (1.6 g, 7.9 mmol, 1 equiv) in HCl (6M, 65 ml) And the reaction mixture was refluxed for 2.5 h. Toluene (15 ml) was then added and reflux was continued for a further 3 h. The reaction mixture was evaporated to dryness. Yield 1.6 g (78.5%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.65 min), MS (ESI) m / z 222.4 [MH ]+.

[0470] Synthesis of 4-benzyl-N-methoxy-N-methyl-2-formamide: a solution of CDI (1.2 g, 1.2 equiv) in THF (12 ml) at 0°C Add to a solution of 4-benzylmethanolinoline-2-carboxylic acid (1.6 g, 6.2 mmol, 1 equiv) and triethylamine (0.8 ml) in THF (12 ml). The mixture was stirred at room temperature for 1 h. The mixture was then cooled to 0 °C and a suspension of triethylamine (1.2 ml) and N,O-dimethylhydroxylamine (0.73 g, 1.2 equiv) in MeCN (17 ml) was added at 0 °C and at room temperature The reaction was stirred for 16 h. The solvent was subsequently evaporated. The residue was dissolved in DCM and the solution was washed with water followed by acetic acid (20% in water) and saturated aqueous NaHCO3. The organic layer was separated, dried over Na2SO4, filtered and the solvent was evaporated. Yield 0.9 g (54.8%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.00 min), MS (ESI) m / z 265.1 [MH ]+.

[0471] Synthesis of 1-(4-benzyl-2-yl)-2-ethoxyprop-2-en-1-one: ethyl vinyl ether (0.34 g, 0.5 ml, 3.3 equivalents) The solution in anhydrous tetrahydrofuran (20 mL) was cooled to -78°C, and tert-butyllithium (1.7M, 2.4 ml, 3 equiv) in pentane was added. The mixture was allowed to warm to 0 °C over a period of 1 h, stirred for 45 min and then cooled to -30 °C. 4-Benzyl-N-methoxy-N-methylmetholine-2-formamide (3.0 g, 7.5 mmol, 1 equiv) was added in THF and the mixture was stirred at 0 °C for 4 h. The progress of the reaction was monitored by TLC. The mixture was poured into aqueous NH4Cl and extracted with Et2O. The combined extracts were dried over Na2SO4, filtered and the solvent was evaporated. The product was used in the next step without additional purification. Yield 0.3 g (82%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.03 min), MS (ESI) m / z 276.1 [MH ]+.

[0472] Synthesis of INT-45 ((2E, 2'E)-2,2'-(1-(4-benzyl-2-yl) propane-1,2-diylidene) bis(N -Ethylhydrazine-1-thioformamide): 1-(4-benzyl-2-yl)-2-ethoxyprop-2-en-1-one (0.3 g, 1 mmol, 1 equiv) was dissolved in EtOH (10 ml) and ethionamide (0.26 g, 2 equiv) was added along with 1 drop of H2SO4. The reaction mixture was stirred and heated to reflux for 4 h and then at ambient temperature for 15 h. The formed precipitate was filtered, washed with EtOH, water, Et2O and dried. Yield 0.08 g (16%), NMR (400MHz, DMSO-d6): 1.05 (t, 6H), 2.37 (s, 3H), 3.50 -3.56 (m, 4H), 3.80 (br.s, 1H), 4.25 (br.s, 2H), 5.65 (br.s, 1H), 7.30-7.48 (m, 4H), 8.09 (br.s, 1H), 8.59 (br.s, 1H), 10.22 (s, 1H), 10.80 (br.s, 1H).LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1 % TFA, gradient 5 to 87% for 3 min, retention time 1.20 min), MS (ESI) m / z 450.4 [MH]+.

[0473] Synthesis of compound 45: CuCl2.2H2O (0.017 g, 1 equiv) was added to ethanol containing INT-45 (0.045 g, 0.1 mmol, 1 equiv). The mixture was stirred at ambient temperature for 15 h. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.035 g (68.5%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.70 min). MS (ESI) m / z 511.3 [MH]+.

[0474] Process 20: Synthesis of Compound 46 Synthesis of 4-(methoxy(methyl)aminoformyl)piperidine-1-benzoic acid benzyl ester: at 4°C to 1-((benzyloxy) Carbonyl)piperidine-4-carboxylic acid (21.2 g, 80.6 mmol), N,O-dimethylhydroxylamine (10.2 g, 96.7 mmol), HOBT (12.1 g, 96.7 mmol) and TEA (18.5 ml, 241.8 mmol) To a mixture in DCM (300 ml) was added EDCI (17.1 g, 96.7 mmol), and the mixture was stirred at ambient temperature for 15 h. The mixture was washed with water (50 ml), 1N HCl(aq) (50 ml), water (100 ml), brine (150 ml). The organic layer was dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent 100% DCM to 5% MeOH) to afford crude product 1. Yield 22.7 g (92%). NMR (400MHz, DMSO-d6): 1.36-1.43 (m, 2H), 1.64-1.70 (m, 2H), 2.84-2.98 (m, 2H), 3.09 (s, 3H), 3.68 (s, 3H), 4.00-4.06 (m, 2H), 5.07-s, 2H), 7.30-7.41 (m, 5H).

[0475] Synthesis of benzyl 4-(2-ethoxyacryloyl)piperidine-1-carboxylate: a solution of ethyl vinyl ether (2.0 g, 28.1 mmol) in anhydrous tetrahydrofuran (45 ml) was cooled to -78°C and tert-butyllithium (1.7M, 15.6 ml, 25.5 mmol) in pentane was added. The mixture was allowed to warm to 0 °C over a period of 1 h, stirred for 45 min and then cooled to -30 °C. Add benzyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (2.6 g, 8.5 mmol) to THF (15 ml), and stir at 0°C for 4 h. The progress of the reaction was monitored by TLC. The mixture was poured into diluted NH4Cl (100 ml) and extracted with Et2O (3x100 ml). The combined extracts were dried over Na2SO4, filtered and the solvent was evaporated. The product was used in the next step without further purification. Yield 0.77 g (29%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.58 min), MS (ESI) m / z 318.2 [MH ]+.

[0476] Synthesis of 4-((6Z,8E)-8-methyl-4,11-dithiol-3,5,6,9,10,12-hexaazatetradecyl-6,8- Dien-7-yl)piperidine-1-carboxylate benzyl ester: 4-(2-Ethoxyacryloyl)piperidine-1-carboxylate benzyl ester (1.5 g, 4.6 mmol) was dissolved in EtOH ( 80 ml), thiocarbamide (1.2 g, 10.1 mmol) and 3 drops of H2SO4 were added. The reaction mixture was stirred and heated to reflux for 4h and then at ambient temperature for 15h. The formed precipitate was filtered, washed with EtOH, water, Et2O and dried. Yield 0.3 g (14%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.47 min), MS (ESI) m / z 492.2 [MH ]+.

[0477] Synthesis of INT-46 ((2Z,2'E)-2,2'-(1-(piperidin-4-yl)propane-1,2-diylidene)bis(N-ethylhydrazine- 1-thioformamide)): 4-((6Z,8E)-8-methyl-4,11-dithiol-3,5,6,9,10,12-hexaazadeca Tetracarbon-6,8-dien-7-yl)piperidine-1-carboxylic acid benzyl ester (0.35 g, 0.7 mmol) was dissolved in CF3COOH (5 ml) and the solution was heated to reflux for 2.5 h. After cooling to ambient temperature, the reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with CH2Cl2 (3 x 15 ml). The organic layer was washed with water, separated, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by column chromatography (silica gel, eluent 100% DCM to 5% MeOH) to afford the crude title product. Yield 0.25 g (98%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.11 min), MS (ESI) m / z 358.5 [MH ]+.

[0478] Synthesis of compound 46: Cu(OAc)2.2H2O (0.02 g, 0.09 mmol) was added to methanol containing INT-46 (0.03 g, 0.08 mmol). The mixture was stirred at ambient temperature for 15 h. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.04 g (90%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 2.85 min). MS (ESI) m / z 419.5 [MH]+.

[0479] Example 3: Preparation of Compounds 47 to 53 Scheme 21: Synthesis of Compound 47 Synthesis of 2-(cyclopent-2-en-1-yl)ethan-1-ol: at 0°C to LiAlH4 (3.76 g, 99.0 To a stirred suspension of mmol, 2.5 equiv) in THF (250 ml) was slowly added a solution of cyclopent-2-eneacetic acid (5.0 g, 39.6 mmol, 1.0 equiv) in THF (50 ml). The mixture was heated to reflux for 3 h, and then cooled to 0 °C. The reaction was quenched with Na2SO4 (10%) and extracted with Et2O (3x100 ml). The combined extracts were dried over Na2SO4, filtered and evaporated. The product was used in the next step without further purification. Yield 4.06 g (91%). 1H-NMR (400MHz, CDCl3): δ (ppm) 1.40-1.48 (m, 1H), 1.50-1.51 (m, 1H), 1.56-1.64 (m, 1H), 1.67-1.76 (m, 1H), 2.04 -2.13 (m, 1H), 2.27-2.37 (m, 2H), 2.78 (br.s, 1H), 3.66-3.75 (m, 2H), 5.68-5.71 (m, 1H), 5.74-5.76 (m, 1H).

[0480] Synthesis of tertiary butyl (2-(cyclopent-2-en-1-yl) ethoxy) diphenylsilane: to 2-(cyclopent-2-en-1-yl) ethyl-1 - To a solution of alcohol (4.05 g, 36.1 mmol) in dichloromethane (200 ml) was added tertiary butyldiphenylsilane chloride (11.9 g, 43.3 mmol), triethylamine (4.7 g, 46.9 mmol) and 4-(Dimethylamino)pyridine (0.22 g, 1.8 mmol), and the mixture was stirred at room temperature for 3 hours. After quenching the reaction by adding 1N hydrochloric acid, the mixture was extracted with dichloromethane. The organic extracts were washed with water, aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated in vacuo. The residue was subjected to flash chromatography (silica gel, hexane-ethyl acetate 50:1) to obtain compound 2. Yield 11.3 g (89%). 1H-NMR (400MHz, DMSO-d6): δ (ppm) 0.99 (s, 9H), 1.26-1.35 (m, 1H), 1.43-1.51 (m, 1H), 1.61-1.69 (m, 1H), 1.88 -1.97 (m, 1H), 2.13-2.30 (m, 2H), 2.70-2.76 (m, 1H), 3.68 (t, 2H), 5.62-5.65 (m, 1H), 5.66-5.70 (m, 1H) , 7.41-7.46 (m, 6H), 7.60-7.62 (m, 4H).

[0481] Synthesis of 3-(2-((tertiary butyldiphenylsilyl)oxy)ethyl)cyclopentane-1,2-diol: the tertiary butyl (2-(cyclopentyl) 2-en-1-yl)ethoxy)diphenylsilane (9.0 g, 25.6 mmol) was dissolved in a H2O-tBuOH (1:3) mixture, followed by the addition of N-methylthioline N-oxide (3.9 g, 33.3 mmol) and OsO4 (0.004 g of a 4% solution in water, 0.001 equiv). The reaction mixture was stirred at 60 °C until completion, monitored by TLC (CHCl3-CH3OH 20:1), the solid catalyst was filtered, rinsed with EtOAc, and the filtrate was quenched with aqueous Na2S2O3 (10%). The aqueous layer was extracted with EtOAc, the organic extracts were combined, dried over Na2SO4, filtered and the solvent was evaporated. The crude product was purified by flash chromatography (gradient CHCl3-MeOH, 1:0 to 95:5) to afford diol 3. Yield 6.3 g (64%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.99 min). MS (ESI) m / z 385.1 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 0.98 (s, 9H), 1.26-1.55 (m, 2H), 1.66-1.68 (m, 1H), 1.69-1.78 (m, 2H), 1.79 -1.88 (m, 2H), 3.59-3.60 (m, 1H), 3.67 (q, 2H), 3.74-3.88 (m, 1H), 4.09 (dd, 1H), 4.32 (dd, 1H), 7.41-7.48 (m, 6H), 7.60-7.62 (m, 4H).

[0482] Synthesis of 3-(2-((tertiary butyldiphenylsilyl)oxy)ethyl)cyclopentane-1,2-dione: Dimethylsulfoxide (3.6 g , 46.8 mmol) was added to a stirred solution of acetyl chloride (2.97 g, 23.4 mmol) in dichloromethane (100 ml). After 15 min, slowly add 3-(2-((tertiary butyldiphenylsilyl)oxy)ethyl)cyclopentane-1,2-diol (3.0 g, 7.9 mmol) in dichloromethane (20 ml) over a period of 15 min and the resulting solution was stirred at -78 °C for 1 h. Triethylamine (7.3 g, 70 mmol) was then added and the mixture was stirred at -78°C for 15 min and then warmed to ambient temperature. The reaction mixture was washed with water, the organic layer was dried over Na2SO4, filtered and evaporated. Yield 1.6 g (54%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 2.01 min). MS (ESI) m / z 381.1 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 0.97 (s, 9H), 1.90 (t, 1H), 2.27-2.35 (m, 2H), 2.46-2.51 (m, 2H), 3.52-3.46 (m, 2H), 3.63-3.86 (m, 2H), 7.41-7.48 (m, 6H), 7.60-7.62 (m, 4H).

[0483] Synthesis of (2E,2'E)-2,2'-(3-(2-((tertiary butyldiphenylsilyl)oxy)ethyl)cyclopentane-1,2-di Subunit) bis(N-ethylhydrazine-1-thioformamide): 3-(2-((tertiary butyldiphenylsilyl)oxy)ethyl)cyclopentane-1, 2-Diketone (1.6 g, 4.2 mmol) was dissolved in EtOH (25 ml), thiocarbamide (1.02 g, 4.4 mmol) and 3 drops of H2SO4 were added, and the reaction mixture was stirred at reflux for 4 h and at ambient temperature Stir for 15h. The formed precipitate was filtered, washed with EtOH, water, Et2O and dried to give product 5. Yield 1.75 g (74%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 2.58 min). MS (ESI) m / z 583.3 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 0.99 (s, 9H), 1.11 (t, 3H), 1.20 (t, 3H), 1.41-1.59 (m, 2H), 1.96-2.03 (m , 2H), 2.21-2.29 (m, 1H), 2.71-2.85 (m, 2H),3.53-3.62 (m, 4H), 3.71-3.83 (m, 2H), 7.41-7.48 (m, 6H), 7.61 -7.63 (m, 4H). 7.75 (t, 1H), 8.57 (t, 1H), 10.73 (s, 1H), 12.26 (s, 1H).

[0484] Synthesis of INT-47 ((2E,2'E)-2,2'-(3-(2-hydroxyethyl)cyclopentane-1,2-diylidene) bis(N-ethylhydrazine -1-thioformamide)): at ambient temperature to (2E,2'E)-2,2'-(3-(2-((tertiary butyldiphenylsilyl)oxy) To a solution of ethyl)cyclopentane-1,2-diylidene)bis(N-ethylhydrazine-1-thioformamide) (0.85 g, 1.46 mmol) in THF (25 ml) was added three Triethylamine Hydrofluoride. The resulting mixture was stirred at ambient temperature for 10 h and treated with saturated aqueous ammonium chloride. The solution was extracted with ether, washed with saturated aqueous ammonium chloride and brine. The organic layer was dried over Na2SO4, filtered, and the solvent was concentrated under reduced pressure to give the crude title product. Yield 0.18 g (36%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.30 min). MS (ESI) m / z 345.0 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.28 (t, 3H), 1.35 (t, 3H), 1.58-1.81 (m, 2H), 1.86-1.95 (m, 1H), 2.03-2.13 (m, 1H), 2.24-2.33 (m, 1H), 2.44-2.57 (m, 1H), 2.65-2.77 (m, 1H), 2.85-2.93 (m, 1H), 3.31-3.53 (m, 1H) , 3.68-2.82 (m, 5H), 7.25-7.32 (m, 1H), 7.41-7.48 (m, 1H), 8.75 (s, 1H), 12.27 (s, 1H).

[0485] Synthesis of ZN-47: Zn(OAc)22H2O (0.58 g, 2.7 mmol) was added to ethanol containing INT-47 (0.61 g, 1.8 mmol). The mixture was refluxed for 4 h. The formed complex precipitated from the mixture as a yellow powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.72 g (99%). 1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.09 (t, 3H), 1.14 (t, 3H), 1.35-1.48 (m, 2H), 2.01-2.11 (m, 2H), 2.51-2.55 (m, 2H), 2.67-2.73 (m, 1H), 2.76-2.84 (m, 1H), 3.47-3.56 (m, 4H), 4.34 (t, 1H), 4.42 (t, 1H), 7.37 (br .s, 1H), 7.85 (t, 1H).

[0486] Synthesis of compound 47: ZN-47 (0.72 g, 1.7 mmol) was dissolved in DMSO (3.6 ml) and a solution of CuCl22H2O (0.39 g, 1.9 mmol) in water (3.6 ml) was added. The mixture was stirred for 5 min, the precipitate was filtered and washed with saturated potassium carbonate solution, water and Et2O. Yield 0.09 g (13%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.81 min). MS (ESI) m / z 406.5 [MH]+.

[0487] Scheme 22: Synthesis of Compound 48 Synthesis of 2-(cyclopent-2-en-1-yl)ethan-1-ol: Cooling of LiAlH4 (4.14 g, 109.0 mmol) in THF (250 ml) to To the stirred suspension at 0°C was slowly added a solution of cyclopent-2-eneacetic acid (5.5 g, 43.6 mmol, 1.0 equiv) in THF (50 ml). The mixture was heated to reflux for 3 h, and then cooled to 0 °C. The reaction was quenched with Na2SO4 (10%) and extracted with Et2O (3x100 ml). The combined extracts were dried over Na2SO4, filtered and evaporated. The product was used in the next step without further purification. Yield 4.4 g (90%). 1H-NMR (400MHz, CDCl3): δ (ppm) 1.40-1.49 (m, 1H), 1.50-1.51 (m, 1H), 1.58-1.64 (m, 1H), 1.67-1.76 (m, 1H), 2.04 -2.13 (m, 1H), 2.42-2.37 (m, 2H), 2.78 (br.s, 1H), 3.69-3.77 (m, 2H), 5.68-5.71 (m, 1H), 5.74-5.77 (m, 1H).

[0488] Synthesis of ((2-(cyclopent-2-en-1-yl) ethoxy) methyl) benzene: to 2-(cyclopent-2-en-1-yl) ethyl-1 at 0°C - To a stirred solution of alcohol (1.0 g, 8.9 mmol) in DMF (12 ml) was added NaH (0.5 g, 13.5 mmol, 60%-65% in mineral oil) in one portion. After stirring for 30 min, chlorotoluene (2.03 g, 16.1 mmol) was added to the solution. The reaction was stirred overnight, then quenched with water (15 ml) and extracted three times with Et2O. The combined extracts were washed with water, brine, dried over Na2SO4, filtered and the solvent was evaporated. The crude product was used without purification. Yield 1.8 g (99%). 1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.33-1.41 (m, 1H), 1.46-1.55 (m, 1H), 1.61-1.69 (m, 1H), 1.93-2.02 (m, 1H) , 2.14-2.33 (m, 2H), 2.70 (t, 1H), 3.47 (t, 2H), 4.45 (s, 2H), 5.70 (t, 2H), 7.25-7.32 (m, 3H), 7.34-7.45 (m, 2H).

[0489] Synthesis of 3-(2-(phenylmethyloxy) ethyl) cyclopentane-1,2-diol: ((2-(cyclopent-2-en-1-yl) ethoxy ) methyl) benzene (2.2 g, 11.1 mmol) was dissolved in H2O-tBuOH mixture (1:3), then N-methyl thioline N-oxide (1.7 g, 14.4 mmol) and OsO4 (0.008 g in 4% solution in water, 0.001 equivalent). The reaction mixture was stirred at 60 °C until completion, monitored by TLC (CHCl3-CH3OH 20:1), the solid catalyst was filtered, rinsed with EtOAc, and the filtrate was quenched with aqueous Na2S2O3 (10%). The aqueous layer was extracted with EtOAc, the organic extracts were combined, dried over Na2SO4, filtered and the solvent was evaporated. The crude product was purified by flash chromatography (CHCl3-MeOH gradient 1:0 to 95:5) to afford the title product. Yield 1.64 g (62%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.20 min). MS (ESI) m / z 237.0 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 0.95-1.03 (m, 1H), 1.29-1.59 (m, 2H), 1.66-1.68 (m, 1H), 1.69-1.78 (m, 2H) , 1.79-1.88 (m, 1H), 3.41-3.48 (m, 2H), 3.45 (qq, 1H), 3.75-3.91 (m, 1H), 4.09 (dd, 1H), 4.32 (dd, 1H), 4.41 -4.48 (m, 2H), 7.25-7.36 (m, 5H).

[0490] Synthesis of 3-(2-(phenylmethyloxy)ethyl)cyclopentane-1,2-dione: Add dimethylsulfoxide (6.1 g, 78.0 mmol) to ethylene dione at -78°C In a stirred solution of acetyl chloride (4.9 g, 39.0 mmol) in dichloromethane (150 ml). After 15 min, a solution of 3-(2-(benzyloxy)ethyl)cyclopentane-1,2-diol (3.1 g, 13.0 mmol) in dichloromethane (20 ml) was added slowly ( The resulting solution was stirred over a period of 15 min) and at -78 °C for 1 h. Triethylamine (11.8 g, 117.0 mmol) was then added, the mixture was stirred at -78°C for 15 min and then warmed to ambient temperature. The reaction mixture was washed with water, the organic layer was dried over Na2SO4, filtered and the solvent was evaporated. Yield 2.6 g (87%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.26 min). MS (ESI) m / z 233.1 [MH]+.

[0491] Synthesis of INT-48 ((2E, 2'E)-2,2'-(3-(2-(benzyloxy) ethyl) cyclopentane-1,2-diylidene) bis (N-ethylhydrazine-1-thioformamide)): 3-(2-(benzyloxy)ethyl)cyclopentane-1,2-dione (2.6 g, 11.4 mmol) Dissolved in EtOH (35 ml), added ethionamide (2.86 g, 23.9 mmol) and 3 drops of H2SO4, and stirred the reaction mixture at reflux for 4h and at ambient temperature for 15h. The formed precipitate was filtered, washed with EtOH, water, Et2O and dried to give the product. Yield 0.40 g (9%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.86 min). MS (ESI) m / z 435.4 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.12 (t, 3H), 1.19 (t, 3H), 1.46-1.58 (m, 2H), 2.05-2.15 (m, 1H), 2.22-2.32 (m, 1H), 2.53-2.58 (m, 1H), 2.74-2.82 (m, 2H),3.41-3.63 (m, 6H), 4.47 (d, 2H), 7.26-7.37 (m, 5H), 7.77 (t, 1H), 8.66 (t, 1H), 10.74 (s, 1H), 12.25 (s, 1H).

[0492] Synthesis of INT-49 ((2E, 2'E)-2,2'-(3-(2-methoxyethyl)cyclopentane-1,2-diylidene) bis(N-ethane Hydrazine-1-thioformamide)): INT-49 was made using a procedure similar to that for the preparation of INT-48. Yield 1.1 g (72%). 1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.73 (t, 2H), 1.97-2.01 (m, 2H), 2.24-2.27 (m, 1H), 2.36-2.39 (m, 1H), 2.53 -2.57 (m, 1H), 2.62-2.67 (m, 1H), 3.12 (d, 3H), 3.38-3.45 (m, 1H).

[0493] Synthesis of Compound 48: Cu(OAc)22H2O (0.26 g, 1.12 mmol) was added to ethanol containing INT-485 (0.4 g, 0.92 mmol). The mixture was stirred at ambient temperature for 15 h. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.1 g (22%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.98 min). MS (ESI) m / z 496.5 [MH]+.

[0494] Synthesis of compound 49: According to the method of preparing compound 48, the title compound was prepared from INT-49. The product precipitated from the reaction mixture in the form of a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.03 g (35%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 2.33 min). MS (ESI) m / z 420.5 [MH]+.

[0495] Process 23: Synthesis of Compound 50 Synthesis of 2-(cyclopent-2-en-1-yl)-1-? To a solution of 2-cyclopentene-1-acetic acid (2.0 g, 16 mmol) in dichloromethane (100 ml), 1 drop of DMF was added and the mixture was stirred at ambient temperature for 2 h. The solvent was evaporated under reduced pressure, the residue was dissolved in EtOAc, and Et3N (1.92 g, 1.2 equiv) and oxoline (1.38 g, 1 equiv) were added to the solution. The reaction was stirred overnight at ambient temperature. The reaction mixture was washed with water, the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2-MeOH, 10:1). Yield 2.1 g (67.8%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.16 min, MS (ESI) m / z 196.4 [MH] +.1H-NMR (400MHz, CDCl3): δ (ppm) 1.41-1.53 ​​(m, 1H), 2.12-2.25 (m, 1H), 2.29-2.46 (m, 4H), 3.09-3.21 (m, 1H) , 3.42-3.54 (m, 2H), 3.58-3.76 (m, 6H), 5.70-5.74 (m, 1H), 5.75-5.83 (m, 1H).

[0496] Synthesis of 2-(2,3-dihydroxycyclopentyl)-1-𠰌linyl ethan-1-ketone: 2-(cyclopent-2-en-1-yl)-1-𠰌linyl Ethan-1-one (2.1 g, 10.7 mmol) was dissolved in H2O-tBuOH mixture (1 :3) and to this stirred solution were added N-methylphospholine-N-oxide (1.64 equiv) and OsO4 ( 0.035 g 4% solution in water, 0.001 equivalent). The reaction mixture was stirred at 60 °C for 4 h and then at ambient temperature for 15 h. The reaction was quenched with Na2S2O3 (10%) and extracted with EtOAc, the organic layer was dried over Na2SO4, filtered and evaporated. Yield 1.7 g (68.9%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.83 min, MS (ESI) m / z 230.3 [MH] +.

[0497] Synthesis of 3-(2-oxolinyl-2-oxoethyl)cyclopentane-1,2-dione: Dimethylsulfoxide (1.5 g, 1.4 ml, 4 eq. ) was added to a stirred solution of acetyl chloride (1.83 g, 1.2 ml, 3 equiv) in dichloromethane (40 ml). After 5 min, 2-(2,3-dihydroxycyclopentyl)-1-?olinylethan-1-one (1.1 g, 4.8 mmol, 1 eq.) in dichloromethane (80 ml) was added slowly (over a period of 15 min) and the resulting solution was stirred at -78 °C for 1 h. Triethylamine (2.9 g, 4 ml, 6 equiv) was then added, the mixture was stirred at -78°C for 15 min and then warmed to ambient temperature. The reaction mixture was washed with water, the organic layer was dried over Na2SO4, filtered and evaporated. Yield 0.89 g (82.3%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.88 min, MS (ESI) m / z 225.9 [MH] +.

[0498] Synthesis of INT-50 ((2Z, 2'Z)-2,2'-(3-(2-𠰌olinyl-2-oxoethyl)cyclopentane-1,2-diylidene ) Bis(N-ethylhydrazine-1-thioformamide)): 3-(2-? , 4 mmol, 1 eq) was dissolved in EtOH (25 ml), ethionamide (0.94 g, 2 eq) and 3 drops of H2SO4 were added, and the reaction mixture was stirred at reflux for 4 h and at ambient temperature for 15 h. The formed precipitate was filtered, washed with EtOH, water and crystallized from isopropanol. Yield 0.6 g (35.5%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.33 min, MS (ESI) m / z 428.5 [MH] +.1H-NMR (400MHz, CDCl3): δ (ppm) 1.14 (t, 3H), 1.20 (t, 3H), 1.46-1.56 (m, 1H), 2.14-2.21 (m, 1H), 2.45-2.55 (m, 2H), 2.74-2.87 (m, 1H), 2.89-2.96 (m, 1H), 3.06-3.13 (m, 1H), 3.46 (br.s, 4H), 3.53-3.65 (m, 8H) , 7.78 (br.s, 1H), 8.69 (br.s, 1H), 10.75 (br.s, 1H), 12.18 (s, 1H).

[0499] Synthesis of ZN-50: Zn(OAc)22H2O (0.15 g, 1.5 equiv) was added to ethanol containing INT-50 (0.2 g, 0.5 mmol, 1 equiv). The mixture was refluxed for 4 h. The formed complex precipitated from the mixture as a yellow powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.1 g (43.5%). 1H-NMR (400MHz, CDCl3): δ (ppm) 1.1 (t, 3H), 1.15 (t, 3H), 1.37-1.49 (m, 1H), 2.06-2.17 (m, 1H), 2.33-2.47 (m , 2H), 2.77-2.87 (m, 1H), 2.88-2.96 (m, 1H), 3.00-3.09 (m, 1H), 3.40-3.65 (m, 12H), 7.40 (br.s, 1H), 7.95 (br.s, 1H). Synthesis of Compound 50: ZN-50 (0.075 g, 0.15 mmol, 1 equiv) was dissolved in DMSO (1.8 ml) and a solution of CuCl22H2O (0.034 g, 1.1 equiv) in water (1.8 ml) was added. The mixture was stirred for 5 min, filtered, and the precipitate was washed with saturated potassium carbonate solution, water and Et2O. Yield 0.044 g (58.8%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.85 min). MS (ESI) m / z 489.4 [MH]+.

[0501] Scheme 24: Synthesis of Compound 51: Synthesis of INT-51 ((2E,2'E)-2,2'-(3-methylcyclopentane-1,2-diylidene)bis(N- Methylhydrazine-1-thioformamide)): Dissolve 3-methyl-1,2-cyclopentanedione (2 g, 17.8 mmol, 1 eq.) in EtOH (100 ml), add formazan Thiamine urea (3.75 g, 2 equiv) and 3 drops of H2SO4, and the reaction mixture was stirred at reflux for 4 h and at ambient temperature for 15 h. The formed precipitate was filtered, washed with EtOH, water, Et2O and dried. Yield 3.87 g (80%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.34 min, MS (ESI) m / z 287.0 [MH] +.1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.05-1.27 (m, 9H), 1.35-1.48 (m, 1H), 2.01-2.15 (m, 1H), 2.47-2.56 (m, 1H), 2.71-2.82 (m, 2H), 3.49-3.63 (m, 4H), 7.74 (br.s, 1H), 8.65 (br.s, 1H), 10.74 (s, 1H), 12.23 (s , 1H).

[0502] Synthesis of INT-52 ((2E, 2'E)-2,2'-(3-methylcyclopentane-1,2-diylidene) bis(N-ethylhydrazine-1-thio Formamide)): INT-52 was made using a procedure similar to that of INT-51. Yield 5 g (90.5%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.59 min, MS (ESI) m / z 315.1 [MH] +.1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.16 (d, 3H), 1.36-1.47 (m, 1H), 2.09-2.16 (m, 1H), 2.45-2.65 (m, 1H) , 2.69-2.82 (m, 2H), 3.02 (br.s, 6H), 7.88 (br.s, 1H), 8.60 (br.s, 1H), 10.82 (s, 1H), 12.33 (s, 1H ).

[0503] Synthesis of INT-53 ((2E, 2'E)-2,2'-(3-methylcyclopentane-1,2-diylidene) bis(N-(2-(diethylamine) yl)ethyl)hydrazine-1-carbothioamide)): INT-53 was made using a procedure similar to that for the preparation of INT-51. Yield 0.5 g (25%). 1H-NMR (400MHz, DMSO-d6): δ (ppm) 0.92-0.99 (m, 12H), 1.17 (d, 3H), 1.38-1.47 (m, 1H), 2.10-2.18 (m, 1H), 2.58 -2.67 (m, 4H), 2.74-2.82 (m, 2H), 3.54-3.63 (m, 4H), 7.79 (br.s, 1H), 8.50 (br.s, 1H), 10.80 (s, 1H ), 12.21 (s, 1H).

[0504] Synthesis of Compound 51: Cu(OAc)22H2O (0.61 g, 1.1 equiv) was added to sulfur-containing semicarbazone 1 (0.73 g, 2.5 mmol, 1 equiv) in ethanol. The mixture was stirred at ambient temperature for 15 h. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.46 g (51.9%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 2.51 min). MS (ESI) m / z 348.0 [MH]+.

[0505] Synthesis of compound 52: The title compound was prepared from INT-52 according to the method for preparing compound 51. The complex precipitated from the reaction mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.7 g (79%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 2.62 min). MS (ESI) m / z 376.3 [MH]+.

[0506] Synthesis of compound 53: The title compound was prepared from INT-53 according to the method for preparing compound 51. The product precipitated from the reaction mixture in the form of a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.07 g (15%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.25 min). MS (ESI) m / z 518.3 [MH]+.

[0507] Example 4: Preparation of Compounds 54 to 65 Synthesis of INT-56 ((2Z,2'E)-2,2'-(1-(pyridin-4-yl)propane-1,2-diylidene) Bis(N-ethylhydrazine-1-thioformamide): INT-55 was made using a procedure similar to that for the preparation of INT-1 of Example 1. Yield 0.030 g (5%). LCMS (C18 column 100×4.6 mm, 5.0 µm, pore size 100Å, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 10 min, retention time 5.01 min). MS (ESI) m / z 352.6 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 0.89 (t, 3H), 1.16 (t, 3H), 2.36 (s, 3H), 3.60 (m, 4H), 6.82 (t, 1H), 7.32 (d, 2H), 7.73 (d, 1H), 8.73 (d, 2H), 9.37 (s, 1H), 10.77 (s, 1H).

[0508] Synthesis of INT-58 ((2Z,2'E)-2,2'-(1-(pyridin-2-yl)propane-1,2-diylidene)bis(N-ethylhydrazine-1 - Thioformamide)): INT-58 was made using a procedure similar to that for the preparation of INT-1 of Example 1. Yield 0.75 g (76.4%). 1H-NMR (400MHz, DMSO D6): δ (ppm) 0.99 (t, 3H), 1.16 (t, 3H), 2.38 (s, 3H), 3.36-3.46 (m, 2H), 3.56-3.66 (m, 2H), 7.36 (t, 1H), 7.55 (dd, 1H), 7.66 (d, 1H), 8.01 (t, 1H), 8.73-8.75 (m, 2H), 10.58 (s, 1H), 11.82 (s , 1H).

[0509] Synthesis of INT-62 ((2Z,2'E)-2,2'-(1-(pyridin-3-yl)propane-1,2-diylidene)bis(N-ethylhydrazine-1 - Thioformamide)): INT-62 was made using a procedure similar to that for the preparation of INT-1 of Example 1. Yield 0.69g (65%). LCMS (C18 column 100×4.6 mm, 5.0 µm, pore size 100Å, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 10 min, retention time 4.71 min). MS (ESI) m / z 352.1 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 0.90 (t, 3H), 1.15 (t, 3H), 2.37 (s, 3H), 3.60 (m, 4H), 6.81 (t, 1H), 7.53 (m, 1H), 7.71 (d, 1H), 8.43 (s, 1H), 8.65-8.70 (m, 2H), 9.73 (br.s, 1H), 10.65 (br.s, 1H).

[0510] Synthesis of INT-64 ((2E, 2'E)-2,2'-(1-(4-(dimethylamino)phenyl) propane-1,2-diylidene) bis(N -Ethylhydrazine-1-thioformamide)): INT-64 was made using a procedure similar to the procedure for the preparation of INT-1 of Example 1. Yield 0.67 g (68.4%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.54 min, MS (ESI) m / z 394.5 [MH] +.1H-NMR (400MHz, DMSO-d6): δ (ppm) 0 / 94 (t, 3H), 1.15 (t, 3H), 2.33 (s, 3H), 2.87 (s, 6H), 6.85 (d , 2H), 7.02 (br.s), 7.11 (d, 2H), 8.71 (br.s, 1H), 10.72 (s, 1H).

[0511] Synthesis of compound 56: The title compound was prepared from INT-56 according to the method for preparing compound 1 of Example 1. The complex was isolated as a reddish-brown powder. After cooling the product was collected by filtration, washed with water (2 x 15 ml), ethanol (2 x 15 ml), and then dried in vacuo to afford the title product. Yield 0.010 g (28%). LCMS (C18 column 20×2 mm, 2.5 µm, pore size 100Å, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 3.41 min). MS (ESI) m / z 413.5 [MH]+.

[0512] Synthesis of compound 58: According to the method of preparing compound 1 of Example 1, the title compound was prepared from INT-58. The product precipitated from the reaction mixture in the form of a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, diethyl ether, and then dried under vacuum. Yield 0.044 g (18.6%). LCMS (C18 column 20×2 mm, 2.5 µm, pore size 100Å, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.36 min). MS (ESI) m / z 413.4 [MH]+.

[0513] Synthesis of Compound 62: The title compound was prepared from INT-62 according to the method of Compound 1 of Preparation Example 1. The product was isolated as a reddish brown powder. After cooling the formed precipitate was collected by filtration, washed with water (2 x 15 ml), ethanol (2 x 15 ml), and then dried in vacuo. Yield 0.094 g (27%). LCMS (C18 column 20×2 mm, 2.5 µm, pore size 100Å, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.72 min). MS (ESI) m / z 413.5 [MH]+. Synthesis of Compound 64 The title compound was prepared from INT-64 according to the method for preparing compound 1 of Example 1. The product precipitated from the reaction mixture in the form of a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.037 g (18%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 2.31 min). MS (ESI) m / z 455.1 [MH]+.

[0515] Synthesis of INT-63 ((2Z, 2'E)-2,2'-(1-(4-(dimethylamino)phenyl) ethane-1,2-diylidene) bis( N-Ethylhydrazine-1-thioformamide)): INT-63 was made using a procedure similar to that for the preparation of INT-34 of Example 2. Yield 0.57 g (35%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.63 min, MS (ESI) m / z 380.5 [MH] +.1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.12-1.24 (m, 6H), 2.96 (s, 6H), 3.53-3.67 (m, 4H), 6.75 (d, 2H), 7.64 (d, 2H), 7.88 (br.s, 1H), 8.22 (s, 1H), 8.76 (br.s, 1H), 11.73 (s, 1H), 12.18 (s, 1H).

[0516] Synthesis of compound 63: The title compound was prepared from INT-63 according to the method for preparing compound 43 of Example 2. The product precipitated from the reaction mixture in the form of a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.075 g (47%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 2.07 min). MS (ESI) m / z 441.1 [MH]+.

[0517] Synthesis of INT-55 ((2E, 2'E)-2,2'-(pentane-2,3-diylidene) bis(N-(tertiary butyl)hydrazine-1-thiomethyl Amide)): INT-55 was made using a procedure similar to that for the preparation of INT-51 of Example 3. Yield 1.97 g (34%). NMR (400MHz, DMSO-d6): 0.96 (s, 3H), 1.50 (s, 9H), 1.52 (s, 9H), 2.10 (s, 3H), 2.74 (q, 2H), 7.75 (s, 1H) , 7.79 (s, 1H), 10.30-10.48 (m, 2H).

[0518] Synthesis of INT-65 ((2E, 2'E)-2,2'-(pentane-2,3-diylidene) bis(N-ethylhydrazine-1-thioformamide)) : INT-65 was made using a procedure similar to that for the preparation of INT-51 of Example 3. Yield 2.37 g (49%). 1H-NMR (400MHz, DMSO-d6): δ (ppm) 0.91 (t, 3H), 1.14 (t, 6H), 2.19 (s, 3H), 2.80 (q, 2H), 3.54 (q, 4H), 8.25-8.40 (m, 2H), 10.15 (s, 1H), 10.27 (s, 1H).

[0519] Synthesis of compound 55: The title compound was prepared from INT-55 according to the method for preparing compound 51 of Example 3. The product precipitated from the reaction mixture in the form of a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.4g (82%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 3.41 min). MS (ESI) m / z 420.6 [MH]+.

[0520] Synthesis of compound 65: The title compound was prepared from INT-65 according to the method for preparing compound 51 of Example 3. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.4 g (82%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 2.68 min). MS (ESI) m / z 364.3 [MH]+.

[0521] Process 25: Synthesis of Compound 54 Synthesis of N-(furan-2-ylmethyl)hydrazinethioformamide: 2-(isothiocyanatomethyl)tetrahydrofuran (10 g, 71.8 mmol ) in EtOH (100 ml) was added hydrazine hydrate (4.5 g, 89.75 mmol) and the reaction mixture was stirred for 3 h. The formed precipitate was collected by filtration, washed with ethanol (2 x 150 ml) and dried to give 1. Yield 9.3 g (76%).1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.52-1.60 (m, 1H), 1.76-1.90 (m, 3H), 3.39-3.45 (m, 1H) , 3.59-3.66 (m, 2H), 3.76 (q, 1H), 3.93-3.99 (m, 1H), 4.47 (s, 2H), 7.74 (s, 1H), 8.67 (s, 1H).

[0522] Synthesis of INT-54 ((2Z, 2'E)-2,2'-(pentane-2,3-diylidene) bis(N-(furan-2-ylmethyl)hydrazine-1- Thioformamide)): 2,3-Pentanedione (0.4 g, 4 mmol) was dissolved in EtOH (60 ml), N-(furan-2-ylmethyl)hydrazine thioformamide was added (1.37 g, 8 mmol) and 3 drops of H2SO4 and the reaction mixture was stirred at reflux for 4 h and at room temperature overnight. The progress of the reaction was monitored by TLC (CHCl3-MeOH 10:1). The precipitate was filtered, washed with EtOH, water, Et2O and dried. Yield 0.9 g (55%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.70 min). MS (ESI) m / z 407.5 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 0.90 (t, 3H), 2.19 (s, 3H), 2.90 (q, 2H), 4.82 (d, 4H), 6.27-6.29 (m, 2H ), 6.40 (s, 2H), 7.58 (s, 2H), 8.65 (t, 1H), 8.73 (t, 1H), 10.42 (s, 1H), 10.53 (s, 1H).

[0523] Synthesis of Compound 54: Cu(OAc)2.2H2O (0.12 g, 1.1 equiv) was added to ethanol containing INT-54 (0.2 g, 0.5 mmol, 1 equiv). The mixture was stirred at ambient temperature for 15 h. The formed complex precipitated from the mixture as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried in vacuo. Yield 0.022 g (9.5%). LCMS (C18 column 20×2 mm, particle size 2.5 µm, pore size 100A, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 2.62 min). MS (ESI) m / z 468.4 [MH]+.

[0524] Process 26: Synthesis of compound 57 Synthesis of 2-oxo-2-(pyridin-2-yl) acetaldehyde: to 1-(pyridin-2-yl) ethyl-1-one (10.0 g, 82.5 mmol ) in DMSO (150 ml) was added 47% HBr (28 ml, 247.5 mmol) and the mixture was stirred at 60 °C overnight. The reaction was quenched with NaHCO3 and diluted with water to a total volume of 1000 ml. The product was extracted with EtOAc (3 x 150 ml), the combined organic layers were dried over anhydrous Na2SO4, filtered and the solvent was removed under reduced pressure to give the crude product as a yellow oil. Yield 2.8 g (23%). LCMS (C18 column 20×2 mm, 2.5 µm, pore size 100Å, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 0.32 min). MS (ESI) m / z 136.1 [MH]+.

[0525] Synthesis of INT-57 ((2Z,2'E)-2,2'-(1-(pyridin-2-yl)ethane-1,2-diylidene)bis(N-ethylhydrazine- 1-thioformamide)): Add thiocarbamide (1.76 g, 14.0 mmol) and 1 drop of H2SO4 to 2-oxo-2-(pyridin-2-yl) acetaldehyde (1.0 g, 7.0 mmol) in EtOH (50 ml), the reaction was heated to reflux for 4 h. The precipitate was filtered, washed with EtOH, Et2O and dried. Yield 0.123 g (5.9%). LCMS (C18 column 20×2 mm, 2.5 µm, pore size 100Å, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 3 min, retention time 1.41 min). MS (ESI) m / z 338.3 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.21 (dt, 6H), 3.56-3.70 (m, 4H), 7.42 (dd, 1H), 7.86-7.93 (m, 2H), 8.41 (d , 1H), 8.58 (d, 1H), 8.89(s, 1H), 8.79 (s, 1H), 9.20 (t, 1H), 12.01 (s, 1H), 12.80 (s, 1H).

[0526] Synthesis of INT-59 ((2Z,2'E)-2,2'-(1-(pyridin-3-yl)ethane-1,2-diylidene)bis(N-methylhydrazine- 1-thioformamide)): INT-59 was made using a procedure similar to that for INT-57. Yield 0.53 g (19%). LCMS (C18 column 20×2 mm, 2.5 µm, pore size 100Å, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 10 min, retention time 4.49 min). MS (ESI) m / z 310.4 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 3.0 (s, 3H), 3.06 (s, 3H), 7.80 (dd, 1H), 8.2(s, 1H), 8.58(d, 1H), 8.78(d, 1H), 8.89(s, 1H), 8.92-8.98(m, 1H), 9.16(s, 1H), 11.78(s, 1H), 12.09(s, 1H).

[0527] Synthesis of INT-60 ((2Z,2'E)-2,2'-(1-(pyridin-3-yl)ethane-1,2-diylidene)bis(N-ethylhydrazine- 1-Thioformamide)): INT-60 was made using a procedure similar to that of INT-57. Yield 0.90 g (30%). LCMS (C18 column 20×2 mm, 2.5 µm, pore size 100Å, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 10 min, retention time 5.26 min). MS (ESI) m / z 338.5 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.17 (t, 6H), 3.61 (q, 4H), 7.47 (dd, 1H), 8.0(t, 1H), 8.18(d, 1H), 8.22(s, 1H), 8.62(d, 1H), 8.98-9.07(m, 1H), 11.77(s, 1H), 12.31(s, 1H).

[0528] Synthesis of INT-61 ((2Z,2'E)-2,2'-(1-(pyridin-4-yl)ethane-1,2-diylidene)bis(N-ethylhydrazine- 1-Thioformamide)): INT-61 was made using a procedure similar to that of INT-57. Yield 180 mg (7%). LCMS (C18 column 20×2 mm, 2.5 µm, pore size 100Å, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 10 min, retention time 4.97 min). MS (ESI) m / z 338.5 [MH]+. 1H-NMR (400MHz, DMSO-d6): δ (ppm) 1.18 (t, 3H), 1.20 (t, 3H), 3.58 (q, 2H), 3.64 (q, 2H), 7.80 (d, 1H), 8.04(t, 1H), 8.24(s, 1H), 8.65(d, 1H), 9.12(t, 1H), 11.79(s, 1H), 12.47(s, 1H).

[0529] Synthesis of Compound 57: To a solution of INT-57 (0.123 g, 0.365 mmol) in EtOH (10 ml) was added a solution of CuCl2.2H2O (0.062 g, 0.365 mmol) in EtOH (2 ml). The mixture was stirred overnight at room temperature. The formed precipitate was collected by filtration, washed with water (2 x 10 ml), ethanol (2 x 10 ml), diethyl ether (5 x 5 ml) and dried in vacuo. Yield 0.06 g (41.4%). LCMS (C18 column 20×2 mm, 2.5 µm, pore size 100Å, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.39). MS (ESI) m / z 399.0 [MH]+.

[0530] Synthesis of compound 59: The title compound was prepared from INT-59 according to the method for preparing compound 57. The title product was collected by filtration, washed with water (2x50 ml), ethanol (2x50 ml) and diethyl ether (5x50 ml), and then dried in vacuo. Yield 230 mg (95%). LCMS (C18 column 20×2 mm, 2.5 µm, pore size 100Å, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.34, 1.47 min. MS (ESI) m / z 371.0 [MH ]+.

[0531] Synthesis of compound 60: The title compound was prepared from INT-60 according to the method for preparing compound 57. The title product was collected by filtration, washed with water (2x50 ml), ethanol (2x50 ml) and diethyl ether (5x50 ml), and then dried in vacuo. Yield 218 mg (92%). LCMS (C18 column 20×2 mm, 2.5 µm, pore size 100Å, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.58, 1.73 min. MS (ESI) m / z 399.0 [MH ]+.

[0532] Synthesis of compound 61: The title compound was prepared from INT-61 according to the method of compound 57. The product was collected by filtration, washed with water (2x50 ml), ethanol (2x50 ml) and diethyl ether (5x50 ml), and then dried in vacuo. Yield 140 mg (66%). LCMS (C18 column 20×2 mm, 2.5 µm, pore size 100Å, water-acetonitrile+0.1% TFA, gradient 5 to 87% for 4 min, retention time 1.48, 1.66 min. MS (ESI) m / z 399.0 [MH ]+.

[0533] Example 5: Preparation of compounds 66 to 78. Scheme 27: Synthesis of compound 66 Synthesis of N-methoxy-N-methyl-2-(pyridin-3-yl) acetamide: at 5°C to 3- Pyridineacetic acid (25.0 g, 0.144 mol), Weinreb amine (16.8 g, 0.172 mol), HOBt (23.3 g, 0.172 mol) and triethylamine (71 ml, 0.5 mol) in DCM (400 ml ) was added EDCI (33.2 g, 172 mol) and the reaction was stirred at ambient temperature for 15 h. The mixture was washed with water (150 ml) and brine (250 ml). The organic layer was dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent EtOAc-hexane, 2:1) to afford compound 1. Yield 20.0 g (77%). 1H-NMR (400 MHz, CDCl3), δ (ppm) : 8.63 - 8.27 (m, 2H), 7.65 (d,J= 7.8 Hz, 1H), 7.28 - 7.03 (m, 1H), 3.76 (s, 2H ), 3.67 (s, 3H), 3.19 (s, 3H).

[0534] Synthesis of 1-(pyridin-3-yl)propan-2-one: N-methoxy-N-methyl-2-(pyridin-3-yl)acetamide (9.5 g, 52.7 mmol, A solution of 1 equiv) in THF (200 ml) was cooled to 5°C and methylmagnesium bromide (1.4M in THF, 46.5 ml, 3 equiv) was added. The reaction mixture was stirred at 5 °C for 2 h, poured into aqueous NH4Cl and extracted with Et2O. The combined extracts were dried over anhydrous Na2SO4 and evaporated in vacuo. Compound 2 was used in the next step without purification. Yield 6.1 g (86%). LC-MS 0.27 min, m / z 136.6 [MH]+. 1H-NMR (400 MHz, CDCl3), δ (ppm) : 8.48 (d,J= 4.7 Hz, 1H), 8.41 (s, 1H), 7.50 (d,J= 7.8 Hz, 1H), 7.31 - 7.12 ( m, 1H), 3.67 (d,J= 19.5 Hz, 2H), 2.18 (s, 3H).

[0535] Synthesis of INT-66 ((2Z, 2'E)-2,2'-(3-(pyridin-3-yl) propane-1,2-diylidene) bis(N-methylhydrazine-1 -thioformamide)): a mixture of 1-(pyridin-3-yl)propan-2-one (1.3 g, 6.9 mmol, 1 equiv), NaBr (0.7 g, 1 equiv) and DMSO (2 ml) The mixture was heated to 85 °C and H2SO4 (6 drops) was added (foaming, exotherm). The reaction was heated at 110°C to 115°C until the formation of dimethyl sulfide ceased and the reaction mixture became viscous. The resulting viscous oil was dissolved in EtOH and methionamide (2.023 g, 2 equiv) was added. The reaction mixture was heated to reflux for 4 h, then stirred at room temperature overnight. The precipitate was collected by filtration, washed with EtOH, MeCN, water, Et2O and dried to give the title product. Yield 0.95 g (30%). LC-MS 0.97 min, m / z 324.6 [MH]+.

[0536] Synthesis of Compound 66: Copper(II) acetate dihydrate (0.72 g, 1.1 equiv) was added to a stirred solution of INT-66 (0.12 g, 0.38 mmol, 1 equiv) in ethanol. The mixture was stirred at room temperature for 15 h. The formed complex was precipitated as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, diethyl ether, and dried in vacuo. Yield 0.14 g (99%).

[0537] Scheme 28: Synthesis of Compound 67 Synthesis of N-methoxy-N-methyl-2-(pyridin-4-yl)acetamide at 5°C to 4-pyridineacetic acid (4.2 g, 24.2 mmol), To a mixture of Weinleamide (2.8 g, 29.0 mmol), HOBt (3.9 g, 29.0 mmol) and triethylamine (11.9 ml, 84.7 mmol) in DCM (100 ml) was added EDCI (5.6 g, 29.0 mmol) And the reaction was stirred at room temperature for 15h. The mixture was washed with water (150 ml) and brine (250 ml). The organic layer was dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent EtOAc-hexane 2:1) to afford the title compound. Yield 2.9 g (66%). LC-MS 0.97 min, m / z 324.6 [MH]+. 1H-NMR (400 MHz, CDCl3), δ (ppm) : 8.55 (d,J= 5.3 Hz, 2H), 7.36 - 7.08 (m, 2H), 3.78 (s, 2H), 3.66 (s, 3H), 3.21 (s, 3H).

[0538] Synthesis of 3-ethoxy-1-(pyridin-4-yl)but-3-en-2-one: Ethyl vinyl ether (4.1 ml, 41.8 mmol) was dissolved in anhydrous THF (30 ml) The resulting solution was cooled to -78°C, and tert-butyllithium (1.7M in pentane, 23 ml, 38.8 mmol) was added. The mixture was allowed to warm to 0 °C over a period of 1 h, stirred for 45 min and cooled to -30 °C. A solution of N-methoxy-N-methyl-2-(pyridin-4-yl)acetamide (0.7 g, 3.8 mmol) in THF (15 mL) was added and the reaction was stirred at 0 °C for 4 h. The progress of the reaction was monitored by TLC. The mixture was poured into aqueous NH4Cl (30 ml) and extracted with Et2O (3x50 ml). The combined extracts were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The product was used in the next step without further purification. Yield 0.2 g (27%). LC-MS 0.66 min, m / z 192.4 [MH]+. 1H-NMR (400 MHz, CDCl3), δ (ppm) : 8.54 (dd,J= 4.4, 1.6 Hz, 2H), 7.23 - 7.06 (m, 2H), 5.23 (t,J= 11.8 Hz, 1H), 4.42 (t,J= 14.5 Hz, 1H), 3.99 (s, 2H), 3.83 (q,J= 7.0 Hz, 2H), 1.40 (t,J= 7.0 Hz, 3H).

[0539] Synthesis of INT-67 ((2Z,2'E)-2,2'-(1-(pyridin-4-yl)butane-2,3-diylidene)bis(N-methylhydrazine- 1-thioformamide)): Dissolve 3-ethoxy-1-(pyridin-4-yl)but-3-en-2-one (0.2 g, 1.05 mmol, 1 equiv) in EtOH (20 ml), methionamide (0.22 g, 2.1 mmol, 2 equiv) and 3 drops of H2SO4 were added, and the reaction mixture was heated to reflux for 4 h and then stirred at room temperature for 15 h. The formed precipitate was filtered, washed with EtOH, water, Et2O and dried. Yield 0.21 g (60.2%). LC-MS 0.91 min, m / z 338.9 [MH]+. 1H-NMR (400 MHz, DMSO), δ (ppm) : 10.85 (s, 1H), 10.35 (s, 1H), 8.78 (d,J= 6.6 Hz, 2H), 8.51 (d,J= 4.6 Hz, 1H), 8.34 (d,J= 4.5 Hz, 1H), 7.72 (d,J= 6.5 Hz, 2H), 4.76 (s, 2H), 3.00 (dd,J= 14.4, 4.6 Hz, 6H), 2.28 ( s, 3H).

[0540] Synthesis of Compound 67: Copper(II) acetate dihydrate (0.09 g, 0.46 mmol) was added to a stirred solution of thiosemicarbazone 3 (0.15 g, 0.44 mmol) in ethanol. The mixture was stirred at room temperature for 15 h. The formed complex was precipitated as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, diethyl ether, and dried in vacuo. Yield 0.075 g (42.3%).

[0541] Scheme 29: Synthesis of Compound 68 Synthesis of ethyl 2-(pyridin-3-yl)acetate: Add 3-pyridineacetic acid (25.0 g, 145 mmol) in small portions at 0 to 5°C over 15 min intervals To a stirred solution in EtOH (250 ml) was added SOCl2 (11.6 ml, 160 mmol). After complete addition, the reaction was heated to reflux for a further 16 h and EtOH was evaporated under reduced pressure. To the residue was added 2M aqueous Na2CO3 (30 ml), and the resulting mixture was extracted with EtOAc (3 x 400 ml). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford Compound 1 as a colorless liquid. Yield 22.3 g (93%). 1H-NMR (400MHz, CDCl3), δ (ppm) : 1.26 (t, 3 H), 3.62 (s, 2 H), 4.17 (q, 2 H), 7.27-7.28 (m, 1 H), 7.64- 7.65 (m, 1H), 8.53 (m, 2H).

[0542] Synthesis of ethyl 1-(pyridin-3-yl)cyclopentane-1-carboxylate: Add sodium hydride (7.3 g, 181 mmol, 60% in mineral oil) in anhydrous THF (160 ml ) was added dropwise to a solution of ethyl 2-(pyridin-3-yl)acetate (10.0 g, 60.5 mmol) in anhydrous THF (35 ml). The reaction mixture was stirred at 0 °C until foaming ceased. Then 1,4-dibromobutane (19.6 g, 90.5 mmol) was added at 0 °C and the reaction mixture was stirred at room temperature for 14 h. Subsequently, the reaction mixture was quenched with saturated aqueous ammonium chloride (60 ml). The reaction mixture was extracted with EtOAc (3 x 40 ml). The organic phase was washed with brine (100 ml), dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The crude material (19 g) was obtained as a dark solid and then purified by flash chromatography (silica gel, eluent hexane / ethyl acetate, 4:1 to 1:1). Yield 9.8 g (74%). LC-MS 1.01 min, m / z 220.6 [MH]+. 1H-NMR (400MHz, CDCl3), δ (ppm) : 1.16 (t, 3H), 1.74-1.78 (m, 4H), 1.88-1.98 (m, 2H), 2.67-2.73 (m, 2H), 4.09 ( q, 2H), 7.23-7.27 (m, 1H), 7.67-7.71 (m, 1H), 8.49 (dd, 1H), 8.65 (dd, 1H).

[0543] Synthesis of 1-(pyridin-3-yl)cyclopentane-1-carboxylic acid: 1-(pyridin-3-yl)cyclopentane-1-carboxylic acid ethyl ester (8.4 g, 38.5 mmol) in MeOH To the solution in (60 ml) was added a solution of LiOH (2.5 g, 96.2 mmol) in water (10 ml). The reaction mixture was stirred at 60 °C for 8 h. The solvent was then removed by lyophilization and the corresponding crude product was used in the next step without further purification. Yield 7 g (80%). LC-MS 0.82 min, m / z 192.1 [MH]+. 1H-NMR (400MHz, DMSO-d6), δ (ppm) : 1.66-1.70 (m, 4H), 1.85-1.92 (m, 2H), 2.52-2.58 (m, 2H), 7.56 (dd, 1H), 7.98-8.02 (m, 1H), 8.58 (dd, 1H), 8.66 (d, 1H), 12.66 (br.s, 1H).

[0544] Synthesis of N-methoxy-N-methyl-1-(pyridin-3-yl)cyclopentane-1-formamide: 1-(pyridin-3-yl)cyclopentane at 4°C -1-carboxylic acid (5.0 g, 22.0 mmol), weinleamide (2.6 g, 26.4 mmol), HOBt (3.6 g, 26.4 mmol) and triethylamine (10.8 ml, 77 mmol) in DCM (150 ml) To the mixture in was added EDCI (5.1 g, 26.4 mmol) and the reaction was stirred at room temperature overnight. The mixture was then washed with water (100 ml) and brine (100 ml). The organic layer was dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent DCM 100% to DCM / MeOH 95:5 v / v) to give crude product. Yield 2.5 g (49%). LC-MS 0.84 min, m / z 235.3 [MH]+. 1H-NMR (400 MHz, CDCl3), δ (ppm) : 1.66-1.81 (m, 4H), 2.05-2.11 (m, 2H), 2.42-2.48 (m, 2H), 2.89 (s, 3H), 3.13 (s, 3H), 7.34 (q, 1H), 7.65 (d, 1H), 8.49 (d, 1H), 8.59 (d, 1H).

[0545] Synthesis of 1-(1-(pyridin-3-yl) cyclopentyl) ethyl-1-ketone: N-methoxy-N-methyl-1-(pyridin-3-yl) cyclopentane - A solution of 1-formamide (1.27 g, 5.42 mmol, 1 eq) in THF (100 ml) was cooled to 5°C and methylmagnesium bromide (1.4M in THF, 39.1 ml, 10 eq) was added. The reaction mixture was stirred at 5 °C for 2 h, poured into aqueous NH4Cl and extracted with Et2O. The combined extracts were dried over anhydrous Na2SO4 and evaporated in vacuo. The title product was used in the next step without purification. Yield 1 g (97%). LC-MS 1.14 min, m / z 190.6 [MH]+.

[0546] Synthesis of INT-68 ((2Z,2'E)-2,2'-(1-(1-(pyridin-3-yl)cyclopentyl)ethane-1,2-diylidene)bis (N-methylhydrazine-1-thioformamide)) compound 6. 1-(1-(pyridin-3-yl)cyclopentyl)ethan-1-one (1.3 g, 6.9 mmol, 1 equivalent ), NaBr (0.7 g, 1 eq) and DMSO (2 ml) was heated to 85 °C and H2SO4 (6 drops) was added (foaming, exotherm). The reaction was heated at 110°C to 115°C until the formation of dimethyl sulfide ceased and the reaction mixture became viscous. The resulting viscous oil was dissolved in EtOH and methionamide (1.44 g, 2 equiv) was added. The reaction mixture was heated to reflux for 4 h, then stirred at room temperature overnight. The precipitate was collected by filtration, washed with EtOH, MeCN, water, Et2O and dried to give the title product. Yield 0.5 g (19%). LC-MS 1.10 min, m / z 378.8 [MH]+. 1H-NMR (400 MHz, DMSO), δ (ppm) : 12.05 (s, 1H), 11.51 (s, 1H), 8.57 (s, 2H), 8.44 (d,J= 3.9 Hz, 1H), 7.76 ( dd,J= 24.5, 5.8 Hz, 2H), 7.59 (s, 1H), 7.36 (dd,J= 7.7, 4.8 Hz, 1H), 3.02 (dd,J= 46.9, 4.3 Hz, 6H), 2.50 (s , 1H), 2.46 (s, 2H), 2.00 (d,J= 12.5 Hz, 2H), 1.64 (s, 4H).

[0547] Synthesis of Compound 68 Copper(II) chloride dihydrate (0.078 g, 0.46 mmol) was added to a stirred solution of INT-68 (0.16 g, 0.42 mmol) in ethanol (30 ml). The mixture was stirred at room temperature for 15 h. The complex was isolated as a reddish-brown powder. The formed precipitate was filtered, washed with water (2x50 ml), ethanol (2x50 ml) and copious diethyl ether (5x50 ml), and then dried in vacuo. Yield 0.04 g (22%).

[0548] Scheme 30: Synthesis of compound 69 Synthesis of ethyl 2-(pyridin-3-yl)acetate: Add 3-pyridineacetic acid (25.0 g, 145 mmol) to EtOH (250 ml ) was added SOCl2 (11.6 ml, 160 mmol) to the stirred solution. After the addition was complete, the reaction was heated to reflux for an additional 16 h, then EtOH was evaporated under reduced pressure. To the residue was added 2M aqueous Na2CO3 (30 ml), and the resulting mixture was extracted with EtOAc (3 x 400 ml). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title product as a colorless liquid. Yield 22.3 g (93%). 1H-NMR (400MHz, CDCl3), δ (ppm) : 1.26 (t, 3 H), 3.62 (s, 2 H), 4.17 (q, 2 H), 7.27-7.28 (m, 1 H), 7.64- 7.65 (m, 1H), 8.53 (m, 2H).

[0549] Synthesis of ethyl 2-(pyridin-3-yl)butanoate: Add in small portions to a solution of ethyl 2-(pyridin-3-yl)acetate (10.08 g, 61 mmol) in THF (100 mL) Sodium hydride (2.54 g, 66 mmol, 60% dispersion in mineral oil) was added. After stirring at room temperature for 10 min, ethyl iodide (5.1 ml, 66 mmol) was added, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then quenched with aqueous NH4Cl, extracted with EtOAc, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford compound 2 as a colorless liquid. Yield 10.6 g (86%). LC-MS 0.77 min, m / z 194.1 [MH]+. 1H-NMR (400MHz, CDCl3), δ (ppm) : 0.91 (t, J=8Hz, 3H), 1.22 (t, J=8Hz, 3H), 1.74-1.85 (m, 1H), 2.07-2.18 (m , 1H), 3.46 (t, J=7.6Hz, 1H), 4.07-4.21 (m, 2H), 7.25-7.28 (m, 1H), 7.67-7.70 (m, 1H), 8.51-8.54 (m, 2H ). Synthesis of 2-(pyridin-3-yl)butanoic acid: A solution of ethyl 2-(pyridin-3-yl)butanoate (10.6 g, 54.8 mmol) in MeOH (60 ml) was added to NaOH ( 5.5 g, 137.2 mmol) in a solution in water (22 ml). The reaction mixture was stirred at room temperature for 8 h. The solvent was then removed by lyophilization and the corresponding crude product was used in the next step without further purification. Yield 10.3 g (93%). LC-MS 0.51 min, m / z 166.1 [MH]+. 1H-NMR (400MHz, CDCl3), δ (ppm) : 0.81 (t, J=6.8Hz, 3H), 1.67-1.78 (m, 1H), 1.96-2.05 (m, 1H), 2.08 (s, 1H) , 3.60 (t, J=7.6Hz, 1H), 7.53-7.56 (m, 1H), 7.92-7.95 (m, 1H), 8.56-8.61 (m, 2H).

[0551] Synthesis of N-methoxy-N-methyl-2-(pyridin-3-yl) butanamide: 2-(pyridin-3-yl) butyric acid (10.3 g, 51.0 mmol) at 4°C , Weinleamide (5.9 g, 61.2 mmol), HOBt (8.3 g, 61.2 mmol) and triethylamine (25 ml, 176 mmol) in DCM (150 ml) were added with EDCI (11.7 g, 61.2 mmol ) and the reaction was stirred overnight at room temperature. The mixture was washed with water (100 ml) and brine (100 ml). The organic layer was dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent DCM 100% to DCM / MeOH 95:5 v / v) to give crude product. Yield 7.3 g (68%). LC-MS 0.76 min, m / z 208.9 [MH]+. 1H-NMR (400MHz, CDCl3), δ (ppm) : 0.90 (t, J=7.6Hz, 3H), 1.73-1.80 (m, 1H), 2.08-2.15 (m, 1H), 3.17 (s, 3H) , 3.57 (s, 3H), 3.91-3.96 (m, 1H), 7.26-7.28 (m, 1H), 7.74-7.77 (m, 1H), 8.48-8.50 (m, 1H), 8.53 (d, J= 2Hz, 1H).

[0552] Synthesis of 2-ethoxy-4-(pyridin-3-yl)hex-1-en-3-one: ethyl vinyl ether (4.3 ml, 45.1 mmol) was dissolved in anhydrous tetrahydrofuran (30 ml) The resulting solution was cooled to -78°C, and tert-butyllithium (1.7M in pentane, 24 ml, 41 mmol) was added. The mixture was allowed to warm to 0 °C over a period of 1 h, stirred for 45 min and cooled to -30 °C. A solution of N-methoxy-N-methyl-2-(pyridin-3-yl)butanamide (1.7 g, 8.2 mmol) in THF (35 ml) was added and the reaction was stirred at 0 °C for 4 h. The progress of the reaction was monitored by TLC. The mixture was poured into aqueous NH4Cl (30 ml) and extracted with Et2O (3x50 ml). The combined extracts were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The product was used in the next step without further purification. Yield 1.15 g (64%). LC-MS 1.15 min, m / z 219.9 [MH]+. 1H-NMR (400 MHz, CDCl3), δ (ppm) : 0.86 (t, J=7.2Hz, 3H), 1.34 (t, J=6.8Hz, 3H), 1.68-1.79 (m, 1H), 2.04- 2.15 (m, 1H), 3.62-3.70 (m, 1H), 3.74-3.82 (m, 1H), 4.27 (t, J=8Hz, 1H), 4.35 (d, J=2Hz, 1H), 5.20(d , J=2.8Hz, 1H), 7.23-7.27 (m, 1H), 7.55-7.58 (m, 1H), 8.47-8.49 (m, 1H), 8.52 (d, J=2Hz, 1H).

[0553] Synthesis of INT-69 ((2Z,2'E)-2,2'-(3-(pyridin-3-yl)pentane-1,2-diylidene)bis(N-methylhydrazine- 1-thioformamide)): Compound 6. To 2-ethoxy-4-(pyridin-3-yl)hex-1-en-3-one (0.89 g, 4.05 mmol, 1 equiv) in EtOH To a stirred solution in (20 ml) methionamide (0.85 g, 8.1 mmol, 2 eq) and 3 drops of H2SO4 were added, and the reaction mixture was heated to reflux for 4 h and then stirred at room temperature for 15 h. The formed precipitate was filtered, washed with EtOH, water, Et2O and dried. Yield 0.67 g (45%). LC-MS 1.01 min, m / z 366.3 [MH]+.

[0554] Synthesis of Compound 69 Copper(II) chloride dihydrate (0.12 g, 0.73 mmol) was added to a stirred solution of INT-69 (0.24 g, 0.67 mmol) in ethanol (30 ml). The mixture was stirred overnight at room temperature. The complex was isolated as a reddish-brown powder. The formed precipitate was filtered, washed with water (2x50 ml), ethanol (2x50 ml) and copious diethyl ether (5x50 ml), and then dried in vacuo. Yield 0.13 g (45%).

[0555] Process 31: Synthesis of 2-oxo-2-(pyridin-4-yl) acetaldehyde from synthetic compound 70: 1-pyridin-4-yl ethyl ketone (10.0 g, 82.5 mmol) in DMSO (100 ml ) was added concentrated HBr (28 ml, 247.5 mmol) and the mixture was stirred at 50 °C overnight. The reaction mixture was quenched with NaHCO3, then diluted with water to a total volume of 1000 ml. The resulting solution was extracted with EtOAc (3 x 150 ml), the combined organic layers were dried over anhydrous Na2SO4 and evaporated in vacuo to give product 1 as a yellow oil. Yield 2.0 g (18%). LC-MS 0.35 min, m / z 136.1 [MH]+.

[0556] Synthesis of INT-70 ((2Z,2'E)-2,2'-(1-(pyridin-4-yl)ethane-1,2-diylidene)bis(N-methylhydrazine- 1-thioformamide)): To a solution of 2-oxo-2-(pyridin-4-yl)acetaldehyde (1.2 g, 8.9 mmol) in EtOH (100 ml) was added thiocarbamate (1.87 g, 19.8 mmol), followed by the addition of 2 drops of H2SO4, and the reaction mixture was heated to reflux for 4 h and stirred at room temperature overnight. The precipitate was filtered, washed with EtOH, Et2O and dried to give compound 2. Yield 70 mg (4%). LC-MS (reversed-phase C18 column 20×2 mm, 2.5 µm, pore size 100Å, water-acetonitrile+0.1% TFA, gradient 5 to 87%, over 10 min). 4.27 min, (ESI) m / z 310.1 [MH]+. Synthesis of Compound 70 To a solution of INT-70 (70 mg, 0.2 mmol) in EtOH (10 ml) was added copper(II) chloride dihydrate (42 mg, 0.22 mmol) in EtOH (2 ml) solution. The mixture was stirred overnight at room temperature. The formed precipitate was collected by filtration, washed with water (2 x 5 ml), ethanol (2 x 5 ml), diethyl ether (5 x 5 ml), and then dried in vacuo to give the product as a dry powder. Yield 42 mg (50%).

[0558] Scheme 32: Synthesis of Compound 71 Synthesis of 1-(pyridin-3-yl)propan-2-one: N-methoxy-N-methyl-2-(pyridin-3-yl)acetamide (9.5 g, 52.7 mmol, 1 eq) in THF (200 ml) was cooled to 5°C and methylmagnesium bromide (1.4M in THF, 46.5 ml, 3 eq) was added. The reaction mixture was stirred at 5 °C for 2 h, poured into aqueous NH4Cl and extracted with Et2O. The combined extracts were dried over anhydrous Na2SO4 and evaporated in vacuo. The title product was used in the next step without purification. Yield 6.1 g (86%). LC-MS 0.27 min, m / z 136.6 [MH]+. 1H-NMR (400 MHz, CDCl3), δ (ppm) : 8.48 (d,J= 4.7 Hz, 1H), 8.41 (s, 1H), 7.50 (d,J= 7.8 Hz, 1H), 7.31 - 7.12 ( m, 1H), 3.67 (d,J= 19.5 Hz, 2H), 2.18 (s, 3H).

[0559] Synthesis of INT-71 ((2Z,2'E)-2,2'-(3-(pyridin-3-yl)propane-1,2-diylidene)bis(N-ethylhydrazine-1 -thioformamide)): a mixture of 1-(pyridin-3-yl)propan-2-one (1.5 g, 11.1 mmol, 1 equiv), NaBr (1.14 g, 1 equiv) and DMSO (2 ml) The mixture was heated to 85 °C and H2SO4 (6 drops) was added (foaming, exotherm). The reaction was heated at 110°C to 115°C until the formation of dimethyl sulfide ceased and the reaction mixture became viscous. The resulting viscous oil was dissolved in EtOH and ethionamide (2.64 g, 2 equiv) was added. The reaction mixture was heated to reflux for 4 h, then stirred at room temperature overnight. The precipitate was collected by filtration, washed with EtOH, MeCN, water, Et2O and dried to give the title product. Yield 0.175 g (4.5%). LC-MS 1.19 min, m / z 352.8 [MH]+.

[0560] Synthesis of Compound 71: Copper(II) acetate dihydrate (0.055 g, 1 equiv) was added to a stirred solution of INT-71 (0.175 g, 0.5 mmol, 1 equiv) in ethanol. The mixture was stirred at room temperature for 15 h. The formed complex was precipitated as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, diethyl ether, and dried in vacuo. Yield 0.14 g (69%).

[0561] Scheme 33: Synthesis of Compound 72 Synthesis of 3-((3r,5r,7r)-adamantan-1-yl)-N-methoxy-N-methylacrylamide: at 5°C to 3- ((3r,5r,7r)-adamantan-1-yl)propionic acid (5 g, 24 mmol), N,O-dimethylhydroxylamine (2.81 g, 1.2 equiv), HOBt (3.89 g, 1.2 equiv) To a stirred mixture of triethylamine (8.5 ml, 6.11 g, 2.5 equiv) in DCM (50 ml) was added EDCI (5.52 g, 1.2 equiv) and the reaction was stirred at room temperature for 15 h. The mixture was washed with water and brine. The organic layer was dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The product was purified by column chromatography (silica gel, eluent CCl4 100%, then CCl4 / EtOAc 8:2). Yield 3.5 g (58%). LC-MS 1.88 min, m / z 252.4 [MH]+. 1H-NMR (400 MHz, CDCl3), δ (ppm) : 3.71 (d,J= 1.6 Hz, 3H), 3.19 (s, 3H), 2.42 - 2.31 (m, 2H), 1.97 (s, 3H), 1.72 (d, J= 11.9 Hz, 3H), 1.68 - 1.58 (m, 4H), 1.50 (s, 6H), 1.43 (dd, J= 9.8, 7.1 Hz, 2H).

[0562] Synthesis of 5-((3r,5r,7r)-adamantan-1-yl)-2-ethoxypent-1-en-3-one: ethyl vinyl ether (2.01 g, 2.7 ml, A solution of 3.3 equiv) in anhydrous THF (150 mL) was cooled to -78 °C and tert-butyllithium (1.7M in pentane, 16 ml, 3 equiv) was added. The mixture was allowed to warm to 0 °C over a period of 1 h, stirred for 45 min and then cooled to -30 °C. A solution of 3-((3r,5r,7r)-adamantan-1-yl)-N-methoxy-N-methylpropanamide (2.12 g, 8.4 mmol) in THF (15 ml) was added and Stirring was continued for 4 h at 0 °C. The mixture was poured into aqueous NH4Cl (100 ml) and extracted with Et2O (3x100 ml). The combined extracts were dried over anhydrous Na2SO4, filtered and the solvent was evaporated in vacuo. The product was used in the next step without further purification. Yield 2.2 g (99.9%). 1H-NMR (400 MHz, CDCl3), δ (ppm) : 5.18 (s, 1H), 4.36 (d,J= 33.6 Hz, 1H), 3.82 (q,J= 6.9 Hz, 2H), 2.64 (dd, J= 20.9, 13.1 Hz, 2H), 1.97 (s, 4H), 1.79 - 1.53 (m, 8H), 1.56 - 1.15 (m, 13H).

[0563] Synthesis of INT-72 ((2E,2'E)-2,2'-(5-((3r,5r,7r)-adamantan-1-yl)pentane-2,3-diylidene ) Bis(N-ethylhydrazine-1-thioformamide): 5-((3r,5r,7r)-adamantane-1-yl)-2-ethoxypent-1-ene-3 - The ketone (2.21 g, 8.4 mmol) was dissolved in EtOH (60 ml), ethionamide (2.01 g, 2 equiv) and 3 drops of H2SO4 were added. The stirred reaction mixture was heated to reflux for 4 h, and then At room temperature for 15 h. The formed precipitate was filtered, washed with EtOH, saturated aqueous Na2CO3, water, Et2O, and dried. Yield 2.2 g (59.6%). LC-MS 2.17 min, m / z 437.5 [MH]+ .

[0564] Synthesis of Compound 72 Copper(II) chloride dihydrate (0.23 g, 1 equiv) was added to a stirred solution of INT-72 (0.59 g) in ethanol. The mixture was stirred at room temperature for 15 h. The formed complex was precipitated as a reddish-brown powder. The precipitate was collected by filtration, washed with water, diethyl ether and dried. Yield 0.61 g (90.8%).

[0565] Process 34: Synthesis of Compound 73 Synthesis of 3-cyclopentyl-N-methoxy-N-methylacrylamide: 3-cyclopentylpropionic acid (3.12 g, 21.9 mmol) at 5°C, To a stirred mixture of N,O-dimethylhydroxylamine (2.57 g, 1.2 eq), HOBt (4.03 g, 1.2 eq) and triethylamine (6.1 ml, 4.43 g, 2 eq) in DCM (100 ml) was added EDCI (5.05 g, 1.2 eq) and the reaction was stirred at room temperature for 15 h. The mixture was washed with water and brine. The organic layer was dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The product was purified by column chromatography (silica gel, eluent DCM 100% to DCM / MeOH 99:1). Yield 3.11 g (76.5%). LC-MS 1.63 min, m / z 186.4 [MH]+. 1H-NMR (400 MHz, CDCl3), δ (ppm) : 3.69 (s, 3H), 3.19 (s, 3H), 2.42 (dd,J= 18.1, 10.2 Hz, 2H), 2.53 - 2.33 (m, 2H ), 1.87 - 1.73 (m, 4H), 1.70 - 1.57 (m, 5H), 1.58 - 1.44 (m, 2H), 1.19 - 1.01 (m, 2H).

[0566] Synthesis of 5-cyclopentyl-2-ethoxypent-1-en-3-one: Ethyl vinyl ether (3.85 g, 5.1 ml, 6.6 equiv) in anhydrous THF (100 mL) The solution was cooled to -78°C, and tert-butyllithium (1.7M in pentane, 28 ml, 6 equiv) was added. The mixture was allowed to warm to 0 °C over a period of 1 h, stirred for 45 min and then cooled to -30 °C. A solution of 3-cyclopentyl-N-methoxy-N-methylpropanamide (1.5 g, 8 mmol) in THF (15 ml) was added and stirring was continued at 0 °C for 4 h. The mixture was poured into aqueous NH4Cl (100 ml) and extracted with Et2O (3x100 ml). The combined extracts were dried over anhydrous Na2SO4, filtered and the solvent was evaporated in vacuo. The product was used in the next step without further purification. Yield 1.05 g (99.0%). LC-MS 0.91 min, m / z 180.9 [MH]+.

[0567] Synthesis of INT-73 ((2E,2'E)-2,2'-(5-cyclopentylpentane-2,3-diylidene) bis(N-ethylhydrazine-1-thio Formamide)): Dissolve 5-cyclopentyl-2-ethoxypent-1-en-3-one (1.05 g, 8 mmol) in EtOH (25 ml), add thiocarbamide (1.93 g, 2 equivalents) and 3 drops of H2SO4. The stirred reaction mixture was heated to reflux for 4 h and then kept at room temperature for 15 h. The formed precipitate was filtered, washed with EtOH, saturated aqueous Na2CO3, water, Et2O, and dried. Yield 2 g (68%). LC-MS 1.83 min, m / z 371.5 [MH]+.

[0568] Synthesis of Compound 73: Copper(II) chloride dihydrate (0.23 g, 1 eq) was added to a stirred solution of INT-73 (0.5 g, 1.3 mmol) in ethanol. The mixture was stirred at room temperature for 15 h. The formed complex was precipitated as a reddish-brown powder. The precipitate was collected by filtration, washed with water, diethyl ether and dried. Yield 0.5 g (88.7%).

[0569] Scheme 35: Synthesis of Compound 74 Synthesis of INT-74 ((2Z,2'Z)-2,2'-(3-methoxypropane-1,2-diylidene)bis(N-ethyl Hydrazine-1-thioformamide)): Charge SeO2 (3.6 g, 1.05 equivalents), 1,4-dioxane (70 mL) and water (14 mL) into a three-necked flask. The mixture was heated to 50 °C and stirred until most of the SeO2 was dissolved. 1-Methoxypropan-2-one (2.72 g, 30.9 mmol) was added and the reaction was heated to gentle reflux overnight. Selenium solids precipitated during the course of the reaction. The mixture was cooled in an ice bath and filtered through celite to remove selenium. The filter cake was washed with a portion of 1,4-dioxane. The filtrate was evaporated to dryness and dissolved in EtOH (100 ml). Ethionamide (7.35 g, 2 equiv) and 3 drops of H2SO4 were added. The stirred reaction mixture was heated to reflux for 4h. The formed precipitate was filtered, washed with EtOH, saturated aqueous Na2CO3, water, Et2O, and dried. Yield 2.4 g (25.5%). LC-MS 1.37 min, m / z 305.5 [MH]+.

[0570] Synthesis of Compound 74: Copper(II) chloride dihydrate (0.1 g, 1 equiv) was added to a stirred solution of INT-74 (0.184 g, 0.6 mmol) in ethanol. The mixture was stirred at room temperature for 15 h. The formed complex was precipitated as a reddish-brown powder. The precipitate was collected by filtration, washed with water, diethyl ether and dried. Yield 0.1 g (45.2%).

[0571] Scheme 36: Synthesis of Compound 75 5-yl)ethane-1,2-diylidene)bis(N-methylhydrazine-1-thioformamide)): Into a three-necked flask, SeO2 (2.12 g, 1.05 equivalents), 1 , 4-dioxane (41 mL) and water (9 mL). The mixture was heated to 50 °C and stirred until most of the SeO2 was dissolved. 1-(Benzo[d][1,3]dioxol-5-yl)ethan-1-one (2.72 g, 30.9 mmol) was added, and the reaction was heated to gentle reflux overnight. Selenium solids precipitated during the course of the reaction. The mixture was cooled in an ice bath and filtered through celite to remove selenium. The filter cake was washed with a portion of 1,4-dioxane. The filtrate was evaporated to dryness and dissolved in EtOH (100 ml). Methionamide (3.84 g, 2 equiv) and 3 drops of H2SO4 were added. The stirred reaction mixture was heated to reflux for 4h. The formed precipitate was filtered, washed with EtOH, saturated aqueous Na2CO3, water, Et2O, and dried. Yield 2.16 g (33.5%). LC-MS 1.53 min, m / z 353.3 [MH]+. 1H-NMR (400 MHz, DMSO-d6), δ (ppm) : 12.13 (s, 1H), 11.71 (s, 1H), 8.82 (d,J= 4.3 Hz, 1H), 8.21 - 8.04 (m, 2H ), 7.60 (d,J= 1.5 Hz, 1H), 7.18 (d,J= 8.2 Hz, 1H), 6.98 (d,J= 8.2 Hz, 1H), 6.08 (s, 2H), 3.04 (dd,J = 15.0, 4.5 Hz, 6H).

[0572] Synthesis of ZN-75: Zinc acetate (0.28 g, 1.5 equiv) was added to INT-75 (0.36 g, 1 mmol) in ethanol. The mixture was heated to reflux for 4 h. The complex formed precipitated as a yellow powder. The precipitate was collected by filtration, washed with water, methanol, diethyl ether, and dried in vacuo. Yield 0.33 g (76.8 %). Synthesis of compound 75: ZN-75 (0.32 g, 0.8 mmol) was dissolved in DMSO (9 ml) and Cu(OAc)2*H2O (0.17 g, 1.1 equiv) was added in water (9 ml) solution. The mixture was stirred for 5 min, filtered, and the precipitate was washed with saturated potassium carbonate solution, water and Et2O. Yield 0.15 g (48.5%).

[0574] Scheme 37: Synthesis of compound 76: Synthesis of 2-(3,5-dimethyl-1H-pyrazol-1-yl)-N-methoxy-N-methylacetamide: at 5°C 2-(3,5-Dimethyl-1H-pyrazol-1-yl)acetic acid (1.95 g, 12.6 mmol), N,O-dimethylhydroxylamine (1.48 g, 1.2 equivalents), HOBt (2.32 g , 1.2 equiv) and triethylamine (3.5 ml, 2.54 g, 2 equiv) in DCM (80 ml) was added EDCI (2.9 g, 1.2 equiv) and the reaction was stirred at room temperature for 15 h. The mixture was washed with water and brine. The organic layer was dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The product was used further without further purification. Yield 1.7 g (68.1%). LC-MS 0.88 min, m / z 198.3 [MH]+. 1H-NMR (400 MHz, CDCl3), δ (ppm) : 5.88 (s, 1H), 4.98 (s, 2H), 3.79 (s, 3H), 3.22 (s, 3H), 2.23 (d, J= 6.6 Hz, 6H).

[0575] Synthesis of 1-(3,5-dimethyl-1H-pyrazol-1-yl)-3-ethoxybut-3-en-2-one: ethyl vinyl ether (6.83 g, 9 ml, 11 equiv) in anhydrous THF (150 mL) was cooled to -78°C, and tert-butyllithium (1.7M in pentane, 50 ml, 10 equiv) was added. The mixture was allowed to warm to 0 °C over a period of 1 h, stirred for 45 min and then cooled to -30 °C. Add 2-(3,5-dimethyl-1H-pyrazol-1-yl)-N-methoxy-N-methylacetamide (1.7 g, 8.6 mmol) in THF (20 ml) solution and continued stirring at 0 °C for 4 h. The mixture was poured into aqueous NH4Cl (100 ml) and extracted with Et2O (3x100 ml). The combined extracts were dried over anhydrous Na2SO4, filtered and the solvent was evaporated in vacuo. The product was used in the next step without additional purification. Yield 0.4 g (22.2%). LC-MS 1.15 min, m / z 209.1 [MH]+.

[0576] Synthesis of INT-76 ((2E, 2'E)-2,2'-(1-(3,5-dimethyl-1H-pyrazol-1-yl) butane-2,3-di Subunit) bis(N-ethylhydrazine-1-thioformamide)): 1-(3,5-dimethyl-1H-pyrazol-1-yl)-3-ethoxybutanyl- 3-en-2-one (0.4 g, 1.9 mmol) was dissolved in EtOH (15 ml), ethionamide (0.46 g, 2 equiv) and 1 drop of H2SO4 were added. The stirred reaction mixture was heated to reflux for 4 h and then kept at room temperature for 15 h. The formed precipitate was filtered, washed with EtOH, saturated aqueous Na2CO3, water, Et2O, and dried. Yield 0.05 g (6.8%). LC-MS 1.62 min, m / z 383.5 [MH]+.

[0577] Synthesis of Compound 76: Copper(II) chloride dihydrate (0.23 g, 1 equiv) was added to a stirred solution of INT-76 (0.5 g, 1.3 mmol) in ethanol. The mixture was stirred at room temperature for 15 h. The formed complex was precipitated as a reddish-brown powder. The precipitate was collected by filtration, washed with water, diethyl ether and dried. Yield 0.5 g (88.7%).

[0578] Scheme 38: Synthesis of Compound 77: Synthesis of INT 77 ((2Z,2'Z)-2,2'-(1-(7-methoxybenzofuran-2-yl)ethane-1, 2-diylidene)bis(N-methylhydrazine-1-thioformamide)): A three-necked flask was charged with SeO2 (1.84 g, 1.05 equivalents), 1,4-dioxane (36 mL ) and water (8 mL). The mixture was heated to 50 °C and stirred until most of the SeO2 was dissolved. 1-(7-Methoxybenzofuran-2-yl)ethan-1-one (3 g, 15.8 mmol) was added, and the reaction was heated to gentle reflux overnight. Selenium solids precipitated during the course of the reaction. The mixture was cooled in an ice bath and filtered through celite to remove selenium. The filter cake was washed with a portion of 1,4-dioxane. The filtrate was evaporated to dryness and dissolved in EtOH (100 ml). Methionamide (3.32 g, 2 equiv) and 3 drops of H2SO4 were added. The stirred reaction mixture was heated to reflux for 4h. The formed precipitate was filtered, washed with EtOH, saturated aqueous Na2CO3, water, Et2O, and dried. Yield 2.15 g (36%). LC-MS 1.63 min, m / z 379.3 [MH]+.

[0579] Synthesis of Compound 77: Copper(II) chloride dihydrate (0.15 g, 1 equiv) was added to a stirred solution of INT-77 (0.34 g, 0.89 mmol) in ethanol. The mixture was stirred at room temperature for 15 h. The formed complex was precipitated as a reddish-brown powder. The precipitate was collected by filtration, washed with water, diethyl ether and dried. Yield 0.34 g (86.8%).

[0580] Scheme 39: Synthesis of compound 78 Synthesis of 4-(benzo[d]thiazol-2-yl)-N-methoxybutyramide: 4-(benzo[d]thiazole-2 at 5°C -yl)butanoic acid (1.22 g, 5.5 mmol), N,O-dimethylhydroxylamine (0.65 g, 1.2 equivalents), HOBt (0.89 g, 1.2 equivalents) and triethylamine (2 ml, 1.44 g, 2.5 equivalents ) to a stirred mixture in DCM (50 ml) was added EDCI (1.27 g, 1.2 equiv) and the reaction was stirred at room temperature for 15 h. The mixture was washed with water and brine. The organic layer was dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The product was used further without further purification. Yield 1.46 g (99.9 %). LC-MS 1.3 min, m / z 265.1 [MH]+. 1H-NMR (400 MHz, CDCl3), δ (ppm) : 7.92 (dd,J= 46.1, 8.1 Hz, 2H), 7.41 (dt,J= 15.2, 7.3 Hz, 2H), 3.66 (s, 3H), 3.33 - 3.11 (m, 5H), 2.60 (t, J= 7.1 Hz, 2H), 2.25 (p, J= 7.3 Hz, 2H).

[0581] Synthesis of 6-(benzo[d]thiazol-2-yl)-2-ethoxyhex-1-en-3-one: ethyl vinyl ether (1.2 g, 1.6 ml, 5.5 equivalents) in The solution in anhydrous THF (40 ml) was cooled to -78°C and tert-butyllithium (1.7M in pentane, 9.4 ml, 5 equiv) was added. The mixture was allowed to warm to 0 °C over a period of 1 h, stirred for 45 min and then cooled to -30 °C. A solution of 4-(benzo[d]thiazol-2-yl)-N-methoxybutanamide (0.8 g, 3 mmol) in THF (5 ml) was added and stirring was continued at 0 °C for 4 h. The mixture was poured into aqueous NH4Cl (15 ml) and extracted with Et2O (3x25 ml). The combined extracts were dried over anhydrous Na2SO4, filtered and the solvent was evaporated in vacuo. The product was used in the next step without further purification. Yield 0.83 g (99.6%). LC-MS 1.62 min, m / z 276.3 [MH]+.

[0582] Synthesis of INT-78 ((2E, 2'E)-2,2'-(6-(benzo[d]thiazol-2-yl) hexane-2,3-diylidene) bis(N -methylhydrazine-1-thioformamide)): 6-(benzo[d]thiazol-2-yl)-2-ethoxyhex-1-en-3-one (0.86 g, 3.1 mmol) was dissolved in EtOH (30 ml), and methionamide (0.66 g, 2 equiv) and 1 drop of H2SO4 were added. The stirred reaction mixture was heated to reflux for 4 h and then kept at room temperature for 15 h. The formed precipitate was filtered, washed with EtOH, saturated aqueous Na2CO3, water, Et2O, and dried. Yield 0.79 g (60.1%). LC-MS 1.57 min, m / z 422.3 [MH]+. 1H-NMR (400 MHz, DMSO-d6), δ (ppm) : 10.61 (s, 1H), 10.24 (s, 1H), 8.40 (d,J= 4.4 Hz, 1H), 8.23 ​​(d,J= 4.5 Hz, 1H), 8.07 (dd,J= 25.5, 8.0 Hz, 2H), 7.44 (dt,J= 33.7, 7.7 Hz, 2H), 3.21 (t,J= 7.2 Hz, 2H), 3.14 - 2.92 (m , 8H), 2.21 (s, 3H), 1.89 (d,J= 7.3 Hz, 2H).

[0583] Synthesis of Compound 78: Copper(II) chloride dihydrate (0.32 g, 1 equiv) was added to a stirred solution of INT-78 (0.79 g, 1.3 mmol) in ethanol. The mixture was stirred at room temperature for 15 h. The formed complex was precipitated as a reddish-brown powder. The precipitate was collected by filtration, washed with water, diethyl ether and dried. Yield 0.66 g (73.2%).

[0584] Example 6: Preparation of Compounds 79 to 127 Scheme 40: Synthesis of Compound 79 To a solution of ethyl 2-carboxylate (5 g, 27 mmol) in CHCN (150 ml) was added piperidine (2.56 g, 1 eq), potassium carbonate (7.33 g, 2 eq) and potassium iodide (1.3 g, 0.3 eq ). The reaction mixture was stirred overnight at room temperature. The solid was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in DCM and washed with water (3 x 50 ml). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and the solvent was evaporated in vacuo. Yield 3.6 g (57%). LC-MS 0.87 min, m / z 238.3 [MH]+. 1H-NMR (400 MHz, DMSO-d6), δ (ppm) : 7.22 (d,J= 3.4 Hz, 1H), 6.48 (d,J= 3.4 Hz, 1H), 4.26 (q,J= 7.1 Hz, 2H), 3.50 (s, 2H), 2.34 (s, 4H), 1.56 - 1.42 (m, 4H), 1.40 - 1.22 (m, 5H).

[0585] Synthesis of 5-(piperidin-1-ylmethyl)furan-2-carboxylic acid: 5-(piperidin-1-ylmethyl)furan-2-carboxylic acid ethyl ester (3.6 g, 15 mmol) To a solution in methanol (80 ml) was added a solution of NaOH (1.52 g, 2.5 equiv) in water (10 ml) and the reaction mixture was stirred at room temperature for 15 h. Methanol was removed in vacuo, the residue was diluted with water and acidified to pH 1. The acidified solution was evaporated to dryness and treated with acetonitrile. The solid was filtered, and the filtrate was evaporated to dryness in vacuo. Yield 2.94 g (79%). LC-MS 0.61 min, m / z 210.4 [MH]+. 1H NMR (400 MHz, DMSO-d6), δ (ppm) : 13.31 (br.s, 1H), δ 10.96 (br.s, 1H), 7.26 (s, 1H), δ 6.92 (s, 1H), 4.40 (s, 1H), 3.14-3.41 (br.s, 2H), 2.76-3.10 (br.s, 2H), 1.34 - 1.91 (m, 6H).

[0586] Synthesis of N-methoxy-N-methyl-5-(piperidin-1-ylmethyl)furan-2-formamide: 5-(piperidin-1-ylmethyl) at 5°C ) furan-2-carboxylic acid (2.94 g, 12 mmol), N, O-dimethylhydroxylamine (1.4 g, 1.2 equivalents), HOBt (2.2 g, 1.2 equivalents) and triethylamine (6.7 ml, 4.84 g, 4 equiv) to a stirred mixture in DCM (100 ml) was added EDCI (2.75 g, 1.2 equiv) and the reaction was stirred at room temperature for 15 h. The mixture was washed with water and brine. The organic layer was dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The product was used without further purification. Yield 2.2 g (73%). LC-MS 0.76 min, m / z 253.4 [MH]+. 1H-NMR (400 MHz, CDCl3), δ (ppm) : 7.09 (d,J= 3.4 Hz, 1H), 6.36 (d,J= 3.4 Hz, 1H), 3.77 (s, 3H), 3.66 (s, 2H), 3.34 (s, 3H), 2.42 (d,J= 68.1 Hz, 4H), 1.61 (dt,J= 11.1, 5.6 Hz, 4H), 1.42 (d,J= 5.4 Hz, 2H).

[0587] Synthesis of 1-(5-(piperidin-1-ylmethyl)furan-2-yl)ethan-1-ketone: N-methoxy-N-methyl-5-(piperidin-1 A solution of -ylmethyl)furan-2-carboxamide (2.2 g, 8.7 mmol) in THF (100 ml) was cooled to 5°C and methylmagnesium bromide (1.4M in THF, 19 ml, 3 equivalent). The reaction mixture was stirred at 5 °C for 2 h, poured into aqueous NH4Cl and extracted with Et2O. The combined extracts were dried over anhydrous Na2SO4, filtered and the solvent was evaporated in vacuo. Compound 5 was used in the next step without purification. Yield 1.7 g (94.6%). LC-MS 0.74 min, m / z 208.1 [MH]+. 1H-NMR (400 MHz, CDCl3), δ (ppm) : 7.14 (d,J= 3.5 Hz, 1H), δ 6.37 (d,J= 3.4 Hz, 1H), δ 3.61 (s, 2H), δ 2.47 (s, 7H), δ 1.60 (dt, J= 11.0, 5.6 Hz, 4H), δ 1.48 - 1.39 (m, 2H).

[0588] Synthesis of INT-79 ((2E,2'E)-2,2'-(1-(5-(piperidin-1-ylmethyl)furan-2-yl)ethane-1,2- Diylidene) bis(N-methylhydrazine-1-thioformamide)): 1-(5-(piperidin-1-ylmethyl)furan-2-yl)ethan-1-one ( A mixture of 1.15 g, 5.5 mmol), NaBr (0.57 g, 1 eq) and DMSO (3 ml) was heated to 85 °C, followed by the addition of H2SO4 (6 drops) (foaming, exothermic). The reaction was heated to 110-115 °C until the formation of dimethyl sulfide ceased and the reaction mixture became viscous. The resulting thick mass was dissolved in EtOH, the solid was filtered and methionamide (1.16 g, 2 equiv) was added to the filtrate. The reaction mixture was heated to reflux for 2 h, then cooled to room temperature, the solvent was evaporated in vacuo, the residue was dissolved in water (25 ml), neutralized with saturated aqueous K2CO3 and extracted with EtOAc (3 x 50 ml). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and the solvent was evaporated in vacuo. Treat the residue with water. The formed precipitate was filtered and washed with EtOH to afford the pure title product. Yield 1.16 g (52.8%). LC-MS 1.08 min, m / z 396.1 [MH]+. 1H-NMR (400 MHz, DMSO-d6), δ (ppm) : 11.67 (s, 1H), 8.75 (s, 1H), 7.19 (s, 1H), 6.93 (d,J= 3.1 Hz, 1H), 6.44 (d,J= 2.9 Hz, 1H), 6.13 (s, 1H), 5.37 (s, 1H), 3.45 (d,J= 22.7 Hz, 2H), 3.33 (m, 3H), 2.76 (d,J = 4.2 Hz, 3H), 2.35 (s, 4H), 1.41-1.55 (m, 6H).

[0589] Synthesis of Compound 79: Copper(II) chloride dihydrate (0.08 g, 1 eq) was added to a stirred solution of INT-79 (0.186 g, 0.47 mmol) in ethanol. The mixture was stirred at room temperature for 15 h. The formed complex was precipitated as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, diethyl ether, and dried in vacuo. Yield 0.1 g (46.5%).

[0590] Process 41: Synthesis of Compound 80 Synthesis of 5-((2,2,6,6-tetramethylpiperidin-1-yl)methyl)furan-2-carboxylic acid ethyl ester: to 5-(chloromethyl 2,2,6,6-tetramethylpiperidine (5.06 g, 1 eq), potassium carbonate (9.89 g, 2 equiv) and sodium iodide (1.07, 0.2 equiv). The reaction mixture was stirred overnight at room temperature. The solid was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in DCM and washed with water (3 x 50 ml). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and the solvent was evaporated in vacuo. Yield 10.5 g (99.9%). LC-MS 1.01 min, m / z 294.6. 1H-NMR (400 MHz, DMSO-d6), δ (ppm): 7.19 (t,J= 10.1 Hz, 1H), 6.43 (t,J= 16.6 Hz, 1H ), 4.24 (q,J= 7.1 Hz, 2H), 3.72 (s, 2H), 1.53 (d,J= 3.3 Hz, 2H), 1.45 - 1.39 (m, 4H), 1.26 (t,J= 7.1 Hz , 3H), 0.99 (s, 12H).

[0591] Synthesis of 5-((2,2,6,6-tetramethylpiperidin-1-yl)methyl)furan-2-carboxylic acid: to 5-((2,2,6,6-tetramethyl) To a solution of methylpiperidin-1-yl)methyl)furan-2-carboxylate (10.5 g, 354.8 mmol) in methanol (200 ml) was added NaOH (3.58 g, 2.5 equiv) in water (20 ml ) and the reaction mixture was stirred overnight at room temperature. Methanol was removed in vacuo, the residue was diluted with water and acidified to pH 1 with concentrated HCl. The acidified solution was evaporated to dryness and treated with acetonitrile. The solid was filtered, and the filtrate was evaporated to dryness in vacuo. Yield 10.8 g (99.8 %). LC-MS 0.88 min, m / z 266.5 [MH]+.

[0592] Synthesis of N-methoxy-N-methyl-5-((2,2,6,6-tetramethylpiperidin-1-yl) methyl) furan-2-formamide: in 5 ℃ to 5-((2,2,6,6-tetramethylpiperidin-1-yl)methyl)furan-2-carboxylic acid (10.8 g, 35.8 mmol), N,O-dimethylhydroxylamine ( To a stirred mixture of 4.18 g, 1.2 eq), HOBt (5.8 g, 1.2 eq) and triethylamine (18 ml, 12.94 g, 3.5 eq) in DCM (200 ml) was added EDCI (8.38 g, 1.2 eq), And the reaction was stirred at room temperature for 15h. The mixture was washed with water and brine. The organic layer was dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The product was purified by column chromatography (SiO2, eluent CCl4 / EtOAc, 8:2 to 7:3, then CHCl3 / MeOH, 99:1 to 98:2). Yield 7.42 g (75.9%). LC-MS 0.74 min, m / z 269.5 [MH]+. 1H-NMR (400 MHz, CDCl3), δ (ppm) : 7.08 (d,J= 3.4 Hz, 1H), 6.33 (s, 1H), 3.76 (s, 3H), 3.71 (m, 6H), 3.33 ( s, 3H), 3.16 - 2.98 (m, 2H), 1.02 (d, J= 6.5 Hz, 12H).

[0593] Synthesis of 1-(5-((2,2,6,6-tetramethylpiperidin-1-yl)methyl)furan-2-yl)ethan-1-one: N-methoxy -N-Methyl-5-((2,2,6,6-tetramethylpiperidin-1-yl)methyl)furan-2-formamide (6 g, 19.4 mmol) in THF (120 ml ) was cooled to 5°C and methylmagnesium bromide (3.4M in THF / toluene, 17 ml, 3 equiv) was added. The reaction mixture was stirred at 5 °C for 2 h, poured into aqueous NH4Cl and extracted with Et2O. The combined extracts were dried over anhydrous Na2SO4, filtered and the solvent was evaporated in vacuo. Compound 5 was used in the next step without purification. Yield 4.2 g (82%). LCMS 0.67 min, m / z 264.6 [MH]+. 1H-NMR (400 MHz, CDCl3), δ (ppm) : 7.12 (d,J= 3.3 Hz, 1H), 6.52 - 6.35 (m, 1H), 3.77 (s, 2H), 2.43 (d,J= 0.9 Hz, 3H), 1.63 - 1.55 (m, 2H), 1.48 (dd,J= 15.2, 10.0 Hz, 4H), 1.03 (t,J= 2.1 Hz, 12H).

[0594] Synthesis of INT-80 ((2E,2'E)-2,2'-(1-(5-((2,2,6,6-tetramethylpiperidin-1-yl)methyl) Furan-2-yl)ethane-1,2-diylidene)bis(N-methylhydrazine-1-thioformamide)): 1-(5-((2,2,6,6 -A mixture of tetramethylpiperidin-1-yl)methyl)furan-2-yl)ethan-1-one (0.93 g, 3.5 mmol), NaBr (0.36 g, 1 equiv) and DMSO (1.8 ml) was heated to 85° C., followed by addition of H2SO4 (6 drops) (foaming, exothermic). The reaction was heated to 110-115 °C until the formation of dimethyl sulfide ceased and the reaction mixture became viscous. The resulting viscous mass was dissolved in EtOH, the solid was filtered and methionamide (1.16 g, 2 equiv) was added to the filtrate. The reaction mixture was heated to reflux for 2 h, then cooled to room temperature, the solvent was evaporated in vacuo, the residue was dissolved in water (25 ml), neutralized with saturated aqueous K2CO3 and extracted with EtOAc (3 x 60 ml). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and the solvent was evaporated in vacuo. Treat the residue with water. The formed precipitate was filtered and washed with EtOH to afford the pure title product. Yield 1.05 g (65.8%). LC-MS 1.17 min, m / z 452.3 [MH]+.

[0595] Synthesis of Compound 80: Copper(II) chloride dihydrate (0.036 g, 1 eq) was added to a stirred solution of INT-80 (0.099 g, 4.7 mmol) in ethanol. The mixture was stirred at room temperature for 15 h. The formed complex was precipitated as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, diethyl ether, and dried in vacuo. Yield 0.08 g (71.2%).

[0596] Process 42: Synthesis of compound 81 Synthesis of ethyl 5-((3,3,5,5-tetramethyl-2-carboxylate) methyl)furan-2-carboxylate: to 5-(chloromethyl)furan - To a solution of ethyl 2-carboxylate (4 g, 21.2 mmol) in CHCN (100 ml) was added 2,2,6,6-tetramethyl 𠰌line hydrochloride (3.81 g, 1 equivalent), potassium carbonate (8.79 g, 3 equiv) and potassium iodide (1.06 g, 0.3 equiv). The reaction mixture was stirred overnight at room temperature. The solid was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in DCM and washed with water (3 x 50 ml). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and the solvent was evaporated in vacuo. Yield 4.9 g (78.2%). LC-MS 0.98 min, m / z 296.5 [MH]+. 1H-NMR (400 MHz, CDCl3), δ (ppm) : 7.10 (d,J= 3.4 Hz, 1H), 6.38 (d,J= 3.4 Hz, 1H), 4.42 - 4.29 (m, 2H), 3.77 ( s, 2H), 3.43 (s, 4H), 1.44 - 1.35 (m, 3H), 1.03 (s, 12H).

[0597] Synthesis of 5-((3,3,5,5-tetramethyl 𠰌linyl) methyl) furan-2-carboxylic acid: to 5-((3,3,5,5-tetramethyl 𠰌 To a solution of ethyl (olyl)methyl)furan-2-carboxylate (4.9 g, 16.6 mmol) in methanol (100 ml) was added a solution of NaOH (1.66 g, 2.5 equiv) in water (10 ml), and The reaction mixture was stirred overnight at room temperature. Methanol was removed in vacuo, the residue was diluted with water and acidified to pH 1 with concentrated HCl. The acidified solution was evaporated to dryness and treated with acetonitrile. The solid was filtered, and the filtrate was evaporated to dryness in vacuo. Yield 3.91 g (77.6 %). LC-MS 0.74 min, m / z 268.6 [MH]+.

[0598] Synthesis of N-methoxy-N-methyl-5-((3,3,5,5-tetramethyl-2-methyl)furan-2-formamide: at 5°C to 5 -((3,3,5,5-Tetramethyl?olinyl)methyl)furan-2-carboxylic acid (3.91 g, 12.9 mmol), N,O-dimethylhydroxylamine (1.51 g, 1.2 equiv) , HOBt (2.36 g, 1.2 eq) and triethylamine (7.2 ml, 5.2 g, 4 eq) in DCM (100 ml) was added to a stirred mixture of EDCI (2.96 g, 1.2 eq) and the reaction was stirred at room temperature Object 15h. The mixture was washed with water and brine. The organic layer was dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The product was purified by column chromatography (SiO2, eluent CCl4 / EtOAc 8:2 to 2:1). Yield 2.3 g (57.6%). LC-MS 0.78 min, m / z 311.5 [MH]+. 1H-NMR (400 MHz, DMSO-d6), δ (ppm) : 7.08 (d,J= 3.1 Hz, 1H), 6.41 (s, 1H), 3.73 (s, 5H), 3.31 (d,J= 2.6 Hz, 6H), 3.21 (s, 3H), 0.98 (s, 12H).

[0599] Synthesis of 1-(5-((3,3,5,5-tetramethyl 𠰌linyl) methyl) furan-2-yl) ethyl-1-one: N-methoxy-N- A solution of methyl-5-((3,3,5,5-tetramethyl-alcolinyl)methyl)furan-2-formamide (1.3 g, 4.2 mmol) in THF (50 ml) was cooled to 5°C and methylmagnesium bromide (1.4M in THF, 9 ml, 3 equiv) was added. The reaction mixture was stirred at 5 °C for 2 h, poured into aqueous NH4Cl and extracted with Et2O. The combined extracts were dried over anhydrous Na2SO4, filtered and the solvent was evaporated in vacuo. Compound 5 was used in the next step without purification. Yield 1.0 g (90%). LC-MS 0.80 min, m / z 266.3 [MH]+. 1H-NMR (400 MHz, DMSO-d6), δ (ppm) : 7.35 (d,J= 3.2 Hz, 1H), 6.48 (s, 1H), 3.74 (s, 2H), 3.31 (s, 6H), 2.35 (s, 3H), 0.97 (s, 12H).

[0600] Synthesis of INT-81 ((2E, 2'E)-2,2'-(1-(5-((3,3,5,5-tetramethyl-olyl)methyl)furan-2 -yl)ethane-1,2-diylidene)bis(N-methylhydrazine-1-thioformamide)): 1-(5-((3,3,5,5-tetramethyl A mixture of (alkolinolinyl)methyl)furan-2-yl)ethan-1-one (0.48 g, 1.8 mmol), NaBr (0.19 g, 1 equiv) and DMSO (1 ml) was heated to 85°C, then added H2SO4 (3 drops) (foaming, heating). The reaction was heated to 110-115 °C until the formation of dimethyl sulfide ceased and the reaction mixture became viscous. The resulting thick mass was dissolved in EtOH, the solid was filtered and methionamide (1.16 g, 2 equiv) was added to the filtrate. The reaction mixture was heated to reflux for 2 h, then cooled to room temperature, the solvent was evaporated in vacuo, the residue was dissolved in water (25 ml), neutralized with saturated aqueous K2CO3 and extracted with EtOAc (3 x 60 ml). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and the solvent was evaporated in vacuo. Treat the residue with water. The formed precipitate was filtered and washed with EtOH to afford the pure title product. Yield 0.28 g (34%). LC-MS 1.05 min, m / z 454.4 [MH]+.

[0601] Synthesis of Compound 81: Copper(II) chloride dihydrate (0.053 g, 1 equiv) was added to a stirred solution of INT-81 (0.14 g, 0.3 mmol) in ethanol. The mixture was stirred at room temperature for 15 h. The formed complex was precipitated as a reddish-brown powder. The precipitate was collected by filtration, washed with water, methanol, diethyl ether, and dried in vacuo. Yield 0.15 g (94.2%).

[0602] Process 43: Synthesis of compound 82 Synthesis of 5-((diisopropylamino) methyl) ethyl furan-2-carboxylate: to 5-(chloromethyl) ethyl furan-2-carboxylate (7.78 g, 41.2 mmol) in CHCN (150 ml) was added diisopropylamine (4.17 g, 5.8 ml, 1 eq), potassium carbonate (11.4 g, 2 eq) and sodium iodide (1.27 g, 0.2 eq) . The reaction mixture was stirred overnight at room temperature. The solid was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in DCM and washed with water (3 x 50 ml). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and the solvent was evaporated in vacuo. Yield 10 g (95.7%). LC-MS 0.93 min, m / z 254.3 [MH]+. 1H-NMR (400MHz, DMSO-d6), δ (ppm) : 7.19 (d,J= 3.4 Hz, 1H), 6.40 (d,J= 3.4 Hz, 1H), 4.25 (q,J= 7.1 Hz, 2H ), 3.66 (s, 2H), 3.00 (hept, J= 6.5 Hz, 2H), 1.27 (t, J= 7.1 Hz, 3H), 0.97 (d, J= 6.6 Hz, 12H).

[0603] Synthesis of 5-((diisopropylamino) methyl) furan-2-carboxylic acid: to 5-((diisopropylamino) methyl) f...

Claims

1. A compound of formula (V) or a pharmaceutically acceptable salt thereof: , wherein: R1 is a C1-C6 alkyl group substituted with a 5- to 10-membered heteroaryl group, NH2, NH(C1-C6 alkyl) or N(C1-C6 alkyl)2 as appropriate; R2 is a C1-C6 alkyl group substituted with a 5- to 10-membered heteroaryl group, NH2, NH(C1-C6 alkyl) or N(C1-C6 alkyl)2 as appropriate; R3 is a furanyl group substituted once with a C1-C3 alkyl-N(C1-C4 alkyl)2 or a C1-C3 alkyl-(5- to 6-membered heterocyclic) group, wherein the 5- to 6-membered heterocyclic group is further substituted with a C1-C3 alkyl group one to four times as appropriate; and R4 is hydrogen or a C1-3 alkyl group.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: R1 is methyl or ethyl; and R2 is methyl or ethyl.

3. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, wherein R3 is selected from the group consisting of: , , , , , and.

4. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen or methyl.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is compound 32: Compound 32 or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is methyl and R2 is methyl.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is ethyl and R2 is ethyl.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R3 is a furanyl group substituted once with a C1-C3 alkyl-(5- or 6-membered heterocycle), wherein the 5- or 6-membered heterocycle is further substituted once to four times with a C1-C3 alkyl group, as appropriate.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R4 is a methyl group.

12. A pharmaceutical composition comprising a compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, diluent or carrier.

13. Use of a compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of neurodegenerative diseases in an individual in need.

14. As claimed in claim 13, wherein the neurodegenerative disease is amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson's disease, Huntington's disease, or Alzheimer's disease.

15. As used in claim 13 or claim 14, wherein the neurodegenerative disease is ALS.

16. As used in claim 15, where the ALS is familial or sporadic.

17. For the purposes of requests 13 or 14, where the individual in need has not previously received treatment.

18. As requested in item 15, wherein the individual in need has received prior treatment for ALS.

19. As requested in claim 15, wherein the individual in need is a human being and the human being has a gene mutation associated with ALS.

20. As used in claim 19, wherein the gene mutation associated with ALS includes a mutation in the SOD1 gene.

21. The use as claimed in claim 15, wherein the compound is administered to the individual in combination with another ALS treatment therapy.

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