Heterocyclic compounds, compositions comprising them and uses thereof

Abstract

Compounds, compositions and their use in the treatment of a human copper deficiency or proliferative disease or condition, for instance the proliferative disease or disorder may have intracellular copper levels sensitivity. Also described in the use of a copper ionophore for the treatment of an SF3B1-mutated cancer. The compounds disclosed are of Formula (I), wherein A, R1 to R4, X1 to X3 and are as defined herein:

Description

[0001] HETEROCYCLIC COMPOUNDS, COMPOSITIONS COMPRISING THEM AND USES THEREOF

[0002] RELATED APPLICATION

[0003] This application claims priority under applicable laws to United States provisional application No. 63 / 595,105 filed on November 1 , 2023, the content of which is incorporated herein by reference in its entirety for all purposes.

[0004] TECHNICAL FIELD

[0005] This disclosure generally relates to compounds, pharmaceutical compositions comprising the same and their use in the treatment and prevention of diseases and conditions.

[0006] BACKGROUND

[0007] Copper is an essential transition metal for all living organisms. It acts as a cofactor in multiple enzymatic reactions due to its redox properties which enhance catalytic functions. Dysregulation of intracellular copper concentration is highly detrimental, as exemplified by Wilson’s and Menke’s diseases, two life-threatening genetic disorders in which mutations in copper transporter cause intracellular copper accumulation or deprivation, respectively. In cancer, increased copper levels have been reported both in serum and in tumor cells and are associated with enhanced proliferation and tumor burden. Therapeutic approaches have thus emerged to disrupt copper homeostasis by using either copper chelators or ionophores. Indeed, copper ionophores are copper-binding small molecules capable to cross the plasma membrane, causing intracellular copper accumulation, and ultimately triggering cuproptosis, a non-canonical cell death program.

[0008] Insights into the mechanism involved in cuproptosis were proposed in a recent publication, but a functional link was missing between copper overload and its impact on cellular respiration. The authors found that copper-induced cell death primarily involves the binding of this cation to lipoylated enzymes (e.g., DLAT, DLST, etc.) that regulate carbon entry points in the TCA cycle. Lipoylation is essential for the activity of these enzymes and is increased in cells that depend on oxidative phosphorylation (OXPHOS), in which the TCA cycle is the key NADH donor for Electron Transfer Chain (ETC) activity. Copper binding to lipoylated proteins generates aggregation and leads to proteotoxic stress. In addition, the authors also noticed that another class of essential proteins, referred to as the iron-sulfur (Fe-S) cluster (ISC)-containing proteins (ISC-CP), is depleted upon exposure to elesclomol, a known copper ionophore. However, mechanistic links are missing regarding how copper impacts ISC-CP stability and how the latter participates to cuproptosis.

[0009] ISC are a series of inorganic protein cofactors strictly assembled in the mitochondrial matrix by a specialized machinery called the ISC assembly machinery. ISCs are necessary for numerous proteins, including the ETCI-II I complexes, where they promote electron transfer, the lipoylation enzyme LIAS, and others involved in DNA synthesis, DNA repair, iron regulation, nucleotide metabolism and ribosome biogenesis. ISCs are exported to the cytosol through a transporter, putatively ABCB7, where they are loaded onto proteins by the cytosolic iron-sulfur assembly (CIA) machinery. Deficiency of the ABCB7 transporter impairs the maturation of cytosolic ISC enzymes and cause X-linked sideroblastic anemia (XLSA) with ataxia. Mutations in the splicing factor SF3B1, frequently found in myelodysplasic syndromes with ring sideroblasts (MDS-RS) and acute myeloid leukemia (AML), lead to missplicing of ABCB7 and resultant protein downregulation, which may contribute to the pathogenesis. In fact, ABCB7 defects in these AMLs result in ISC deficiency that appears synthetic lethal to cuproptosis.

[0010] In this context, the activity of copper ionophore molecules could be potentiated in cancers associated with a genetic predisposition to copper-overload-based therapies, such as SF3B1- mutated leukemias (e.g. AML) and other SF3B 7-mutated cancers.

[0011] There is thus a need for the discovery of copper ionophore molecules and their use in the treatment of diseases and conditions that could benefit from the effect associated therewith.

[0012] SUMMARY

[0013] According to one aspect, the present technology relates to a compound of Formula I: Formula I wherein:

[0014] A is a Cs- cycloalkyl, C4- heterocycloalkyl, Ce-waryl or Cs-wheteroaryl;

[0015] R1, R2, and R3are each independently selected from H, halo, OH, OR5, ON, NO2, C(O)R5, OC(O)R6, C(O)OR6, C(O)N(R6)2, C(R7)=NR7, SO2R5, SO2N(R6)2, N(R7)C(O)R5, N(R7)C(O)OR5, N(R7)SO2R5, N(R7)C(O)N(R6)2, N(R7)SO2N(R6)2, N(R6)2, P(O)(R6)2, P(O)(OR6)2, B(OR6)2, and optionally substituted Ci-salkyl, C2-8alkenyl, C2-8alkynyl, Ce- aryl, Cs-wheteroaryl, Cs-wcycloalkyl, and Cs-wheterocycloalkyl groups, or R1is absent when X1is N, or R2is absent when X2is N;

[0016] R4is independently in each occurrence selected from halo, OH, OR5, CN, NO2, C(O)R5, OC(O)R6, C(O)OR6, C(O)N(R6)2, C(R7)=NR7, SO2R5, SO2N(R6)2, N(R7)C(O)R5, N(R7)C(O)OR5, N(R7)SO2R5, N(R7)C(O)N(R6)2, N(R7)SO2N(R6)2, N(R6)2, P(O)(R6)2, P(O)(OR6)2, B(OR6)2, and optionally substituted Ci-salkyl, C2-8alkenyl, C2-8alkynyl, Ce-waryl, Cs-wheteroaryl, Cs-wcycloalkyl, and Cs-wheterocycloalkyl groups;

[0017] R5is independently in each occurrence selected from optionally substituted Ci-Cealkyl, C2. salkenyl, C2-8alkynyl, Cs-Cycycloalkyl, Cs-Cwheterocycloalkyl, Ce-waryl, Cs-Cwheteroaryl;

[0018] R6is independently in each occurrence selected from H or a group selected from optionally substituted Ci-Cealkyl, C2-8alkenyl, C2-8alkynyl, Cs-Cycycloalkyl, Cs-Cwheterocycloalkyl, Ce- waryl and Cs-Ceheteroaryl, or two R6groups are taken together with their adjacent nitrogen atom to form an optionally substituted Cs-Cwheterocycloalkyl or Cs-Cwheteroaryl;

[0019] R7is independently in each occurrence selected from H or a group selected from optionally substituted Ci-Cealkyl, C2-8alkenyl, C2-8alkynyl, Cs-Cycycloalkyl, C4-Cwheterocycloalkyl, Ce- waryl, and Cs-Ceheteroaryl;

[0020] X1and X2are each independently selected from C and N;

[0021] X3is selected from CH and N; n is an integer selected from 0 to 5 and denotes the number of R4replacing hydrogen atoms on A; and

[0022] — - designates a single or double bond; or a pharmaceutically acceptable salt or solvate thereof. The present technology also relates to any examples and embodiments of these compounds as further described herein.

[0023] In another aspect, the present technology further relates to pharmaceutical compositions comprising a compound as herein defined together with a pharmaceutically acceptable carrier, diluent or excipient.

[0024] In a further aspect, this technology also relates to uses and methods for the treatment of proliferative diseases or disorders, for the treatment of human copper deficiency diseases such as Menkes disease, for inhibiting tumor growth, and / or inducing tumor cell death, and / or treating of cancer, preferably wherein said inhibiting tumor growth, and / or inducing tumor cell death, and / or treating cancer comprising inducing cuproptosis.

[0025] According to another aspect, the present technology relates to a copper ionophore for use in the treatment of an SF3B 7 -mutated cancer. In one embodiment, the copper ionophore is a compound as described herein.

[0026] The present technology also further encompasses a copper ionophore or compound as defined herein for use in a treatment, inhibition, or induction as defined herein, or the use of a copper ionophore or compound as defined herein for the manufacture of a medicament for the same purposes.

[0027] Additional objects and features of the present compound, compositions, methods and uses will become more apparent upon reading of the following non-restrictive description of exemplary embodiments and examples section, which should not be interpreted as limiting the scope of the invention.

[0028] BRIEF DESCRIPTION OF THE FIGURES

[0029] Figure 1 shows the quantification of DLAT immunostaining in OCI-AML5 cells exposed 16 hours to 300nM Compound 1 or 20 nM elesclomol in media supplemented or not with 1 pM copper (unpaired t test compared to DMSO condition).

[0030] Figure 2 shows the intra-mitochondrial copper quantification by ICP-MS in HEK293 cells exposed 3 hours to the indicated compounds. Data is represented as mean + / - SD (n=3, unpaired t test compared to DMSO condition). Figure 3 presents representative dose-response curves for (A) Compound 1 and (B) elesclomol obtained in OCI-AML5 cells pre-treated with 10 pM Ferrostatin-1 (ferroptosis inhibitor), Z-DEVD- FMK (caspase 3 inhibitor) or Emricasan (pan caspase inhibitor). Error bars indicate SD of technical duplicates.

[0031] Figure 4 shows volcano plot representing the results of whole genome CRISPR / Cas9 screen performed in EKO OCI-AML5 cells upon exposure to Compound 1 (110 nM).

[0032] DETAILED DESCRIPTION

[0033] All technical and scientific terms and expressions used herein have the same definitions as those commonly understood by a person skilled in the art to which the present technology pertains. The definition of some terms and expressions used is nevertheless provided below. To the extent the definitions of terms in the publications, patents, and patent applications incorporated herein by reference are contrary to the definitions set forth in this specification, the definitions in this specification will control. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter disclosed.

[0034] / . Definitions

[0035] Chemical structures described herein are drawn according to conventional standards. Also, when an atom, such as a carbon atom, as drawn seems to include an incomplete valency, then the valency is assumed to be satisfied by one or more hydrogen atoms even though these are not necessarily explicitly drawn. Hydrogen atoms should be inferred to be part of the compound.

[0036] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. It should be noted that, the singular forms "a", "an", and "the" include plural forms as well, unless the content clearly dictates otherwise. Thus, for example, reference to a composition containing "a compound" also contemplates a mixture of two or more compounds. It should also be noted that the term "or" is generally employed in its sense including "and / or" unless the context clearly dictates otherwise. Furthermore, to the extent that the terms “including”, "includes", "having", "has", "with", or variants thereof are used in either the detailed description and / or the claims, such terms are intended to be inclusive in a manner similar to the term "comprising”.

[0037] The term "about" or "approximately" means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, "about" can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1 % of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value. Where particular values are described in the application and claims, unless otherwise stated the term "about" meaning within an acceptable error range for the particular value should be assumed.

[0038] As used herein, the terms "compounds”, "compounds herein described", "compounds of the present application", “copper ionophore compounds”, “copper ionophores” and equivalent expressions refer to compounds described in the present application, e.g. those encompassed by structural Formulae I, II, III and IV, optionally with reference to any of the applicable embodiments, and also includes exemplary compounds, such as Compounds 1 to 138, as well as their pharmaceutically acceptable salts, solvates, esters, and prodrugs when applicable. When a zwitterionic form is possible, the compound may be drawn as its neutral form for practical purposes, but the compound is understood to also include its zwitterionic form. Embodiments herein may also exclude one or more of the compounds. Compounds may be identified either by their chemical structure or their chemical name. In a case where the chemical structure and chemical name would conflict, the chemical structure will prevail.

[0039] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure when applicable; for example, the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the present description. The therapeutic compound unless otherwise noted, also encompasses all possible tautomeric forms of the illustrated compound, if any. The term also includes isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass most abundantly found in nature. Examples of isotopes that may be incorporated into the present compounds include, but are not limited to,2H (D),3H (T),11C,13C,14C,15N,18O,17O, any one of the isotopes of sulfur, etc. The compound may also exist in unsolvated forms as well as solvated forms, including hydrated forms. The compound may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present invention. Where a particular enantiomer is preferred, it may, in some embodiments be provided substantially free of the corresponding enantiomer and may also be enantiomerically enriched. "Enantiomerically enriched" means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments the compound is made up of at least about 90% by weight of a preferred enantiomer. In other embodiments the compound is made up of at least about 95%, 98%, or 99% by weight of a preferred enantiomer. Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including high- pressure liquid chromatography (HPLC) on chiral support and the formation and crystallization of chiral salts or be prepared by asymmetric syntheses.

[0040] The expression "pharmaceutically acceptable salt" refers to those salts of the compounds of the present description which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the present description, or separately by reacting a free base function of the compound with a suitable organic or inorganic acid (acid addition salts) or by reacting an acidic function of the compound with a suitable organic or inorganic base (base-addition salts).

[0041] The term “solvate” refers to a physical association of one of the present compounds with one or more solvent molecules, including water and non-aqueous solvent molecules. This physical association may include hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. The term “solvate” encompasses both solution-phase and isolable solvates. Exemplary solvates include, without limitation, hydrates, hemihydrates, ethanolates, hemiethanolates, n-propanolates, iso-propanolates, 1 -butanolates, 2-butanolate, and solvates of other physiologically acceptable solvents, such as the Class 3 solvents described in the International Conference on Harmonization (ICH), Guide for Industry, Q3C Impurities: Residual Solvents (1997). Accordingly, the compound as herein described also includes each of its solvates and mixtures thereof.

[0042] As used herein, the expression "pharmaceutically acceptable ester" refers to esters of the compounds formed by the process of the present description which may hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates of hydroxyl groups, and alkyl esters of an acidic group. Other ester groups include sulfonate or sulfate esters.

[0043] The expression "pharmaceutically acceptable prodrugs" as used herein refers to those prodrugs of the compounds formed by the process of the present description which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective fortheir intended use. "Prodrug", as used herein means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to afford any compound delineated by the formulae of the instant description.

[0044] Abbreviations may also be used throughout the application, unless otherwise noted, such abbreviations are intended to have the meaning generally understood by the field. Examples of such abbreviations include Me (methyl), Et (ethyl), Pr (propyl), i-Pr (isopropyl), Bu (butyl), t-Bu (tert-butyl), i-Bu (iso-butyl), s-Bu (sec-butyl), c-Bu (cyclobutyl), Ph (phenyl), Bn (benzyl), Bz (benzoyl), CBz or Cbz or Z (carbobenzyloxy), Boc or BOC (tert-butoxycarbonyl), and Su or Sue (succinimide). For more certainty, additional definitions of specific abbreviations are also included in the introduction of the Examples section.

[0045] The number of carbon atoms in a hydrocarbyl substituent can be indicated by the prefix "Cx-Cy" or "Cx-y" where x is the minimum and y is the maximum number of carbon atoms in the substituent. However, when the prefix “Cx-Cy” or "Cx-y" is associated with a group incorporating one or more heteroatom(s) by definition (e.g. heterocycloalkyl, heteroaryl, etc), then x and y define respectively the minimum and maximum number of atoms in the cycle, including carbon atoms as well as heteroatom(s).

[0046] The term "alkyl" as used herein, refers to a saturated, straight- or branched-chain hydrocarbon radical typically containing from 1 to 20 carbon atoms. For example, "Ci-Cs alkyl" contains from one to eight carbon atoms. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, fert-butyl, neopentyl, n-hexyl, heptyl, octyl radicals and the like.

[0047] The term "alkenyl" as used herein, denotes a straight- or branched-chain hydrocarbon radical containing one or more double bonds and typically from 2 to 20 carbon atoms. For example, "C2- 8 alkenyl" contains from two to eight carbon atoms. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, heptenyl, octenyl and the like.

[0048] The term "alkynyl" as used herein, denotes a straight- or branched-chain hydrocarbon radical containing one or more triple bonds and typically from 2 to 20 carbon atoms. For example, "C2-8 alkynyl" contains from two to eight carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl,1-propynyl, 1-butynyl, heptynyl, octynyl and the like.

[0049] The terms “cycloalkyl”, “alicyclic”, “carbocycle”, “carbocyclic” and equivalent expressions refer to a group comprising a saturated or partially unsaturated (non-aromatic) carbocyclic ring in a monocyclic or polycyclic ring system, including spiro (sharing one atom), fused (sharing at least one bond) or bridged (sharing two or more bonds) carbocyclic ring systems, having from three to fifteen ring members. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclopenten-2-yl, cyclopenten-3-yl, cyclohexyl, cyclohexen-1-yl, cyclohexen-2-yl, cyclohexen-3-yl, cycloheptyl, bicyclo[4,3,0]nonanyl, norbornyl, and the like. The term cycloalkyl includes both unsubstituted cycloalkyl groups and substituted cycloalkyl groups. The term “Cs-Cncycloalkyl” refers to a cycloalkyl group having from 3 to the indicated “n” number of carbon atoms in the ring structure. Unless the number of carbons is otherwise specified, “lower cycloalkyl” groups as herein used, have at least 3 and equal or less than 8 carbon atoms in their ring structure.

[0050] As used herein, the term "heteroatom" includes but is not limited to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.

[0051] As used herein, the terms "heterocycle", "heterocycloalkyl", "heterocyclyl", "heterocyclic radical", and "heterocyclic ring" are used interchangeably and refer to a chemically stable 3- to 7- membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 1-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR (as in N-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a chemically stable structure and any of the ring atoms can be optionally substituted. Examples of heterocycloalkyl groups include, but are not limited to, 1 ,3-dioxolanyl, pyrrolidinyl, pyrrolidonyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrodithienyl, tetrahydrothienyl, thiomorpholino, thioxanyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1 ,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2H-pyranyl, 4H- pyranyl, dioxanyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, di hydrofuranyl, 3- azabicyclo[3,1 ,0]hexanyl, 3-azabicyclo[4,1 ,0]heptanyl, quinolizinyl, quinuclidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, and the like. Heterocyclic groups also include groups in which a heterocyclic ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, chromenyl, phenanthridinyl, 2- azabicyclo[2.2.1]heptanyl, octahydroindolyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group may be mono- or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. The term “Cs-nheterocycloalkyl” refers to a heterocycloalkyl group having from 3 to the indicated “n” number of atoms in the ring structure, including carbon atoms and heteroatoms.

[0052] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond between ring atoms but is not aromatic. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0053] The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", "aryloxy", or "aryloxyalkyl", refers to aromatic groups having 4n+2 conjugated ir(pi) electrons, wherein n is an integer from 1 to 3, in a monocyclic moiety or a bicyclic or tricyclic fused ring system having a total of six to 15 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the present description, "aryl" refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, azulenyl, anthracyl and the like, which may bear one or more substituents. The term "aralkyl" or "arylalkyl" refers to an alkyl residue attached to an aryl ring. Examples of aralkyl include, but are not limited to, benzyl, phenethyl, and the like. Also included within the scope of the term “aryl”, as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, indenyl, phthalimidyl, naphthimidyl, fluorenyl, phenanthridinyl, or tetrahydronaphthyl, and the like. The term “Ce-naryl” refers to a aryl group having from 6 to the indicated “n” number of atoms in the ring structure. The term "heteroaryl", used alone or as part of a larger moiety, e.g., "heteroaralkyl", or "heteroaralkoxy", refers to aromatic groups having 4n+2 conjugated ir(pi) electrons, wherein n is an integer from 1 to 3 (e.g. having 5 to 18 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 TT electrons shared in a cyclic array); and having, in addition to carbon atoms, from one to five heteroatoms. The term "heteroatom" includes but is not limited to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. A heteroaryl may be a single ring, or two or more fused rings. The term "heteroaryl", as used herein, also includes groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclic rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples of heteroaryl groups include thienyl, furanyl (furyl), pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, 3H-indolyl, isoindolyl, indolizinyl, benzothienyl (benzothiophenyl), benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, pyrrolopyridinyl (e.g. pyrrolo[3,2- b]pyridinyl or pyrrolo[3,2-c]pyridinyl), pyrazolopyridinyl (e.g. pyrazolo[1,5-a]pyridinyl), furopyridinyl, purinyl, imidazopyrazinyl (e.g. imidazo[4,5-b]pyrazinyl), quinolyl (quinolinyl), isoquinolyl (isoquinolinyl), quinolonyl, isoquinolonyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, naphthyridinyl, and pteridinyl carbazolyl, acridinyl, phenanthridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. A heteroaryl group may be mono- or bicyclic. Heteroaryl groups include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. Examples include, but are not limited to, pyridinylmethyl, pyrimidinylethyl and the like. For instance, the term “Cs-nheteroaryl” refers to a heteroaryl group having from 5 to the indicated “n” number of atoms in the ring structure, including carbon atoms and heteroatoms.

[0054] As described herein, compounds of the present description may contain "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position. Combinations of substituents envisioned under the present description are preferably those that result in the formation of chemically stable or chemically feasible compounds. The term "chemically stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0055] The term “halo” designates a halogen atom, i.e. a fluorine, chlorine, bromine or iodine atom, preferably fluorine or chlorine.

[0056] The term "optionally substituted" refers to groups that are substituted or unsubstituted by independent replacement of one, two, or three or more of the hydrogen atoms thereon with substituents including, but not limited to F, Cl, Br, I, OH, CO2H, alkoxy, oxo, thiooxo, NO2, CN, CF3, NH2, NHalkyl, NHalkenyl, NHalkynyl, NHcycloalkyl, NHaryl, NHheteroaryl, NHheterocyclic, dialkylamino, diarylamino, diheteroarylamino, O-alkyl, O-alkenyl, O-alkynyl, O-cycloalkyl, O-aryl, O-heteroaryl, O-haloalkyl, O-heterocyclic, C(O)alkyl, C(O)alkenyl, C(O)alkynyl, C(O)cycloalkyl, C(O)aryl, C(O) heteroaryl, C(O)heterocycloalkyl, CO2alkyl, CO2alkenyl, CO2alkynyl, CO2cycloalkyl, CO2aryl, CO2heteroaryl, CO2heterocycloalkyl, OC(O)alkyl, OC(O)alkenyl, OC(O)alkynyl, OC(O)cycloalkyl, OC(O)aryl, OC(O)heteroaryl, OC(O)heterocycloalkyl, C(O)NH2, C(O)NHalkyl, C(O)NHalkenyl, C(O)NHalkynyl, C(O)NHcycloalkyl, C(O)NHaryl, C(O) NHheteroaryl, C(O)NHheterocycloalkyl, OCO2alkyl, OCO2alkenyl, OCO2alkynyl, OCO2cycloalkyl, OCO2aryl, OCO2heteroaryl, OCO2heterocycloalkyl, OC(O)NH2, OC(O)NHalkyl, OC(O)NHalkenyl, OC(O) NHalkynyl, OC(O)NHcycloalkyl, OC(O)NHaryl, OC(O) NHheteroaryl, OC(O)NHheterocycloalkyl, NHC(O)alkyl, NHC(O)alkenyl, NHC(O)alkynyl, NHC(O)cycloalkyl, NHC(O)aryl, NHC(O)heteroaryl, NHC(O)heterocycloalkyl, NHCO2alkyl, NHCO2alkenyl, NHCO2alkynyl, NHCO2cycloalkyl, NHCO2aryl, NHCO2heteroaryl, NHCO2heterocycloalkyl, NHC(O)NH2, NHC(O)NHalkyl, NHC(O)NHalkenyl, NHC(O)NHalkenyl, NHC(O)NHcycloalkyl, NHC(O)NHaryl, NHC(O) NHheteroaryl, NHC(O)NHheterocycloalkyl, NHC(S)NH2, NHC(S)NHalkyl, NHC(S)NHalkenyl, NHC(S)NHalkynyl, NHC(S)NHcycloalkyl, NHC(S)NHaryl, NHC(S)NHheteroaryl, NHC(S)NHheterocycloalkyl, NHC(NH)NH2, NHC(NH)NHalkyl, NHC(NH)NHalkenyl, NHC(NH)NHalkenyl, NHC(NH)NHcycloalkyl, NHC(NH)NHaryl, NHC(NH)NHheteroaryl, NHC(NH)NHheterocycloalkyl, NHC(NH)alkyl, NHC(NH)alkenyl, NHC(NH)alkenyl, NHC(NH)cycloalkyl, NHC(NH)aryl, NHC(NH)heteroaryl, NHC(NH)heterocycloalkyl, C(NH)NHalkyl, C(NH)NHalkenyl, C(NH)NHalkynyl, C(NH)NHcycloalkyl, C(NH)NHaryl, C(NH) NHheteroaryl, C(NH)NHheterocycloalkyl, S(O)alkyl, S(O)alkenyl, S(O)alkynyl, S(O)cycloalkyl, S(O)aryl, S(O)2alkyl, S(O)2alkenyl, S(O)2alkynyl, S(O)2cycloalkyl, S(O)2aryl, S(O)heteroaryl, S(O)heterocycloalkyl, SO2NH2, SO2NHalkyl, SO2NHalkenyl, SO2NHalkynyl, SO2NHcycloalkyl, SO2NHaryl, SO2NHheteroaryl, SO2NHheterocycloalkyl, NHSO2alkyl, NHSO2alkenyl, NHSO2alkynyl, NHSO2cycloalkyl, NHSO2aryl, NHSO2heteroaryl, NHSO2heterocycloalkyl, CH2NH2, CH2CN, CH2F, CH2OH, CH2OCH3, C(CH3)2OH, CH2SO2CH3, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, cycloalkyl, carbocyclic, heterocyclic, phenyl, phenol, polyalkoxyalkyl, polyalkoxy, methoxymethoxy, methoxyethoxy, SH, S-alkyl, S-alkenyl, S-alkynyl, S-cycloalkyl, S-aryl, S-heteroaryl, S-heterocycloalkyl, or methylthiomethyl.

[0057] / / . Compounds

[0058] The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof. As such, the following embodiments are present alone or in combination if applicable.

[0059] The present compounds present a heterocyclic core structure to which is attached defined substituents to achieve the product’s beneficial activity. Examples of heterocyclic compounds as defined herein are illustrated by general Formula I: wherein:

[0060] A is a Cs- cycloalkyl, C4- heterocycloalkyl, Ce- aryl or Cs-wheteroaryl;

[0061] R1, R2, and R3are each independently selected from H, halo, OH, OR5, ON, NO2, C(O)R5, OC(O)R6, C(O)OR6, C(O)N(R6)2, C(R7)=NR7, SO2R5, SO2N(R6)2, N(R7)C(O)R5, N(R7)C(O)OR5, N(R7)SO2R5, N(R7)C(O)N(R6)2, N(R7)SO2N(R6)2, N(R6)2, P(O)(R6)2, P(O)(OR6)2, B(OR6)2, and optionally substituted Ci-salkyl, C2-salkenyl, C2-salkynyl, Ce-waryl, Cs-wheteroaryl, Cs-wcycloalkyl, and Cs-wheterocycloalkyl groups, or R1is absent when X1is N, or R2is absent when X2is N;

[0062] R4is independently in each occurrence selected from halo, OH, OR5, ON, NO2, C(O)R5, OC(O)R6, C(O)OR6, C(O)N(R6)2, C(R7)=NR7, SO2R5, SO2N(R6)2, N(R7)C(O)R5, N(R7)C(O)OR5, N(R7)SO2R5, N(R7)C(O)N(R6)2, N(R7)SO2N(R6)2, N(R6)2, P(O)(R6)2, P(O)(OR6)2, B(OR6)2, and optionally substituted Ci-salkyl, 02-salkenyl, 02-salkynyl, Ce- aryl, Cs-wheteroaryl, Cs-wcycloalkyl, and Cs-wheterocycloalkyl groups;

[0063] R5is independently in each occurrence selected from optionally substituted Ci-Cealkyl, 02- salkenyl, 02-salkynyl, Cs-Cycycloalkyl, Cs-Cwheterocycloalkyl, Ce-waryl, Cs-Cwheteroaryl;

[0064] R6is independently in each occurrence selected from H or a group selected from optionally substituted Ci-Cealkyl, C2-salkenyl, 02-salkynyl, Cs-Cycycloalkyl, Cs-Cwheterocycloalkyl, Ce- waryl and Cs-Ceheteroaryl, or two R6groups are taken together with their adjacent nitrogen atom to form an optionally substituted Cs-Cwheterocycloalkyl or Cs-Cwheteroaryl;

[0065] R7is independently in each occurrence selected from H or a group selected from optionally substituted Ci-Cealkyl, Cs-salkenyl, Cs-salkynyl, Cs-Cycycloalkyl, C4-Cwheterocycloalkyl, Ce- waryl, and Cs-Ceheteroaryl;

[0066] X1and X2are each independently selected from C and N;

[0067] X3is selected from CH and N; n is an integer selected from 0 to 5 and denotes the number of R4replacing hydrogen atoms on A; and

[0068] — - designates a single or double bond; or a pharmaceutically acceptable salt or solvate thereof.

[0069] In some examples of the present compounds, X1is C and R1is present. In other examples, X1is N and R1is absent. In some examples, X3is CH. Alternatively, X3is N.

[0070] In some examples, the heterocyclic compound is of Formula II:

[0071]

[0072] Formula II wherein,

[0073] R1, R2, R3, X1, X2, X3, and — are as defined above;

[0074] X4to X8are each independently selected from N, CH, and CR4, wherein at most 2 of X4to

[0075] X8are N, and wherein R4is as defined herein; and or a pharmaceutically acceptable salt or solvate thereof.

[0076] In some examples, X4is N, and / or X6is CR4, and / or X7is N, and / or X7is CH, and / or X7is CR4, and / or X5and X8are CH.

[0077] Examples of compounds of Formula I or II includes compounds wherein R4is N(R6)2. For instance, when R4is N(R6)2, the two R6may be taken together with their adjacent nitrogen atom to form an optionally substituted C4-C heterocycloalkyl or Cs-Ceheteroaryl, preferably an optionally substituted C4-C heterocycloalkyl.

[0078] In some examples, R4is selected from: wherein,

[0079] R8is independently in each occurrence selected from halo, OH, OR5, CN, NO2, C(O)R5, OC(O)R6, C(O)OR6, C(O)N(R6)2, C(R7)=NR7, SO2R5, SO2N(R6)2, N(R7)C(O)R5, N(R7)C(O)OR5, N(R7)SO2R5, N(R7)C(O)N(R6)2, N(R7)SO2N(R6)2, N(R6)2, P(O)(R6)2, P(O)(OR6)2, B(OR6)2, and optionally substituted Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, Cearyl, C5- eheteroaryl, Cs-ecycloalkyl, and Cs-eheterocycloalkyl groups, or two R8are taken together with an adjacent carbon atom to form an oxo or a spiro Cs-scycloalkyl or Cs-sheterocycloalkyl group;

[0080] R9is selected from H, C(O)R5, C(O)OR6, C(O)N(R6)2, C(R7)=NR7, SO2R5, SO2N(R6)2, and optionally substituted Ci-ealkyl, C2-6alkenyl, C2-6alkynyl, Cearyl, Cs-eheteroaryl, C3- ecycloalkyl, and Cs-eheterocycloalkyl groups, preferably R9is SO2R5;

[0081] R5, R6, and R7are as previously defined; p is an integer selected from 0 to 3; m is between 1 and 4; and

[0082] (— ) represents a bond.

[0083] For instance, R8may be independently selected from OH, OR5, and optionally substituted Ci- ealkyl. Alternatively, two R8may be taken together with an adjacent carbon atom to form an oxo group or a spiro Cs-scycloalkyl or Cs-sheterocycloalkyl group.

[0084] In other examples, R4is selected from a halo, N(R7)C(O)R5, N(R7)C(O)OR5, and optionally substituted Ci-salkyl and Cs-yheterocycloalkyl groups.

[0085] In preferred examples of compounds of Formula I or II, — - is a double bond in each instance.

[0086] In the compounds of Formula I or II, R1may be selected from N(R6)2, N(R7)C(O)R5, N(R7)C(O)OR5, N(R7)SO2R5, N(R7)C(O)N(R6)2, and N(R7)SO2N(R6)2. In some examples, R2is H or R2is absent and X2is N.

[0087] In other compounds of Formula I or II, wherein R2may be selected from N(R6)2, N(R7)C(O)R5, N(R7)C(O)OR5, N(R7)SO2R5, N(R7)C(O)N(R6)2, and N(R7)SO2N(R6)2. In these example, R1may be H or R1may be absent when X1is N.

[0088] In some examples of the present compounds, R3is selected from H, halo, OH, OR5, ON, NH2, and optionally substituted Ci-salkyl, C2-8alkenyl, C2-8alkynyl, Ce- aryl, Cs-wheteroaryl, C3- locycloalkyl, or Cs-wheterocycloalky.

[0089] In some examples, the heterocyclic compound is of Formula III:

[0090]

[0091] Formula III wherein,

[0092] A, R1, R2, R3, R8, X1, X2, X3, m, p, and — - are as defined above; and X9is selected from CH2, CHR8, C(R8)2, and an optionally substituted heteroatom; or a pharmaceutically acceptable salt or solvate thereof. In some examples of the compounds of Formula III, X9is selected from CH2, S, S=O, O, or CH2NR9, wherein R9is as previously defined.

[0093] In further examples, the heterocyclic compound is of Formula IV: Formula IV wherein,

[0094] X9is an optionally substituted heteroatom or CH2;

[0095] R8is independently in each occurrence selected from halo, OH, OR5, ON, NO2, C(O) R5, OC(O)R6, C(O)OR6, C(O)N(R6)2, C(R7)=NR7, SO2R5, SO2N(R6)2, N(R7)C(O)R5, N(R7)C(O)OR5, N(R7)SO2R5, N(R7)C(O)N(R6)2, N(R7)SO2N(R6)2, N(R6)2, P(O)(R6)2, P(O)(OR6)2, B(OR6)2, and optionally substituted Ci-ealkyl, C2-6alkenyl, C2-6alkynyl, Cearyl, Cs- eheteroaryl, Cs-ecycloalkyl, and Cs-eheterocycloalkyl groups, or two R8on adjacent carbon atoms are taken together to form a Cs-eheterocycloalkyl group or two R8on non-adjacent carbon atoms are taken together to form a 6-8 membered bicyclic group, or two R8on a same carbon atom are taken together to form an oxo, a spiro Cs-scycloalkyl group or a spiro Cs-eheterocycloalkyl group;

[0096] R5, R6, and R7are as previously defined; q is an integer selected from 0 to 3; and r is between 0 and 4.

[0097] In some examples of the compounds of Formula IV, X9is S, S=O, NR9, O, or CH2, and R9is Ci- ealkyl, phenol, Cs-eheterocycloalkyl group or Cs-eheteroaryl group optionally substituted with CH3.

[0098] In further examples of the compounds of Formula IV, R8is independently in each occurrence selected from F, OH, CN, CH2CN, CH2F, CH2OH, CH2OCH3, CH3, C(CH3)2OH, NH(C=O)CH3, SO2CHS, phenyl, phenol, C4-6heterocycloalkyl group and Ceheteroaryl group optionally substituted with CH3, or two R10on adjacent carbon atoms are taken together to form a Csheterocycloalkyl group, or two R10on non-adjacent carbon atoms are taken together to form a 8-membered bicyclic group, or two R10on a same carbon atom are taken together to form an oxo or a spiro C4- eheterocycloalkyl group, or two R10on a same sulfur atom are taken together to form an oxo.

[0099] Exemplary compounds as defined herein include each single compound described in the present application, including Compounds 1 to 138:

[0100] Compound 3 Compound 4

[0101]

[0102] Compound 7 Compound 8

[0103] Compound 11 Compound 12

[0104] Compound 19 Compound 20

[0105] Compound 23 Compound 24

[0106] Compound 27 Compound 28

[0107] Compound 31 Compound 32

[0108]

[0109] Compound 49 Compound 50

[0110]

[0111] Compound 61 Compound 62

[0112] Compound 63 Compound 64

[0113] Compound 67 Compound 68

[0114] Compound 71 Compound 72

[0115] Compound 77 Compound 78

[0116]

[0117] Compound 83 Compound 84

[0118]

[0119] Compound 91 Compound 92

[0120] Compound 95 Compound 96

[0121]

[0122] Compound 103 Compound 104

[0123]

[0124] Compound 115 Compound 116

[0125] Compound 119 Compound 120

[0126]

[0127] Compound 123 Compound 124

[0128] Compound 127 Compound 128

[0129]

[0130] Compound 133

[0131]

[0132] Compound 137 Compound 138 or a pharmaceutically acceptable salt or solvate thereof.

[0133] Examples of preferred compounds include, namely, Compounds 4, 7, 8, 10, 11 , 13 to 15, 17, 18, 20, 21 , 23 to 50, and 52 to 80 as defined herein, or a salt and / or solvate thereof. Alternatively, examples of preferred compounds also include Compounds 1 , 4, 6, 10, 11 , 13 to 17, 21 to 24, 37, 39 to 41, 43, 47, 48, 50 to 53, 58, 60, 62, 64 to 66, 69, and 72 to 74 as defined herein, or a salt and / or solvate thereof. More specifically, the compound may be selected from Compounds 4, 10, 11 , 13 to 15, 17, 21 , 23, 24, 37, 39 to 41 , 43, 47, 48, 50, 52, 53, 58, 60, 62, 64 to 66, 69, and 72 to 74 as defined herein, or a salt and / or solvate thereof.

[0134] Other examples of preferred compounds include, namely, Compounds 82 to 119, 121 to 123, 125 to 128 and 130 to 138 as defined herein, or a salt and / or solvate thereof.

[0135] Other examples of preferred compounds include, namely, Compounds 50, 89, 90, 100, 111 , 121 , 122, 123, 125, 128, 130, 131 and 136 as defined herein, or a salt and / or solvate thereof.

[0136] It is understood that any of the above compounds may be in any amorphous, crystalline or polymorphic form, including any salt or solvate form, or a mixture thereof. The compounds of the present description may be further modified by appending various functionalities via any synthetic means delineated herein to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.

[0137] These compounds may be prepared by conventional chemical synthesis, such as those exemplified in the Schemes and Examples of the present disclosure. As can be appreciated by the skilled artisan, further methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. Hi. Methods, Uses, Formulations and Administration

[0138] As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in treatment, healing, prevention, or amelioration of a disease, disorder, or symptom thereof, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

[0139] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0140] In one embodiment, the disease or condition to be treated is a proliferative disease or disorder or a disease or disorder sensitive to copper ionophores. More specifically, the disease or disorder to be treated include a proliferative disease or disorder such as a neoplasm which includes a sensitivity to increases in intracellular copper levels, especially intramitochondrial copper levels. More specifically, tumor or cancers to be treated, inhibited or which cell death may be induced include factors causing an increase in copper level sensitivity, i.e. in which cuproptosis may be induced. Examples of such tumor or cancer cells are those exhibiting iron-sulfur cluster (ISC) deficiency or including mutations of genes resulting in increased sensitivity to increases in copper levels (e.g., SF3B1 mutations).

[0141] According to one embodiment, the disease or disorder is characterized by uncontrolled cell proliferation, i.e. a “proliferative disorder” or “proliferative disease”. More specifically, these diseases and disorders relate to cells having the capacity for autonomous growth, i.e. an abnormal state of condition characterized by rapidly proliferating cell growth which generally forms a distinct mass that show partial or total lack of structural organization and functional coordination with normal tissue. For instance, the proliferative disorder or disease is defined as a “neoplasm”, “neoplastic disorder”, “neoplasia” “cancer,” and “tumor” which terms are collectively meant to encompass hematopoietic neoplasms (e.g. lymphomas or leukemias) as well as solid neoplasms (e.g. sarcomas or carcinomas), including all types of pre-cancerous and cancerous growths, or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues, or organs, irrespective of histopathologic type or stage of invasiveness. Hematopoietic neoplasms are malignant tumors affecting hematopoietic structures (structures pertaining to the formation of blood cells) and components of the immune system, including leukemias (related to leukocytes (white blood cells) and their precursors in the blood and bone marrow) arising from myeloid, lymphoid or erythroid lineages, and lymphomas (related to lymphocytes). Solid neoplasms include sarcomas, which are malignant neoplasms that originate from connective tissues such as muscle, cartilage, blood vessels, fibrous tissue, fat or bone. Solid neoplasms also include carcinomas, which are malignant neoplasms arising from epithelial structures, including external epithelia (e.g., skin and linings of the gastrointestinal tract, lungs, and cervix), and internal epithelia that line various glands (e.g., breast, pancreas, thyroid). Examples of neoplasms include leukemia, and hepatocellular cancers, sarcoma, vascular endothelial cancers, breast cancers, central nervous system cancers (e.g. astrocytoma, gliosarcoma, neuroblastoma, oligodendroglioma and glioblastoma), prostate cancers, lung and bronchus cancers, larynx cancers, esophagus cancers, colon cancers, colorectal cancers, gastro-intestinal cancers, melanomas, ovarian and endometrial cancer, renal and bladder cancer, liver cancer, endocrine cancer (e.g. thyroid), and pancreatic cancer. For instance, the disease or disorder is selected from colon cancer, lung cancer, pancreatic cancer, thyroid cancer, breast cancer and skin cancer. Examples of neoplasm include melanoma, thyroid carcinoma, colorectal, ovarian, breast cancer, endometrial cancer, liver cancer, sarcoma, stomach cancer, pancreatic carcinoma, adenocarcinoma, glioma, lung cancer, head and neck cancer, myelodysplastic syndrome, leukemia, and lymphoma.

[0142] For example, to date, SF3B1 mutations (one possible cause of increased copper level sensitivity) have been identified in leukemias, lymphomas, myelodysplastic syndromes (MDS), melanomas, neuroblastomas, pancreatic cancers, prostate cancers, prolactinomas, breast cancers, and other cancers, for example MDS subtype characterized by ring sideroblasts (MDS-RARS), solid tumors such as pigmented tumors, including uveal melanoma (UM), mucosal melanoma, leptomeningeal melanoma, blue nevus-like cutaneous melanoma, neuroblastomas that arise following chromothripsis, estrogen receptor-positive breast cancers (BC), pancreatic ductal adenocarcinoma, prostate cancer, prolactinomas, acute myeloid leukemia, and the like. In another embodiment, the disease or condition to be treated is human copper deficiency diseases such as Menkes disease.

[0143] The term "patient or subject" as used herein refers to an animal such as a mammal. A subject may therefore refer to, for example, mice, rats, dogs, cats, horses, cows, pigs, guinea pigs, primates including humans and the like. Preferably the subject is a human.

[0144] The present description therefore further relates to a method of treating a subject, such as a human subject, suffering from a proliferative disease or disorder, e.g. a copper level sensitive proliferative disease or disorder. The method comprises administering a therapeutically effective amount of a copper ionophore, such as a compound as defined herein, to a subject in need of such treatment.

[0145] In certain embodiments, the present description provides a method of treating a disorder (as described herein) in a subject, comprising administering to the subject identified as in need thereof, a copper ionophore, such as a compound of the present description. The identification of those patients who are in need of treatment for the disorders described above is well within the ability and knowledge of one skilled in the art. Certain of the methods for identification of patients which are at risk of developing the above disorders which can be treated by the subject method are appreciated in the medical arts, such as family history, and the presence of risk factors associated with the development of that disease state in the subject patient. A clinician skilled in the art can readily identify such candidate patients, by the use of, for example, clinical tests, physical examination, medical / family history, and genetic determination.

[0146] A method of assessing the efficacy of a treatment in a subject includes determining the pretreatment symptoms of a disorder by methods well known in the art and then administering a therapeutically effective amount of a compound of the present description, to the subject. After an appropriate period of time following the administration of the compound (e.g., 1 week, 2 weeks, one month, six months), the symptoms of the disorder are determined again. The modulation (e.g., decrease) of symptoms and / or of a biomarker of the disorder indicates efficacy of the treatment. The symptoms and / or biomarker of the disorder may be determined periodically throughout treatment. For example, the symptoms and / or biomarker of the disorder may be checked every few days, weeks or months to assess the further efficacy of the treatment. A decrease in symptoms and / or biomarker of the disorder indicates that the treatment is efficacious. In some embodiments, the therapeutically effective amount of a copper ionophore, such as a compound as defined herein, can be administered to a patient alone or in a composition, admixed with a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0147] The expression "pharmaceutically acceptable carrier, adjuvant, or vehicle" and equivalent expressions, refer to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0148] Compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Other modes of administration also include intradermal or transdermal administration.

[0149] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, surfactants, sweetening, flavoring, and perfuming agents.

[0150] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, ll.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0151] Injectable formulations can be sterilized, for example, by filtration through a bacterial -retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0152] In order to prolong the effect of a provided compound, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled.

[0153] Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0154] Compositions for rectal administration are preferably suppositories which can be prepared by mixing the compounds of the present description with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound.

[0155] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone (PVP), sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0156] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0157] The composition can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0158] Dosage forms for topical or transdermal administration of a compound of the present description include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of the present description. Additionally, the description contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0159] Pharmaceutically acceptable compositions provided herein may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promotors to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0160] Pharmaceutically acceptable compositions provided herein may be formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this disclosure are administered without food. In other embodiments, pharmaceutically acceptable compositions of this disclosure are administered with food.

[0161] The amount of compound that may be combined with carrier materials to produce a composition in a single dosage form will vary depending upon the patient to be treated and the particular mode of administration. Provided compositions may be formulated such that a dosage of between 0.01 - 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0162] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the symptoms associated with the proliferative disease or disorder. The amount of a provided compound in the composition will also depend upon the particular compound in the composition.

[0163] Compounds or compositions described herein may be administered using any amount and any route of administration effective for treating or lessening the severity of the symptoms as contemplated herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Provided compounds are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. The expression "unit dosage form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment.

[0164] Pharmaceutically acceptable compositions of this disclosure can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, provided compounds may be administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg and preferably from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[0165] It will be understood, that the total daily usage of the compounds and compositions of the present description will be decided by the attending physician within the scope of sound medical judgment. The total daily inhibiting dose of the compound of the present description administered to a subject in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg / kg body weight or more usually from 0.1 to 25 mg / kg body weight. Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. In one embodiment, treatment regimens according to the present description comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of the present description per day in single or multiple doses.

[0166] Depending upon the disease or disorder to be treated, additional therapeutic agents may also be present in the compositions of this disclosure or administered separately as part of a dosage regimen, e.g. an additional chemotherapeutic agent. Non-limiting examples of additional therapeutic agents which could be used in combination with the present compounds include antiproliferative compounds such as aromatase inhibitors; anti-estrogens; anti-androgens; gonadorelin agonists; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active agents; alkylating agents; retinoids, carotenoids, tocopherol; cyclooxygenase inhibitors; MMP inhibitors; antimetabolites; cellular metabolism inhibitors; cellular apoptosis modulators; platin compounds; methionine aminopeptidase inhibitors; bisphosphonates; antiproliferative antibodies; heparanase inhibitors; inhibitor of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematologic malignancies; kinesin spindle protein inhibitors; BCL-2 inhibitors; ETC1 inhibitors; Hsp90 inhibitors; mTOR inhibitors; PI3K inhibitors; Flt-3 inhibitors; CDK4 / 6 inhibitors; HER2 inhbiitors (Herceptin, Trastuzumab); EGFR inhibitors (Iressa, Tarceva, Nerlynx, Tykerb, Erbitux); RAS inhibitors; MEK inhibitors (Trametinib, Binimetinib, Cobimetinib); ERK inhibitors (Ulixertinib); anti-PD-1 antibodies (Opdivo, Keytruda); anti-CTLA4 antibodies (Yervoy); antitumor antibiotics; nitrosoureas; compounds targeting / decreasing protein or lipid kinase activity, compounds targeting / decreasing protein or lipid phosphatase activity, or any further anti-angiogenic compounds.

[0167] The treatment may also be complemented with other treatments or interventions such as surgery, radiotherapy (e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes), a biologic response modifier (e.g., an interferon, an interleukin, tumor necrosis factor (TNF)), and agents used to attenuate an adverse effect.

[0168] The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

[0169] EXAMPLES

[0170] The following non-limiting examples are illustrative embodiments and should not be construed as further limiting the scope of the present invention. These examples will be better understood with reference to the accompanying figures.

[0171] The Examples set forth herein below provide syntheses and experimental results obtained for certain exemplary compounds. As it is well known to a person skilled in the art, reactions are performed in an inert atmosphere (nitrogen or argon) where necessary to protect reaction components from air and moisture. Temperatures are given in degrees Celsius (°C). Solution percentages and ratios express a volume-to-volume relationship, unless otherwise stated. The reactants used in the examples below may be obtained either as described herein, or if not described herein, are themselves either commercially available or may be prepared from commercially available materials by methods known in the art.

[0172] All chemicals were of the highest purity and commercially available ones were used without further purification. Purification by column chromatography was performed with silica gel on CombiFlash and Teledyne-lsco with solvent mixtures specified for each compound where applicable. Purification by preparative HPLC were performed on Agilent system with an elution phase of methanol, water and 0.1% formic acid or NH4OAC when specified. NMR spectra were recorded using Varian or Bruker 400 MHz spectrometer. Chemical shifts are reported as parts per million and referenced according to the residual solvent peak and coupling constants (J) are reported in hertz (Hz). High Resolution mass spectra were obtained by using an LC / MSD Agilent TOF 1100 series. All new compounds have been characterized by 1 NMR, LCMS and / or HRMS.

[0173] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, concentrations, properties, stabilities, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the present specification and attached claims are approximations that may vary depending upon the properties sought to be obtained. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the embodiments are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contain certain errors resulting from variations in experiments, testing measurements, statistical analyses and such.

[0174] Synthesis, biological activity and characterization of examples:

[0175] All compounds as herein defined were prepared according to methods as indicated below. Characterization data by mass spectrometry and NMR are provided for each of the examples when available. The compounds are tested in the assays described in the biological Experimental section. The convention used for reporting biological data is provided as a footnote in the respective Tables.

[0176] Synthetic Route 1

[0177]

[0178] General procedure A for acylation of amine.

[0179] N-(quinolin-8-yl)picolinamide (Compound 1): Quinolin-8-amine (240 mg, 1.67 mmol, 1 eq.) was dissolved in 6 mL of DCM and pyridine (400 pl, 5.01 mmol, 3 eq.) was added. Picolinoyl chloride (236 mg, 1.67 mmol, 1 eq.) was dropwise added and the solution was stirred at room temperature for 30 minutes. LCMS indicated complete consumption of the starting material. Solvent was evaporated and the residue purified by silica gel column chromatography eluted with a gradient EtOAc in n-Hexane from 0 to 30 % to afford compound 1 (282 mg, 1.131 mmol, 68.0 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.16 (s, 1 H) 9.03 (dd, J=4.3, 2 Hz, 1 H) 8.92 (dd, J=7.6, 1.4 Hz, 1 H) 8.87 - 8.85 (m, 1 H) 8.47 (dd, J=8.2, 1.6 Hz, 1 H) 8.28 (dt, J=7.6, 1.1 Hz, 1 H) 8.14 (td, J=7.7, 1.8 Hz, 1 H) 7.77 - 7.66 (m, 4 H); LC-MS (ESI, Pos) m / z (%): 250.1 (100) [M+H]+ N-(5,6, 7,8-tetrahydroquinolin-8-yl)picolinamide (Compound 20): The product was obtained following general procedure A with 5,6,7,8-tetrahydroquinolin-8-amine (30 mg, 0.202 mmol, 1 eq.) and picolinoyl chloride. The crude was purified by prep-HPLC eluted with a gradient MeOH in Water to afford compound 20 (25 mg, 0.099 mmol, 49 % yield) as a pink glass.1H NMR (DMSO- d6, 400 MHz, 298 K) 68.93 (d, J=7.4 Hz, 1 H) 8.61 (dq, J=4.7, 0.9 Hz, 1 H) 8.36 (dd, J=4.7, 1.6 Hz, 1 H) 8.06 - 8.10 (m, 1 H) 7.97 - 8.03 (m, 1 H) 7.51 - 7.63 (m, 2 H) 7.22 (dd, J=7.8, 4.7 Hz, 1 H) 5.03 (d, J=7.0 Hz, 1 H) 2.80 (d, J=6.3 Hz, 2 H) 2.29 (d, J=2.0 Hz, 1 H) 1.84 (td, J=8.8, 1.9 Hz, 3 H); LC-MS (ESI, Pos) m / z (%): 254.2 (100) [M+H]+

[0180] N-(quinoxalin-5-yl)picolinamide (Compound 19). The product was obtained following general procedure A with quinoxalin-5-amine (50 mg, 0.344 mmol, 1 eq.) and picolinoyl chloride to afford compound 19 (10 mg, 0.034 mmol, 10 % yield) as a yellow solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 6 12.01 (s, 1 H) 9.11 (d, J=2.0 Hz, 1 H) 9.07 (d, J=1 .6 Hz, 1 H) 8.92 - 8.97 (m, 1 H) 8.85 (d, J=4.7 Hz, 1 H) 8.28 (d, J=7.8 Hz, 1 H) 8.15 (td, J=7.6, 1.6 Hz, 1 H) 7.91 - 7.97 (m, 1 H) 7.85 - 7.90 (m, 1 H) 7.76 (ddd, J=7.7, 4.8, 1.2 Hz, 1 H); LC-MS (ESI, Pos) m / z (%): 251.1 (100) [M+H]+

[0181] General procedure B for amide bounds formation.

[0182] N-(quinolin-8-yl)quinoline-2-carboxamide (Compound 2). The reaction mixture was prepared by combining quinolin-8-amine (50 mg, 0.347 mmol, 1 eq.), quinoline-2-carboxylic acid (60.1 mg, 0.347 mmol, 1 eq.), triphenyl phosphite (108 mg, 0.347 mmol, 1 eq.), and tetrabutylammonium bromide (112 mg, 0.347 mmol, 1 eq.). The mixture was heated at 120°C for 30 minutes until a homogeneous solution was formed. LCMS analysis confirmed the complete consumption of the starting material and the formation of the desired product. The solution was then cooled to room temperature, and the product was partitioned between DCM and water. The organic layer was dried over sodium sulfate (Na2SO4), filtered, and evaporated to yield a residue which was purified using silica gel column chromatography eluted with a gradient EtOAc in n-hexane from 0 to 30 % to afford compound 2 as a yellow solid.1H NMR (CDCI3, 400 MHz, 298 K) 5 12.51 (br. s., 1 H) 9.07 (dd, J=7.4, 1.2 Hz, 1 H) 9.03 (dd, J=4.1 , 1.8 Hz, 1 H) 8.48 (d, J=8.6 Hz, 1 H) 8.4 (d, J=8.6 Hz, 2H) 8.22 (dd, J=8.2, 1.6 Hz, 1 H) 7.94 (d, J=8.1 Hz, 1 H) 7.85 (td, J=7, 1.4 Hz, 1 H) 7.70 - 7.58 (m, 3 H) 7.53 (dd, J=8.4, 4.1 Hz, 1 H); LC-MS (ESI, Pos) m / z (%): 300.1 (100) [M+H]+

[0183] N-(quinolin-8-yl)isoquinoline-1 -carboxamide (Compound 3). The product was obtained following general procedure B with quinolin-8-amine (50 mg, 0.347 mmol, 1 eq.) and the corresponding isoquinoline-1 -carboxylic acid to afford compound 3 (48 mg, 0.160 mmol, 46 % yield) as a yellow solid.1H NMR (CDCh, 400 MHz, 298 K) 5 12.43 (br. s., 1 H) 9.76 - 9.73 (m, 1 H) 9.1 (dd, J=7.6, 1.4 Hz, 1 H) 8.98 (dd, J=4.1 , 1.8 Hz, 1 H) 8.73 (d, J=5.5 Hz, 1 H) 8.21 (dd, J=8.2, 1.6 Hz, 1 H) 7.94 - 7.89 (m, 2 H) 7.79 - 7.73 (m, 2 H) 7.67 - 7.62 (m, 2 H) 8.5 (dd, J=8.4, 4.1 Hz, 1 H); LC- MS (ESI, Pos) m / z (%): 300.1 (100) [M+H]+

[0184] N-(quinolin-8-yl)pyrazine-2-carboxamide (Compound 6). The product was obtained following general procedure B with quinolin-8-amine (50 mg, 0.347 mmol, 1 eq.) and pyrazine-2-carboxylic acid to afford compound 6 (52 mg, 0.208 mmol, 60 % yield) as a tan solid.1H NMR (CDCh, 400 MHz, 298 K) 5 12.07 (br. s., 1 H) 9.59 (d, J=1.6 Hz, 1 H) 8.97 (dd, J=4.3, 1.6 Hz, 1 H) 8.84 (d, J=2.35 Hz, 1 H) 8.77 (dd, J=2.3, 1.6 Hz, 1 H) 8.23 (dd, J=8.2, 1.6 Hz, 1 H) 7.59 - 7.68 (m, 2 H) 7.52 (dd, J=8.22, 4.30 Hz, 1 H); LC-MS (ESI, Pos) m / z (%): 251.1 (100) [M+H]+

[0185] 5-(4-fluorophenyl)-N-(quinolin-8-yl)picolinamide (Compound 7). The product was obtained following general procedure B with quinolin-8-amine (50 mg, 0.347 mmol, 1 eq.) and 5-(4- fluorophenyl)picolinic acid to afford compound 7 (12 mg, 0.035 mmol, 13 % yield) as a white solid.1H NMR (CDCI3, 400 MHz, 298 K) 5 12.29 (br. s., 1 H) 9.04 (dd, J=7.43, 1.17 Hz, 1 H) 9.00 (s, 2 H) 8.43 (d, J=7.8 Hz, 1 H) 8.21 (dd, J=8.2, 1.6 Hz, 1 H) 8.08 (dd, J=8.2, 2 Hz, 1 H) 7.57 - 7.68 (m, 3 H) 7.51 (dd, J=8.2, 4.3 Hz, 1 H) 7.24 (t, J=8.6 Hz, 2 H); LC-MS (ESI, Pos) m / z (%): 344.1 (100) [M+H]+ tert-butyl 4-(2-(quinolin-8-ylcarbamoyl)pyridin-4-yl)piperidine-1 -carboxylate (Compound 8). The product was obtained following general procedure B with quinolin-8-amine (50 mg, 0.347 mmol,

[0186] 1 eq.) and 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)picolinic acid to afford compound 8 (21 mg, 0.049 mmol, 18 % yield) as a tan solid.1H NMR (CDCI3, 400 MHz, 298 K) 5 12.28 (s, 1 H) 9.01 (d, J=8.6 Hz, 1 H) 8.98 (dd, J=4.3, 1.6 Hz, 1 H) 8.71 (d, J=5.1 Hz, 1 H) 8.23 (s, 1 H) 8.20 (d, J=6.7 Hz, 1 H) 7.56 - 7.66 (m, 2 H) 7.50 (dd, J=8.2, 4.3 Hz, 1 H) 7.34 (d, J=3.9 Hz, 1 H) 4.14 - 4.41 (m,

[0187] 2 H) 2.73 - 2.93 (m, 3 H) 1.92 (d, J=13.30 Hz, 2 H) 1.71 (m, 2 H) 1.46 - 1.56 (m, 9 H); LC-MS (ESI, Pos) m / z (%): 433.3 (100) [M+H]+

[0188] 6-methyl-N-(quinolin-8-yl)picolinamide (Compound 9). The product was obtained following general procedure B with quinolin-8-amine (50 mg, 0.347 mmol, 1 eq.) and 6-methylpicolinic acid to afford compound 9 (15 mg, 0.055 mmol, 20 % yield) as a white solid.1H NMR (CDCI3, 400 MHz, 298 K) 5 12.32 (br. s., 1 H) 9.01 (dd, J=7.4, 1.2 Hz, 1 H) 8.97 (dd, J=3.9, 1.6 Hz, 1 H) 8.2 - 8.2 (m, 2 H) 7.81 (t, J=7.6 Hz, 1 H) 7.55 - 7.65 (m, 2 H) 7.50 (dd, J=8.2, 3.9 Hz, 1 H) 7.37 (d, J=7.8 Hz, 1 H) 2.77 (s, 3 H); LC-MS (ESI, Pos) m / z (%): 264.1 (100) [M+H]+ 3-bromo-N-(quinolin-8-yl)picolinamide (Compound 10). The product was obtained following general procedure B with quinolin-8-amine (50 mg, 0.347 mmol, 1 eq.) and 3-bromopicolinic acid to afford compound 10 (19 mg, 0.058 mmol, 21 % yield) as a white solid.1H NMR (CDCh, 400 MHz, 298 K) 5 12.07 (br. s., 1 H) 9.04 (dd, J=7.0, 2 Hz, 1 H) 8.93 (dd, J=3.9, 1.6 Hz, 1 H) 8.76 (dd, J=4.5, 1.4 Hz, 1 H) 8.20 (dd, J=8.4, 1.8 Hz, 1 H) 8.13 (dd, J=8.2, 1.2 Hz, 1 H) 7.55 - 7.65 (m, 2 H) 7.49 (dd, J=8.2, 4.3 Hz, 1 H) 7.36 (dd, J=8.0, 4.5 Hz, 1 H); LC-MS (ESI, Pos) m / z (%): 328.1 (100) [M+H]+

[0189] 4-bromo-N-(quinolin-8-yl)picolinamide (Compound 11). The product was obtained following general procedure B with quinolin-8-amine (50 mg, 0.347 mmol, 1 eq.) and 4-bromopicolinic acid to afford compound 14 (9 mg, 0.027 mmol, 10 % yield) as a white solid.1H NMR (CDCh, 400 MHz, 298 K) 5 12.21 (br. s., 1 H) 8.94 - 9.03 (m, 2 H) 8.62 (d, J=5.1 Hz, 1 H) 8.54 (d, J=2.0 Hz, 1 H) 8.21 (dd, J=8.4, 1.4 Hz, 1 H) 7.69 (dd, J=5.3, 1.8 Hz, 1 H) 7.57 - 7.66 (m, 2 H) 7.51 (dd, J=8.2, 4.3 Hz, 1 H); LC-MS (ESI, Pos) m / z (%): 328.1 (100) [M+H]+

[0190] 5-bromo-N-(quinolin-8-yl)picolinamide (Compound 12). The product was obtained following general procedure B with quinolin-8-amine (50 mg, 0.347 mmol, 1 eq.) and 5-bromopicolinic acid to afford compound 12 (28 mg, 0.085 mmol, 31 % yield) as a white solid.1H NMR (CDCI3, 400 MHz, 298 K) 5 12.16 (br. s., 1 H) 8.93 - 9.02 (m, 2 H) 8.86 (d, J=2 Hz, 1 H) 8.21 (dd, J=8.2, 1.6 Hz, 1 H) 8.07 (dd, J=8.4, 2.2 Hz, 1 H) 7.56 - 7.65 (m, 3 H) 7.51 (dd, J=8.2, 4.3 Hz, 1 H); LC-MS (ESI, Pos) m / z (%): 328.1 (100) [M+H]+

[0191] 5-fluoro-N-(quinolin-8-yl)picolinamide (Compound 13). The product was obtained following general procedure B with quinolin-8-amine (50 mg, 0.347 mmol, 1 eq.) and 5-fluoropicolinic acid to afford compound 13 (51 mg, 0.191 mmol, 69 % yield) as a white solid.1H NMR (CDCh, 400 MHz, 298 K) 5 12.13 (br. s., 1 H) 8.94 - 9.02 (m, 2 H) 8.63 (d, J=2.7 Hz, 1 H) 8.41 (dd, J=8.8, 4.5 Hz, 1 H) 8.20 (dd, J=8.2, 1.6 Hz, 1 H) 7.56 - 7.66 (m, 3 H) 7.51 (dd, J=8.2, 4.3 Hz, 1 H); LC-MS (ESI, Pos) m / z (%): 268.1 (100) [M+H]+

[0192] 3-fluoro-N-(quinolin-8-yl)picolinamide (Compound 14). The product was obtained following general procedure B with quinolin-8-amine (50 mg, 0.347 mmol, 1 eq.) and 3-fluoropicolinic acid to afford compound 14 (23 mg, 0.086 mmol, 31 % yield) as a white solid.1H NMR (CDCh, 400 MHz, 298 K) 5 12.09 (br. s., 1 H) 9.03 (dd, J=7.0, 1.6 Hz, 1 H) 8.95 (dd, J=4.1 , 1.8 Hz, 1 H) 8.58 - 8.66 (m, 1 H) 8.20 (dd, J=8.2, 2.0 Hz, 1 H) 7.54 - 7.67 (m, 4 H) 7.50 (dd, J=8.2, 3.9 Hz, 1 H); LC-MS (ESI, Pos) m / z (%): 268.1 (100) [M+H]+

[0193] 3-chloro-N-(quinolin-8-yl)picolinamide (Compound 15). The product was obtained following general procedure B with quinolin-8-amine (50 mg, 0.347 mmol, 1 eq.) and 3-chloropicolinic acid to afford compound 15 (13 mg, 0.046 mmol, 17 % yield) as a white solid.1H NMR (CDCI3, 400 MHz, 298 K) 5 12.06 (br. s., 1 H) 9.03 (dd, J=7.0, 1.8 Hz, 1 H) 8.93 (dd, J=4.3, 1.6 Hz, 1 H) 8.71 (dd, J=4.5, 1.4 Hz, 1 H) 8.20 (dd, J=8.2, 1.6 Hz, 1 H) 7.91 (dd, J=8.2, 1.2 Hz, 1 H) 7.55 - 7.65 (m, 2 H) 7.5 (ddd, J=12.3, 8.0, 4.3 Hz, 2 H); LC-MS (ESI, Pos) m / z (%): 284.0 (100) [M+H]+

[0194] 4-chloro-N-(quinolin-8-yl)picolinamide (Compound 16). The product was obtained following general procedure B with quinolin-8-amine (50 mg, 0.347 mmol, 1 eq.) and 4-chloropicolinic acid to afford compound 16 (33 mg, 0.116 mmol, 42 % yield) as a white solid.1H NMR (CDCI3, 400 MHz, 298 K) 5 12.21 (br. s., 1 H) 8.94 - 9.02 (m, 2 H) 8.70 (d, J=5.1 Hz, 1 H) 8.37 (d, J=2.0 Hz, 1 H) 8.21 (dd, J=8.2, 1.6 Hz, 1 H) 7.56 - 7.66 (m, 2 H) 7.46 - 7.54 (m, 2 H); LC-MS (ESI, Pos) m / z (%): 284.0 (100) [M+H]+

[0195] N-(6-bromoquinolin-8-yl)picolinamide (Compound 17). The product was obtained following general procedure B with 6-bromoquinolin-8-amine (30 mg, 0.134 mmol, 1 eq.) and picolinic acid to afford compound 17 (16 mg, 0.049 mmol, 36 % yield) as a white solid.1H NMR (CDCh, 400 MHz, 298 K) 5 12.25 (br. s., 1 H) 9.18 (d, J=2.35 Hz, 1 H) 8.97 (dd, J=4.3, 1.6 Hz, 1 H) 8.81 (d, J=4.30 Hz, 1 H) 8.36 (d, J=7.83 Hz, 1 H) 8.10 (dd, J=8.2, 1.6 Hz, 1 H) 7.96 (td, J=7.6, 1.6 Hz, 1 H) 7.75 (d, J=2.4 Hz, 1 H) 7.48 - 7.56 (m, 2 H); LC-MS (ESI, Pos) m / z (%): 328.0 (100) [M+H]+

[0196] N-(isoquinolin-5-yl)picolinamide (Compound 18). The product was obtained following general procedure B with 1 ,7-naphthyridin-8-amine (50 mg, 0.344 mmol, 1 eq.) and picolinic acid to afford compound 18 (20 mg, 0.079 mmol, 23 % yield) as a white solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.46 (s, 1 H) ) 9.14 (dd, J=4.3, 1.6 Hz, 1 H) 8.84 - 8.90 (m, 1 H) 8.53 (dd, J=8.6, 1.6 Hz, 1 H) 8.38 (d, J=5.5 Hz, 1 H) 8.29 (dt, J=7.8, 1.2 Hz, 1 H) 8.16 (td, J=7.7, 1.7 Hz, 1 H) 7.95 (dd, J=8.4, 4.1 Hz, 1 H) 7.79 (ddd, J=7.7, 4.8, 1.2 Hz, 1 H) 7.72 (d, J=5.8 Hz, 1 H); LC-MS (ESI, Pos) m / z (%): 250.1 (100) [M+H]+

[0197] N-(4-chloro-8-quinolyl)pyridine-2-carboxamide (Compound 21). The product was obtained following general procedure B with 4-chloroquinolin-8-amine (40 mg, 0.22 mmol, 1eq.) and picolinic acid to afford compound 21 (23 mg, 0.079 mmol, 36 % yield) as a white solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.16 (s, 1 H) 8.97 (d, J=4.7 Hz, 1 H) 9.01 (dd, J=7.8, 1.2 Hz, 1 H) 8.84 - 8.86 (m, 1 H) 8.28 (dt, J=7.8, 1.2 Hz, 1 H) 8.14 (td, J=7.4, 1.6 Hz, 1 H) 7.93 - 7.97 (m, 2 H) 7.84 (t, J=8.2 Hz, 1 H) 7.75 (ddd, J=7.8, 4.7, 1.6 Hz, 1 H); LC-MS (ESI, Pos) m / z (%): 284.1 (100) [M+H]+

[0198] N-(quinolin-8-yl)pyridazine-3-carboxamide (Compound 5). The product was obtained following general procedure B with quinolin-8-amine (50 mg, 0.347 mmol, 1 eq.) and pyridazine-3- carboxylic acid to afford compound 5 (42 mg, 0.168 mmol, 48 % yield) as a white solid.1H NMR (CDCI3, 400 MHz, 298 K) 5 12.47 (br. s., 1 H) 9.39 (dd, J=4.9, 1.8 Hz, 1 H) 8.93 - 9.03 (m, 2 H) 8.50 (dd, J=8.4, 1.8 Hz, 1 H) 8.22 (dd, J=8.4, 1.8 Hz, 1 H) 7.76 (dd, J=8.4, 4.9 Hz, 1 H) 7.64 (d, J=2.4 Hz, 1 H) 7.63 (s, 1 H) 7.52 (dd, J=8.2, 4.3 Hz, 1 H); LC-MS (ESI, Pos) m / z (%): 251.1 (100) [M+H]+

[0199] N-(6-fluoroquinolin-8-yl)picolinamide (Compound 4). The product was obtained following general procedure B with 6-fluoroquinolin-8-amine (30 mg, 0.185 mmol, 1 eq.) and picolinic acid to afford compound 4 (22 mg, 0.082 mmol, 44 % yield) as a white solid.1H NMR (CDCI3, 400 MHz, 298 K) 5 12.31 (br. s., 1 H) 8.93 (dd, J=4.3, 1.6 Hz, 1 H) 8.87 (dd, J=10.9, 2.7 Hz, 1 H) 8.78 - 8.83 (m, 1 H) 8.34 - 8.39 (m, 1 H) 8.14 (dd, J=8.2, 1.6 Hz, 1 H) 7.96 (td, J=7.7, 1.8 Hz, 1 H) 7.49 - 7.56 (m, 2 H) 7.19 (dd, J=8.6, 2.7 Hz, 1 H); LC-MS (ESI, Pos) m / z (%): 268.1 (100) [M+H]+

[0200] General C for amide bounds formation.

[0201] 5-methyl-N-(quinolin-8-yl)pyrazine-2-carboxamide (Compound 22). Quinolin-8-amine (30 mg, 0.208 mmol, 1 eq.) and 5-methyl-2-pyrazinecarboxylic acid (43 mg, 0.312 mmol, 1.5 eq.) were solubilized in 2 mL of DMF. Et3N (87 pl, 0.624 mmol, 3 eq.) was added followed by TBTU (134 mg, 0.416 mmol, 2eq.) and the reaction mixture was stirred at room temperature overnight. LCMS indicated complete conversion of the starting material. EtOAc was added to the resulting mixture and the organic layer was separated from the aqueous phase. The organic layer was then washed with NaHCOs sat., water, brine and subsequently dried over MgSC filtered and evaporated. The residue was then purified by prep-HPLC eluted with a gradient MeOH in water to afford compound 22 (16 mg, 0.060 mmol, 29 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 11.91 (s, 1 H) 9.28 (d, J=1 .3 Hz, 1 H) 9.03 (dd, J=4.3, 1.6 Hz, 1 H) 8.89 (dd, J=7.6, 1.3 Hz, 1 H) 8.81 (d, J=0.9 Hz, 1 H) 8.48 (dd, J=8.3, 1.6 Hz, 1 H) 7.75 - 7.80 (m, 1 H) 7.65 - 7.73 (m, 2 H) 2.67 (s, 3 H); LC-MS (ESI, Pos) m / z (%): 265.1 (100) [M+H]+

[0202] 5-methoxy-N-(quinolin-8-yl)picolinamide (Compound 23). The product was obtained following general procedure C with quinolin-8-amine (30 mg, 0.208 mmol, 1 eq.) and 5-methoxypyridine-2- carboxylic acid to afford compound 23 (18 mg, 0.064 mmol, 31 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.00 (s, 1 H) 9.02 (dd, J=4.3, 1.6 Hz, 1 H) 8.90 (dd, J=7.6, 1.3 Hz, 1 H) 8.55 (d, J=2.8 Hz, 1 H) 8.46 (dd, J=8.3, 1.6 Hz, 1 H) 8.24 (d, J=8.6 Hz, 1 H) 7.60 - 7.77 (m, 4 H) 3.97 (s, 3 H); LC-MS (ESI, Pos) m / z (%): 280.1 (100) [M+H]+

[0203] 5-hydroxy-N-(quinolin-8-yl)picolinamide (Compound 24). The product was obtained following general procedure C with quinolin-8-amine (30 mg, 0.208 mmol, 1 eq.) and 5-hydroxypicolinic acid to afford compound 24 (50 mg, 0.189 mmol, 91 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.16 (br. s., 1 H) 11.89 (s, 1 H) 9.05 (dd, J=4.3, 1.6 Hz, 1 H) 8.81 (dd, J=7.6, 1.1 Hz, 1 H) 8.49 (dd, J=8.3, 1.6 Hz, 1 H) 8.37 (d, J=4.3 Hz, 1 H) 7.81 (dd, J=8.3, 1.2 Hz, 1 H) 7.62 - 7.75 (m, 3 H) 7.56 (dd, J=8.5, 1.3 Hz, 1 H); LC-MS (ESI, Pos) m / z (%): 266.1 (100) [M+H]+ 5-amino-N-(quinolin-8-yl)picolinamide (Compound 60). The product was obtained following general procedure C with quinolin-8-amine (30 mg, 0.208 mmol, 1 eq.) and 5-aminopicolinic acid to afford compound 60 (20 mg, 0.076 mmol, 44 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 11.82 (s, 1 H) 9.00 (d, J=3.1 Hz, 1 H) 8.87 (d, J=7.1 Hz, 1 H) 8.43 (d, J=7.6 Hz, 1 H) 8.07 (d, J=2.5 Hz, 1 H) 7.92 (d, J=8.5 Hz, 1 H) 7.56 - 7.72 (m, 3 H) 7.08 (dd, J=8.5, 2.6 Hz, 1 H) 6.19 (s, 2 H); LC-MS (ESI, Pos) m / z (%): 265.1 (100) [M+H]+

[0204] 5-amino-N-(6-(quinolin-8-ylcarbamoyl)pyridin-3-yl)picolinamide (Compound 59). The product was obtained following general procedure C with quinolin-8-amine (30 mg, 0.208 mmol, 1 eq.) and 5- aminopicolinic acid to afford compound 59 (9 mg, 0.024 mmol, 14 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.04 (s, 1 H) 10.88 (s, 1 H) 9.23 (d, J=2.1 Hz, 1 H) 9.06 (d, J=3.1 Hz, 1 H) 8.91 (d, J=7.4 Hz, 1 H) 8.68 (d, J=2.3 Hz, 1 H) 8.47 (d, J=7.5 Hz, 1 H) 8.24 (d, J=8.6 Hz, 1 H) 8.07 (d, J=2.4 Hz, 1 H) 7.90 (d, J=8.6 Hz, 1 H) 7.57 - 7.78 (m, 3 H) 7.00 - 7.12 (m, 1 H) 6.24 (s, 2 H); LC-MS (ESI, Pos) m / z (%): 385.1 (100) [M+H]+

[0205] 4-chloro-N-(5-chloroquinolin-8-yl)picolinamide (Compound 25). The product was obtained following general procedure C with 5-chloroquinolin-8-amine (20 mg, 0.112 mmol, 1 eq.) and 4- chloropicolinic acid to afford compound 25 (2 mg, 0.006 mmol, 5 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.16 (s, 1 H) 9.13 (d, J=4.1 Hz, 1 H) 8.87 (d, J=8.4 Hz, 1 H) 8.85 (d, J=5.4 Hz, 1 H) 8.66 (d, J=8.6 Hz, 1 H) 8.26 (d, J=1.9 Hz, 1 H) 7.92 (dd, J=5.3, 2.0 Hz, 1 H) 7.86 - 7.90 (m, 2 H); LC-MS (ESI, Pos) m / z (%): 318.0 (100) [M+H]+ 4-chloro-N-(4-chloroquinolin-8-yl)picolinamide (Compound 26). The product was obtained following general procedure C with 4-chloroquinolin-8-amine (20 mg, 0.112 mmol, 1 eq.) and 4- chloropicolinic acid to afford compound 26 (10 mg, 0.031 mmol, 28 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.09 (s, 1 H) 8.97 (m, 2 H) 8.84 (d, J=5.3 Hz, 1 H) 8.26 (s, 1 H) 7.94 - 7.99 (m, 2 H) 7.92 (dd, J=5.3, 1.6 Hz, 1 H) 7.85 (t, J=8.0 Hz, 1 H); LC-MS (ESI, Pos) m / z (%): 318.0 (100) [M+H]+

[0206] 3,5-dichloro-N-(5-chloroquinolin-8-yl)picolinamide (Compound 27). The product was obtained following general procedure C with 5-chloroquinolin-8-amine (20 mg, 0.112 mmol, 1 eq.) and 3,5- dichloropicolinic acid to afford compound 27 (3 mg, 0.009 mmol, 8 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 11.74 (s, 1 H) 9.08 (m, 1 H) 8.88 (d, J=1.9 Hz, 1 H) 8.83 (d, J=8.5 Hz, 1 H) 8.64 (dd, J=7.6, 1 Hz, 1 H) 8.49 (d, J=1 .9 Hz, 1 H) 7.84 - 7.88 (m, 2 H); LC-MS (ESI, Pos) m / z (%): 352.0 (100) [M+H]+

[0207] 3,5-dichloro-N-(4-chloroquinolin-8-yl)picolinamide (Compound 28). The product was obtained following general procedure C with 4-chloroquinolin-8-amine (20 mg, 0.112 mmol, 1 eq.) and 3,5- dichloropicolinic acid to afford compound 28 (5 mg, 0.015 mmol, 13 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 11.75 (s, 1 H) 8.91 - 8.94 (m, 2 H) 8.87 (d, J=1.9 Hz, 1 H) 8.49 (d, J=2.0 Hz, 1 H) 7.97 (d, J=8.5 Hz, 1 H) 7.93 (d, J=4.8 Hz, 1 H) 7.83 (t, J=8.4, 1 H); LC- MS (ESI, Pos) m / z (%): 352.0 (100) [M+H]+ 3,5-difluoro-N-(5-chloroquinolin-8-yl)picolinamide (Compound 29). The product was obtained following general procedure C with 5-chloroquinolin-8-amine (20 mg, 0.112 mmol, 1 eq.) and 3,5- difluoropicolinic acid to afford compound 29 (4 mg, 0.012 mmol, 11 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 11.80 (s, 1 H) 9.11 (dd, J=4.3, 1.5Hz, 1 H) 8.83 (d, J=8.4 Hz, 1 H) 8.81 (d, J=2.3 Hz, 1 H) 8.65 (dd, J=8.5, 1.5 Hz, 1 H) 8.24 (ddd, J=11.2, 9.0, 2.1 Hz, 1 H) 7.85 - 7.88 (m, 2 H); LC-MS (ESI, Pos) m / z (%): 320.1 (100) [M+H]+

[0208] 5-bromo-N-(5-chloroquinolin-8-yl)-3-fluoropicolinamide (Compound 30). The product was obtained following general procedure C with 5-chloroquinolin-8-amine (20 mg, 0.112 mmol, 1 eq.) and 5-bromo-3-fluoropicolinic acid to afford compound 30 (4 mg, 0.004 mmol, 9 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 6 11.81 (s, 1 H) 9.10 (d, J=4.0 Hz 1 H) 8.87 (s, 1 H) 8.83 (d, J=8.5 Hz, 1 H) 8.65 (d, J=8.5, 8.5 Hz, 1 H) 8.50 (d, J=10.9 Hz, 1 H) 7.85 - 7.88 (m, 2 H); LC-MS (ESI, Pos) m / z (%): 380.0 (100) [M+H]+

[0209] 4-chloro-N-(quinoxalin-5-yl)picolinamide (Compound 32). The product was obtained following general procedure C with quinoxalin-5-amine (25 mg, 0.172 mmol, 1 eq.) and 4-chloropicolinic acid to afford compound 40 (2 mg, 0.007 mmol, 8 % yield) as a white solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 6 11.93 (s, 1 H) 9.12 (s, 1 H) 9.07 (s, 1 H) 8.93 (d, J=7.5 Hz, 1 H) 8.85 (d, J=5.3 Hz, 1 H) 8.28 (s, 1 H) 7.86 - 7.99 (m, 3 H); LC-MS (ESI, Pos) m / z (%): 285.1 (100) [M+H]+ 5-amino-N-(4-chloroquinolin-8-yl)pyrimidine-4-carboxamide (Compound 33). The product was obtained following general procedure C with 4-chloroquinolin-8-amine (15 mg, 0.084, 1 eq.) and 5-aminopyrimidine-4-carboxylic acid to afford compound 33 (2 mg, 0.007 mmol, 8 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.01 (s, 1 H) 8.90 - 8.97 (m, 2 H) 8.37 (d, J=2.0 Hz, 1 H) 8.03 (d, J=2.3 Hz, 1 H) 7.91 - 7.97 (m, 2 H) 7.82 (t, J=8.0 Hz, 1 H) 7.66 - 7.76 (m, 1 H) 6.60 (s, 2 H); LC-MS (ESI, Pos) m / z (%): 300.0 (100) [M+H]+

[0210] 4-hydroxy-N-(quinolin-8-yl)picolinamide (Compound 35). The product was obtained following general procedure C with quinolin-8-amine (25 mg, 0.088 mmol, 1 eq.) and 4-hydroxypicolinic acid to afford compound 35 (5 mg, 0.018 mmol, 21 % yield) as a white solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.15 (s, 1 H) 9.02 (dd, J=4.2, 1.6 Hz, 1 H) 8.89 (d, J=7.5 Hz, 1 H) 8.52 (d, J=5.6 Hz, 1 H) 8.46 (dd, J=8.3, 1.5 Hz, 1 H) 7.57 - 7.85 (m, 4 H) 7.05 (dd, J=5.5, 2.4 Hz, 1 H); LC-MS (ESI, Pos) m / z (%): 266.1 (100) [M+H]+

[0211] 4-amino-N-(quinolin-8-yl)picolinamide (Compound 40). The product was obtained following general procedure C with quinolin-8-amide (400 mg, 2.29 mmol, 1 eq.) and 4-aminopicolinic acid to afford compound 40 (350 mg, 1.33 mmol, 64 % yield) as a yellow solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.14 (s, 1 H) 9.01 (dd, J=4.1 , 1.8 Hz, 1 H) 8.88 (dd, J=7.4, 1.2 Hz, 1 H) 8.44 (dd, J=8.2, 1.6 Hz, 1 H) 8.21 (d, J=5.5 Hz, 1 H) 7.60 - 7.75 (m, 3 H) 7.42 (d, J=2.4 Hz, 1 H) 6.70 (dd, J=5.5, 2.4 Hz, 1 H) 6.50 (s, 2 H); LC-MS (ESI, Pos) m / z (%): 265.1 (100) [M+H]+

[0212] 4-acrylamido-N-(quinolin-8-yl)picolinamide (Compound 45). The product was obtained following general procedure A with 4-amino-N-(quinolin-8-yl)picolinamide 40 (20 mg, 0.076 mmol, 1 eq.) and acryloyl chloride. The crude was purified by EZ prep eluted with a gradient MeOH in water to afford compound 45 (7 mg, 0.08 mmol, 29 % yield) as a white solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.16 (s, 1 H) 10.87 (s, 1 H) 9.03 (dd, J=4.1 , 1.4 Hz, 1 H) 8.91 (d, J=7.4 Hz, 1 H) 8.72 (d, J=5.9 Hz, 1 H) 8.52 (d, J=2.0 Hz, 1 H) 8.47 (dd, J=8.2, 1.6 Hz, 1 H) 7.99 (dd, J=5.5, 2.4 Hz, 1 H) 7.66 - 7.77 (m, 3 H) 6.45 - 6.52 (m, 1 H) 6.36 - 6.41 (m, 1 H) 5.91 (dd, J=9.4, 2.4 Hz, 1 H); LC- MS (ESI, Pos) m / z (%): 319.1 (100) [M+H]+

[0213] 4-(3-(3-methyl-3H-diazirin-3-yl)propanamido)-N-(quinolin-8-yl)picolinamide (Compound 42). The product was obtained following general procedure A with 4-amino-N-(quinolin-8-yl)picolinamide 40 (20 mg, 0.076 mmol, 1 eq.) and 3-(3-methyl-3H-diazirin-3-yl)propanoyl chloride. The crude was purified by EZ prep eluted with a gradient MeOH in water to afford compound 42 (10 mg, 0.028 mmol, 35 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.15 (s, 1 H) 10.66 (s, 1 H) 9.03 (dd, J=4.3, 1.6 Hz, 1 H) 8.90 (dd, J=7.6, 1.4 Hz, 1 H) 8.68 (d, J=5.5 Hz, 1 H) 8.41 - 8.49 (m, 2 H) 7.87 (dd, J=5.7, 2.2 Hz, 1 H) 7.73 - 7.77 (m, 1 H) 7.64 - 7.72 (m, 2 H) 2.32 (t, J=7.4 Hz, 2 H) 1.73 (t, J=7.6 Hz, 2 H) 1.05 (s, 3 H); LC-MS (ESI, Pos) m / z (%): 474.0 (100) [M+H]+

[0214] 4-(hex-5-ynamido)-N-(quinolin-8-yl)picolinamide (Compound 46). The product was obtained following general procedure A with 4-amino-N-(quinolin-8-yl)picolinamide 40 (20 mg, 0.076 mmol, 1 eq.) and hex-5-ynoyl chloride. The crude was purified by EZ prep eluted with a gradient MeOH in water to afford compound 46 (26 mg, 0.077 mmol, 96 % yield) as a tan solid.1H NMR (DMSO- cfe, 400 MHz, 298 K) 5 11.99 (s, 1 H) 10.58 (s, 1 H) 9.03 (dd, J=4.3, 1.6 Hz, 1 H) 8.93 (d, J=2.3 Hz, 1 H) 8.89 (d, J=7.4 Hz, 1 H) 8.46 (dd, J=8.4, 1.4 Hz, 1 H) 8.37 (dd, J=8.8, 2.2 Hz, 1 H) 8.22 (d, J=8.6 Hz, 1 H) 7.64 - 7.75 (m, 3 H) 2.85 (t, J=2.7 Hz, 1 H) 2.54 (t, J=7.4 Hz, 2 H) 2.27 (td, J=7.0, 2.3 Hz, 2 H) 1.81 (quin, J=2.0 Hz, 2 H); LC-MS (ESI, Pos) m / z (%):0 (100) [M+H]+

[0215] General procedure D for carbamate synthesis. hept-6-yn-1-yl (2-(quinolin-8-ylcarbamoyl)pyridin-4-yl)carbamate (Compound 44). 4-amino-N- (quinolin-8-yl)picolinamide 40 (25 mg, 0.090 mmol, 1 eq.) was dissolved in 2 mL of DCM. Et3N (30 pL, 0.19 mmol, 2 eq.) was added and the mixture was cooled to 0°C before bis(trichloromethyl)carbonate (10 mg, 0.031 mmol, 0.33 eq.) was added portionwise. The solution was then stirred for 30 minutes following by addition of 6-heptyn-1-ol (12 mg, 0.11 mmol, 1.1 eq.). The stirring continued at room temperature overnight to ensure the completion of the reaction. Solvent was evaporated and the residue was purified using an EZ prep purification method eluted with a gradient MeOH in water leading to compound 44 (18 mg, 0.042 mmol, 47 % yield) as an off-white solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.15 (s, 1 H) 10.46 (s, 1 H) 8.98 - 9.04 (m, 1 H) 8.84 - 8.91 (m, 1 H) 8.63 (d, J=5.6 Hz, 1 H) 8.43 - 8.48 (m, 1 H) 8.36 (d, J=2.0 Hz, 1 H) 7.73 (s, 2 H) 7.66 (s, 2 H) 4.16 (s, 2 H) 2.76 (s, 1 H) 2.18 (d, J=2.4 Hz, 2 H) 1.62 - 1.72 (m, 2 H) 1.40 - 1.56 (m, 4 H); LC-MS (ESI, Pos) m / z (%): 403.1 (100) [M+H]+ Synthetic Route 3

[0216] General procedure E for acetylation. N-(4-chloroquinolin-8-yl)acetamide (Compound A). 4-chloroquinolin-8-amine (39 mg, 0.218 mmol, 1 eq.) was solubilized in 2 mL of DCM, and acetic anhydride (20.6 pL, 0.218 mmol, 1 eq.) was added. The reaction mixture was stirred at room temperature for 1 hour, resulting in a 50 % conversion of the starting material. To complete the conversion, an additional portion of acetic anhydride (20.6 pL, 0.218 mmol, 1 eq.) was added, and the reaction was stirred for an additional 3 hours until complete conversion was achieved. The solvent was evaporated, and the crude purified using silica gel column chromatography, eluting with a gradient EtOAc in hexane ranging from 0 % to 50 % to afford compound A (25 mg, 0.113 mmol, 52 % yield) as a white solid; LC-MS (ESI, Pos) m / z (%): 221.1 (100) [M+H]+

[0217] General procedure F for chlorination.

[0218] N-(4,5-dichloroquinolin-8-yl)acetamide (Compound B). N-(4-chloroquinolin-8-yl)acetamide A (25 mg, 0.113 mmol, 1 eq.) was dissolved in 3 mL of acetonitrile (ACN), and 97% trichloroisocyanuric acid (8 mg, 0.034 mmol, 0.3 eq.) was added to the solution. The mixture was stirred at room temperature overnight, resulting in the formation of a dichloro compound, but some starting material remained unreacted. To complete the reaction, an additional portion of 97% trichloroisocyanuric acid (8 mg, 0.034 mmol, 0.3 eq.) was added, and the reaction was stirred overnight. After completion of the reaction, the solvent was evaporated and the crude product was purified using silica gel column chromatography, eluting with a gradient EtOAc in hexane ranging from 0 % to 50 % to afford compound B (28 mg, 0.110 mmol, 97 % yield).1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 10.21 (s, 1 H) 8.85 (d, J=4.5 Hz, 1 H), 8.64 (d, J=8.6 Hz, 1 Hz) 7.9 (d, J=4.8 Hz, 1 H) 7.80 (d, J=8.6 Hz, 1 H) 2.28 (s, 3 H); LC-MS (ESI, Pos) m / z (%): 255.1 (100) [M+H]+

[0219] General procedure G for amide hydrolysis.

[0220] 4,5-dichloroquinolin-8-amine (Compound C). N-(4,5-dichloroquinolin-8-yl)acetamide B (28 mg, 0.110 mmol, 1 eq.) was dissolved in 1.5 mL of a 15% sulfuric acid solution (4.23 mmol) and heated under refluxed conditions for 30 minutes until the reaction reached completion. After cooling, the reaction mixture was neutralized by the slow addition of a 2N NaOH solution. EtOAc was added to the resulting suspension and the organic layer was separated from the aqueous phase. The organic layer was then washed with water and subsequently dried over MgSO4, filtered and evaporated to afford compound C (16 mg, 0.074 mmol, 68 % yield) as a yellow solid, which was used in the next step without any further purification.1H NMR (DMSO-cfe, 400 MHz, 298 K) 58.63 (d, J=4.5 Hz, 1 H), 7.71 (d, J=4.6 Hz, 1 H) 7.48 (d, J=8.4 Hz, 1 H) 7.26 (d, J=8.3 Hz, 1 H) 6.29 (s, 2 H); LC-MS (ESI, Pos) m / z (%): 213.1 (100) [M+H]+

[0221] N-(4,5-dichloroquinolin-8-yl)picolinamide (Compound 31). The product was obtained following general procedure C with 4,5-dichloroquinolin-8-amine C (16 mg, 0.075 mmol, 1 eq.) to afford compound 31 (6 mg, 0.019 mmol, 25 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.20 (s, 1 H) 8.97 (d, J=4.6 Hz, 1 H) 8.93 (d, J=8.6 Hz, 1 H) 8.82 - 8.86 (m, 1 H) 8.27 (d, J=7.8 Hz, 1 H) 8.14 (t, J=7.8 Hz, 1 H) 7.97 (d, J=4.8 Hz, 1 H) 7.93 (d, J=8.50 Hz, 1 H) 7.75 (dd, J=7.5, 4.8 Hz, 1 H); LC-MS (ESI, Pos) m / z (%): 318.0 (100) [M+H]+Synthetic Route 4

[0222] General procedure H for nucleophilic aromatic substitution. tert-butyl 4-(2-(quinolin-8-ylcarbamoyl)pyridin-4-yl)piperazine-1-carboxylate (Compound 52). 4- chloro-N-(8-quinolyl)pyridine-2-carboxamide 16 (100 mg, 0.35 mmol, 1 eq.), tert-butyl 1- piperazinecarboxylate (99 mg, 0.529 mmol, 1.5 eq.) and cesium carbonate (230 mg, 0.705 mmol, 2 eq.) were solubilized in 4 mL of DMSO and the reaction mixture was stirred at 100°C overnight. LCMS indicated complete conversion into good product. After cooling, EtOAc was added to the resulting suspension and the organic layer was separated from the aqueous phase. The organic layer was then washed with water, brine, and subsequently dried over Na2SC>4, filtered and evaporated. The crude product was purified using silica gel column chromatography, eluting with a gradient EtOAc in hexane ranging from 0 % to 30 % to afford compound 52 (45 mg, 0.102 mmol, 29 % yield) as a yellow solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.19 (s, 1 H) 9.01 (dd, J=4.1 , 1.3 Hz, 1 H) 8.90 (d, J=7.5 Hz, 1 H) 8.45 (dd, J=8.3, 1.3 Hz, 1 H) 8.41 (d, J=5.9 Hz, 1 H) 7.65 - 7.75 (m, 4 H) 7.09 (dd, J=5.9, 2.66 Hz, 1 H) 3.49 (s, 8 H) 1.43 (s, 9 H); LC-MS (ESI, Pos) m / z (%): 434.3 (100) [M+H]+

[0223] 4-(4-(2-hydroxyethyl)piperidin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 37). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (75 mg, 0.26 mmol, 1 eq.), and 4-piperidineethanol. The residue was then purified by prep-HPLC eluted with a gradient MeOH in water to afford compound 53 (38 mg, 0.098 mmol, 38 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.10 (br. s., 1 H) 9.01 (dd, J=4.3, 1.6 Hz, 1 H) 8.85 (d, J=7.4 Hz, 1 H) 8.45 (dd, J=8.2, 1.6 Hz, 1 H) 8.34 (d, J=6.3 Hz, 1 H) 7.72 - 7.77 (m, 1 H) 7.69 (t, J=4.1 Hz, 1 H) 7.65 - 7.67 (m, 2 H) 7.08 (dd, J=6.1 , 2.5 Hz, 1 H) 4.06 (d, J=13.3 Hz, 2 H) 3.47 (t, J=6.7 Hz, 2 H) 2.96 (t, J=12.0 Hz, 2 H) 1.64 - 1.82 (m, 3 H) 1.39 (q, J=6.5 Hz, 2 H) 1.08 - 1.24 (m, 2 H); LC-MS (ESI, Pos) m / z (%): 377.2 (100) [M+H]+ tert-butyl (3-(methyl(2-(quinolin-8-ylcarbamoyl)pyridin-4-yl)amino)propyl)carbamate (Compound 36). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8- yl)picolinamide 16 (16 mg, 0.056 mmol, 1 eq.) and tert-butyl (3-(methylamino)propyl)carbamate. The residue was purified by prep-HPLC eluted with a gradient MeOH in water to afford compound 36 (5 mg, 0.012 mmol, 21 % yield) as a white solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 11.95 (br. s., 1 H) 9.01 (dd, J=4.3, 1.6 Hz, 1 H) 8.78 (br. s., 1 H) 8.47 (dd, J=8.2, 1.6 Hz, 1 H) 8.31 (d, J=5.9 Hz, 1 H) 7.77 (d, J=7.8 Hz, 1 H) 7.66 - 7.70 (m, 2 H) 7.53 (br. s., 1 H) 6.96 (br. s., 1 H) 6.92 (br. s., 1 H) 3.53 (t, J=6.7 Hz, 2 H) 3.10 (s, 3 H), 3.01 (q, J=6.4, 2 H), 1.71 (quin, J=7.0, 2 H), 1.37 (s, 9 H); LC-MS (ESI, Pos) m / z (%): 436.2 (100) [M+H]+

[0224] 4-((2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)amino)-N-(quinolin-8-yl)picolinamide

[0225] (Compound 38). The product was obtained following general procedure H with 4-chloro-N- (quinolin-8-yl)picolinamide 16 (75 mg, 0.26 mmol, 1 eq.) and 2-(2-(2-(2- aminoethoxy)ethoxy)ethoxy). The residue was purified by prep-HPLC eluted with a gradient MeOH in water to afford compound 38 (10 mg, 0.023 mmol, 9 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.16 (s, 1 H) 9.03 (dd, J=4.3, 1.6 Hz, 1 H) 8.90 (dd, J=7.8, 1.2 Hz, 1 H) 8.66 (d, J=5.9 Hz, 1 H) 8.47 (dd, J=8.2, 1.6 Hz, 1 H) 7.73 - 7.79 (m, 2 H) 7.65 - 7.72 (m, 2 H) 7.30 (dd, J=5.9, 2.7 Hz, 1 H) 4.31 - 4.38 (m, 2 H) 3.79 - 3.85 (m, 2 H) 3.60 - 3.64 (m, 2 H) 3.51 - 3.58 (m, 6 H) 3.48 (t, J=5.5 Hz, 2 H) 2.81 (br. s., 2 H); LC-MS (ESI, Pos) m / z (%): 441.3 (100) [M+H]+

[0226] 4-(but-3-yn-1-ylamino)-N-(quinolin-8-yl)picolinamide (Compound 39). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (75 mg, 0.26 mmol, 1 eq.) and but-3-yn-1-amine. The residue was purified by prep-HPLC eluted with a gradient MeOH in water to compound 39 (4 mg, 0.013 mmol, 5 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.16 (s, 1 H) 9.01 (dd, J=4.1 , 1.8 Hz, 1 H) 8.90 (dd, J=7.6, 1.4 Hz, 1 H) 8.45 (dd, J=8.4, 1.8 Hz, 1 H) 8.28 (d, J=5.9 Hz, 1 H) 7.63 - 7.75 (m, 3 H) 7.44 (d, J=2.0 Hz, 1 H) 7.20 (t, J=5.9 Hz, 1 H) 6.78 (dd, J=5.9, 2.7 Hz, 1 H) 3.33 - 3.39 (m, 2 H) 2.91 (t, J=2.7 Hz, 1 H) 2.47 (td, J=6.9, 2.7 Hz, 2 H); LC-MS (ESI, Pos) m / z (%): 317.1 (100) [M+H]+

[0227] 4-(pent-4-yn-1-ylamino)-N-(quinolin-8-yl)picolinamide (Compound 43) . The product was obtained following general procedure H with 4-amino-N-(quinolin-8-yl)picolinamide 16 (100 mg, 0.35 mmol, 1 eq.) and pent-4-yn-1-amine. The residue was then purified by prep-HPLC eluted with a gradient MeOH in water to afford compound 43 (7 mg, 0.021 mmol, 6 % yield) as a white solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 11.98 - 12.18 (m, 1 H) 9.01 (dd, J=4.3, 1.6 Hz, 1 H) 8.81 - 8.90 (m, 1 H) 8.45 (d, J=8.2 Hz, 1 H) 8.26 (d, J=5.9 Hz, 1 H) 7.62 - 7.77 (m, 2 H) 7.44 (br. s., 1 H) 6.69 - 6.79 (m, 1 H) 3.26 (d, J=4.7 Hz, 2 H) 2.80 - 2.89 (m, 1 H) 2.30 (td, J=7.1 , 2.5 Hz, 2 H) 1.76 (t, J=7.0 Hz, 2 H); LC-MS (ESI, Pos) m / z (%): 331.0 (100) [M+H]+

[0228] 4-(3-hydroxy-3-methylpiperidin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 47). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (25 mg, 0.088 mmol, 1 eq.) and 3-methylpiperidin-3-ol. The crude product was purified using silica gel column chromatography, eluting with a gradient MeOH in DCM ranging from 0 % to 10 % to afford compound 47 (7 mg, 0.019 mmol, 22 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.18 (s, 1 H) 9.01 (dd, J=4.2, 1.6 Hz, 1 H) 8.85 - 8.93 (m, 1 H) 8.45 (dd, J=8.3, 1.6 Hz, 1 H) 8.30 (d, J=6.0 Hz, 1 H) 7.63 - 7.75 (m, 3 H) 7.60 (d, J=2.8 Hz, 1 H) 7.02 (dd, J=6.1 , 2.3 Hz, 1 H) 4.52 (s, 1 H) 3.56 - 3.67 (m, 1 H) 3.48 (d, J=12.9 Hz, 1 H) 3.15 - 3.27 (m, 2 H) 1.81 (dt, J=12.9, 4.0 Hz, 1 H) 1.47 - 1.69 (m, 3 H) 1.15 (s, 3 H); LC-MS (ESI, Pos) m / z (%): 363.1 (100) [M+H]+ 4-(4-hydroxy-4-(trifluoromethyl)piperidin- 1-yl)-N-(quinolin-8-yl)picolinamide (Compound 48). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (25 mg, 0.088 mmol, 1 eq.) and 4-(trifluoromethyl)piperidin-4-ol. The residue was then purified by prep-HPLC eluted with a gradient MeOH in water to afford compound 48 (8 mg, 0.019 mmol, 22 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.18 (s, 1 H) 9.01 (d, J=3.1 Hz, 1 H) 8.90 (d, J=7.5 Hz, 1 H) 8.45 (d, J=7.3 Hz, 1 H) 8.40 (d, J=5.9 Hz, 1 H) 7.58 - 7.78 (m, 4 H) 7.14 (dd, J=5.8, 2.6 Hz, 1 H) 6.17 (s, 1 H) 4.04 (d, J=12.4 Hz, 2 H) 3.13 - 3.26 (m, 3 H) 1.65 - 1.85 (m, 4 H); LC-MS (ESI, Pos) m / z (%): 417.1 (100) [M+H]+

[0229] N-(quinolin-8-yl)-4-(6-azaspiro[2.5]octan-6-yl)picolinamide (Compound 49). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (25 mg, 0.088 mmol, 1 eq.) and 6-azaspiro[2.5]octane. The residue was then purified by prep-HPLC eluted with a gradient MeOH in water to afford compound 49 (8 mg, 0.022 mmol, 25 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.19 (s, 1 H) 9.02 (d, J=3.5 Hz, 1 H) 8.90 (d, J=7.4 Hz, 1 H) 8.45 (d, J=7.9 Hz, 1 H) 8.36 (d, J=6.0 Hz, 1 H) 7.58 - 7.76 (m, 4 H) 7.10 (dd, J=5.9, 2.6 Hz, 1 H) 3.50 - 3.62 (m, 4 H) 1.35 - 1.50 (m, 4 H) 0.38 (s, 4 H); LC-MS (ESI, Pos) m / z (%): 359.1 (100) [M+H]+

[0230] 4-(3-(2-hydroxypropan-2-yl)azetidin- 1-yl)-N-(quinolin-8-yl)picolinamide (Compound 50). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (100 mg, 0.35 mmol, 1 eq.) and 2-(azetidin-3-yl)propan-2-ol. The crude product was purified using silica gel column chromatography, eluting with a gradient MeOH in DCM ranging from 0 % to 10 % to afford compound 50 (122 mg, 0.338 mmol, 96 % yield) as a tan solid.1H NMR (DMSO- d6, 400 MHz, 298 K) 5 12.17 (s, 1 H) 9.01 (d, J=4.1 Hz, 1 H) 8.89 (d, J=7.5 Hz, 1 H) 8.45 (d, J=8.3 Hz, 1 H) 8.31 (d, J=5.5 Hz, 1 H) 7.60 - 7.77 (m, 3 H) 7.15 (s, 1 H) 6.55 (d, J=5.6 Hz, 1 H) 4.54 (s, 1 H) 3.85 - 4.02 (m, 4 H) 2.79 (t, J=7.1 Hz, 1 H) 1.00 - 1.17 (m, 6 H); LC-MS (ESI, Pos) m / z (%):

[0231] 363.1 (100) [M+H]+

[0232] 4-morpholino-N-(quinolin-8-yl)picolinamide (Compound 51). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 19 (25 mg, 0.088 mmol, 1 eq.) and morpholine. The crude product was purified using silica gel column chromatography, eluting with a gradient MeOH in DCM ranging from 0 % to 10 % to afford compound 62 (6 mg, 0.018 mmol, 20 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.19 (s, 1 H) 9.02 (dd, J=4.2, 1.4 Hz, 1 H) 8.90 (d, J=6.9 Hz, 1 H) 8.46 (dd, J=8.3, 1.4 Hz, 1 H) 8.43 (d, J=5.9 Hz, 1 H) 7.64 - 7.75 (m, 4 H) 7.11 (dd, J=5.9, 2.6 Hz, 1 H) 3.70 - 3.82 (m, 4 H) 3.43 (d, J=5.0 Hz, 4 H); LC- MS (ESI, Pos) m / z (%): 335.1 (100) [M+H]+

[0233] General procedure I for N-Boc deprotection.

[0234] 4-(piperazin-1-yl)-N-(quinolin-8-yl)picolinamide hydrochloride (Compound D). Tert-butyl 4-(2- (quinolin-8-ylcarbamoyl)pyridin-4-yl)piperazine-1 -carboxylate 52 (45 mg, 0.104 mmol, 1 eq.) was solubilized in 1 mL of dioxane and 4M HCI in dioxane (260 pL, 1.04 mmol, 10 eq.) was dropwise added. The solution was then stirred at room temperature overnight leading to completion of the reaction. Solvent was evaporated and the crude used in the next step without any further purification. Compound D (38 mg, 0.103 mmol, 99 % yield) was obtained as a yellow HCI salt. LC-MS (ESI, Pos) m / z (%): 334.2 (100) [M+H]+

[0235] General procedure J for methylsulfonation.

[0236] 4-(4-(methylsulfonyl)piperazin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 53). 4-(piperazin-1- yl)-N-(quinolin-8-yl)picolinamide hydrochloride D (12 mg, 0.036 mmol, 1 eq.) was solubilized in 2 mL of DCM, and Et3N (15 pL, 0.108 mmol, 3 eq.) was added followed by methanesulfonyl chloride (8 pL, 0.072 mmol, 2 eq.). The solution was stirred at room temperature for 1 hour leading to completion of the reaction. Solvent was evaporated and the crude purified by prep-HPLC eluted with a gradient MeOH in water to afford compound 53 (6 mg, 0.015 mmol, 41 % yield) as a yellow solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.19 (s, 1 H) 9.02 (dd, J=4.1 , 1.1 Hz, 1 H) 8.90 (d, J=7.1 Hz, 1 H) 8.43 - 8.47 (m, 2 H) 7.65 - 7.75 (m, 4 H) 7.16 (dd, J=5.9, 2.6 Hz, 1 H) 3.57 - 3.70 (m, 4 H) 3.19 - 3.29 (m, 4 H) 2.93 (s, 3 H); LC-MS (ESI, Pos) m / z (%): 412.2 (100) [M+H]+

[0237] 4-(4-(dimethylglycyl) piperazin-1 -yl)-N-(quinolin-8-yl)picolinamide (Compound 54). The product was obtained following general procedure C with 4-(piperazin-1-yl)-N-(quinolin-8-yl)picolinamide hydrochloride D (12 mg, 0.036 mmol, 1 eq.) and N,N-dimethylglycine to afford compound 54 (6 mg, 0.015 mmol, 40 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.19 (s, 1 H) 9.02 (dd, J=4.2, 1.6 Hz, 1 H) 8.91 (dd, J=7.6, 1.1 Hz, 1 H) 8.46 (dd, J=8.3, 1.5 Hz, 1 H) 8.42 (d, J=5.9 Hz, 1 H) 7.65 - 7.75 (m, 4 H) 7.11 (dd, J=6.0, 2.6 Hz, 1 H) 3.72 (m, 2 H) 3.61 (m, 2 H) 3.46 - 3.55 (m, 4 H) 3.14 (s, 2 H) 2.21 (s, 6 H); LC-MS (ESI, Pos) m / z (%): 419.3 (100) [M+H]+ 4-(4-(pent-4-ynoyl)piperazin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 41). The product was obtained following general procedure C with 4-(piperazin-1-yl)-N-(quinolin-8-yl)picolinamide hydrochloride D (25 mg, 0.070 mmol, 1 eq.) and 4-pentynoic acid. The crude product was purified using silica gel column chromatography, eluting with a gradient EtOAc in hexane ranging from 0 % to 100 % to afford compound 41 (12 mg, 0.030 mmol, 43 % yield) as a white solid.1H NMR

[0238] (DMSO-cfe, 400 MHz, 298 K) 5 12.19 (s, 1 H) 9.02 (dd, J=4.3, 1.6 Hz, 1 H) 8.90 (dd, J=7.4, 1.2 Hz, 1 H) 8.38 - 8.49 (m, 2 H) 7.62 - 7.77 (m, 4 H) 7.10 (dd, J=5.8, 2.7 Hz, 1 H) 3.64 (br. s., 4 H) 3.45 - 3.59 (m, 4 H) 2.76 - 2.80 (m, 1 H) 2.57 - 2.65 (m, 2 H) 2.39 (td, J=7.4, 2.5 Hz, 2 H); LC-MS (ESI, Pos) m / z (%): 414.2 (100) [M+H]+Synthetic Route 5

[0239] 5-acrylamido-N-(quinolin-8-yl)picolinamide (Compound 55). The product was obtained following general procedure A from 5-amino-N-(quinolin-8-yl)picolinamide 60 (10 mg, 0.04 mmol, 1 eq.) and acryloyl chloride. The residue was then purified by prep-HPLC eluted with a gradient MeOH in water to afford compound 55 (7 mg, 0.029 mmol, 58 % yield) as a tan solid.1H NMR (DMSO- cfe, 400 MHz, 298 K) 612.01 (s, 1 H) 10.85 (br. s., 1 H) 9.04 (dd, J=4.1 , 1.4 Hz, 1 H) 9.02 (d, J=2.3 Hz, 1 H) 8.9 (d, J=7.4 Hz, 1 H) 8.46 (dd, J=8.2, 1.2 Hz, 1 H) 8.43 (dd, J=8.6, 2.3 Hz, 1 H) 8.26 (d, J=9.0 Hz, 1 H) 7.65 - 7.75 (m, 3 H) 6.49 - 6.56 (m, 1 H) 6.33 - 6.41 (m, 1 H) 5.85 - 5.93 (m, 1 H);

[0240] LC-MS (ESI, Pos) m / z (%): 319.1 (100) [M+H]+

[0241] 5-(3-(3-methyl-3H-diazirin-3-yl)propanamido)-N-(quinolin-8-yl)picolinamide (Compound 56). The product was obtained following general procedure A from 5-amino-N-(quinolin-8-yl)picolinamide 60 (25 mg, 0.09 mmol, 1 eq.) and 3-(3-methyl-3H-diazirin-3-yl)propanoyl chloride to afford compound 56 (23 mg, 0.059 mmol, 65 % yield) as a yellow solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 11.99 (s, 1 H) 10.59 (s, 1 H) 9.03 (dd, J=4.1 , 1.7 Hz, 1 H) 8.87 - 8.93 (m, 2 H) 8.46 (dd, J=8.4, 1.8 Hz, 1 H) 8.35 (dd, J=8.61 , 2.7 Hz, 1 H) 8.23 (d, J=8.2 Hz, 1 H) 7.63 - 7.76 (m, 3 H) 2.33 (t, J=7.6 Hz, 2 H) 1.74 (t, J=7.6 Hz, 2 H) 1.05 (s, 3 H); LC-MS (ESI, Pos) m / z (%): 375.1 (100) [M+H]+

[0242] 5-(hex-5-ynamido)-N-(quinolin-8-yl)picolinamide (Compound 58). The product was obtained following general procedure A from 5-amino-N-(quinolin-8-yl)picolinamide 60 (20 mg, 0.080 mmol, 1 eq.) and hex-5-ynoyl chloride to afford compound 58 (23 mg, 0.067 mmol, 85 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.15 (s, 1 H) 10.66 (s, 1 H) 9.02 (dd, J=3.9, 1.6 Hz, 1 H) 8.90 (d, J=6.6 Hz, 1 H) 8.67 (d, J=5.8 Hz, 1 H) 8.46 (td, J=4.1 , 1.6 Hz, 2 H) 7.89 (dd, J=5.5, 2.4 Hz, 1 H) 7.72 - 7.78 (m, 1 H) 7.63 - 7.71 (m, 2 H) 2.84 (t, J=2.6 Hz, 1 H) 2.54 (t, J=7.0 Hz, 2 H) 2.26 (td, J=7.0, 2.6 Hz, 2 H) 1.80 (quin, J=7.1 Hz, 2 H); LC-MS (ESI, Pos) m / z (%): 359.1 (100) [M+H]+ hept-6-yn-1-yl (6-(quinolin-8-ylcarbamoyl)pyridin-3-yl)carbamate (Compound 57). The product was obtained following general procedure D from 5-amino-N-(quinolin-8-yl)picolinamide 60 (20 mg, 0.080 mmol, 1 eq.) and 6-heptyn-1-ol to afford compound 57 (25 mg, 0.066 mmol, 82 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.00 (s, 1 H) 10.35 (s, 1 H) 9.03 (dd, J=4.3, 1.6 Hz, 1 H) 8.88 (dd, J=7.4, 1.2 Hz, 1 H) 8.82 (m, 1 H) 8.46 (dd, J=8.2, 1.6 Hz, 1 H) 8.21 (d, J=1.2 Hz, 2 H) 7.64 - 7.74 (m, 3 H) 4.16 (t, J=6.5 Hz, 2 H) 2.77 (t, J=2.7 Hz, 1 H) 2.19 (td, J=6.7, 2.7 Hz, 2 H) 1.68 (quin, J=6.7 Hz, 2 H) 1.43 - 1.55 (m, 4 H); LC-MS (ESI, Pos) m / z (%): 403.1 (100) [M+H]+

[0243] 2-(3-(but-3-yn-1-yl)-3H-diazirin-3-yl)ethyl (6-(quinolin-8-ylcarbamoyl)pyridin-3-yl)carbamate (Compound 61). The product was obtained following procedure D from 5-amino-N-(quinolin-8- yl)picolinamide 60 (20 mg, 0.080 mmol, 1 eq.) and 2-(3-but-3-ynyldiazirin-3-yl)ethanol to afford compound 61 (7 mg, 0.018 mmol, 22 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.00 (s, 1 H) 10.40 (s, 1 H) 9.03 (dd, J=4.3, 1.6 Hz, 1 H) 8.89 (dd, J=7.8, 1.2 Hz, 1 H) 8.84 (m, 1 H) 8.46 (dd, J=8.2, 1.6 Hz, 1 H) 8.22 (br. s., 2 H) 7.64 - 7.74 (m, 3 H) 4.05 (t, J=6.3 Hz, 2 H) 2.86 (t, J=2.7 Hz, 1 H) 2.19 (td, J=7.3, 2.5 Hz, 2 H) 1.85 (t, J=6.3 Hz, 2 H) 1.68 (t, J=7.4 Hz, 2 H); LC-MS (ESI, Pos) m / z (%): 429.1 (100) [M+H]+ tert-butyl (3-((2-(quinolin-8-ylcarbamoyl)pyridin-3-yl)amino)propyl)carbamate (Compound 81). The product was obtained following general procedure H from 3-fluoro-N-(quinolin-8- yl)picolinamide 14 (30 mg, 0.112 mmol, 1 eq.) and tert-butyl (3-aminopropyl)carbamate. The residue was then purified by silica gel column chromatography eluted with a gradient EtOAc in hexane 0 to 100 % then by prep-HPLC eluted with a gradient MeOH in water to afford to afford compound 81 (10 mg, 0.024 mmol, 21 % yield) as a yellow solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.22 (s, 1 H) 9.01 (dd, J=4.3, 1.6 Hz, 1 H) 8.85 (dd, J=7.4, 1.2 Hz, 1 H) 8.44 (dd, J=8.2, 1.6 Hz, 1 H) 8.4 (t, J=5.5 Hz, 1 H) 8.00 (dd, J=4.1 , 1.4 Hz, 1 H) 7.59 - 7.74 (m, 3 H) 7.47 (dd, J=8.6, 4.3 Hz, 1 H) 7.33 (dd, J=8.6, 1.2 Hz, 1 H) 6.94 (t, J=5.3 Hz, 1 H) 3.28 (q, J=6.7 Hz, 2 H) 3.07 (q, J=6.7 Hz, 2 H) 1.74 (quin, J=6.7 Hz, 2 H) 1.38 (s, 9 H); LC-MS (ESI, Pos) m / z (%): 422.2

[0244] (100) [M+H]+

[0245] Synthetic Route 6 tert-butyl (3-(methyl(8-nitroquinolin-5-yl)amino)propyl)carbamate (Compound F). The product was obtained following procedure H with 5-chloro-8-nitroquinoline (400 mg, 1.93 mmol, 1 eq.) and tert-butyl (3-(methylamino)propyl)carbamate (400 mg, 2.125 mmol, 1.1 eq.). The residue was purified by silica gel column chromatography eluted with a gradient EtOAc in hexane from 0 to 100 % to afford compound F (449 mg, 1.254 mmol, 65 % yield) as a yellow solid.1H NMR (DMSO- d6, 400 MHz, 298 K) 68.99 (dd, J=4.3, 1.6 Hz, 1 H) 8.53 (dd, J=8.6, 1.2 Hz, 1 H) 8.19 (d, J=8.2 Hz, 1 H) 7.64 (dd, J=8.6, 4.3 Hz, 1 H) 7.13 (d, J=8.6 Hz, 1 H) 6.82 (t, J=5.1 Hz, 1 H) 3.23 (t, J=7.2 Hz, 2 H) 2.89 - 2.99 (m, 5 H) 1.76 (quin., J=6.9 Hz, 2 H) 1.31 (s, 9 H); LC-MS (ESI, Pos) m / z (%): 361.2 (100) [M+H]+

[0246] The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (20 mg, 0.07 mmol, 1 eq.) and 3-Piperidinemethanol. The crude product was purified using C-18 column chromatography, eluting with a gradient MeOH in water ranging from 30 % to 100 % to afford compound 82 (6 mg, 0.017 mmol, 22 % yield) as a colourless solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.19 (s, 1 H) 9.01 (dd, J=4.2, 1.6 Hz, 1 H) 8.90 (dd,J=7.5, 1.2 Hz, 1 H) 8.45 (dd, J=8.2, 1.6 Hz, 1 H) 8.35 (d, J=6.0 Hz, 1 H) 7.60 - 7.77 (m, 4 H) 7.04 (dd, J=6.1 , 2.8 Hz, 1 H) 4.67 (br. s, 1 H) 3.89 - 4.08 (m, 2 H) 2.93 - 3.04 (m, 1 H) 2.78 (dd, J=13.0, 10.4 Hz, 1 H) 1.60 - 1.81 (m, 3 H) 1.42 - 1.57 (m, 1 H) 1.16 - 1.32 (m, 2 H); LC-MS (ESI, Pos) m / z (%): 363.1 (100)

[0247] [M+H]+ The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and Thiomorpholine. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 90% to afford compound 83 (6 mg, 0.017 mmol, 16 % yield) as a yellow solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.18 (s, 1 H) 9.01 (d, J=2.9 Hz, 1 H) 8.90 (d, J=7.5 Hz, 1 H) 8.45 (d, J=8.3 Hz, 1 H) 8.39 (d, J=5.9 Hz, 1 H) 7.58 - 7.77 (m, 4 H) 7.09 (dd, J=5.9, 2.6 Hz, 1 H) 3.82 - 3.94 (m, 4 H) 2.62 - 2.72 (m, 4 H); LC-MS (ESI, Pos) m / z (%): 351.1 (100) [M+H]+

[0248] The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and 1-Methyl homopiperazine. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 90% to afford compound 84 (16 mg, 0.044 mmol, 42 % yield) as a yellow solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.20 (s, 1 H) 9.01 (d, J=3.4 Hz, 1 H) 8.89 (d, J=7.5 Hz, 1 H) 8.45 (d, J=7.8 Hz, 1 H) 8.32 (d, J=5.9 Hz, 1 H) 7.62 - 7.76 (m, 3 H) 7.48 (d, J=2.4 Hz, 1 H) 6.90 (dd, J=5.8, 2.6 Hz, 1 H) 3.61 - 3.69 (m, 2 H) 3.57 (t, J=6.13 Hz, 2 H) 2.62 - 2.69 (m, 2 H) 2.27 (s, 3 H) 1.88 - 1.97 (m, 2 H); LC-MS (ESI, Pos) m / z (%): 362.2 (100) [M+H]+ The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and 4-(Methylsulfonyl)piperidine hydrochloride. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 90% to afford compound 85 (20 mg, 0.049 mmol, 46 % yield) as a yellow solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.18 (s, 1 H) 9.01 (dd, J=4.2, 1.4 Hz, 1 H) 8.90 (d, J=6.8 Hz, 1 H) 8.45 (dd, J=8.3, 1.3 Hz, 1 H)

[0249] 8.40 (d, J=6.0 Hz, 1 H) 7.63 - 7.75 (m, 4 H) 7.14 (dd, J=5.9, 2.7 Hz, 1 H) 4.23 (d, J=13.4 Hz, 2 H)

[0250] 3.40 - 3.50 (m, 1 H) 3.05 (t, J=11.8 Hz, 2 H) 2.96 (s, 3 H) 2.13 (d, J=11 .0 Hz, 2 H) 1.64 (qd, J=12.4, 3.9 Hz, 2 H); LC-MS (ESI, Pos) m / z (%): 411.1 (100) [M+H1+

[0251] The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and 1 ,4-Oxazepan-6-ol hydrochloride. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 90% to afford compound 86 (9 mg, 0.024 mmol, 23 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.19 (s, 1 H) 9.01 (dd, J=4.1 , 1.3 Hz, 1 H) 8.90 (d, J=7.0 Hz, 1 H) 8.45 (dd, J=8.3, 1.3 Hz, 1 H) 8.34 (d, J=5.9 Hz, 1 H) 7.63 - 7.76 (m, 3 H) 7.60 (d, J=2.5 Hz, 1 H) 7.00 (dd, J=5.9, 2.6 Hz, 1 H) 5.19 (br. s., 1 H) 3.88 - 4.01 (m, 2 H) 3.71 - 3.86 (m, 3 H) 3.56 - 3.66 (m, 2 H) 3.44 - 3.53 (m, 2 H); LC-MS (ESI, Pos) m / z (%): 365.1 (100) [M+H]+ product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and 1-(3-Methylpyridin-2-yl)piperazine dihydrochloride. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 90% to afford compound 87 (18 mg, 0.042 mmol, 40 % yield) as a brown solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.20 (s, 1 H) 9.02 (dd, J=4.1 , 1.3 Hz, 1 H) 8.91 (d, J=7.4 Hz, 1 H) 8.41 - 8.48 (m, 2 H) 8.14 (d, J=3.6 Hz, 1 H) 7.63 - 7.77 (m, 4 H) 7.55 (d, J=7.0 Hz, 1 H) 7.16 (dd, J=5.9, 2.6 Hz, 1 H) 6.97 (dd, J=7.3, 4.8 Hz, 1 H) 3.57 - 3.66 (m, 4 H) 3.20 - 3.26 (m, 4 H) 2.31 (s, 3 H); LC-MS (ESI, Pos) m / z (%): 425.3 (100) [M+H]+

[0252]

[0253] (S)-4-(3-hydroxypyrrolidin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 88). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and (S)-3-Pyrrolidinol. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 90% to afford compound 88 (21 mg, 0.063 mmol, 59 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.21 (s, 1 H) 9.01 (dd, J=4.1 , 1.6 Hz, 1 H) 8.90 (dd, J=7.5, 1.3 Hz, 1 H) 8.45 (dd, J=8.3, 1.6 Hz, 1 H) 8.32 (d, J=5.9 Hz, 1 H) 7.60 - 7.76 (m, 3 H) 7.30 (d, J=2.3 Hz, 1 H) 6.70 (dd, J=5.8, 2.4 Hz, 1 H) 5.09 (d, J=2.6 Hz, 1 H) 4.45 (br. s., 1 H) 3.44 - 3.56 (m, 3 H) 3.25 (d, J=10.9 Hz, 1 H) 2.02 - 2.13 (m, 1 H) 1.91 - 2.01 (m, 1 H); LC-MS (ESI, Pos) m / z (%): 335.1 (100) [M+H]+

[0254] (S)-4-(2-(hydroxymethyl)pyrrolidin- 1-yl)-N-(quinolin-8-yl)picolinamide (Compound 89). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and L-Prolinol. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 10 to 70% to afford compound 89 (18 mg, 0.048 mmol, 45 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.20 (s, 1 H) 9.01 (dd, J=4.2, 1.7 Hz, 1 H) 8.89 (dd, J=7.5, 1.4 Hz, 1 H) 8.44 (dd, J=8.30, 1.6 Hz, 1 H) 8.31 (d, J=5.9 Hz, 1 H) 7.60 - 7.77 (m, 3 H) 7.41 (br. s., 1 H) 6.77 (d, J=3.5 Hz, 1 H) 4.94 (br. s., 1 H) 3.86 - 3.97 (m, 1 H) 3.44 - 3.56 (m, 2 H) 3.16 - 3.26 (m, 2 H) 1.86 - 2.11 (m, 4 H); LC-MS (ESI, Pos) m / z (%): 349.2(100) [M+H]+

[0255]

[0256] (R)-4-(2-(hydroxymethyl)pyrrolidin- 1-yl)-N-(quinolin-8-yl)picolinamide (Compound 90). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and D-Prolinol. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 90% to afford compound 90 (22 mg, 0.064 mmol, 60 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.20 (s, 1 H) 9.01 (dd, J=4.2,

[0257] 1.3 Hz, 1 H) 8.90 (d, J=7.1 Hz, 1 H) 8.45 (dd, J=8.3, 1.3 Hz, 1 H) 8.32 (d, J=5.9 Hz, 1 H) 7.61 - 7.76 (m, 3 H) 7.41 (br. s., 1 H) 6.77 (d, J=3.6 Hz, 1 H) 3.88 - 3.96 (m, 1 H) 3.49 - 3.54 (m, 2 H) 3.17 - 3.31 (m, 3 H) 1.88 - 2.12 (m, 4 H); LC-MS (ESI, Pos) m / z (%): 349.2 (100) [M+H]+

[0258] 4-(4-(oxetan-3-yl)piperazin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 91). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and 1-(Oxetan-3-yl)piperazine. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 90% to afford compound 91 (22 mg, 0.056 mmol, 53 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.18 (s, 1 H) 9.01 (dd, J=4.1 ,

[0259] 1.4 Hz, 1 H) 8.89 (d, J=7.4 Hz, 1 H) 8.45 (dd, J=8.3, 1.3 Hz, 1 H) 8.39 (d, J=5.9 Hz, 1 H) 7.62 - 7.77 (m, 4 H) 7.10 (dd, J=6.0, 2.6 Hz, 1 H) 4.57 (t, J=6.5 Hz, 2 H) 4.48 (t, J=6.1 Hz, 2 H)

[0260] 2.4 (t, J=4.9 Hz, 4 H); LC-MS (ESI, Pos) m / z (%): 390.1 (100) [M+H]+

[0261]

[0262] 4-(4-methyl-3-oxopiperazin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 92). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and 1-Methylpiperazin-2-one. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 90% to afford compound 92 (6 mg, 0.017 mmol, 16 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.19 (s, 1 H) 9.02 (dd, J=4.2, 1.3 Hz, 1 H) 8.90 (d, J=7.3 Hz, 1 H) 8.45 (dd, J=8.3, 1.3 Hz, 1 H) 8.42 (d, J=5.9 Hz, 1 H) 7.57 - 7.78 (m, 4 H) 7.08 (dd, J=6.0, 2.7 Hz, 1 H) 4.04 (s, 2 H) 3.71 - 3.80 (m, 2 H) 3.50 (m, 2 H) 2.93 (s, 3 H); LC-MS (ESI, Pos) m / z (%): 362.2 (100) [M+H]+

[0263] (S)-4-(2-(hydroxymethyl)morpholino)-N-(quinolin-8-yl)picolinamide (Compound 93). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and (S)-Morpholin-2-ylmethanol. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 90% to afford compound 93 (20 mg, 0.055 mmol, 52 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.19 (s, 1 H) 9.02 (d, J=4.1 Hz, 1 H) 8.90 (d, J=7.5 Hz, 1 H) 8.39 - 8.49 (m, 2 H) 7.61 - 7.77 (m, 4 H) 7.10 (d, J=3.8 Hz, 1 H) 4.88 (br. s., 1 H) 3.97 (dd, J=17.4, 12.3 Hz, 2 H) 3.86 (d, J=12.5 Hz, 1 H) 3.62 (t, J=10.9 Hz, 1 H) 3.46 - 3.57 (m, 3 H) 2.96 (td, J=12.0, 3.1 Hz, 1 H) 2.73 (t, J=11.2 Hz, 1 H); LC-MS (ESI, Pos) m / z (%): 365.2 (100) [M+H]+

[0264]

[0265] 4-((3S,4S)-3,4-dihydroxypyrrolidin- 1-yl)-N-(quinolin-8-yl)picolinamide (Compound 94). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and (3S,4S)-Pyrrolidine-3,4-diol hydrochloride. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 90% to afford compound 94 (21 mg, 0.060 mmol, 57 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.21 (s, 1 H) 9.01 (dd, J=4.1 , 1.3 Hz, 1 H) 8.90 (d, J=7.3 Hz, 1 H) 8.45 (dd, J=8.3, 1.3 Hz, 1 H) 8.32 (d, J=5.9 Hz, 1 H) 7.62 - 7.77 (m, 3 H) 7.30 (d, J=2.4 Hz, 1 H) 6.70 (dd, J=5.8, 2.4 Hz, 1 H) 5.26 (br. s., 2 H) 4.11 (d, J=2.9 Hz, 2 H) 3.59 (d, J=7.8 Hz, 2 H) 3.27 (d, J=10.8 Hz, 2 H); LC-MS (ESI, Pos) m / z (%): 351.1

[0266] 4-(1-oxidothiomorpholino)-N-(quinolin-8-yl)picolinamide (Compound 95). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and Thiomorpholine-1 -oxide hydrochloride. The residue was purified by prep- HPLC eluted with a gradient MeOH in water eluted from 20 to 90% to afford compound 95 (3 mg, 0.007 mmol, 7 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.19 (s, 1 H) 8.98 - 9.05 (m, 1 H) 8.90 (d, J=7.5 Hz, 1 H) 8.45 (t, J=6.1 Hz, 2 H) 7.62 - 7.78 (m, 4 H) 7.20 (dd, J=5.9, 2.6 Hz, 1 H) 3.92 - 4.09 (m, 4 H) 2.88 - 3.00 (m, 2 H) 2.72 - 2.76 (m, 2 H); LC-MS (ESI, Pos) m / z (%): 367.0 (100) [M+H1+

[0267]

[0268] 4-(4-hydroxy-4-methylazepan-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 96). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and 4-Methylazepan-4-ol hydrochloride. The residue was purified by prep- HPLC eluted with a gradient MeOH in water eluted from 20 to 90% to afford compound 96 (22 mg, 0.058 mmol, 55 % yield) as a brown solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.20 (s, 1 H) 9.01 (d, J=4.0 Hz, 1 H) 8.89 (d, J=7.5 Hz, 1 H) 8.44 (d, J=8.3 Hz, 1 H) 8.30 (d, J=5.9 Hz, 1 H) 7.60 - 7.78 (m, 3 H) 7.45 (d, J=2.0 Hz, 1 H) 6.80 - 6.89 (m, 1 H) 4.38 (br. s., 1 H) 3.45 - 3.61 (m, 4 H) 2.01 - 2.16 (m, 1 H) 1.57 - 1.82 (m, 4 H) 1.30 - 1.43 (m, 1 H) 1.06 - 1.21 (m, 3 H); LC- MS (ESI, Pos) m / z (%): 377.3 (

[0269] 4-(4,4-difluoropiperidin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 97). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and 4,4-Difluoropiperidine HCI. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 90% to afford compound 97 (2 mg, 0.005 mmol, 5 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.18 (s, 1 H) 9.02 (d, J=4.0 Hz, 1 H) 8.90 (d, J=7.4 Hz, 1 H) 8.38 - 8.51 (m, 2 H) 7.62 - 7.77 (m, 4 H) 7.19 (dd, J=5.9, 2.6 Hz, 1 H) 3.62 - 3.70 (m, 4 H) 1.99 - 2.15 (m, 4 H); LC-MS (ESI, Pos) m / z (%): 369.1 (100) [M+H1+

[0270] (S)-4-(2-(hydroxymethyl)azetidin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 98). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and (S)-Azetidin-2-ylmethanol. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 90% to afford compound 98 (19 mg, 0.057 mmol, 54 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.18 (s, 1 H) 9.01 (dd, J=4.25, 1.63 Hz, 1 H) 8.89 (dd, J=7.50, 1.25 Hz, 1 H) 8.45 (dd, J=8.25, 1.63 Hz, 1 H) 8.33 (d, J=5.75 Hz, 1 H) 7.35 (br. s., 1 H) 7.62 - 7.76 (m, 3 H) 6.75 (br. s., 1 H) 5.14 (br. s., 1 H) 4.28 - 4.39 (m, 1 H) 4.02 (td, J=8.38, 5.13 Hz, 1 H) 3.71 - 3.84 (m, 2 H) 3.63 - 3.71 (m, 1 H) 2.35 - 2.46 (m, 1 H) 2.14 - 2.25 (m, 1 H); LC-MS (ESI, Pos) m / z (%): 335.1 (100) [M+H]+

[0271] 4-(3-(hydroxymethyl)azetidin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 99). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and Azetidin-3-ylmethanol. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 90% to afford compound 99 (28 mg, 0.084 mmol, 79 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.17 (s, 1 H) 9.01 (dd, J=4.2, 1.7 Hz, 1 H) 8.88 (dd, J=7.6, 1.3 Hz, 1 H) 8.45 (dd, J=8.3, 1.6 Hz, 1 H) 8.32 (d, J=5.6 Hz, 1 H)7.62 - 7.76 (m, 3 H) 7.15 (d, J=2.4 Hz, 1 H) 6.56 (dd, J=5.6, 2.5 Hz, 1 H) 4.86 (br. s., 1 H) 4.05 (t, J=8.2 Hz, 2 H) 3.77 (dd, J=8.1 , 5.4 Hz, 2 H) 3.61 (d, J=5.4 Hz, 2 H) 2.83 - 2.93 (m, 1 H); LC-MS (ESI, Pos) m / z (%): 335.3 (100) [M+H]+

[0272]

[0273] 4-(3-(methoxymethyl)azetidin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 100). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and 3-(Methoxymethyl)azetidine hydrochloride. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 90% to afford compound 100 (28 mg, 0.081 mmol, 76 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.17 (s, 1 H) 9.01 (dd, J=4.3, 1.6 Hz, 1 H) 8.89 (dd, J=7.6, 1.2 Hz, 1 H) 8.45 (dd, J=8.3, 1.6 Hz, 1 H) 8.33 (d, J=5.6 Hz, 1 H) 7.62 - 7.77 (m, 3 H) 7.16 (d, J=2.3 Hz, 1 H) 6.57 (dd, J=5.7, 2.4 Hz, 1 H) 4.09 (t, J=8.2 Hz, 2 H) 3.76 (dd, J=8.0, 5.5 Hz, 2 H) 3.56 (d, J=6.4 Hz, 2 H) 3.30 (s, 3 H) 2.94 - 3.08 (m, 1 H); LC-MS (ESI, Pos) m / z (%): 349.1 (100) [M+H]+

[0274] 4-(2-azabicyclo[2.2.2]octan-2-yl)-N-(quinolin-8-yl)picolinamide (Compound 101). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and 2-Azabicyclo[2.2.2]octane hydrochloride. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 90% to afford compound 101

[0275] (19 mg, 0.053 mmol, 50 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.21 (s, 1 H) 9.02 (dd, J=4.3, 1.6 Hz, 1 H) 8.91 (dd, J=7.6, 1.4 Hz, 1 H) 8.46 (dd, J=8.3, 1.6 Hz, 1 H) 8.30 (d, J=5.9 Hz, 1 H) 7.63 - 7.75 (m, 3 H) 7.41 (br. s., 1 H) 6.72 - 6.90 (m, 1 H) 4.10 (br. s., 1 H) 2.01 - 2.09 (m, 1 H) 1.63 - 1.89 (m, 8 H); LC-MS (ESI, Pos) m / z (%): 359.1 (100) [M+H]+

[0276]

[0277] 4-(3-fluoroazetidin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 102). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and 3-Fluoroazetidine HCI. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 90% then purified a second time by silica gel column chromatography eluted with a gradient EtOAc in Hexane from 0 to 50% to afford compound 102 (20 mg, 0.021 mmol, 59 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.17 (s,

[0278] 1 H) 9.01 (dd, J=4.3, 1.6 Hz, 1 H) 8.89 (dd, J=7.6, 1.3 Hz, 1 H) 8.45 (dd, J=8.3, 1.6 Hz, 1 H) 8.38 (d, J=5.6 Hz, 1 H) 7.62 - 7.77 (m, 3 H) 7.24 (d, J=2.4 Hz, 1 H) 6.66 (dd, J=5.6, 2.5 Hz, 1 H) 5.64 (tt, J=5.8, 2.9 Hz, 1 H) 5.50 (dtt, J=57.4, 5.80, 3.02 Hz, 1 H) 4.30 - 4.46 (m, 2 H) 4.07 - 4.22 (m,

[0279] 2 H); LC-MS (ESI, Pos) m / z (%): 323.1 (100) [M+H]+

[0280] 4-(3,3-difluoroazetidin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 103). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and 3,3-Difluoroazetidine HCI. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 90% then purified a second time by silica gel column chromatography eluted with a gradient EtOAc in Hexane from 0 to 50% to afford compound 103 (3 mg, 0.008 mmol, 8 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.17 (s, 1 H) 9.02 (dd, J=4.3, 1.5 Hz, 1 H) 8.82 - 8.94 (m, 1 H) 8.36 - 8.53 (m, 2 H) 7.61 - 7.79 (m, 3 H) 7.35 (d, J=2.4 Hz, 1 H) 6.77 (dd, J=5.6, 2.4 Hz, 1 H) 1.23 (s, 4 H) 4.55 (t, J=12.4 Hz, 4 H); LC-MS (ESI, Pos) m / z (%): 341.1 (100) [M+H]+

[0281]

[0282] 4-(pyrrolidin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 104). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and Pyrrolidine. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 90% then purified a second time by silica gel column chromatography eluted with a gradient EtOAc in Hexane from 0 to 50% to afford compound 104 (13 mg, 0.041 mmol, 39 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.21 (s, 1 H) 9.01 (dd, J=4.2, 1.6 Hz, 1 H) 8.90 (dd, J=7.6, 1.3 Hz, 1 H) 8.45 (dd, J=8.3, 1.6 Hz, 1 H) 8.32 (d, J=5.8 Hz, 1 H) 7.61 - 7.76 (m, 3 H) 7.31 (d, J=2.5 Hz, 1 H) 6.70 (dd, J=5.8, 2.6 Hz, 1 H) 3.37 - 3.45 (m, 4 H) 1.93 - 2.07 (m, 4 H); LC-MS (ESI, Pos) m / z (%): 319.1 (100) [M+H]+

[0283] 4-(2-(hydroxymethyl)-1,4-oxazepan-4-yl)-N-(quinolin-8-yl)picolinamide (Compound 105). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (20 mg, 0.07 mmol, 1 eq.) and 2-(Hydroxymethyl)homomorpholine hydrochloride. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 30 to 100% to afford compound 105 (14 mg, 0.037 mmol, 50 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.20 (s, 1 H) 9.01 (dd, J=4.2, 1.6 Hz, 1 H) 8.90 (dd, J=7.6, 1.3 Hz, 1 H) 8.45 (dd, J=8.2,

[0284] 1.6 Hz, 1 H) 8.35 (d, J=5.9 Hz, 1 H) 7.59 - 7.79 (m, 3 H) 7.54 (d, J=2.6 Hz, 1 H) 6.94 (dd, J=6.0,

[0285] 2.7 Hz, 1 H) 4.91 (br. s., 1 H) 3.94 - 4.09 (m, 2 H) 3.81 - 3.91 (m, 1 H) 3.58 - 3.68 (m, 1 H) 3.48 - 3.58 (m, 2 H) 3.43 (dd, J=10.8, 5.3 Hz, 1 H) 1.86 - 2.06 (m, 2 H);LC-MS (ESI, Pos) m / z (%): 379.2 (100) [M+H]+

[0286]

[0287] N-(quinolin-8-yl)-4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)picolinamide (Compound 106). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and 2-Oxa-7-azaspiro[3.5]nonane oxalate(2:1). The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 30 to 100% to afford compound 106 (23 mg, 0.061 mmol, 58 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.17 (s, 1 H) 9.01 (dd, J=4.3, 1.6 Hz, 1 H) 8.89 (dd, J=7.6, 1.3 Hz, 1 H) 8.45 (dd, J=8.3, 1.6 Hz, 1 H) 8.36 (d, J=6.0 Hz, 1 H) 7.61 - 7.76 (m, 4 H) 7.09 (dd, J=5.9, 2.6 Hz, 1 H) 4.36 (s, 4 H) 3.40 - 3.47 (m, 4 H) 1.80 - 1.91 (m, 4 H); LC-MS (ESI, Pos) m / z (%): 375.1 (100) [M+H]+

[0288] 4-(3-hydroxyazetidin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 107). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (20 mg, 0.07 mmol, 1 eq.) and 3-Hydroxyazetidine HCI. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 30 to 100% to afford compound 107 (11 mg, 0.034 mmol, 46 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.17 (s, 1 H) 9.01 (dd, J=4.1 , 1.6 Hz, 1 H) 8.89 (dd, J=7.5, 1.2 Hz, 1 H) 8.45 (dd, J=8.3, 1.6 Hz, 1 H) 8.33 (d, J=5.6 Hz, 1 H) 7.57 - 7.79 (m, 3 H) 7.17 (d, J=2.4 Hz, 1 H) 6.58 (dd,J=5.6, 2.4 Hz, 1 H) 5.82 (d, J=5.7 Hz, 1 H) 4.66 (d, J=4.5 Hz, 1 H) 4.26 (t, J=7.7 Hz, 2 H) 3.76 (dd,J=8.9, 4.4 Hz, 2 H); LC-MS (ESI, Pos) m / z (%): 321.1 (100) [M+H1+

[0289]

[0290] 4-(3-(fluoromethyl)azetidin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 108). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and 3-(Fluoromethyl)azetidine hydrochloride. The residue was purified by prep- HPLC eluted with a gradient MeOH in water eluted from 20 to 90% to afford compound 108 (15 mg, 0.045 mmol, 42 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.17 (s, 1 H) 9.01 (dd, J=4.3, 1.6 Hz, 1 H) 8.89 (dd, J=7.6, 1.3 Hz, 1 H) 8.45 (dd, J=8.4, 1.6 Hz, 1 H) 8.35 (d, J=5.6 Hz, 1 H) 7.60 - 7.78 (m, 3 H) 7.18 (d, J=2.4 Hz, 1 H) 6.60 (dd, J=5.6, 2.5 Hz, 1 H) 4.72 (d, J=5.8 Hz, 1 H) 4.60 (d, J=5.6 Hz, 1 H) 4.14 (t, J=8.1 Hz, 2 H) 3.85 (dd, J=8.3, 5.4 Hz, 2 H) 3.07 - 3.24 (m, 1 H); LC-MS (ESI, Pos) m / z (%): 337.2 (100) [M+H]+

[0291] 4-(2-phenylmorpholino)-N-(quinolin-8-yl)picolinamide (Compound 109). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and 2-Phenylmorpholine. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 90% then purified a second time by silica gel column chromatography eluted with a gradient EtOAc in Hexane from 0 to 50% to afford compound 109 (14 mg, 0.034 mmol, 32 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.19 (s, 1 H) 8.99 - 9.04 (m, 1 H) 8.90 (dd, J=7.6, 1.3 Hz, 1 H) 8.41 - 8.49 (m, 2 H) 7.63 - 7.77 (m, 4 H) 7.52 (d, J=7.0 Hz, 2 H) 7.33 - 7.45 (m, 3 H) 7.22 (dd, J=5.9, 2.7 Hz, 1 H) 4.65 (dd, J=10.6, 2.5 Hz, 1 H) 4.17 (dd, J=11.6, 2.8 Hz, 1 H) 4.10 (d, J=12.5 Hz, 1 H) 3.99 (d, J=12.6 Hz, 1 H) 3.82 (td, J=11.7, 2.7 Hz, 1 H) 3.10 (td, J=12.1 , 3.3 Hz, 1 H) 2.89 (dd, J=12.4, 10.8 Hz, 1 H); LC-MS (ESI, Pos) m / z (%): 411.1(100) [M+H]+

[0292]

[0293] (R)-4-(3-hydroxypiperidin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 110). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and (R)-Piperidin-3-ol hydrochloride. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 90% then purified a second time by silica gel column chromatography eluted with a gradient EtOAc in Hexane from 0 to 50% to afford compound 110 (18 mg, 0.052 mmol, 49 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.18 (s, 1 H) 9.01 (dd, J=4.3, 1.6 Hz, 1 H) 8.90 (dd, J=7.6, 1.3 Hz, 1 H) 8.45 (dd, J=8.3, 1.6 Hz, 1 H) 8.34 (d, J=6.0 Hz, 1 H) 7.58 - 7.76 (m, 4 H) 7.04 (dd, J=6.0, 2.8 Hz, 1 H) 4.96 (br. s., 1 H) 3.82 (dd, J=12.9, 3.5 Hz, 1 H) 3.73 (d, J=12.7 Hz, 1 H) 3.54 - 3.64 (m, 1 H) 3.07 - 3.17 (m, 1 H) 2.99 (dd, J=12.8, 8.6 Hz, 1 H) 1.86 - 1.97 (m, 1 H) 1.72 - 1.83 (m, 1 H) 1.39 - 1.55 (m, 2 H); LC-MS (ESI, Pos) m / z (%): 349.2 (100) [M+H]+

[0294] 4-(3-hydroxy-3-methylpyrrolidin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 111). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (20 mg, 0.07 mmol, 1 eq.) and 3-Methylpyrrolidin-3-ol. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 30 to 100% to afford compound 111 (16 mg, 0.046 mmol, 62 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.20 (s, 1 H) 9.01 (dd, J=4.1 , 1.6 Hz, 1 H) 8.90 (dd, J=7.6, 1.3 Hz, 1 H) 8.45 (dd, J=8.2, 1.6 Hz, 1 H) 8.31 (d, J=5.7 Hz, 1 H) 7.63- 7.77 (m, 3 H) 7.27 (s, 1 H) 6.67 (dd, J=5.6, 2.2 Hz, 1 H) 3.46 - 3.55 (m, 2 H) 1.88 - 2.03 (m, 2 H) 1.38 (s, 3 H); LC-MS (ESI, Pos) m / z (%): 349.2 (100) [M+H1+

[0295]

[0296] 4-(4-methylpiperazin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 112). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (20 mg, 0.07 mmol, 1 eq.) and 1 -Methylpiperazine. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 30 to 100% to afford compound 112 (18 mg, 0.052 mmol, 70 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.18 (s, 1 H) 9.01 (dd, J=4.2, 1.7 Hz, 1 H) 8.90 (dd, J=7.5, 1.4 Hz, 1 H) 8.45 (dd, J=8.4, 1.6 Hz, 1 H) 8.39 (d, J=5.9 Hz, 1 H) 7.62 - 7.76 (m, 4 H) 7.09 (dd, J=6.0, 2.7 Hz, 1 H) 3.42 - 3.48 (m, 5 H) 2.42 - 2.48 (m, 4 H) 2.23 (s, 3 H); LC-MS (ESI, Pos) m / z (%): 348.3 (100) [M+H]+

[0297] 4-(3,3-difluoropyrrolidin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 113). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (20 mg, 0.07 mmol, 1 eq.) and 3,3-Difluoropyrrolidine hydrochloride. The residue was purified by prep- HPLC eluted with a gradient MeOH in water eluted from 30 to 100% to afford compound 113 (17 mg, 0.052 mmol, 65 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.20 (s, 1 H) 9.01 (dd, J=4.2, 1.6 Hz, 1 H) 8.90 (dd, J=7.6, 1.3 Hz, 1 H) 8.45 (dd, J=8.4, 1.6 Hz, 1 H) 8.41 (d, J=5.7 Hz, 1 H) 7.61 - 7.78 (m, 3 H) 7.38 (d, J=2.5 Hz, 1 H) 6.80 (dd, J=5.8, 2.6 Hz, 1 H) 3.91 (t, J=13.1 Hz, 2 H) 3.67 (t, J=7.3 Hz, 2 H) 2.53 - 2.67 (m, 2 H); LC-MS (ESI, Pos) m / z (%): 355.1 (100) [M+H1+

[0298]

[0299] 4-(4-fluoropiperidin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 114). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (20 mg, 0.07 mmol, 1 eq.) and 4-Fluoropiperidine. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 30 to 100% to afford compound 114 (10 mg, 0.028 mmol, 38 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.18 (s, 1 H) 9.01 (dd, J=4.2, 1.6 Hz, 1 H) 8.90 (dd, J=7.5, 1.2 Hz, 1 H) 8.45 (dd, J=8.3, 1.6 Hz, 1 H) 8.39 (d,J=5.9 Hz, 1 H) 7.61 - 7.77 (m, 4 H) 7.13 (dd, J=6.0, 2.7 Hz, 1 H) 5.00 (dt, J=6.9, 3.4 Hz, 1 H) 4.88 (dt, J=6.9, 3.4 Hz, 1 H) 3.58 - 3.73 (m, 2 H) 3.42-3.56 (m, 2 H) 1.98 (m, 2 H) 1.78 (m, 2 H); LC-MS (ESI, Pos) m / z (%): 351.1 (100) [M+H]+

[0300] 4-(3,3-difluoropiperidin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 115). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (20 mg, 0.07 mmol, 1 eq.) and 3,3-Difluoropiperidine hydrochloride. The residue was purified by prep- HPLC eluted with a gradient MeOH in water eluted from 30 to 100% to afford compound 115 (12 mg, 0.032 mmol, 44 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.17 (s, 1 H) 9.01 (dd, J=4.2, 1.6 Hz, 1 H) 8.90 (dd, J=7.6, 1.3 Hz, 1 H) 8.45 (dd, J=8.4, 1.6 Hz, 1 H) 8.40 (d, J=6.0 Hz, 1 H) 7.63 - 7.77 (m, 4 H) 7.20 (dd, J=5.9, 2.8 Hz, 1 H) 3.90 (t, J=12.0 Hz, 2 H) 3.55 - 3.64 (m, 2 H) 2.12 (m, 2 H) 1.72 - 1.83 (m, 2 H); LC-MS (ESI, Pos) m / z (%): 369.1 (100) [M+H]+

[0301]

[0302] 4-(azepan-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 116). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (20 mg, 0.07 mmol, 1 eq.) and Hexamethyleneimine. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 30 to 100% to afford compound 116 (14 mg, 0.040 mmol, 54 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.19 (s, 1 H) 9.01 (dd, J=4.1 , 1.6 Hz, 1 H) 8.90 (dd, J=7.6, 1.3 Hz, 1 H) 8.45 (dd, J=8.3, 1.6 Hz, 1 H) 8.31 (d, J=5.88 Hz, 1 H) 7.61 - 7.77 (m, 3 H) 7.46 (d, J=2.63 Hz, 1 H) 6.87 (dd, J=6.0, 2.7 Hz, 1 H) 3.58 (t, J=6.0 Hz, 4 H) 1.76 (br. s., 4 H) 1.39 - 1.57 (m, 4 H); LC-MS (ESI, Pos) m / z (%): 347.3 (100) [M+H]+

[0303] 4-(4-hydroxypiperidin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 117). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (20 mg, 0.07 mmol, 1 eq.) and 4-Hydroxypiperidine. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 30 to 100% to afford compound 117 (16 mg, 0.046 mmol, 65 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.18 (s, 1 H) 9.01 (dd, J=4.2, 1.6 Hz, 1 H) 8.90 (dd, J=7.6, 1.3 Hz, 1 H) 8.45 (dd, J=8.4, 1.6 Hz, 1 H) 8.36 (d, J=6.0 Hz, 1 H) 7.59 - 7.77 (m, 4 H) 7.08 (dd, J=6.0, 2.7 Hz, 1 H) 4.78 (br. s., 1 H) 3.69 - 3.89 (m, 3 H) 3.20 (m, 2 H) 1.83 (dt, J=8.9, 4.2 Hz, 2 H) 1.35 - 1.50 (m, 2 H); LC-MS (ESI, Pos) m / z (%): 349.2 (100) [M+H1+

[0304]

[0305] 4-(2,2-dimethylmorpholino)-N-(quinolin-8-yl)picolinamide (Compound 118). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (20 mg, 0.07 mmol, 1 eq.) and 2,2-Dimethylmorpholine HCI. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 30 to 100% to afford compound 118 (12 mg, 0.03 mmol, 45 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.19 (s, 1 H) 9.01 (dd, J=4.2, 1.7 Hz, 1 H) 8.90 (dd, J=7.6, 1.3 Hz, 1 H) 8.45 (dd, J=8.4, 1.6 Hz, 1 H) 8.38 (d, J=5.9 Hz, 1 H) 7.59 - 7.79 (m, 4 H) 7.09 (dd, J=5.9, 2.8 Hz, 1 H) 3.69 - 3.83 (m, 2 H) 3.37 - 3.48 (m, 2 H) 1.22 (s, 6 H); LC-MS (ESI, Pos) m / z (%): 363.1 (100) [M+H]+

[0306] 4-(3-hydroxy-3-methylazetidin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 119). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and 3-Methylazetidin-3-ol hydrochloride. The residue was purified by prep- HPLC eluted with a gradient MeOH in water eluted from 30 to 90% to afford compound 106 (16 mg, 0.048 mmol, 45% yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.17 (s, 1 H) 9.01 (dd, J=4.2, 1.6 Hz, 1 H) 8.89 (dd, J=7.6, 1.1 Hz, 1 H) 8.45 (dd, J=8.3, 1.6 Hz, 1 H) 8.34 (d, J=5.6 Hz, 1 H) 7.62 - 7.76 (m, 3 H) 7.18 (d, J=2.4 Hz, 1 H) 6.60 (dd, J=5.7, 2.4 Hz, 1 H) 3.95 (d, J=8.40 Hz, 2 H) 3.85 (d, J=8.3 Hz, 2 H) 1.47 (s, 3 H); LC-MS (ESI, Pos) m / z (%): 335.1 (100) [M+H]+

[0307]

[0308] 4-((2-hydroxyethyl)(methyl)amino)-N-(quinolin-8-yl)picolinamide (Compound 120). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and 2-(Methylamino)ethanol. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 90% to afford compound 120 (11 mg, 0.034 mmol, 32 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.20 (s, 1 H) 9.01 (dd, J=4.3, 1.6 Hz, 1 H) 8.90 (dd, J=7.6, 1.3 Hz, 1 H) 8.45 (dd, J=8.3, 1.7 Hz, 1 H) 8.31 (d, J=6.0 Hz, 1 H) 7.59 - 7.77 (m, 3 H) 7.49 (d, J=2.6 Hz, 1 H) 6.87 (dd, J=5.9, 2.8 Hz, 1 H) 4.84 (t, J=5.1 Hz, 1 H) 3.50 - 3.66 (m, 4 H) 3.08 (s, 3 H); LC-MS (ESI, Pos) m / z (%): 323.3 (100) [M+H]+

[0309] 4-(3-morpholinoazetidin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 121). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and 4-(3-Azetidinyl)morpholine dihydrochloride. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 90% to afford compound 121 (10 mg, 0.025 mmol, 24 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.16 (s, 1 H) 8.97 - 9.02 (m, 1 H) 8.83 - 8.91 (m, 1 H) 8.41 - 8.47 (m, 1 H) 8.34 (d, J=5.8 Hz, 1 H) 7.62 - 7.76 (m, 3 H) 7.18 (d, J=2.3 Hz, 1 H) 6.55 - 6.61 (m, 1 H) 4.07 (d, J=7.6 Hz, 2 H) 3.87 (dd, J=8.4, 4.9 Hz, 2 H) 2.38 (br. s., 4 H); LC-MS (ESI, Pos) m / z (%): 390.1(100) [M+H]+

[0310]

[0311] 44-((2S,6R)-2,6-dimethylmorpholino)-N-(quinolin-8-yl)picolinamide (Compound 122). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and Cis-2,6-dimethylmorpholin. The residue was purified by prep- HPLC eluted with a gradient MeOH in water eluted from 50 to 100% to afford compound 122 (13 mg, 0.036 mmol, 34 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.19 (s, 1 H) 9.02 (dd, J=4.3, 1.6 Hz, 1 H) 8.90 (dd, J=7.6, 1.3 Hz, 1 H) 8.46 (dd, J=8.3, 1.6 Hz, 1 H) 8.41 (d, J=6.0 Hz, 1 H) 7.64 - 7.77 (m, 4 H) 7.13 (dd, J=6.0, 2.8 Hz, 1 H) 3.95 (d, J=10.9 Hz, 2 H) 3.62 - 3.73 (m, 2 H) 1.20 (d, J=6.1 Hz, 6 H); LC-MS (ESI, Pos) m / z (%): 363.1(100) [M+H]+

[0312] (R)-4-(3-(2-hydroxypropan-2-yl)pyrrolidin- 1-yl)-N-(quinolin-8-yl)picolinamide ( Compound 123) . The product was obtained following general procedure H with 4-chloro-N-(quinolin-8- yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and (R)-2-(Pyrrolidin-3-yl)propan-2-ol. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 90% then purified a second time by silica gel column chromatography eluted with a gradient EtOAc in Hexane from 0 to 50% to afford compound 123 (12 mg, 0.032 mmol, 30 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.21 (s, 1 H) 9.02 (dd, J=4.2, 1.7 Hz, 1 H) 8.90 (dd, J=7.5, 1.4 Hz, 1 H) 8.46 (dd, J=8.3, 1.6 Hz, 1 H) 8.32 (d, J=5.9 Hz, 1 H) 7.62 - 7.76 (m, 3 H) 7.31 (d, J=2.5 Hz, 1 H) 6.70 (dd, J=5.9, 2.5 Hz, 1 H) 4.45 (s, 1 H) 3.55 (t, J=8.6 Hz, 1 H) 3.40 - 3.47 (m, 2 H) 3.23 - 3.30 (m, 1 H) 2.30 - 2.43 (m, 1 H) 1.86 - 2.06 (m, 2 H) 1.18 (d, J=9.5 Hz, 6 H); LC- MS (ESI, Pos) m / z (%): 377.3 (100) [M+H]+

[0313]

[0314] 4-(methyl(2-morpholinoethyl)amino)-N-(quinolin-8-yl)picolinamide (Compound 124). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and N-methyl-2-morpholin-4-ylethanamine. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 90% then purified a second time by silica gel column chromatography eluted with a gradient EtOAc in Hexane from 0 to 50% to afford compound 124 (9 mg, 0.023 mmol, 22 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.20 (s, 1 H) 9.02 (dd, J=4.2, 1.7 Hz, 1 H) 8.91 (dd, J=7.6, 1.3 Hz, 1 H) 8.46 (dd, J=8.3, 1.6 Hz, 1 H) 8.34 (d, J=5.9 Hz, 1 H) 7.63 - 7.77 (m, 3 H) 7.49 (d, J=2.6 Hz, 1 H) 6.87 (dd, J=6.0, 2.8 Hz, 1 H) 3.61 (t, J=6.8 Hz, 2 H) 3.54 - 3.59 (m, 4 H) 3.08 (s, 3 H) 2.47 (d, J=4.1 Hz, 4 H); LC-MS (ESI, Pos) m / z (%): 392.3 (100) [M+H]+

[0315] N-(quinolin-8-yl)-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)picolinamide (Compound 125). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and 2-Oxa-6-azaspiro[3.3]heptane oxalate. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 95% to afford compound afford compound 125 (8 mg, 0.023 mmol, 22 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.16 (s, 1 H) 9.01 (dd, J=4.3, 1.6 Hz, 1 H) 8.88 (dd, J=7.6, 1.2 Hz, 1 H) 8.45 (dd, J=8.3, 1.6 Hz, 1 H) 8.34 (d, J=5.6 Hz, 1 H) 7.62 - 7.76 (m, 3 H) 7.18 (d, J=2.4 Hz, 1 H) 6.60 (dd, J=5.6, 2.4 Hz, 1 H) 4.75 (s, 4 H) 4.22 (s, 4 H); LC-MS (ESI, Pos) m / z (%): 347.3 (100) [M+H]+

[0316]

[0317] N-(quinolin-8-yl) -4-((3aR, 6a S) -tetrahydro- 1H-furo[3, 4-c]pyrrol-5(3H) -yl) picolinamide ( Compound 126). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8- yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and (3aR,6aS)-rel-Hexahydro-1 H-furo[3,4-c]pyrrole hydrochloride. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 95% to afford compound afford compound 126 (24 mg, 0.067 mmol, 63 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.20 (s, 1 H) 9.01 (dd, J=4.1 , 1.5 Hz, 1 H) 8.90 (dd, J=7.5, 1.0 Hz, 1 H) 8.45 (dd, J=8.3, 1.4 Hz, 1 H) 8.35 (d, J=5.8 Hz, 1 H) 7.61 - 7.78 (m, 3 H) 7.35 (d, J=2.4 Hz, 1 H) 6.74 (dd, J=5.9, 2.5 Hz, 1 H) 3.84 (dd, J=8.8, 6.5 Hz, 2 H) 3.56 - 3.68 (m, 4 H) 3.01 - 3.16 361.2 (100) [M+H]+

[0318] 4-(4-hydroxy-4-methylpiperidin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 127). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and 4-Methylpiperidin-4-ol. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 95% to afford compound afford compound 127 (30 mg, 0.083 mmol, 78 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.18 (s,

[0319] 1 H) 9.01 (dd, J=4.3, 1.6 Hz, 1 H) 8.89 (dd, J=7.6, 1.3 Hz, 1 H) 8.45 (dd, J=8.3, 1.6 Hz, 1 H) 8.35 (d, J=5.9 Hz, 1 H) 7.58 - 7.77 (m, 4 H) 7.07 (dd, J=6.1 , 2.7 Hz, 1 H) 4.47 (s, 1 H) 3.64 - 3.74 (m,

[0320] 2 H) 3.39 (d, J=3.8 Hz, 1 H) 1.46 - 1.63 (m, 4 H) 1.16 (s, 3 H); LC-MS (ESI, Pos) m / z (%): 363.1 (100) [M+H]+

[0321]

[0322] 4-(3-cyano-3-methylazetidin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 128). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and 3-methylazetidine-3-carbonitrile hydrochloride. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 30 to 100% to afford compound afford compound 128 (20 mg, 0.058 mmol, 55 % yield) as a tan solid.1H NMR (DMSO- d6, 400 MHz, 298 K) 5 12.17 (s, 1 H) 9.01 (dd, J=4.2, 1.6 Hz, 1 H) 8.89 (dd, J=7.6, 1.2 Hz, 1 H) 8.37 - 8.49 (m, 2 H) 7.62 - 7.78 (m, 3 H) 7.25 (d, J=2.3 Hz, 1 H) 6.68 (dd, J=5.6, 2.4 Hz, 1 H) 4.41 (d, J=8.1 Hz, 2 H) 4.05 (d, J=8.1 Hz, 2 H) 1.69 (s, 3 H); LC-MS (ESI, Pos) m / z (%): 344.1 (100) [M+H]+

[0323] 4-((3-hydroxypropyl)(methyl)amino)-N-(quinolin-8-yl)picolinamide (Compound 129). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and 3-(Methylamino)-1-propanol. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 80% to afford compound afford compound 129 (7 mg, 0.021 mmol, 20 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.20 (s, 1 H) 9.01 (dd, J=4.3, 1.6 Hz, 1 H) 8.89 (dd, J=7.6, 1.3 Hz, 1 H) 8.45 (dd, J=8.3, 1.6 Hz, 1 H) 8.32 (d, J=6.0 Hz, 1 H) 7.59 - 7.76 (m, 3 H) 7.47 (d, J=2.7 Hz, 1 H) 6.86 (dd, J=6.0, 2.7 Hz, 1 H) 4.69 (t, J=4.9 Hz, 1 H) 3.04 (s, 3 H) 1.63 - 1.79 (m, 2 H); LC-MS (ESI, Pos) m / z (%): 337.2 (100) [M+H]+

[0324]

[0325] (S)-4-(3-(hydroxymethyl)pyrrolidin- 1-yl)-N-(quinolin-8-yl)picolinamide (Compound 130). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and (S)-Pyrrolidin-3-ylmethanol hydrochloride. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 80% to afford compound afford compound 130 (25 mg, 0.072 mmol, 68 % yield) as a tan solid.1H NMR (DMSO- d6, 400 MHz, 298 K) 5 12.20 (s, 1 H) 9.01 (dd, J=4.3, 1.6 Hz, 1 H) 8.89 (dd, J=7.6, 1.3 Hz, 1 H) 8.45 (dd, J=8.3, 1.6 Hz, 1 H) 8.31 (d, J=5.9 Hz, 1 H) 7.62 - 7.76 (m, 3 H) 7.30 (d, J=2.5 Hz, 1 H) 6.68 (dd, J=5.9, 2.5 Hz, 1 H) 4.85 (br. s., 1 H) 3.33 - 3.40 (m, 3 H) 3.18 (dd, J=10.0, 6.5 Hz, 1 H) 2.48 (d, J=7.0 Hz, 1 H) 2.02 - 2.13 (m, 1 H) 1.74 - 1.87 (m, 1 H); LC-MS (ESI, Pos) m / z (%): 349.2 (100) [M+H]+

[0326] N-(quinolin-8-yl)-4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)picolinamide (Compound 131). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) 7-Oxa-2-azaspiro[3.5]nonane hydrochloride. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 30 to 100% to afford compound afford compound 131 (19 mg, 0.051 mmol, 48 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.18 (s, 1 H) 9.02 (dd, J=4.2, 1.7 Hz, 1 H) 8.90 (dd, J=7.6, 1.3 Hz, 1 H) 8.46 (dd, J=8.3, 1.6 Hz, 1 H) 8.35 (d, J=5.6 Hz, 1 H) 7.61 - 7.78 (m, 3 H) 7.19 (d, J=2.4 Hz, 1 H) 6.59 (dd, J=5.7, 2.4 Hz, 1 H) 3.82 (s, 4 H) 3.51 - 3.63 (m, 4 H) 1.70 - 1.84 (m, 4 H); LC-MS (ESI, Pos) m / z (%): 375.1 (100) [M+H]+

[0327]

[0328] N-(quinolin-8-yl)-4-(1-oxa-8-azaspiro[4.5]decan-8-yl)picolinamide (Compound 132). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) 1-Oxa-8-azaspiro[4.5]decane hydrochloride. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 30 to 100% to afford compound afford compound 132 (14 mg, 0.036 mmol, 34 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.18 (s, 1 H) 9.01 (dd, J=4.3, 1.6 Hz, 1 H) 8.89 (dd, J=7.6, 1.3 Hz, 1 H) 8.45 (dd, J=8.4, 1.6 Hz, 1 H) 8.36 (d, J=5.9 Hz, 1 H) 7.59 - 7.77 (m, 4 H) 7.09 (dd, J=6.1 , 2.8 Hz, 1 H) 3.77 (t, J=6.8 Hz, 2 H) 3.63 (dt, J=13.3, 4.6 Hz, 2 H) 3.41 - 3.50 (m, 2 H) 1.85 - 1.95 (m, 2 H) 1.67 - 1.74 (m, 2 H) 1.56 - 1.66 (m, 4 H); LC-MS (ESI, Pos) m / z (%): 389.3 (100) [M+H]+

[0329] 4-(4-(3-hydroxyphenyl)piperazin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 133). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) 1-(3-hydroxyphenyl)-piperazine. The residue was purified by prep- HPLC eluted with a gradient MeOH in water eluted from 30 to 100% to afford compound afford compound 133 (13 mg, 0.031 mmol, 29 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.14 (s, 1 H) 8.98 - 9.07 (m, 1 H) 8.84 (d, J=7.5 Hz, 1 H) 8.72 (d, J=5.5 Hz, 1 H) 8.47 (d, J=8.13 Hz, 1 H) 8.20 (s, 1 H) 7.73 - 7.80 (m, 1 H) 7.56 - 7.72 (m, 4 H) 7.38 (t, J=8.2 Hz, 1 H) 7.29 (dd, J=5.5, 2.5 Hz, 1 H) 6.94 (dd, J=8.3, 1.9 Hz, 1 H) 6.84 (s, 1 H) 6.66 (dd, J=7.9, 1.8 Hz, 1 H) 3.19 - 3.26 (m, 9 H) 2.92 - 3.02 (m, 6 H); LC-MS (ESI, Pos) m / z (%): 426.2 (100) [M+H]+

[0330]

[0331] 4-(4-hydroxy-4-phenylpiperidin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 134). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) 1-(3-hydroxyphenyl)-piperazine. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 30 to 100% to afford compound afford compound 134 (19 mg, 0.045 mmol, 42 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.20 (s, 1 H) 9.02 (dd, J=4.2, 1.6 Hz, 1 H) 8.90 (dd, J=7.6, 1.2 Hz, 1 H) 8.45 (dd, J=8.3, 1.6 Hz, 1 H) 8.38 (d, J=5.9 Hz, 1 H) 7.61 - 7.77 (m, 4 H) 7.49 (d, J=7.4 Hz, 2 H) 7.33 (t, J=7.6 Hz, 2 H) 7.18 - 7.26 (m, 1 H) 7.14 (dd, J=6.0, 2.8 Hz, 1 H) 5.22 (s, 1 H) 3.98 (d, J=12.7 Hz, 2 H) 3.42 (br. s., 2 H) 2.00 (td, J=13.0, 4.3 Hz, 2 H) 1.75 (d, J=12.9 Hz, 2 H); LC-MS (ESI, Pos) m / z (%): 425.2 (100) [M+H]+

[0332] (R)-4-(3-hydroxypyrrolidin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 135). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and (r)-3-pyrrolidinol. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 80% to afford compound afford compound 135 (9 mg, 0.027 mmol, 25 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.20 (s, 1 H) 9.00 (dd, J=4.3, 1.6 Hz, 1 H) 8.88 (dd, J=7.6, 1.3 Hz, 1 H) 8.44 (dd, J=8.3, 1.6 Hz, 1 H) 8.31 (d, J=5.8 Hz, 1 H) 7.61 - 7.75 (m, 3 H) 7.29 (d, J=2.3 Hz, 1 H) 6.69 (dd, J=5.9, 2.5 Hz, 1 H) 5.14 (d, J=3.5 Hz, 1 H) 4.41 - 4.49 (m, 1 H) 3.24 (d, J=10.5 Hz, 2 H) 2.06 (s, 1 H) 1.90 - 2.01 (m, 1 H); LC- MS (ESI, Pos) m / z (%): 335.1 (100) [M+H]+

[0333]

[0334] (R)-4-(2-methylmorpholino)-N-(quinolin-8-yl)picolinamide (Compound 136). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and (R)-2-Methylmorpholine hydrochloride. The residue was purified by prep- HPLC eluted with a gradient MeOH in water eluted from 40 to 95% to afford compound afford compound 136 (20 mg, 0.057 mmol, 54 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.20 (s, 1 H) 9.02 (dd, J=4.2, 1.7 Hz, 1 H) 8.91 (dd, J=7.6, 1.3 Hz, 1 H) 8.39 - 8.51 (m, 2 H) 7.62 - 7.77 (m, 4 H) 7.13 (dd, J=6.0, 2.6 Hz, 1 H) 3.92 - 4.00 (m, 2 H) 3.86 (d, J=12.3 Hz, 1 H) 3.56 - 3.68 (m, 2 H) 2.93 (td, J=12.1 , 3.6 Hz, 1 H) 2.61 (dd, J=12.4, 10.5 Hz, 1 H) 1.17 - 1.25 (m, 3 H); LC-MS (ESI, Pos) m / z (%): 349.2 (100) [M+H]+

[0335] 4-(3-(cyanomethyl)azetidin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 137). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and (2-(Azetidin-3-yl)acetonitrile hydrochloride. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 40 to 95% to afford compound afford compound 137 (9 mg, 0.027 mmol, 25 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.17 (s, 1 H) 9.01 (dd, J=4.3, 1.6 Hz, 1 H) 8.89 (dd, J=7.6, 1.3 Hz, 1 H) 8.45 (dd, J=8.3, 1.6 Hz, 1 H) 8.36 (d, J=5.6 Hz, 1 H) 7.61 - 7.76 (m, 3 H) 7.19 (d, J=2.4 Hz, 1 H) 6.63 (dd, J=5.6, 2.4 Hz, 1 H) 4.21 (t, J=8.2 Hz, 2 H) 3.79 (dd, J=8.4, 5.5 Hz, 2 H) 3.07 - 3.20 (m, 1 H) 2.96 (d, J=6.8 Hz, 2 H); LC-MS (ESI, Pos) m / z (%): 344.1 (100) [M+H]+

[0336]

[0337] 4-(3-acetamidopyrrolidin-1-yl)-N-(quinolin-8-yl)picolinamide (Compound 138). The product was obtained following general procedure H with 4-chloro-N-(quinolin-8-yl)picolinamide 16 (30 mg, 0.11 mmol, 1 eq.) and (R)-3-Acetamidopyrrolidine. The residue was purified by prep-HPLC eluted with a gradient MeOH in water eluted from 20 to 80% to afford compound afford compound 138 (10 mg, 0.027 mmol, 25 % yield) as a tan solid.1H NMR (DMSO-d6, 400 MHz, 298 K) 5 12.20 (s, 1 H) 9.00 (dd, J=4.25, 1.63 Hz, 1 H) 8.88 (dd, J=7.57, 1.31 Hz, 1 H) 8.44 (dd, J=8.38, 1.63 Hz, 1 H) 8.32 (d, J=5.75 Hz, 1 H) 8.23 (d, J=6.75 Hz, 1 H) 7.62 - 7.75 (m, 3 H)7.30 (d, J=2.38 Hz, 1 H) 6.71 (dd, J=5.88, 2.50 Hz, 1 H) 4.34 - 4.44 (m, 1 H) 3.62 (dd, J=10.44, 6.19 Hz, 2 H) 3.22 (dd, J=10.38, 3.88 Hz, 2 H) 2.21 (dd, J=12.69, 6.07 Hz, 1 H) 1.89 - 2.00 (m, 1 H) 1.82 (s, 3 H); LC-MS (ESI, Pos) m / z (%): 376.2 (100) [M+H]+

[0338] General procedure K for reduction of nitro compound. tert-butyl (3-((8-aminoquinolin-5-yl)(methyl)amino)propyl)carbamate (Compound G). Tert-butyl (3-(methyl(8-nitroquinolin-5-yl)amino)propyl)carbamate F (67 mg, 0.186 mmol, 1 eq.) was solubilized in 10 mL of a mixture THF:EtOH:H2O:NH4CI saturated (50:30:15:5) and iron (73 mg, 1.301 mmol, 7 eq.) was added. The suspension was stirred at 50°C for 2 hours leading to completion of the reaction. EtOH and THF were evaporated under reduced pressure. The reaction mixture was portionwise between EtOAc and NaHCCh saturated and the organic layer was washed twice with NaHCCh sat., water and brine. The organic layer was dried over Na2SC>4, filtered, and evaporated to yield compound G (53 mg, 0.160 mmol, 86 % yield) as a yellow solid which was used in the next step without any further purification.1H NMR (DMSO-cfe, 400 MHz, 298 K) <58.72 (dd, J=4.1 , 1.8 Hz, 1 H) 8.45 (dd, J=8.4, 1.8 Hz, 1 H) 7.46 (dd, J=8.4, 4.1 Hz, 1 H) 7.8 (d, J=8.2 Hz, 1 H) 6.81 (d, J=8.2 Hz, 1 H) 6.75 (t, J=5.1 Hz, 1 H) 5.63 (s, 2 H) 2.95 (q., J=6.65 Hz, 2 H) 2.88 (t, J=7.0 Hz, 2 H) 2.64 (s, 3 H) 1.57 (quin., J=7.1 Hz, 2 H) 1.34 (s, 9 H); LC-MS (ESI, Pos) m / z (%): 331.3 (100) [M+H]+ tert-butyl (3-(methyl(8-(picolinamido)quinolin-5-yl)amino)propyl)carbamate (Compound 76). The product was obtained following general procedure A with tert-butyl (3-((8-aminoquinolin-5- yl)(methyl)amino)propyl)carbamate G (238 mg, 0.72 mmol, 1 eq.) to afford compound 76 (200 mg, 0.460 mmol, 64 % yield) as a yellow solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.02 (s, 1 H) 9.01 (dd, J=4.3, 1.6 Hz, 1 H) 8.79 - 8.87 (m, 2 H) 8.58 (dd, J=8.4, 1.7 Hz, 1 H) 8.26 (d, J=7.8 Hz, 1 H) 8.12 (td, J=7.7, 1.8 Hz, 1 H) 7.72 (ddd, J=7.7, 4.8, 1.2 Hz, 1 H) 7.67 (dd, J=8.4, 4.1 Hz, 1 H) 7.31 (d, J=8.2 Hz, 1 H) 6.80 (t, J=5.3 Hz, 1 H) 3.04 (t, J=7.2 Hz, 2 H) 2.97 (q, J=6.3 Hz, 2 H) 2.79 (s, 3 H) 1.69 (quin, J=7.0 Hz, 2 H) 1.33 (s, 9 H); LC-MS (ESI, Pos) m / z (%): 436.2 (100) [M+H]+ tert-butyl (3-((8-(4-chloropicolinamido)quinolin-5-yl)(methyl)amino)propyl)carbamate (Compound 77). The product was obtained following general procedure A with tert-butyl (3-((8-aminoquinolin- 5-yl)(methyl)amino)propyl)carbamate G (47 mg, 0.142 mmol, 1 eq.) and 4-chloropicolinoyl chloride. The crude was purified by silica gel column chromatography eluted with a gradient EtOAc in hexane from 0 to 100 % to afford compound 77 (7 mg, 0.016 mmol, 11 % yield) as a yellow solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 11.96 (s, 1 H) 9.01 (dd, J=4.3, 1.6 Hz, 1 H) 8.83 (d, J = 4.7 Hz, 1 H) 8.82 (d, J = 8.2 Hz, 1 H) 8.58 (dd, J=8.6, 1.6 Hz, 1 H) 8.25 (d, J=2.7 Hz,

[0339] 1 H) 7.9 (dd, J=5.1 , 2.3 Hz, 1 H) 7.68 (dd, J=8.4, 4.1 Hz, 1 H) 7.31 (d, J=8.6 Hz, 1 H) 6.80 (t, J=5.3 Hz, 1 H) 3.04 (t, J=7.2 Hz, 2 H) 2.97 (q, J=6.3 Hz, 2 H) 2.79 (s, 3 H) 1.69 (quin, J=7.0 Hz,

[0340] 2 H) 1.33 (s, 9 H); LC-MS (ESI, Pos) m / z (%): 470.2 (100) [M+H]+

[0341] N-(5-((3-aminopropyl)(methyl)amino)quinolin-8-yl)picolinamide hydrochloride (Compound 80- HCI salt). The product was obtained following general procedure I with tert-butyl (3-(methyl(8- (picolinamido)quinolin-5-yl)amino)propyl)carbamate 76 (200 mg, 0.459 mmol, 1 eq.) to afford compound 80-HCI salt (188 mg, 0.459 mmol, 99 % yield) as an orange solid.1H NMR (DMSO- d6, 400 MHz, 298 K) 5 12.06 (s, 1 H) 9.05 (dd, J=4.1 , 1.4 Hz, 1 H) 8.84 - 8.87 (m, 2 H) 8.68 (br. s., 1 H) 8.27 (d, J=7.8 Hz, 1 H) 8.13 (dt, J=7.8, 0.8 Hz, 1 H) 7.82 (br. s., 2 H) 7.71 - 7.75 (m, 2 H) 7.44 (br. s., 1 H) 3.21 (br. s., 2 H) 2.82 (br. s., 5 H) 1.80 - 1.87 (m, 2 H); LC-MS (ESI, Pos) m / z (%): 336.2 (100) [M+H]+

[0342] N-(5-((3-acetamidopropyl)(methyl)amino)quinolin-8-yl)picolinamide (Compound 78). The product was obtained following general procedure E with N-(5-((3-aminopropyl)(methyl)amino)quinolin-8- yl)picolinamide hydrochloride 80-HCI salt (20 mg, 0.049 mmol, 1 eq.). The residue was purified by silica gel column chromatography eluted with a gradient MeOH in DCM 0 to 5% to afford compound 78 (11 mg, 0.029 mmol, 60 % yield) as yellow solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.03 (s, 1 H) 9.02 (dd, J=4.3, 1.6 Hz, 1 H) 8.82 - 8.85 (m, 2 H) 8.58 (dd, J=8.6, 1.6 Hz, 1 H) 8.26 (d, J=7.80 Hz, 1 H) 8.12 (dt, J=7.7, 1.8 Hz, 1 H) 7.80 (t, J=5.5 Hz, 1 H) 7.73 (ddd, J=7.4, 4.7, 1.2 Hz, 1 H) 7.68 (dd, J=8.4, 4.1 Hz, 1 H) 7.32 (d, J=8.2 Hz, 1 H) 3.03 - 3.10 (m, 4 H) 2.79 (s, 3 H) 1.75 (s, 3 H) 1.69 (quin, J=7.4 Hz, 2 H); LC-MS (ESI, Pos) m / z (%): 378.2 (100) [M+H]+ N-(5-(methyl(3-(picolinamido)propyl)amino)quinolin-8-yl)picolinamide (Compound 75). The product was obtained following general procedure A with N-(5-((3- aminopropyl)(methyl)amino)quinolin-8-yl)picolinamide hydrochloride 80-HCI salt (20 mg, 0.049 mmol, 1 eq.). The residue was purified by prep-HPLC eluted with a gradient MeOH in water to afford compound 75 (5 mg, 0.010 mmol, 19 % yield) as a yellow solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.02 (s, 1 H) 8.97 (dd, J=4.3, 1.6 Hz, 1 H) 8.84 (m, 1 H) 8.82 (d, J=8.2 Hz, 1 H) 8.61 (m, 2 H) 8.25 (d, J=7.8 Hz, 1 H) 8.12 9td, J = 7.7, 1.8 Hz, 1 H) 7.98 (m, 2 H) 7.72 (ddd, J=7.5, 4.8, 1.4 Hz, 1 H) 7.56 - 7.60 (m, 2 H) 7.32 (d, J= 8.6 Hz, 1 H) 3.38 (q, J=6.7 Hz, 2 H) 3.1 (t, J=7.2 Hz, 2 H) 2.81 (s, 3 H) 1.88 (quin, J=6.90 Hz, 2 H); LC-MS (ESI, Pos) m / z (%): 441.2 (100) [M+H]+

[0343] N-(5-(methyl(3-(pent-4-ynamido)propyl)amino)quinolin-8-yl)picolinamide (Compound 79). The product was obtained following general procedure C with N-(5-((3- aminopropyl)(methyl)amino)quinolin-8-yl)picolinamide hydrochloride 80-HCI salt (30 mg, 0.090 mmol, 1 eq.) and 4-pentynoic acid. The residue was purified by prep-HPLC eluted with a gradient MeOH in water to afford compound 79 (12 mg, 0.029 mmol, 32 % yield) as yellow solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.03 (s, 1 H) 9.02 (dd, J=4.1 , 1.4 Hz, 1 H) 8.82 - 8.85 (m, 2 H) 8.59 (dd, J=8.6, 1.6 Hz, 1 H) 8.26 (d, J=7.80 Hz, 1 H) 8.12 (dt, J=7.8, 1.6 Hz, 1 H) 7.86 (t, J=5.3 Hz, 1 H) 7.73 (dd, J=7.2, 4.9 Hz, 1 H) 7.68 (dd, J=8.4, 4.1 Hz, 1 H) 7.32 (d, J=8.2 Hz, 1 H) 3.04 - 3.13 (m, 4 H) 2.79 (s, 3 H) 2.72 (t, J=2.5 Hz, 1 H) 2.29 - 2.33 (m, 2 H) 2.19 - 2.22 (m, 2 H) 1.69 (quin, J=6.8 Hz, 2 H); LC-MS (ESI, Pos) m / z (%): 416.2 (100) [M+H]+

[0344] Synthetic Route 7

[0345] tert-butyl (3-(methyl(8-nitroquinolin-4-yl)amino)propyl)carbamate (Compound H). The product was obtained following procedure H with 4-chloro-8-nitroquinoline (300 mg, 1.44 mmol, 1 eq.) and tert-butyl (3-(methylamino)propyl)carbamate (325 mg, 1.73 mmol, 1.2 eq.). The residue was purified by silica gel column chromatography eluted with a gradient EtOAc in hexane from 0 to 100 % to afford compound H (395 mg, 1.094 mmol, 76 % yield) as a yellow solid.1H NMR (DMSO- d6, 400 MHz, 298 K) 68.63 (d, J=5.5 Hz, 1 H), 8.23 (dd, J=8.4, 1.0 Hz, 1 H) 8.12 (dd, J=7.4, 1.2 Hz, 1 H) 7.59 (dd, J=8.4, 7.6 Hz, 1 H) 7.02 (d, J=5.1 Hz, 1 H) 6.85 (t, J=5.3 Hz, 1 H) 3.34 - 3.41 (m, 2 H) 3.01 (s, 3 H) 2.97 (q, J=6.3 Hz, 2 H) 1.81 (quin., J=6.9 Hz, 2 H) 1.32 (s, 9 H); LC-MS

[0346] (ESI, Pos) m / z (%): 361.1 (100) [M+H]+ tert-butyl (3-((8-aminoquinolin-4-yl)(methyl)amino)propyl)carbamate (Compound I). The product was obtained following procedure K with tert-butyl (3-(methyl(8-nitroquinolin-4- yl)amino)propyl)carbamate H (395 mg, 1.10 mmol, 1 eq.) to afford compound I (300 mg, 0.913 mmol, 83 % yield) as a brown solid which was used in the next step without any further purification.1H NMR (DMSO-cfe, 400 MHz, 298 K) 58.46 (d, J=5.1 Hz, 1 H) 7.17 (d, J=7.8 Hz, 1 H) 7.05 - 7.13 (m, 1 H) 6.88 (d, J=5.1 Hz, 1 H) 6.83 (t, J=5.3 Hz, 1 H) 6.78 (d, J=7.4 Hz, 1 H) 5.80 (s, 2 H) 3.17 - 3.21 (m, 2 H) 2.95 (q, J=6.0 Hz, 2 H) 2.87 (s, 3 H) 1.761 (quin., J=7.0 Hz, 2 H) 1.34 (s, 9 H); LC-MS (ESI, Pos) m / z (%): 331.3 (100) [M+H]+ tert-butyl (3-(methyl(8-(picolinamido)quinolin-4-yl)amino)propyl)carbamate (Compound 62). The product was obtained following general procedure C with tert-butyl N-[3-[(8-amino-4-quinolyl)- methyl-amino]propyl]carbamate I (70 mg, 0.212 mmol, 1 eq.) to afford compound 62 (61 mg, 0.048 mmol, 66 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.22 (s, 1 H) 8.83 - 8.85 (m, 2 H) 8.70 (d, J=5.1 Hz, 1 H) 8.26 (d, J=7.8 Hz, 1 H) 8.12 (dd, J= 7.8, 1.6 Hz, 1 H) 7.71 - 7.75 (m, 2 H) 7.53 (t, J=8.1 Hz, 1 H) 7.03 (d, J=5.3 Hz, 1 H) 6.86 (t, J=5.3 Hz, 1 H) 2.95 - 2.99 (m, 5 H) 1.82 (quin, J=6.6 Hz, 2 H) 1.34 (s, 9 H); LC-MS (ESI, Pos) m / z (%): 436.2 (100) [M+H]+ tert-butyl (3-((8-(4-chloropicolinamido)quinolin-4-yl)(methyl)amino)propyl)carbamate (Compound 68). The product was obtained following general procedure C with tert-butyl N-[3-[(8-amino-4- quinolyl)-methyl-amino]propyl]carbamate I (70 mg, 0.212 mmol, 1 eq.) and 4-chloro-pyridine-2- carboxylic acid to afford compound 68 (59 mg, 0.125 mmol, 59 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.09 (s, 1 H) 8.91 (s, 1 H) 8.81 (d, J=7.5 Hz, 1 H) 8.69 (d, J=5.3 Hz, 1 H) 8.25 (s, 3 H) 7.75 (d, J=8.1 Hz, 1 H) 7.53 (t, J=8.1 Hz, 1 H) 7.03 (d, J=5.3 Hz, 1 H) 6.86 (t, J=5.5 Hz, 1 H) 3.22 - 3.31 (m, 3 H) 2.99 (s, 5 H) 1.82 (quin, J=7.0 Hz, 2 H) 1.33 (s, 9 H); LC- MS (ESI, Pos) m / z (%): 470.2 (100) [M+H]+ tert-butyl (3-((8-(3-fluoropicolinamido)quinolin-4-yl)(methyl)amino)propyl)carbamate (69). The product was obtained following general procedure C with tert-butyl N-[3-[(8-amino-4-quinolyl)- methyl-amino]propyl]carbamate I (70 mg, 0.212 mmol, 1eq.) to afford compound 69 (90 mg, 0.105 mmol, 94 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.03 (s, 1 H) 8.79 (d, J=7.5 Hz, 1 H) 8.62 - 8.73 (m, 3 H) 7.94 - 8.05 (m, 1 H) 7.82 - 7.85 (m, 1 H) 7.72 - 7.75 (m, 1 H) 7.52 (t, J = 8.1 Hz, 1 H) 7.03 (d, J=5.3 Hz, 1 H) 6.86 (t, J=5.3 Hz, 1 H) 3.29 (br. s., 2 H) 2.90 - 3.04 (m, 5 H) 1.82 (quin, 454.2 (100) [M+H]+

[0347] N-(4-((3-aminopropyl)(methyl)amino)quinolin-8-yl)picolinamide hydrochloride (Compound J). The product was obtained following general procedure I with tert-butyl N-[3-[(8-amino-4-quinolyl)- methyl-amino]propyl]carbamate 62 (25 mg, 0.058 mmol, 1 eq.) to afford compound J (21 mg, 0.057 mmol, 98 % yield) as a tan solid. LC-MS (ESI, Pos) m / z (%): 336.2 (100) [M+H]+

[0348] N-(4-((3-aminopropyl)(methyl)amino)quinolin-8-yl)-4-chloropicolinamide hydrochloride

[0349] (Compound 74-HCI salt). The product was obtained following general procedure I with tert-butyl (3-((8-(4-chloropicolinamido)quinolin-4-yl)(methyl)amino)propyl)carbamate 68 (59 mg, 0.126 mmol, 1 eq.) to afford compound 74-HCI salt (51 mg, 0.126 mmol, 99 % yield) as a yellow solid. LC-MS (ESI, Pos) m / z (%): 370.2

[0350] N-(4-((3-aminopropyl)(methyl)amino)quinolin-8-yl)-3-fluoropicolinamide hydrochloride

[0351] (Compound K). The product was obtained following general procedure I with tert-butyl (3-((8-(3- fluoropicolinamido)quinolin-4-yl)(methyl)amino)propyl)carbamate 69 (90 mg, 0.198 mmol, 1 eq.) to afford compound K (77 mg, 0.198 mmol, 99 % yield) as a yellow solid. LC-MS (ESI, Pos) m / z (%): 354.2 (100) [M+H]+

[0352] N-(4-(methyl(3-(pent-4-ynamido)propyl)amino)quinolin-8-yl)picolinamide (Compound 63). The product was obtained following general procedure C with N-(4-((3- aminopropyl)(methyl)amino)quinolin-8-yl)picolinamide hydrochloride J (27 mg, 0.080 mmol, 1eq.) and 4-pentynoic acid. The crude was purified by silica gel column chromatography eluted with a gradient of MeOH in DCM from 0 to 20 % followed by an EZ-prep purification with a gradient of MeOH in water to afford compound 63 (14 mg, 0.034 mmol, 42 % yield) as a white solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.22 (s, 1 H) 8.84 (d, J=6.3 Hz, 2 H) 8.71 (d, J=5.5 Hz, 1 H) 8.26 (d, J=7.8 Hz, 1 H) 8.12 (td, J=7.6, 1.6 Hz, 1 H) 7.93 (t, J=5.3 Hz, 1 H) 7.71 - 7.74 (m, 2 H) 7.54 (t, J=8.0 Hz, 1 H) 7.04 (d, J=5.5 Hz, 1 H) 3.11 (q, J=6.4 Hz, 2 H) 2.99 (s, 3 H) 2.73 (t, J=2.5 Hz, 1 H) 2.28 - 2.35 (m, 2 H) 2.18 - 2.26 (m, 2 H) 1.82 (quin, J=6.6 Hz, 2 H); LC-MS (ESI, Pos) m / z (%):

[0353] 416.3 (100) [M+H]+

[0354] 4-chloro-N-(4-(methyl(3-(pent-4-ynamido)propyl)amino)quinolin-8-yl)picolinamide (Compound 64). The product was obtained following general procedure C with N-(4-((3- aminopropyl)(methyl)amino)quinolin-8-yl)-4-chloropicolinamide hydrochloride 74(HCI salt) (106 mg, 0.260 mmol, 1 eq.) and 4-pentynoic acid to afford compound 64 (83 mg, 0.185 mmol, 71 % yield) as an off-white solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.15 (s, 1 H) 8.77 - 8.84 (m, 2 H) 8.68 (d, J=5.1 Hz, 1 H) 8.23 (d, J=2.0 Hz, 1 H) 7.89 - 7.94 (m, 2 H) 7.75 (d, J=8.2 Hz, 1 H) 7.53 (t, J=8.0 Hz, 1 H) 7.02 (d, J=5.1 Hz, 1 H) 3.09 (q, J=5.8 Hz, 2 H) 2.98 (s, 2 H) 2.71 (t, J=2.54 Hz, 1 H) 2.29 (dd, J=6.65, 2.35 Hz, 2 H) 2.21 (d, J=6.65 Hz, 2 H) 1.76 - 1.86 (quin, J=7.0 Hz, 2 H); LC-MS (ESI, Pos) m / z (%): 450.2 (100) [M+H]+

[0355] 4-chloro-N-(4-(methyl(3-pivalamidopropyl)amino)quinolin-8-yl)picolinamide (Compound 73). The product was obtained following general procedure C with N-(4-((3- aminopropyl)(methyl)amino)quinolin-8-yl)-4-chloropicolinamide hydrochloride 74(HCI salt) (20 mg, 0.049 mmol, 1 eq.) and trimethylacetic acid to afford compound 73 (9 mg, 0.020 mmol, 40 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.09 (s, 1 H) 8.91 (s, 1 H) 8.81 (d, J=7.6 Hz, 1 H) 8.69 (d, J=5.1 Hz, 1 H) 8.25 (s, 2 H) 7.74 (d, J=8.6 Hz, 1 H) 7.53 (t, J=8.1 Hz, 1 H) 7.46 (t, J=5.5 Hz, 1 H) 7.03 (d, J=5.3 Hz, 1 H) 3.09 (q, J=6.3 Hz, 2 H) 2.98 (s, 3 H) 1.82 (quin, J=7.0 Hz, 2 H) 1.02 (s, 9 H); LC-MS (ESI, Pos) m / z (%): 454.2 (100) [M+H]+

[0356] General procedure L for benzyl carbamate synthesis. benzyl (3-(methyl(8-(picolinamido)quinolin-4-yl)amino)propyl)carbamate (Compound 70). N-(4- ((3-aminopropyl)(methyl)amino)quinolin-8-yl)picolinamide hydrochloride J (15 mg, 0.040 mmol, 1eq.) was solubilized in 1 mL of DMF and N,N-diisopropylethylamine (DIPEA) (14 pL, 0.081 mmol, 2 eq.) was added followed by benzyl 4-nitrophenyl carbonate (12 mg, 0.044 mmol, 1.1 eq.). The solution was then stirred at room tenperature overnight leading to completion of the reaction. The crude was directly purified by prep-HPLC eluted with a gradient MeOH in water to afford compound 70 (4 mg, 0.009 mmol, 21 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.23 (s, 1 H) 8.78 - 8.88 (m, 2 H) 8.71 (d, J=5.1 Hz, 1 H) 8.27 (d, J=7.8 Hz, 1 H) 8.13 (td, J=7.7, 1.6 Hz, 1 H) 7.67 - 7.78 (m, 2 H) 7.50 (t, J=8.1 Hz, 1 H) 7.24 - 7.38 (m, 6 H) 7.04 (d, J=5.1 Hz, 1 H) 4.99 (s, 2 H) 3.06 (q, J=6.4 Hz, 2 H) 2.99 (s, 3 H) 1.86 (quin, J=6.8 Hz, 2 H); LC-MS (ESI, Pos) m / z (%): 470.2 (100) [M+H]+ benzyl (3-((8-(4-chloropicolinamido)quinolin-4-yl)(methyl)amino)propyl)carbamate (Compound 71). The product was obtained following general procedure L with N-(4-((3- aminopropyl)(methyl)amino)quinolin-8-yl)-4-chloropicolinamide hydrochloride 74(HCI salt) (15 mg, 0.037 mmol, 1 eq.) to afford compound 71 (9 mg, 0.018 mmol, 48 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.09 (s, 1 H) 8.86 - 8.94 (m, 1 H) 8.80 (d, J=7.6 Hz, 1 H) 8.69 (d, J=5.1 Hz, 1 H) 8.21 - 8.29 (m, 2 H) 7.74 (d, J=8.4 Hz, 1 H) 7.50 (t, J=8.1 Hz, 1 H) 7.27 - 7.36 (m, 6 H) 7.03 (d, J=5.3 Hz, 1 H) 4.99 (s, 2 H) 306 (q, J=6.4 Hz, 2 H) 2.98 (s, 3 H) 1.86 (quin, J=7.8 Hz, 2 H); LC-MS (ESI, Pos) m / z (%): 504.2 (100) [M+H]+ benzyl (3-((8-(3-fluoropicolinamido)quinolin-4-yl)(methyl)amino)propyl)carbamate (Compound 72). The product was obtained following procedure with N-(4-((3- aminopropyl)(methyl)amino)quinolin-8-yl)-3-fluoropicolinamide hydrochloride K (15 mg, 0.037 mmol, 1 eq.) to afford compound 72 (2 mg, 0.004 mmol, 11 % yield) as a tan solid.1H NMR

[0357] (DMSO-cfe, 400 MHz, 298 K) 6 12.03 (s, 1 H) 8.78 (d, J=7.6 Hz, 1 H) 8.67 - 8.69 (m, 2 H) 8.00 (ddd, J=11.4, 8.6, 1.1 Hz, 1 H) 7.83 (dt, J=8.5, 4.0 Hz, 1 H) 7.73 (d, J=8.4 Hz, 1 H) 7.49 (t, J=8.1 Hz, 1 H) 7.27 - 7.36 (m, 6 H) 7.03 (d, J=5.3 Hz, 1 H) 4.99 (s, 2 H) 3.06 (q, J=6.5 Hz, 2 H) 2.98 (s, 3 H) 1.82 (quin, J=6.9 Hz, 2 H); LC-MS (ESI, Pos) m / z (%): 488.2 (100) [M+H]+Synthetic Route 8 N-(3-morpholinopropyl)-8-nitroquinolin-4-amine (Compound L). The product was obtained following procedure H with 4-chloro-8-nitroquinoline (100 mg, 0.48 mmol, 1 eq.) and N-(3- morpholinopropyl)-8-nitroquinolin-4-amine (295 pL, 1.92 mmol, 4 eq.). The reaction mixture was stirred at 70°C overnight and DMF co-evaporated with heptane after completion of the reaction. The crude was purified by silica gel column chromatography eluted with a gradient MeOH in DCM from 0 to 20 % to afford compound L (80 mg, 0.254 mmol, 53 % yield) as a yellow solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 58.38 - 8.49 (m, 2 H) 8.03 (d, J=7.4 Hz, 1 H) 7.61 (t, J=5.2 Hz, 1 H) 7.53 (t, J=8.0 Hz, 1 H) 6.62 (d, J=5.5 Hz, 1 H) 3.59 (t, J=4.5 Hz, 4 H) 3.35 (q, J=6.6 Hz, 2 H) 2.29 - 2.44 (m, 6 H) 1.82 (quin, 317.2 (100) [M+H]+

[0358] N4-(3-morpholinopropyl)quinoline-4,8-diamine (Compound M). The product was obtained following general procedure K with N-(3-morpholinopropyl)-8-nitroquinolin-4-amine L (100 mg, 0.316 mmol, 1 eq.) in 25 mL of a mixture THF:EtOH:H2O:NH4CI saturated (50:30:15:5) to yield compound M (70 mg, 0.123 mmol, 77 % yield) as a green solid which was used in the next step without any further purification.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 8.25 (d, J=5.3 Hz, 1 H) 7.23 (d, J=8.3 Hz, 1 H) 7.10 (t, J=7.9 Hz, 1 H) 6.97 (t, J=5.1 Hz, 1 H) 6.74 (d, J=7.4 Hz, 1 H) 6.40 (d, J=5.3 Hz, 1 H) 5.68 (s, 2 H) 3.60 (t, J=4.5 Hz, 4 H) 3.24 - 3.31 (m, 2 H) 2.29 - 2.45 (m, 6 H) 1.81 (quin, J=6.75 Hz, 2 H); LC-MS (ESI, Pos) m / z (%): 287.2 (100) [M+H]+

[0359] N-(4-((3-morpholinopropyl)amino)quinolin-8-yl)picolinamide (Compound 65). The product was obtained following general procedure C with N4-(3-morpholinopropyl)quinoline-4,8-diamine M (23 mg, 0.080 mmol, 1 eq.). The purification was performed by prep-HPLC with NH4OAC as a buffer to afford compound 65 (22 mg, 0.056 mmol, 70 % yield) as a green solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.20 (s, 1 H) 8.83 (d, J=4.6 Hz, 1 H) 8.83 (d, J=4.6 Hz, 1 H) 8.80 (d, J=7.6 Hz, 1 H) 8.49 (d, J=5.4 Hz, 1 H) 8.25 (d, J=7.8 Hz, 1 H) 8.11 (t, J=7.7 Hz, 1 H) 7.93 (d, J=8.5 Hz, 1 H) 7.67 - 7.75 (m, 1 H) 7.46 (t, J= 8.1 Hz, 1 H) 7.40 (t, J= 5.2 Hz, 1 H) 6.59 (d, J=5.5 Hz, 1 H) 3.60 (t, J=4.4 Hz, 4 H) 3.36 (q, J=6.3 Hz, 2 H) 2.30 - 2.46 (m, 6 H) 1.84 (quin, J=6.8 Hz, 2 H); LC- MS (ESI, Pos) m / z (%): 392.2 (100) [M+H]+

[0360] 3-fluoro-N-(4-((3-morpholinopropyl)amino)quinolin-8-yl)picolinamide (Compound 66). The product was obtained following general procedure C with N4-(3-morpholinopropyl)quinoline-4,8- diamine M (23 mg, 0.080 mmol, 1 eq.) and 3-fluoropyridine-2-carboxylic acid. The purification was performed by prep-HPLC with NH4OAC as a buffer to afford compound 66 (22 mg, 0.054 mmol, 67 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.01 (s, 1 H) 8.75 (d, J=7.6 Hz, 1 H) 8.67 (d, J=4.1 Hz, 1 H) 8.47 (d, J=5.4 Hz, 1 H) 7.89 - 8.05 (m, 2 H) 7.81 (dt, J=8.3, 4.0 Hz, 1 H) 7.45 (t, J= 8.1 Hz, 1 H) 7.41 (t, J= 4.2 Hz, 1 H) 6.59 (d, J=5.4 Hz, 1 H) 3.60 (t, J=4.2 Hz, 4 H) 3.33 - 3.40 (m, 2 H) 2.30 - 2.45 (m, 6 H) 1.83 (quin, J=6.7 Hz, 2 H); LC-MS (ESI, Pos) m / z (%): 410.2 (100) [M+H]+

[0361] 5-amino-N-(4-((3-morpholinopropyl)amino)quinolin-8-yl)picolinamide (Compound 67). The product was obtained following general procedure C with N4-(3-morpholinopropyl)quinoline-4,8- diamine M (23 mg, 0.080 mmol, 1 eq.) and 5-aminopicolinic acid. The purification was performed by prep-HPLC with NH4OAC as a buffer to afford compound 67 (22 mg, 0.054 mmol, 67 % yield) as a tan solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 11.84 (s, 1 H) 8.75 (d, J=7.6 Hz, 1 H) 8.46 (d, J=5.4 Hz, 1 H) 8.05 (d, J=2.4 Hz, 1 H) 7.89 (d, J=8.5 Hz, 1 H) 7.85 (d, J=8.6 Hz, 1 H) 7.41 (t, J=8.1 Hz, 1 H) 7.34 (t=5.2 Hz, 1 H) 7.06 (dd, J=8.6, 2.6 Hz, 1 H) 6.57 (d, J=5.5 Hz, 1 H) 6.14 (s, 2 H) 3.60 (t, J=4.4 Hz, 4 H) 3.33 - 3.40 (m, 4 H) 2.29 - 2.45 (m, 6 H) 1.83 (quin, J=6.82 Hz, 2 H); LC-MS (ESI, Pos) m / z (%): 407.2 4-(piperidin-4-yl)-N-(quinolin-8-yl)picolinamide hydrochloride (Compound 34-HCI salt). The product was obtained from tert-butyl 4-(2-(quinolin-8-ylcarbamoyl)pyridin-4-yl)piperidine-1- carboxylate 8 (22 mg, 0.051 mmol, 1 eq.) to afford compound 34(HCI salt) (4 mg, 0.011 mmol, 21 % yield) as a white solid.1H NMR (DMSO-cfe, 400 MHz, 298 K) 5 12.16 (s, 1 H) 9.03 (d, J=4.3 Hz, 1 H) 8.91 (d, J=7.4 Hz, 1 H) 8.76 (d, J=5.0 Hz, 1 H) 8.47 (d, J=8.4 Hz, 1 H) 7.64 - 7.79 (m, 4 H) 7.61 (d, J=4.6 Hz, 1 H) 3.16 (d, J=11.8 Hz, 3 H) 2.90 (t, J=12.13 Hz, 1 H) 2.73 (t, J=11.7 Hz, 2 H) 1.81 - 1.91 (m, 2 H) 1.58 - 1.72 (m, 2 H); LC-MS (ESI, Pos) m / z (%): 333.1 (100) [M+H]+

[0362] In vitro biological activity

[0363] / . Induction of cell death by cuproptosis

[0364] (i) Immunofluorescence

[0365] OCI-AML5 cells were treated 16 hrs with compounds, washed in PBS and plated onto poly-l- lysine coated Ibidi microscopy chambers. Cells were fixed with 1 % paraformaldehyde for 8 min at room temperature and were then washed in PBS. After blocking in PBS with 1% bovine serum albumin and 0.25% Triton, cells were stained for 2 h at room temperature with DLAT antibody (Cell Signaling Technology 12362, dilution 1 :100). Cells were further washed and stained with Alexa Fluor 647 anti-mouse secondary antibody (ThermoFisher A-21236) and finally counterstained with DAPI. Following immunostaining, images were captured on a Zeiss LSM 880 confocal microscope driven by ZEN software at 60X. Total DLAT signal was quantified using Image J software (NIH) and is reported as total DLAT intensity divided by the number of cells in each image.

[0366] (ii) Inductively coupled plasma mass spectrometry (ICP-MS)

[0367] OCI-AML5 cells to be analyzed were treated with the indicated compounds for 3 hours in media supplemented by 1 pM of copper. For intra-mitochondrial quantification, 2 X 107HEK293 cells were used per replicate. The mitochondria were isolated based on the scaled down (20X) procedure described in Wieckowski et al. (Nature Protocols 4, 1582-1590 (2009)). Crude mitochondrial pellets were resuspended and digested overnight in 100 pL of Suprapur® 65% nitric acid at room temperature. The samples were then diluted 50x in HPLC grade water (Fisher Scientific W5-4) and analyzed. Blank samples were spiked with reference metal standards and used for quantification. The quantification of copper by ICP-MS was performed by the CACEN platform at Universite de Montreal on a NexION 5000 apparatus (Perkin Elmer).

[0368] (iii) Whole genome CRISPR / Cas9 deletion screens The Extended Knockout (EKO) pooled lentiviral library composed of 278,754 sgRNAs targeting 19,084 RefSeq genes, 3,872 hypothetical ORFs and 20,852 alternatively spliced isoforms developed by Bertomeu et al. (Mol. Cell. Biol. 38, 387-24 (2017)) was used for whole genome CRISPR / Cas9 screen. This library, for which each gene is targeted by approximatively 10 sgRNAs, was introduced within a clone of OCI-AML5 cells expressing a doxycycline-inducible Cas9. The EKO library (maintained at a minimum of 500 cells per sgRNA) was cultured in 10 % FBS DMEM supplemented with 2 pg / mL doxycycline for a period of 7 days to induce knockouts. The knockout library was maintained in culture 14 more days with exposure to 110 nM of Compound 1 or DMSO. Finally, genomic DNA was extracted by cell lysis in buffer containing 50 mM Tris, 50 mM EDTA, 1 % SDS and treated with proteinase K followed by RNAse and then precipitation of proteins with 7.5 M ammonium acetate and isopropanol precipitation of gDNA. SgRNA sequences were recovered and fitted with Illumina adaptors by PCR and NGS performed on an Illumina HiSeq 2000 device (IRIC). Resulting reads were trimmed using Trim Galore (https: / / www.bioinformatics.babraham.ac.uk / projects / trim_galore / ) and aligned to the sgRNA sequences using Bowtie aligner v2.3.3 (Langmead, B. et al., Genome Biol. 10, R25-10 (2009)). Synthetic rescue / positive selection and synthetic lethality / negative selection beta scores, as well as statistical significance, were determined using MAGeCK-VISPRMAGeCK-MLE method (Li, W. et a!., Genome Biol. 16, 281-13 (2015)).

[0369] (iv) Statistical analyses

[0370] Statistical testing was performed by using the MAGeCK-VISPR-MLE method (Li, W. et al., see above) for CRISPR screens or GraphPad Prism version 6.0. for statistical functions. Results having p-value <0.05 were considered significant. Statistical differences of p<0.05, p<0.005, p<0.0005 and p<0.0001 are depicted as *, **, *** and **** respectively in figures.

[0371] (v) Results

[0372] To confirm that the present Compound 1 is a copper ionophore and that cuproptosis is causing cell death, DLAT protein aggregation that occurs through the binding of excess copper to lipoylated DLAT and leads to proteotoxic stress was evaluated (Tsvetkov. P. et al., Science, 2022, 375, 1254-1261). The presence of DLAT aggregates is observed by immunofluorescence upon Compound 1 and elesclomol (comparative) treatment, which is exacerbated in the presence of copper supplementation (Figure 1). It was also confirmed that Compound 1 increases intra- mitochondrial copper levels by ICP-MS analysis on mitochondria extracts (Figure 2). Of note, pre- treatment with ferroptosis inhibitor (Ferrostatin-1), caspase 3 inhibitor (Z-DEVD-FMK) or pan caspase inhibitor (Emricasan) failed to rescue Compound 1 cytotoxic effect (Figure 3) confirming that ferroptosis or apoptosis are not involved in Compound 1 cytotoxic activity.

[0373] Finally, a genome-wide CRISPR / Cas9 loss-of-function screen was conducted with Compound 1 to identify synthetic interactions (Figure 4). Results first revealed that, knock-down of HK2 or PFKP, two enzymes involved in glycolysis, showed strong synthetic lethality, supporting a mechanism of action through inhibition of cellular respiration. Strikingly, genetic suppression of the pyruvate dehydrogenase complex (PDC) by targeting DLAT, PDHB and PDHA 1 rescued cells from Compound 1 treatment. These results are in line with Tsvetkov et al. showing that disruption of PDC rescues ovarian cells from elesclomol-mediated cuproptosis. Accordingly, disruption of DLAT or key enzymes mediating its lipoylation (LIAS: Lipoic Acid Synthetase and LIPT1) provides synthetic rescue over Compound 1 treatment (Figure 4).

[0374] Altogether, without wishing to be bond by theory, these data would support the hypothesis that Compound 1 mediates cuproptosis.

[0375] / / . In vitro AML5 cells inhibition assay:

[0376] OCI-AML5 cell line was cultured in aMEM, 10% heat-inactivated FBS supplemented with 10 ng / mL GM-CSF. Cells were maintained at 37°C in 5% CO2 atmosphere. Media was supplemented with 1 pM copper where indicated.

[0377] Lentiviral vector carrying shRNA targeting ABCB7 was generated by cloning shRNA sequence into MNDll vector comprising miR-E sequences (Fellmann C, et al., Cell Rep. 2013;5(6):1704- 1713. Control vector (shRNA Ctrl 3093) contained shRNA targeting Renilla luciferase. Sequence of the 22-mer guide shRNA ABCB7_1101 is as follow: TTGTAATAAATAGTATTATGGA. HEK293T cells were transfected with 5 pg lentiviral plasmid, 3.3 pg PAX2 packaging plasmid and

[0378] I pg VSV-G envelope plasmid using 20 pL of JetPrime Transfection reagent (PolyPlus Transfection), according to manufacturer’s directions to produce lentiviruses. Viral supernatants were collected after 48 hours, filtered and used to infect cell lines at a multiplicity of infection of 5 in media supplemented with 10 ng / mL polybrene for 48 hours. Infection efficiency, as determined by the percentage of GFP positive cells, was monitored by flow cytometry usinga BD FACSCanto

[0379] II and infected cells were selected with puromycin. Established OCI-AML5 cell lines constitutively expressing shRNA ABCB7 1101 or shRNA control 3093 were then used for dose-response assays. For dose-response assay, compounds were dissolved in DMSO at a stock concentration of 10 mM, transferred in 384-well white plates using the Echo 555 (Labcyte) where cells were added subsequently. Each compound was tested in duplicate and in serial dilution as follow: 8 dilutions, 1 :4, 10 pM down to 0.6 nM. 300 cells were seeded per well in 50 pL of media. Control wells received DMSO (0.1%) only. Cell viability was evaluated after 4 days in culture using the CellTiterGlo assay (Promega) according to the manufacturer’s instruction. We report the absolute IC50 value for each compound. For cases where compounds failed to inhibit cell survival / proliferation, IC50 values were arbitrarily reported at the highest dose tested (10 pM).

[0380] Anti-proliferative activity of compounds was evaluated by determining the absolute half-maximal inhibitory (IC50) concentrations in OCI-AML5 cells. This allowed us to monitor the potency of the newly generated molecules and eliminate the non-active ones.

[0381] To make sure that the newly synthetized analogs were on-target, we monitored the IC50 values of the compounds in cells depleted for ABCB7. Indeed, it shows that ABCB7 depletion sensitizes the cells to copper ionophores by altering iron-sulfur cluster containing proteins. It was determined that molecules for which IC50 values would be at least 2 times lower in the presence of ABCB7 shRNA compared to the control shRNA are on-target. It is thus herein reported the ratio of IC50 shRNA Ctrl 3093 I IC50 shRNA ABCB7 1101. Results are presented in Table 1 below. When a ratio of around 2 or above, molecules are considered to have the same mechanism of action as Compound 1.

[0382] Table 1. Biological activities of Compounds 1 to 138

[0383] * denotes a 1000nM to less than 10,000nM IC50 range; ** denotes a 500nM to less than 1000nM IC50 range; *** denotes a 100nM to less than 500nm IC50 range; **** denotes a 10nM to less than 100nM IC50 range; ***** denoted an

[0384] IC5o<1OnM. N / A: not available. Numerous modifications could be made to any of the embodiments described above without departing from the scope of the present invention. Any references, patents or scientific literature documents referred to in the present document are incorporated herein by reference in their entirety for all purposes.

Claims

CLAIMS1 . A compound of Formula I:wherein:A is a Cs- cycloalkyl, C4- heterocycloalkyl, Ce-waryl or Cs-wheteroaryl;R1, R2, and R3are each independently selected from H, halo, OH, OR5, ON, NO2, C(O)R5, OC(O)R6, C(O)OR6, C(O)N(R6)2, C(R7)=NR7, SO2R5, SO2N(R6)2, N(R7)C(O)R5, N(R7)C(O)OR5, N(R7)SO2R5, N(R7)C(O)N(R6)2, N(R7)SO2N(R6)2, N(R6)2, P(O)(R6)2, P(O)(OR6)2, B(OR6)2, and optionally substituted Ci-salkyl, C2-8alkenyl, C2-8alkynyl, Ce- aryl, Cs-wheteroaryl, Cs-wcycloalkyl, and Cs-wheterocycloalkyl groups, or R1is absent when X1is N, or R2is absent when X2is N;R4is independently in each occurrence selected from halo, OH, OR5, CN, NO2, C(O)R5, OC(O)R6, C(O)OR6, C(O)N(R6)2, C(R7)=NR7, SO2R5, SO2N(R6)2, N(R7)C(O)R5, N(R7)C(O)OR5, N(R7)SO2R5, N(R7)C(O)N(R6)2, N(R7)SO2N(R6)2, N(R6)2, P(O)(R6)2, P(O)(OR6)2, B(OR6)2, and optionally substituted Ci-salkyl, C2-8alkenyl, C2-8alkynyl, Ce-waryl, Cs-wheteroaryl, Cs-wcycloalkyl, and Cs-wheterocycloalkyl groups;R5is independently in each occurrence selected from optionally substituted Ci-Cealkyl, C2. salkenyl, C2-8alkynyl, Cs-Cycycloalkyl, Cs-Cwheterocycloalkyl, Ce-waryl, Cs-Cwheteroaryl;R6is independently in each occurrence selected from H or a group selected from optionally substituted Ci-Cealkyl, C2-8alkenyl, C2-8alkynyl, Cs-Cycycloalkyl, Cs-Cwheterocycloalkyl, Ce- waryl and Cs-Ceheteroaryl, or two R6groups are taken together with their adjacent nitrogen atom to form an optionally substituted Cs-Cwheterocycloalkyl or Cs-Cwheteroaryl;R7is independently in each occurrence selected from H or a group selected from optionally substituted Ci-Cealkyl, C2-salkenyl, C2-salkynyl, Cs-Cycycloalkyl, C4-C heterocycloalkyl, Ce- aryl, and Cs-Ceheteroaryl;X1and X2are each independently selected from C and N;X3is selected from CH and N; n is an integer selected from 0 to 5 and denotes the number of R4replacing hydrogen atoms on A; and— - designates a single or double bond; or a pharmaceutically acceptable salt or solvate thereof.

2. The compound of claim 1 , wherein X1is C.

3. The compound of claim 1 or 2, wherein X3is CH.

4. The compound of claim 1 or 2, wherein X3is N.

5. The compound of any one of claims 1 to 4, wherein the compound is of Formula II:Formula II wherein,R1, R2, R3, X1, X2, X3, and — are as defined above;X4to X8are each independently selected from N, CH, and CR4, wherein at most 2 of X4toX8are N, and wherein R4is as defined in claim 1 ; and or a pharmaceutically acceptable salt or solvate thereof.

6. The compound of claim 5, wherein X4is N.

7. The compound of claim 5 or 6, wherein X6is CR4.

8. The compound of any one of claims 5 to 7, wherein X7is N.

9. The compound of any one of claims 5 to 7, wherein X7is CH.

10. The compound of claim 5 or 6, wherein X7is CR4.

11. The compound of any one of claims 5 to 10, wherein X5and X8are CH.

12. The compound of any one of claims 1 to 11 , wherein R4is N(R6)2.

13. The compound of claim 12, wherein R4is N(R6)2 and the two R6are taken together with their adjacent nitrogen atom to form an optionally substituted C4-C heterocycloalkyl or Cs- Ceheteroaryl.

14. The compound of claim 13, wherein the two R6are taken together with their adjacent nitrogen atom to form an optionally substituted C4-C heterocycloalkyl.

15. The compound of claim 14, wherein R4is selected from:wherein,R8is independently in each occurrence selected from halo, OH, OR5, CN, NO2, C(O)R5, OC(O)R6, C(O)OR6, C(O)N(R6)2, C(R7)=NR7, SO2R5, SO2N(R6)2, N(R7)C(O)R5, N(R7)C(O)OR5, N(R7)SO2R5, N(R7)C(O)N(R6)2, N(R7)SO2N(R6)2, N(R6)2, P(O)(R6)2, P(O)(OR6)2, B(OR6)2, and optionally substituted Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, Cearyl, C5- eheteroaryl, Cs-ecycloalkyl, and Cs-eheterocycloalkyl groups, or two R8on the same carbon are taken together to form an oxo or a spiro Cs-scycloalkyl or Cs-sheterocycloalkyl group;R9is selected from H, C(O)R5, C(O)OR6, C(O)N(R6)2, C(R7)=NR7, SO2R5, SO2N(R6)2, and optionally substituted Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, Cearyl, Cs-eheteroaryl, C3- ecycloalkyl, and Cs-eheterocycloalkyl groups, preferably R9is SO2R5;R5, R6, and R7are as previously defined;p is an integer selected from 0 to 3; m is between 1 and 4; and(— ) represents a bond.

16. The compound of claim 15, wherein R8is independently selected from OH, OR5, and optionally substituted Ci-ealkyl.

17. The compound of claim 15, wherein two R8are taken together with an adjacent carbon atom to form an oxo or a spiro Cs-scycloalkyl or Cs-sheterocycloalkyl group.

18. The compound of any one of claims 1 to 11 , wherein R4is selected from a halo, N(R7)C(O)R5, N(R7)C(O)OR5, and optionally substituted Ci-salkyl and Cs-yheterocycloalkyl groups.

19. The compound of any one of claims 1 to 12, wherein the compound is of Formula III:Formula III wherein, A, R1, R2, R3, R8, X1, X2, X3, m, p, and — - are as defined above; andX9is selected from CH2, CHR8, C(R8)2, and an optionally substituted heteroatom; or a pharmaceutically acceptable salt or solvate thereof.

20. The compound of claim 19, wherein the X9is selected from CH2, S, S=O, O, or CH2NR9, wherein R9is as defined above.

21. The compound of any one of clams 1 to 20, wherein - — is a double bond in each occurrence.

22. The compound of any one of clams 1 to 21 , wherein R1is selected from N(R6)2, N(R7)C(O)R5, N(R7)C(O)OR5, N(R7)SO2R5, N(R7)C(O)N(R6)2, and N(R7)SO2N(R6)2.

23. The compound of claim 22, wherein R2is H or R2is absent and X2is N.

24. The compound of any one of clams 1 to 21 , wherein R2is selected from N(R6)2, N(R7)C(O)R5, N(R7)C(O)OR5, N(R7)SO2R5, N(R7)C(O)N(R6)2, and N(R7)SO2N(R6)2.

25. The compound of claim 24, wherein R1is H or R1is absent and X1is N.

26. The compound of any one of claims 1 to 25, wherein R3is selected from H, halo, OH, OR5, ON, NH2, and optionally substituted Ci-salkyl, C2-8alkenyl, C2-8alkynyl, Ce- aryl, Cs- wheteroaryl, Cs- cycloalkyl, or Cs-wheterocycloalkyl.

27. The compound of claim 1 , wherein the compound is of Formula IV:Formula IV wherein,X9is an optionally substituted heteroatom or CH2;R8is independently in each occurrence selected from halo, OH, OR5, ON, NO2, C(O) R5, OC(O)R6, C(O)OR6, C(O)N(R6)2, C(R7)=NR7, SO2R5, SO2N(R6)2, N(R7)C(O)R5, N(R7)C(O)OR5, N(R7)SO2R5, N(R7)C(O)N(R6)2, N(R7)SO2N(R6)2, N(R6)2, P(O)(R6)2, P(O)(OR6)2, B(OR6)2, and optionally substituted Ci-ealkyl, C2-6alkenyl, C2-6alkynyl, Cearyl, Cs- eheteroaryl, Cs-ecycloalkyl, and Cs-eheterocycloalkyl groups, or two R8on adjacent carbonatoms are taken together to form a Cs-eheterocycloalkyl group or two R8on non-adjacent carbon atoms are taken together to form a 6-8 membered bicyclic group, or two R8on a same carbon atom are taken together to form an oxo, a spiro Cs-scycloalkyl group or a spiro Cs-eheterocycloalkyl group;R5, R6, and R7are as previously defined; q is an integer selected from 0 to 3; and r is between 0 and 4.

28. The compound of claim 27, wherein:X9is S, S=O, NR9, O, or CH2; andR9is Ci-ealkyl, phenol, Cs-eheterocycloalkyl group or Cs-eheteroaryl group optionally substituted with CH3.

29. The compound of claim 27 or 28, wherein R8is independently in each occurrence selected from F, OH, CN, CH2CN, CH2F, CH2OH, CH2OCH3, CH3, C(CH3)2OH, NH(C=O)CH3, SO2CHS, phenyl, phenol, C4-6heterocycloalkyl group and Ceheteroaryl group optionally substituted with CH3, or two R10on adjacent carbon atoms are taken together to form a Csheterocycloalkyl group, or two R10on non-adjacent carbon atoms are taken together to form a 8-membered bicyclic group, or two R10on a same carbon atom are taken together to form an oxo or a spiro C4-6heterocycloalkyl group, or two R10on a same sulfur atom are taken together to form an oxo.

30. The compound of claim 1 , wherein said compound is selected from Compounds 1 to 138 as defined herein, or a salt and / or solvate thereof.

31. The compound of claim 30, wherein said compound is selected from Compounds 4, 7, 8, 10, 11 , 13 to 15, 17, 18, 20, 21 , 23 to 50, and 52 to 80 as defined herein, or a salt and / or solvate thereof.

32. The compound of claim 30, wherein said compound is selected from Compounds 1 , 4, 6, 10, 11 , 13 to 17, 21 to 24, 37, 39 to 41 , 43, 47, 48, 50 to 53, 58, 60, 62, 64 to 66, 69, and 72 to 74 as defined herein, or a salt and / or solvate thereof.

33. The compound of claim 30, wherein said compound is selected from Compounds 4, 10, 11, 13 to 15, 17, 21, 23, 24, 37, 39 to 41 , 43, 47, 48, 50, 52, 53, 58, 60, 62, 64 to 66, 69, and 72 to 74 as defined herein, or a salt and / or solvate thereof.

34. The compound of claim 30, wherein said compound is selected from Compounds 82 to 119, 121 to 123, 125 to 128 and 130 to 138.

35. The compound of claim 30, wherein said compound is selected from Compounds 50, 89, 90, 100, 111, 121, 122, 123, 125, 128, 130, 131 and 136.

36. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 35, together with a pharmaceutically acceptable carrier, diluent or excipient.

37. Use of a compound as defined in any one of claims 1 to 35 for the treatment of a proliferative disease or disorder.

38. The use of claim 37, wherein said disease or disorder is a neoplasm.

39. The use of claim 38, wherein said neoplasm is selected from melanoma, thyroid carcinoma, colorectal, ovarian, breast cancer, endometrial cancer, liver cancer, sarcoma, stomach cancer, pancreatic carcinoma, adenocarcinoma, glioma, lung cancer, head and neck cancer, myelodysplastic syndrome, leukemia, and lymphoma.

40. The use of claim 39, wherein said neoplasm is selected from leukemia, lymphoma, myelodysplastic syndrome (MDS), melanoma, and breast cancer.

41. The use of claim 40, wherein said leukemia is selected from acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloblastic leukemia.

42. Use of a compound as defined in any one of claims 1 to 35 for inhibiting tumor growth, and / or inducing tumor cell death, and / or treating of cancer.

43. Use of a compound as defined in any one of claims 1 to 35 for inhibiting tumor growth, and / or inducing tumor cell death, and / or treating cancer, wherein said inhibiting tumor growth, and / or inducing tumor cell death, and / or treating cancer comprising inducing cuproptosis.

44. The use of claim 42 or 43, wherein cells of said tumor or cancer present iron-sulfur cluster (ISC) deficiency.

45. The use of any one of claims 42 to 44, wherein said tumor or cancer is selected from leukemia, lymphoma, myelodysplastic syndrome (MDS), melanoma, neuroblastoma, pancreatic cancer, prostate cancer, prolactinoma, and breast cancer.

46. The use of claim 45, wherein said leukemia is selected from acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloblastic leukemia.

47. Use of a copper ionophore for the treatment of an SF3B 7-mutated cancer.

48. The use of claim 47, wherein said cancer is selected from MDS subtype characterized by ring sideroblasts (MDS-RARS), solid tumors such as pigmented tumors, including uveal melanoma (UM), mucosal melanoma, leptomeningeal melanoma, blue nevus-like cutaneous melanoma, neuroblastomas that arise following chromothripsis, estrogen receptor-positive breast cancers (BC), pancreatic ductal adenocarcinoma, prostate cancer, prolactinomas, acute myeloid leukemia, and the like.

49. The use of claim 47 or 48, wherein said copper ionophore is a compound as defined in any one of claims 1 to 35.

50. Use of a compound as defined in any one of claims 1 to 35 for the treatment of human copper deficiency diseases.

51. The use of claim 50, wherein the human copper deficiency disease is Menkes disease.

52. Method for the treatment of a proliferative disease or disorder, comprising administering a compound as defined in any one of claims 1 to 35 to a subject in need thereof.

53. The method of claim 52, wherein said disease or disorder is a neoplasm.

54. The method of claim 53, wherein said neoplasm is selected from melanoma, thyroid carcinoma, colorectal, ovarian, breast cancer, endometrial cancer, liver cancer, sarcoma, stomach cancer, pancreatic carcinoma, adenocarcinoma, glioma, lung cancer, head and neck cancer, myelodysplastic syndrome, leukemia, and lymphoma.

55. The method of claim 54, wherein said neoplasm is selected from leukemia, lymphoma, myelodysplastic syndrome (MDS), melanoma, and breast cancer.

56. The method of claim 55, wherein said leukemia is selected from acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloblastic leukemia.

57. Method for inhibiting tumor growth, and / or inducing tumor cell death, and / or treating of cancer, comprising administering a compound as defined in any one of claims 1 to 35 to a subject in need thereof.

58. Method for inhibiting tumor growth, and / or inducing tumor cell death, and / or treating cancer, comprising administering a compound as defined in any one of claims 1 to 35 to a subject in need thereof, wherein said inhibiting tumor growth, and / or inducing tumor cell death, and / or treating cancer comprise inducing cuproptosis.

59. The method of claim 57 or 58, wherein cells of said tumor or cancer present iron-sulfur cluster (ISC) deficiency.

60. The method of any one of claims 57 to 59, wherein said tumor or cancer is selected from leukemia, lymphoma, myelodysplastic syndrome (MDS), melanoma, neuroblastoma, pancreatic cancer, prostate cancer, prolactinoma, and breast cancer.

61. The method of claim 60, wherein said leukemia is selected from acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloblastic leukemia.

62. Method for the treatment of an SF3B 7-mutated cancer, comprising administering a copper ionophore to a subject in need thereof.

63. The method of claim 62, wherein said cancer is selected from MDS subtype characterized by ring sideroblasts (MDS-RARS), solid tumors such as pigmented tumors, including uveal melanoma (UM), mucosal melanoma, leptomeningeal melanoma, blue nevus-like cutaneous melanoma, neuroblastomas that arise following chromothripsis, estrogen receptor-positive breast cancers (BC), pancreatic ductal adenocarcinoma, prostate cancer, prolactinomas, acute myeloid leukemia, and the like.

64. The method of claim 62 or 63, wherein said copper ionophore is a compound as defined in any one of claims 1 to 35.

65. Method for the treatment of human copper deficiency diseases, comprising administering a compound as defined in any one of claims 1 to 35 to a subject in need thereof.

66. The method of claim 65, wherein the human copper deficiency diseases is Menkes disease.

Images