EP4629980A1 - Antimicrobial compounds - Google Patents

Antimicrobial compounds

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Publication number
EP4629980A1
EP4629980A1 EP23901388.1A EP23901388A EP4629980A1 EP 4629980 A1 EP4629980 A1 EP 4629980A1 EP 23901388 A EP23901388 A EP 23901388A EP 4629980 A1 EP4629980 A1 EP 4629980A1
Authority
EP
European Patent Office
Prior art keywords
mmol
group
tert
carbazol
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23901388.1A
Other languages
German (de)
French (fr)
Inventor
Ling Jong
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SRI International Inc
Original Assignee
SRI International Inc
Stanford Research Institute
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Filing date
Publication date
Application filed by SRI International Inc, Stanford Research Institute filed Critical SRI International Inc
Publication of EP4629980A1 publication Critical patent/EP4629980A1/en
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • LOXs Lipoxygenases
  • LTs inflammatory leukotrienes
  • HETEs hydroxyeicosatetraenoic acids
  • LOX inhibitors are known to be useful for the treatment of all kinds of LOXs-related inflammatory diseases, including neurodegenerative diseases, such as Alzheimer's disease; See, Haeggstrom, Chem.
  • the present invention is directed to overcoming the above-mentioned challenges and others related to compounds, including compounds that provide antimicrobial activity and/or are a LOX inhibitor.
  • ring A is a 5-7 membered heterocyclic ring or a 5-6 membered heteroaryl ring that is independently substituted with one to three R 1 groups, and wherein at least one of the 5-7 members of the heterocyclic ring or at least one of the 5-6 members of the heteroaryl ring is N;
  • ring B is a 5-6 membered heterocyclic ring, a 5-6 membered heteroaryl ring, a 6 membered aromatic ring, or a 6 membered cycloalkyl ring that is unsubstituted or independently substituted with up to four R 2 groups, and optionally wherein at least one of the 5-6 members of the heterocyclic ring or at least one of the 5-6 members of the heteroaryl ring is N;
  • ring C is a 6 membered aromatic ring that is unsubstituted or independently substituted with up to four R 3 groups; each R 1 group independently comprising
  • each R a and R b group is independently selected from the group consisting of: oxidized forms thereof.
  • the compound (of Formula I) is selected from the group consisting of:
  • the compound is configured to provide antimicrobial activity in cells in vitro and in situ.
  • the compound is configured to provide the antimicrobial activity against bacteria selected from the group consisting of: Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Enterococcus faecalis, Staphylococcus aureus, Serratia marcescens, Shigella dysenteriae, Enterobacter aerogenes, Salmonella paratyphi, and a combination thereof.
  • the compound is compound is configured to provide antimicrobial activity and inhibit a lipoxygenase (LOX) in cells in vitro and in situ.
  • the compound is configured to: provide the antimicrobial activity against bacteria selected from the group consisting of: Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Enterococcus faecalis, Staphylococcus aureus, Serratia marcescens, Shigella dysenteriae, Enterobacter aerogenes, Salmonella paratyphi, and a combination thereof; and/or inhibit the LOX selected from the group consisting of: 5-LOX, 15-LOX, and a combination thereof.
  • ring A is a 5 membered heterocyclic ring or a 5 membered heteroaryl ring that is substituted with one R 1 group
  • ring B is a 6 membered heterocyclic ring, a 6 membered heteroaryl ring, a 6 membered aromatic ring, or a 6 membered cycloalkyl ring that is unsubstituted or independently substituted with up to four R 2 groups
  • ring C is a 6 membered aromatic ring that is unsubstituted or independently substituted with up to four R 3 groups; each X independently comprising a C or N; the R 1 group comprising a H, a halo, C 1-6 alkyl, NH(CH 2 ) 1-6 R a , (CH 2 ) 1-6 R a, (CH 2 ) 1-6 NH-R a , NH(CH 2 ) 1- 6 R a R b
  • the R 1 group is selected from the group consisting of: , [0016] In some aspects, the R 1 group is selected from the group consisting of: [0017] In some aspects, each R 2 group is independently selected from the group consisting of: [0018] In some aspects, each R 3 group is independently selected from the group consisting of:
  • each R a and R b group is independently selected from the group consisting of: oxidized forms thereof.
  • the compound (of Formula II) is selected from the group consisting of:
  • the compound is configured to: provide an antimicrobial activity against bacteria selected from the group consisting of: Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Enterococcus faecalis, Staphylococcus aureus, Serratia marcescens, Shigella dysenteriae, Enterobacter aerogenes, Salmonella paratyphi, and a combination thereof; and/or inhibit a LOX in cells in vitro and in situ, the LOX being selected from the group consisting of: 5-LOX, 15-LOX, and a combination thereof.
  • ring A is a 6 membered heteroaryl ring that is independently substituted with one to three R 1 groups
  • ring B is a 6 membered heterocyclic ring, a 6 membered aromatic ring, or a 6 membered cycloalkyl ring that is unsubstituted or independently substituted with up to four R2 groups
  • ring C is a 6 membered aromatic ring that is unsubstituted or independently substituted with up to four R 3 groups
  • each X independently comprising a C or N
  • each R 1 group independently comprising a H, a halo, C 1-6 alkyl, NH(CH 2 ) 1-6 R a , (CH 2 ) 1-6 R a , (CH 2 ) 1-6 NH-R a , NH(CH 2 ) 1-6 R a R b , CH 2 NH(CH 2 ) 1-6 R a ,
  • each R 1 group is independently selected from the group consisting of: , [0024] In some aspects, each R 2 group is independently selected from the group consisting of: , [0025] In some aspects, each R 2 group is independently selected from the group consisting of: . [0026] In some aspects, each R 3 group is independently selected from the group consisting of:
  • each R 3 group is independently selected from the group consisting of: .
  • at least one R 3 group comprises NH bound to a 6 membered aromatic ring that is substituted with one to three Cl.
  • each R a and R b group is independently selected from the group consisting oxidized forms thereof.
  • each R a and R b group is independently selected from the group consisting of: , , , , , , , and oxidized forms thereof.
  • the compound (of Formula III) is selected from the group consisting of: , [0032] In some aspects, the compound is configured to: provide an antimicrobial activity against bacteria selected from the group consisting of: Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Enterococcus faecalis, Staphylococcus aureus, Serratia marcescens, Shigella dysenteriae, Enterobacter aerogenes, and Salmonella paratyphi and a combination thereof; and/or inhibit a LOX in cells in vitro and in situ, the LOX being selected from the group consisting of: 5-LOX, 15-LOX, and a combination thereof.
  • compounds show broad-spectrum antimicrobial activities against a panel of pathogens, such as Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Enterococcus faecalis, Staphylococcus aureus (including Methicillin-resistant Staphylococcus aureus), Serratia marcescens, Shigella dysenteriae, Enterobacter aerogenes, and Salmonella paratyphi.
  • pathogens such as Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Enterococcus faecalis, Staphylococcus aureus (including Methicillin-resistant Staphylococcus aureus), Serratia marcescens, Shigella dysenteriae, Enterobacter aerogenes, and Salmonella paratyphi.
  • LOX target
  • the various compounds inhibit LOX enzymes, such as: 1) 15- LOX, and 2) human 5-LOX, thereby providing reduced inflammation by hindering biosynthesis of harmful inflammatory leukotriene B4 (LTB4), which can complicate some infections, such as in sepsis.
  • the compounds, which provide antimicrobial activity have no LOX inhibiting activity.
  • the dual-activity inhibitors e.g., LOX inhibiting and antibacterial properties
  • MDR multidrug-resistant
  • the compounds provide the dual activity providing broad- spectrum bactericidal activity and anti-inflammatory properties.
  • the dual-activity compounds can target enzymes involved in bacterial infection and inflammatory diseases.
  • the dual-activity compounds can inhibit enzymes including, but not limited to LOX, involved in bacterial infections and inflammatory diseases.
  • the compounds can target any enzyme(s) involved in bacterial infections.
  • the compounds can target any enzyme(s) involved in inflammatory diseases.
  • a dash at the front or end of a chemical group is a matter of convenience to indicate the point of attachment to a parent moiety; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning.
  • a line drawn through a line in a chemical structure or a dashed line drawn through a line in a chemical structure indicates a point of attachment of a group.
  • a dashed line within a chemical structure indicates an optional bond.
  • Cx-y indicates that the following group has from x (e.g., 1) to y (e.g., 6) carbon atoms, one or more of which, in certain groups (e.g., heteroalkyl, heteroaryl, heteroarylalkyl, etc.), may be replaced with one or more heteroatoms or heteroatomic groups.
  • x e.g., 1 to y
  • y e.g., 6 carbon atoms
  • C1-6 alkyl indicates that the alkyl group has from 1 to 6 carbon atoms.
  • x-y membered rings wherein x and y are numerical ranges, such as “3-12 membered heterocyclyl”, refers to a ring containing x-y atoms (e.g., 3-12), of which up to half may be heteroatoms, such as N, O, S, P, and the remaining atoms are carbon. Also, certain commonly used alternative chemical names may or may not be used.
  • a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc.
  • a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc.
  • Alkyl refers to any group derived from a linear or branched saturated hydrocarbon.
  • Alkyl groups include, but are not limited to, methyl, ethyl, propyl such as propan-1-yl, propan-2-yl (iso- propyl), butyls such as butan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (iso-butyl), 2-methyl- propan-2-yl (t-butyl), pentyls, hexyls, octyls, and dectyls, among others.
  • an alkyl group has from 1 to 10 carbon atoms, for example from 1 to 6 carbon atoms, for example from 1 to 4 carbon atoms.
  • Alkenyl refers to any group derived from a straight or branched hydrocarbon with at least one carbon-carbon double bond. Alkenyl groups include, but are not limited to, ethenyl (vinyl), propenyl (allyl), 1-butenyl, and 1,3-butadienyl, among others. Unless otherwise specified, an alkenyl group has from 2 to 10 carbon atoms, for example from 2 to 6 carbon atoms, for example from 2 to 4 carbon atoms. [0043] “Alkynyl” refers to any group derived from a straight or branched hydrocarbon with at least one carbon-carbon triple bond and includes those groups having one triple bond and one double bond.
  • alkynyl groups include, but are not limited to, ethynyl (—CH ⁇ CH), propargyl (— CH2C ⁇ CH), and (E)-pent-3-en-1-ynyl, among others. Unless otherwise specified, an alkynyl group has from 2 to 10 carbon atoms, for example from 2 to 6 carbon atoms, for example from 2 to 4 carbon atoms.
  • Amino groups may also be substituted as described herein, such as with alkyl, carbonyl or other amino groups.
  • Alkylamino refers to an amino group substituted with one or two alkyl substituents (e.g., dimethylamino or propylamino).
  • Aromatic ring or “arenes” refers to an aromatic ring of carbon atoms. Unless otherwise specified, an aromatic ring can have between 3 to 20 or more carbon atoms, for example, between 3 to 10 carbon atoms or between 3 to 8 carbon atoms.
  • Aryl refers to any group derived from one or more aromatic rings, that is, a single aromatic ring, a bicyclic or a multicyclic ring system.
  • Aryl groups include, but are not limited to, those groups derived from acenaphthylene, anthracene, azulene, benzene, chrysene, a cyclopentadienyl anion, naphthalene, fluoranthene, fluorene, indane, perylene, phenalene, phenanthrene, and pyrene, among others.
  • Arylalkyl (also “aralkyl”) refers to any combination an aryl group and an alkyl group.
  • Arylalkyl groups include, but are not limited to, those groups derived from benzyl, tolyl, dimethylphenyl, 2-phenylethan-1-yl, and 2-naphthylmethyl, among others.
  • An arylalkyl group comprises from 1 to 30 carbon atoms, for example the alkyl group can comprise from 1 to 10 carbon atoms and the aryl group can comprise from 5 to 20 carbon atoms.
  • Carboxyl refers to —COOH.
  • Carbonyl refers to a carbon atom double bonded to an oxygen atom.
  • Cycloalkyl or “cycloalkyl ring” refers to a cyclic alkyl and alkenyl groups.
  • a cycloalkyl group can have one or more cyclic rings and includes fused and bridged groups that are fully saturated or partially unsaturated. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, methylcycloproyl (cyclopropylmethyl), ethylcyclopropyl, and cyclohexenyl, among others. Another example includes C5-7 cycloakenyl.
  • Cycloalkyl-aryl refers to a cycloalkyl ring bonded to an aryl ring. Cycloalkyl is defined above as is the term ‘Aryl’. Examples include, but are not limited to, 2,3-dihydro-1H-indene and 1,2,3,4-tetrahydronaphthalene.
  • “Halo” and “halogen” refer to fluoro, chloro, bromo, and iodo.
  • Haloalkyl refers to an alkyl wherein one or more hydrogen atoms are each replaced by a halogen.
  • Examples include, but are not limited to, —CH 2 Cl, —CH 2 F, —CH 2 Br, —CFClBr, — CH 2 CH 2 Cl, —CH 2 CH 2 F, —CF 3 , —CH 2 CF 3 , and —CH 2 CCl 3 , among others, as well as alkyl groups, such as perfluoroalkyl in which all hydrogen atoms are replaced by fluorine atoms.
  • “Hydroxyalkyl” refers to an alkyl wherein one or more hydrogen atoms are each replaced by a hydroxyl group. Examples include, but are not limited to, —CH2OH, —CH 2 CH 2 OH, and — C(CH3)2OH, among others.
  • Heteroalkyl refers to an alkyl in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatom or heteroatomic group.
  • Heteroatoms include, but are not limited to, N, P, O, S, etc.
  • Heteroatomic groups include, but are not limited to, —NR—, —O—, —S—, —PH—, —P(O) 2 —, —S(O)—, and — S(O) 2 —, among others, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or cycloheteroalkyl.
  • Heteroalkyl groups include, but are not limited to, —OCH 3 , —CH 2 OCH 3 , —SCH 3 , —CH 2 SCH 3 , —NRCH 3 , —CH 2 NRCH 3 , and —CH 2 OH, among others, where R is H, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted.
  • a heteroalkyl group can comprise from 1 to 10 carbon and up to three hetero atoms, e.g., from 1 to 6 carbon and from 1 to 2 hetero atoms.
  • Heteroaryl refers to mono or multicyclic aryl group in which one or more of the aromatic carbon atoms (and associated hydrogen atoms) are independently replaced with the same or different heteroatom or heteroatomic group, as defined above. Multicyclic ring systems are included in heteroaryl and may be attached at the ring with the heteroatom or the aryl ring.
  • Heteroaryl groups include, but are not limited to, groups derived from acridine, benzoimidazole, benzothiophene, benzofuran, benzoxazole, benzothiazole, carbazole, carboline, cinnoline, furan, imidazole, imidazopyridine, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline
  • Heteroaryl groups may have between 3 to 14 members, 3 to 10 members, or 3 to 6 members, among others.
  • “Heterocycle,” “heterocyclic ring,” and “heterocyclyl” refer to a saturated or partially unsaturated non-aromatic ring or a partially non-aromatic multiple-ring system with at least one heteroatom or heteroatomic group, as defined above.
  • Heterocycles include, but are not limited to, groups derived from azetidine, aziridine, imidazolidine, morpholine, thiomorpholine, tetrahydro-2H- thiopyran, 1-iminotetrahydro-2H-thiopyran 1-oxide, oxirane (epoxide), oxetane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, N-bromopyrrolidine, and N-chloropiperidine, among others.
  • Heterocyclyl groups also include partially unsaturated ring systems containing one or more double bonds, including fused ring systems with one aromatic ring and one non-aromatic ring, but not fully aromatic ring systems.
  • Examples include dihydroquinolines, e.g., 3,4-dihydroquinoline, dihydroisoquinolines, e.g., 1,2-dihydroisoquinoline, dihydroimidazole, tetrahydroimidazole, etc., indoline, isoindoline, isoindolones (e.g., isoindolin-1-one), isatin, dihydrophthalazine, quinolinone, and spiro[cyclopropane-1,1′-isoindolin]-3′-one, among others.
  • dihydroquinolines e.g., 3,4-dihydroquinoline
  • dihydroisoquinolines e.g., 1,2-dihydroisoquino
  • Heterocycle groups may have between 3 to 12 members, 3 to 10 members, 3 to 7 members, or 5 to 6 members, among others. Other examples include cyclopente-type rings.
  • “Hydroxyl” and “hydroxy” are used interchangeably and refer to —OH.
  • Nirile refers to —C ⁇ N or any group containing a carbon atom triple bonded to a nitrogen atom.
  • R and R can be any group, such as H or other groups.
  • hydroxyalkyl refers to a hydroxyl group attached to an alkyl group. A number of such combinations may be readily envisaged.
  • substituent combinations used herein include: C 1-6 alkylamiocarbonyl (e.g., CH 3 CH 2 NHC(O)—) C 1-6 alkoxycarbonyl (e.g., CH 3 O—C(O)—), 5-7 membered heterocyclyl-C 1-6 alkyl (e.g., piperazinyl-CH 2 —), C 1-6 alkylsulfonyl- 5-7 membered heterocyclyl (e.g., CH 3 S(O) 2 - morpholinyl-), 5-7 membered heterocyclyl C 1-6 alkoxy (e.g., pyrrolidinyl-O—), 5-7 membered heterocyclyloxy, (4-7 membered heterocyclyl)- 4-7 membered heterocyclyl (e.g., oxetanyl- pyrrolidinyl-), C 3-6 cycloalkylaminocarbonyl (e.g., cyclopropyl-NH
  • the present disclosure includes both racemic mixtures of a compound of the disclosed formulas and isolated isomers or any variation thereof. Where more than one chiral center is present in a compound of the present disclosure, some, none, or all of the chiral centers may be enantiomerically enriched. Thus, mixtures of a compound of the disclosed formulas may be racemic with respect to one or more chiral centers and/or enantiomerically enriched with respect to one or more chiral centers.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound that is pharmaceutically acceptable and that possesses (or can be converted to a form that possesses) the desired pharmacological activity of the parent compound.
  • Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, among others; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2- napththalenesulfonic acid, oleic acid, palmitic acid, propionic acid, stearic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, among others, and salts formed when an acidic proton present in the parent compound is replaced by either a metal ion, e.g., an alkali metal ion, an alkaline earth
  • ammonium and substituted or quaternized ammonium salts are also included.
  • Representative non-limiting examples of pharmaceutically acceptable salts can be found in S. M. Berge et al., J. Pharma Sci., 66(1), 1-19 (1977), and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, Pa., (2005), at p.732, Table 38-5, both of which are hereby incorporated by reference in their entireties for their teachings.
  • “hydrogen” and “H”, “oxygen” and “O”, “carbon” and “C”, “F” and “fluorine”, “Cl” and “chlorine”, “S” and “sulfur”, and “nitrogen” and “N” are interchangeably used, and each respectively refer to a hydrogen atom, an oxygen atom, a carbon atom, a fluorine atom, a chlorine atom, a sulfur atom, and/or a nitrogen atom.
  • the rings of various compounds are sometimes interchangeably referred to as “ring A” or “A” and “ring B” or “B”, both of which respectively refer to the specifically referenced ring.
  • Subject and “subjects” refers to humans, domestic animals (e.g., dogs and cats), farm animals (e.g., cattle, horses, sheep, goats and pigs), and laboratory animals (e.g., mice, rats, hamsters, guinea pigs, pigs, pocket pets, rabbits, dogs, and monkeys), among others.
  • domestic animals e.g., dogs and cats
  • farm animals e.g., cattle, horses, sheep, goats and pigs
  • laboratory animals e.g., mice, rats, hamsters, guinea pigs, pigs, pocket pets, rabbits, dogs, and monkeys
  • Treating” and “treatment” of a disease include the following: (1) preventing or reducing the risk of developing the disease, e.g., causing the clinical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease, (2) inhibiting the disease, e.g., arresting or reducing the development of the disease or its clinical symptoms, or (3) relieving the disease, e.g., causing regression of the disease or its clinical symptoms.
  • Effective amount refers to an amount that may be effective to elicit the desired biological, clinical, or medical response, including the amount of a compound that, when administered to a subject for treating a disease, is sufficient to affect such treatment.
  • the effective amount will vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject to be treated.
  • the effective amount can include a range of amounts.
  • “Antimicrobial” or “antimicrobial agent” refers to a compound which kills, inactivates, or slows the growth of a microbe.
  • microbes include bacteria, viruses, fungi, and parasites.
  • the disclosed compounds may be antibacterial agents, which is a compound that kills or prevents growth of bacteria.
  • the compounds of the invention include solvates, hydrates, tautomers, stereoisomers and salt forms thereof.
  • n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom, or tritiated with a tritium atom, in which n is the number of hydrogen atoms in the molecule.
  • the deuterium atom is a non-radioactive isotope of the hydrogen atom and tritium is a radioactive isotope.
  • Such compounds, particularly deuterated compounds may increase resistance to metabolism, and thus may be useful for increasing the half-life of the compounds when administered to a mammal. See, e.g., Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol.
  • compositions of compounds of the disclosed formulas may be administered in single or multiple doses by any accepted modes of administration of agents having similar utilities, for example as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.
  • the compounds described herein may be administered orally. Oral administration may be via, for example, capsule or enteric coated tablets.
  • Oral administration may be via, for example, capsule or enteric coated tablets.
  • an excipient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propyl hydroxy-benzoates; sweetening agents; and flavoring agents.
  • compounds of Formula I have the following structure: Formula I [0078]
  • ring A is a 5-7 membered heterocyclic ring or a 5-6 membered heteroaryl ring that is independently substituted with one to three R 1 groups.
  • at least one of the 5-7 members of the heterocyclic ring or at least one of the 5-6 members of the heteroaryl ring is N, with the remaining members being C.
  • one of the 5-7 members of the heterocyclic ring or one of the 5-6 members of the heteroaryl ring is N.
  • two (or more) of the 5-7 members of the heterocyclic ring or two (or more) of the 5-6 members of the heteroaryl ring are N.
  • the ring A is independently substituted with three R 1 groups, two R 1 groups, or one R 1 group.
  • ring B is a 5-6 membered heterocyclic ring, a 5-6 membered heteroaryl ring, a 6 membered aromatic ring, or a 6 membered cycloalkyl ring that is unsubstituted or independently substituted with up to four R 2 groups.
  • At least one of the 5-6 members of the heterocyclic ring or at least one of the 5-6 members of the heteroaryl ring is N, with the remaining members being C.
  • one of the 5-6 members of the heterocyclic ring or one of the 5-6 members of the heteroaryl ring is N.
  • two (or more) of the 5-6 members of the heterocyclic ring or two (or more) of the 5-6 members of the heteroaryl ring are N.
  • 3 members or 4 members of ring B are N.
  • ring B is independently substituted with up to three R 2 groups.
  • ring B is independently substituted with four R 2 groups, three R 2 groups, two R 2 groups, one R 2 group, or is unsubstituted.
  • ring C is a 6 membered aromatic ring that is unsubstituted or independently substituted with up to four R 3 groups. In some embodiments, ring C is independently substituted with up to three R 3 groups. In some embodiments, ring C is independently substituted with four R 3 groups, three R 3 groups, two R 3 groups, one R 3 group, or is unsubstituted.
  • each R 1 group independently comprises a H, a halo, C 1-6 alkyl, NH(CH 2 ) 1-6 R a , (CH 2 ) 1-6 R a , (CH 2 ) 1-6 NH-R a , NH(CH 2 ) 1-6 R a R b , CH 2 NH(CH 2 ) 1-6 R a , or a 5-7 membered heterocyclic ring substituted with R a R b .
  • each R 1 group independently comprises a H, a halo, CH 3 , NH(CH 2 ) 2 R a , (CH 2 ) 2-3 R a , (CH 2 ) 2 NH-R a , NH(CH 2 ) 2 R a R b , CH 2 NH(CH 2 ) 2 R a , or a 5-7 membered heterocyclic ring substituted with R a R b .
  • at least one R 1 is H.
  • at least one R 1 group is a halo, such as Cl.
  • each R 1 group is selected from and/or is one of the following structures: , [0083]
  • each R 2 group independently comprises a H, a halo, C 1-6 alkyl, NH(CH 2 ) 1-6 R a , NHR a , (CH 2 ) 1-6 R a , R a , or C-(R a ) 3 .
  • each R 2 group independently comprises a H, a halo, NH(CH 2 ) 2 R a , NHR a , (CH 2 ) 1-2 R a , R a , or C-(R a ) 3 .
  • at least one R 2 group is H.
  • At least one R 2 group is a halo, such as Cl and/or F.
  • at least one R 2 group is or includes an aminoalkyl or a hydrocarbon containing an amine and an imine.
  • at least one R 2 group is CH 2 -dichlorophenyl.
  • at least one R 2 is NH-dichlorophenyl.
  • at least one R 2 group is trifluoromethyl or CF 3 .
  • each R 2 group is selected from and/or is one of the following structures: , [0085]
  • each R 3 group independently comprises a H, a halo, C 1-6 alkyl, NHR a, NHR a R b , NH(CH 2 ) 1-6 R a , O(CH 2 ) 1-6 R a , OR a , O(CH 2 ) 1-6 R a -(R b ) 2 , O(CH 2 ) 1-6 R a R b, (CH 2 ) 1-6 R a , (CH 2 ) 1-6 R a R b, R a R b , or R a.
  • each R 3 group independently comprises a halo, NHR a, NHR a R b , NH(CH 2 ) 1-2 R a , O(CH 2 ) 1-3 R a , OR a , O(CH 2 ) 2 R a -(R b ) 2 , O(CH 2 ) 2-3 R a R b, (CH 2 ) 1-3 R a , (CH 2 ) 2 R a R b, R a R b , or R a .
  • at least one R 3 group is CH 2 CH 3 .
  • at least one R 3 group is dichlorophenyl or chlorophenyl.
  • At least one R 3 group is NH- aromatic ring, NH-heteroaryl, NH-heterocycle, NH-aryl, NH-fused rings (e.g., heterocylic, aryl, and other rings), such as, but not limited to, NH-phenyl, NH-chlorophenyl, NH-dichlorophenyl, NH- chloroflurophenyl, NH-cyclohexyl, NH-dichlorofluorophenyl, NH-chloropyridine, NH-pyrazole, NH- imidazole, NH-imidazole substituted with CH 3 , NH-thiazole, NH-dichloropyridine, NH- chloropyridazine, NH-chloropyrimidine, NH-chlorobenzonitrile, and/or NH-dichlorobezothiazole.
  • NH-phenyl NH-chloropheny
  • At least one R 3 group is an O-alkylamine, such as, but not limited to, O- ethylamine, O-propylamine, and/or O-(CH 2 ) 2 -dimethlyamine.
  • at least one R 3 group is an O-alkyl-aryl, an O-alkyl-aromatic ring, an O-alkyl-heteroaryl, O-alkyl-heterocyclic ring, O-alkyl-cycloalkyl ring, O-heterocyclic ring, or an O-fused rings, such as, but not limited to, O- pyrrolidine, O-CH 2 -pyrrolidine, O-CH 2 -azetidine, O-CH 2 -piperidine, and/or O-(CH 2 ) 2 -piperazine.
  • at least one R 3 group is ethyl.
  • each R 3 group is selected from and/or is one of the following structures: ,
  • each R a and R b group independently comprise a halo, an amine, an imine, a carboxyl, a carbonyl, a hydroxyl, a thioamide, a nitrile, -O-alkyl, C 1-6 alkyl, C-(CH 3 ) 3 , a 5-6 membered aromatic ring (which is unsubstituted or substituted), a 5-6 membered cycloalkyl ring, or a 4-6 membered heterocyclic ring.
  • each R a and R b group independently comprise a halo, an amine, an imine, a carboxyl, a carbonyl, a hydroxyl, a thioamide, a nitrile, -O-CH 3 , CH 3 , C- (CH 3 ) 3 , a 5-6 membered aromatic ring, such as an aryl, a 5-6 membered cycloalkyl ring, or a 4-6 membered heterocyclic ring.
  • at least one R a and/or R b group is methyl.
  • at least one R a group and/or R b group is an amine.
  • at least one R a group and/or R b group is or includes a hydroxyl or a hydroxyalkyl, such as, but not limited to, OH or O-CH 3 .
  • at least one R a group and/or R b group is an aromatic ring (which is substituted or unsubstituted), a cycloalkyl ring, or a heterocyclic ring, such as, but not limited to, phenyl, chlorophenyl, dichlorophenyl, dichlorofluorophenyl, chlorofluorophenyl, cyclohexane, imidazoline, imidazoline further substituted with methyl, pyrrolidine, azetidine, piperidine, piperazine, pyrimidine, pyrimidine further substituted with chloro and/or an amine, chloropyridine, pyrazole, thiazole, dichloropyridine, oxetane, and/or chloropyridazine.
  • any of the disclosed compounds may be configured to provide antimicrobial activity such that compounds are antimicrobial agents.
  • the compounds are antibacterial agents.
  • any of the disclosed compounds may provide the antimicrobial activity against bacteria selected from the group consisting of: Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Enterococcus faecalis, Staphylococcus aureus (including Methicillin-resistant S. aureus), Serratia marcescens, Shigella dysenteriae, Enterobacter aerogenes, Salmonella paratyphi, and a combination thereof.
  • any of the disclosed compounds can be configured to inhibit LOX in cells, in vitro and in situ, which may be in addition to or alternative to the antimicrobial activity.
  • any of the disclosed compounds may inhibit 5-LOX and/or 15-LOX in cells in vitro and/or in situ.
  • any of the disclosure comound may provide antibacterial activated and inhibit LOX activity, and may be referred to as “dual-activity compounds”.
  • the compounds can provide the antimicrobial activity against bacteria selected from the group consisting of: Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Enterococcus faecalis, Staphylococcus aureus, Serratia marcescens, Shigella dysenteriae, Enterobacter aerogenes, Salmonella paratyphi, and a combination thereof, and inhibit LOX selected from the group consisting of 5-LOX, 15-LOX, and a combination thereof.
  • the compounds disclosed herein have the structure of Formula II, wherein Formula II is: Formula II [0094]
  • ring A is a 5 membered heterocyclic ring or a 5 membered heteroaryl ring that is substituted with one R 1 group.
  • ring B is a 6 membered heterocyclic ring, a 6 membered heteroaryl, a 6 membered aromatic ring, or a 6 membered cycloalkyl ring that is unsubstituted or independently substituted with up to four R 2 groups. In some embodiments, ring B is independently substituted with up to two R 2 groups.
  • ring B is independently substituted with four R 2 groups, three R 2 groups, two R 2 groups, one R 2 group, or is unsubstituted.
  • each X is independently a C or N.
  • two (or more) members of ring B are N.
  • one member of ring B is N.
  • three members of ring B are N.
  • four members of ring B are N.
  • ring C is a 6 membered aromatic ring that is unsubstituted or independently substituted with up to four R 3 groups.
  • ring C is independently substituted with up to three R 3 groups.
  • ring C is independently substituted with four R 3 groups, three R 3 groups, two R 3 groups, one R 3 group, or is unsubstituted.
  • the R 1 , R 2 , R 3 , R a , and/or R b groups of Formula II can include any of the previously described R 1 , R 2 , R 3 , R a , and/or R b groups of Formula I. The full details of which are not repeated.
  • the R 1 group comprises a H, a halo, C 1-6 alkyl, NH(CH 2 ) 1-6 R a , (CH 2 ) 1-6 R a, (CH 2 ) 1-6 NH-R a , NH(CH 2 ) 1-6 R a R b , CH 2 NH(CH 2 ) 1-6 R a , or a 5-7 membered heterocyclic ring substituted with R a R b .
  • the R 1 group is a H or (CH 2 ) 2-3 R a .
  • the R 1 group is selected from and/or is one of the following structures: , [00101] In some embodiments, the R 1 group is selected from and/or is one of the following structures: . [00102] In some example, each R 2 group independently comprises a H, a halo, C 1-6 alkyl, NH(CH 2 ) 1-6 R a , NHR a , or (CH 2 ) 1-6 R a , R a, or C-(R a ) 3.
  • each R 2 group independently comprises a H, a halo, NH(CH 2 ) 2 R a , NHR a , or (CH 2 ) 1-2 R a , or a R a .
  • each R 2 group is independently selected from and/or is one of the following structures: , or is independently selected from and/or is one of the following structures:
  • each R3 group independently comprises a H, a halo, C1-6 alkyl, NHR a, NHR a R b , NH(CH 2 ) 1-6 R a , O(CH 2 ) 1-6 R a ,OR a , O(CH 2 ) 1-6 R a -(R b ) 2 , O(CH 2 ) 1-6 R a R b, (CH 2 ) 1-6 R a , (CH 2 ) 1-6 R a R b, R a R b, or R a .
  • each R 3 group independently comprises a halo, NHR a, NHR a R b , NH(CH 2 ) 1-2 R a , O(CH 2 ) 1-3 R a ,OR a , O(CH 2 ) 2 R a -(R b ) 2 , O(CH 2 ) 2-3 R a R b, (CH 2 ) 1-3 R a , (CH 2 ) 2 R a R b, R a R b, or R a .
  • each R 3 group is selected from and/or is one of the
  • each R a and R b group independently comprises an amine, an imine, a carbonyl, a hydroxyl, a thioamide, a nitrile, -O-alkyl, C 1-6 alkyl, a 5-6 membered aromatic ring (which is unsubstituted or substituted), a 5-6 membered cycloalkyl ring, or a 4-6 membered heterocyclic ring.
  • each R a and R b group is selected from and/or is one of the following structures: , oxidized forms thereof, or is selected from and/or is one of the following structures: thereof.
  • the compound is selected from: C
  • the compounds disclosed herein have the structure of Formula III, wherein Formula III is: Formula III [00110]
  • ring A is a 6 membered heteroaryl ring that is independently substituted with one to three R 1 groups.
  • ring A is independently substituted with three R 1 groups, two R 1 groups, or one R 1 group.
  • ring B is a 6 membered heterocyclic ring, a 6 membered aromatic ring, or a 6 membered cycloalkyl ring that is unsubstituted or independently substituted with up to four R 2 groups.
  • ring B is independently substituted with up to two R 2 groups. In some embodiments, ring B is independently substituted with four R 2 groups, three R 2 groups, two R 2 groups, one R 2 group, or is unsubstituted.
  • each X independent comprises C or N. In some embodiments, one member or two members of ring B are N. While Formula III includes two X atoms in ring B, in some embodiments, ring B may include additional X atoms, such as illustrated by Formulas I and II.
  • ring C is a 6 membered aromatic ring that is unsubstituted or independently substituted with up to four R 3 groups.
  • ring C is independently substituted with one to three R 3 groups. In some embodiments, ring C is independently substituted with four R 3 groups, three R 3 groups, two R 3 groups, one R 3 group, or is unsubstituted.
  • the R 1 , R 2 , R 3 , R a , and/or R b groups of Formula III can include any of the previously described R 1 , R 2 , R 3 , R a , and/or R b groups of Formula I. The full details of which are not repeated.
  • each R 1 group independently comprises a H, a halo, C 1-6 alkyl, NH(CH 2 ) 1-6 R a , (CH 2 ) 1-6 R a , (CH 2 ) 1-6 NH-R a , NH(CH 2 ) 1-6 R a R b , CH 2 NH(CH 2 ) 1-6 R a , or a 5-7 membered heterocyclic ring substituted with R a R b .
  • each R 1 group independently comprises a halo, NH(CH 2 ) 2 R a , (CH 2 ) 2 R a , NH(CH 2 ) 2 R a R b , CH 2 NH(CH 2 ) 2 R a , or a 6 membered heterocyclic ring substituted with R a R b .
  • each R 1 group is independently selected from and/or is one of the following structures: , independently selected from and/or is one of the following structures: .
  • each R2 group independently comprises a H, a halo, C1-6 alkyl, NH(CH 2 ) 1-6 R a , NHR a , (CH 2 ) 1-6 R a , R a, or C-(R a ) 3 .
  • each R 2 group independently comprises a halo or C-(R a ) 3 .
  • each R 2 group is independently selected from and/or is one of the following structures: , .
  • each R 2 group is independently selected from and/or is one of the following structures: .
  • each R 3 group independently comprises a H, a halo, C 1-6 alkyl, NHR a , NHR a R b , NH(CH 2 ) 1-6 R a , O(CH 2 ) 1-6 R a , OR a , O(CH 2 ) 1-6 R a -(R b ) 2 , O(CH 2 ) 1-6 R a R b, (CH 2 ) 1-6 R a , (CH2)1-6RaRb, RaRb, or Ra.
  • at least one R3 group is NHRa.
  • At least one R 3 group (or the R 3 group) is NH bound to a 6 membered aromatic ring that is substituted with one to three Cl.
  • each R 3 group is independently selected from and/or is one of the following structures: , , [00122] In some embodiments, each R 3 group is independently selected from and/or is one of the following structures: .
  • each R a and R b group independently comprises a halo, an amine, an imine, a carboxyl, a carbonyl, a hydroxyl, a thioamide, a nitrile, -O-alkyl, C1-6 alkyl, C-(CH3)3, a 5- 6 membered aromatic ring, a 5-6 membered cycloalkyl ring, or a 4-6 membered heterocyclic ring.
  • each R a and R b group independently comprises a halo, an amine, an imine, a carboxyl, CH 3 , C-(CH 3 ) 3 , or a 6 membered aromatic ring which is unsubstituted or substituted.
  • each R a and R b group is selected from and/or is one of the following structures: , forms thereof.
  • each R a and R b group is selected from and/or is one of the following structures: , and oxidized forms thereof.
  • a compound having the structure of Formula III can be selected from:
  • Formula II and/or Formula III can include an implementations of Formula I.
  • Some embodiments are directed to methods of inhibiting a LOX and/or providing antimicrobial activity in cells determined to be in need thereof, comprising contacting the cells with (or administering to the cells) a compound having structure disclosed in any of the compounds above, where the cells are human cells that are either in vivo or isolated in vitro.
  • the cells are in situ as part of a person determined to be in need of LOX inhibition, microbe inhibition, or suffering from a disease associated with pathogenic LOX and/or microbe activity, such as a bacterial infection.
  • the antimicrobial activity is against a bacteria selected from: Acinetobacter baumannii (A. baumannii), Klebsiella pneumoniae (K. pneumoniae), Pseudomonas aeruginosa (P. aeruginosa), Escherichia coli (E. coli), Enterococcus faecalis (E. faecalis), Staphylococcus aureus (S. aureus), Serratia marcescens (S. marcescens), Shigella dysenteriae (S. dysenteriae), Enterobacter aerogenes (E. aerogenes), Salmonella paratyphi (S. paratyphi), and a combination thereof.
  • Acinetobacter baumannii A. baumannii
  • Klebsiella pneumoniae K. pneumoniae
  • Pseudomonas aeruginosa P. aeruginosa
  • Escherichia coli E. coli
  • the method includes inhibiting LOX of 5-LOX and/or 15- LOX.
  • the method includes providing antimicrobial activity against bacterial of A. baumannii, K. pneumoniae, P. aeruginosa, E. coli, E. faecalis, S. aureus (including Methicillin- resistant S. aureus), S. marcescens, S. dysenteriae, E. aerogenes, and S. paratyphi, and inhibiting LOX of 5-LOX and/or 15-LOX.
  • the disease when inhibiting LOX, can be selected from an acute or chronic inflammatory disease or a neurodegenerative disease.
  • Some of the methods further comprising: (i) measuring a lipoxygenase activity in a sample of the person; (ii) determining a level of a lipoxygenase metabolite in a sample of the person; or (iii) determining the person has the disease.
  • the disease is: (i) an acute or chronic inflammatory disease that is asthma, rheumatoid arthritis, inflammatory bowel disease, psoriasis, hereditary ichthyosis, dermatitis, nephritis, atherosclerosis, or cardiovascular disease, or (ii) a neurodegenerative disease that is age- related neurodegeneration, amyloid beta- associated disease, Alzheimer's Disease, ischemia-related disorder, creutzfeldt-jakob disease/prion peptide toxicity, ALS, dementia or Parkinson Disease.
  • an acute or chronic inflammatory disease that is asthma, rheumatoid arthritis, inflammatory bowel disease, psoriasis, hereditary ichthyosis, dermatitis, nephritis, atherosclerosis, or cardiovascular disease
  • a neurodegenerative disease that is age- related neurodegeneration, amyloid beta- associated disease, Alzheimer's Disease, ischemia-related disorder, creutzfeldt-ja
  • Embodiments include pharmaceutical compositions comprising a compound disclosed above for inhibiting LOX activity and/or providing antimicrobial activity, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Further conceived of are pharmaceutical compositions comprising compounds disclosed above for inhibiting lipoxygenase activity and/or inhibiting microbe (e.g., bacteria) activity, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Further embodiments include compositions comprising a compound of Formula I, Formula II, and/or Formula III and a second anti- neurodegenerative disease drug and/or antimicrobial drug.
  • compositions are directed to methods for identifying a LOX inhibitor and/or antimicrobial agent comprising the step of screening for LOX inhibitory activity and/or antimicrobial activity of the compound(s).
  • subject compounds can be used in pharmaceutically acceptable alternative forms, such as pharmaceutically acceptable salts, and prodrugs (e.g., sulfamates, phosphates, esters, ethers, amides, etc.), among others.
  • pharmaceutically acceptable and pharmaceutically active combinations of such forms, such as salts of prodrugs are within the scope of the disclosure.
  • Example salts and prodrugs are provided herein.
  • subject compounds are used to prepare a composition that is effective in treating neurodegenerative diseases (also referred to herein as “neurodegenerative conditions”) and/or treating a bacterial infection.
  • neurodegenerative diseases include neuroinflammation- associated neurodegeneration, Alzheimer's Disease, ischemia-related disorder, creutzfeldt-jakob disease/prion peptide toxicity, ALS, dementia, and Parkinson Disease.
  • treatment of a neurodegenerative disease involves administering a formulation containing a subject compound.
  • Example bacterial infections include infections from A. baumannii, K. pneumoniae, P. aeruginosa, E. coli, E. faecalis, S. aureus (including Methicillin-resistant S.
  • the composition may comprise one or more antimicrobial agents and one or more pharmaceutically acceptable additives.
  • the compositions may be formulated into any suitable dosage form.
  • the subject compositions contain a compound according to Formula I, Formula II, and/or Formula III as the sole active agent; such formulations may include pharmaceutically inactive components, such as carriers.
  • the compounds are administered in combination with one or more additional anti-neurodegenerative disease drug(s) and/or antimicrobial drugs.
  • the additional drug may be present with a subject compound in a single formulation, and therefore administered at the same time.
  • the additional drug may be in a separate formulation, and may be administered according to a regimen that is separate from the regimen for administration of the formulation containing a subject compounds.
  • the two regimens may be related; for example, the second formulation is administered along with, or immediately before, or immediately after administration of the first formulation.
  • additional anti-neurodegenerative disease drugs include acetylcholinesterase inhibitors (e.g., tacrine, rivastigmine, galantamine, donepezil, etc.), N- methyl-D-aspartate (NMDA) receptor antagonists (e.g., memantine), hyperzine A, latrepirdine, and hypothalamic proline-rich peptide 1 (PRP-1), among others.
  • acetylcholinesterase inhibitors e.g., tacrine, rivastigmine, galantamine, donepezil, etc.
  • NMDA N- methyl-D-aspartate
  • PRP-1 hypothalamic proline-rich peptide 1
  • additional antimicrobial drugs include various antibiotics, such as but not limited to cephalexin, amoxicillin, azithromycin, sulfamethoxazole, trimethoprim, metronidazole, and ciprofloxacin, among others.
  • the compounds may be administered as a free base, or in the form of a salt, ester, amide, prodrug, active metabolite, and an analog, among others, provided that the salt, prodrug, active metabolite or analog is pharmaceutically acceptable and pharmacologically active in the present context.
  • Salts, esters, amides, prodrugs, active metabolites, analogs, and other derivatives of the active agents may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, by J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 5th Ed. (New York: Wiley-Interscience, 2001), and Green, Protective Groups in Organic Synthesis, 3rd Ed.
  • a pharmaceutically acceptable salt may be prepared from any pharmaceutically acceptable organic acid or base, any pharmaceutically acceptable inorganic acid or base, or combinations thereof.
  • Suitable organic acids for preparing acid addition salts include, e.g., C 1 -C 6 alkyl and C 6 - C 12 aryl carboxylic acids, di-carboxylic acids, and tri-carboxylic acids such as acetic acid, propionic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, glycolic acid, citric acid, pyruvic acid, oxalic acid, malic acid, malonic acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, phthalic acid, and terephthalic acid, and aryl and alkyl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and p-toluenesulf
  • Suitable inorganic acids for preparing acid addition salts include, e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, among others.
  • An acid addition salt may be reconverted to the free base by treatment with a suitable base.
  • Suitable organic bases for preparing basic addition salts include, e.g., primary, secondary and tertiary amines, such as trimethylamine, triethylamine, tripropylamine, N,N- dibenzylethylenediamine, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, glucamine, glucosamine, histidine, and polyamine resins, cyclic amines such as caffeine, N-ethylmorpholine, N- ethylpiperidine, and purine, and salts of amines such as betaine, choline, and procaine, among others.
  • primary, secondary and tertiary amines such as trimethylamine, triethylamine, tripropylamine, N,N- dibenzylethylenediamine, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, glucamine, glucosamine, histidine, and polyamine resins, cyclic amine
  • Suitable inorganic bases for preparing basic addition salts include, e.g., salts derived from sodium, potassium, ammonium, calcium, ferric, ferrous, aluminum, lithium, magnesium, or zinc such as sodium hydroxide, potassium hydroxide, calcium carbonate, sodium carbonate, and potassium carbonate, among others.
  • a basic addition salt may be reconverted to the free acid by treatment with a suitable acid.
  • Prodrugs and active metabolites may be prepared using techniques known to those skilled in the art. Prodrugs are typically prepared by covalent attachment of a moiety that results in a compound that is therapeutically inactive until modified by an individual's metabolic system.
  • a compound according to Formula I, Formula II, and/or Formula III may be in the form of a pharmaceutically acceptable prodrug such as the sulfamate prodrug.
  • a pharmaceutically acceptable prodrug such as the sulfamate prodrug.
  • Other derivatives and analogs of the active agents may be prepared using standard techniques known to those skilled in the art of synthetic organic chemistry or may be deduced by reference to the pertinent literature.
  • Any of the compounds described herein may be the active agent in a subject formulation.
  • Formulations containing the compounds of the disclosure may include 1, 2, 3 or more of the subject compounds, and may also include one or more additional active agents such as analgesics and other antibiotics.
  • any of the compounds of the disclosure is meant any compound selected from a subject compound per se (e.g., as a free base) and salts, prodrugs, etc. thereof.
  • the amount of active agent in the formulation typically ranges from about 0.05 weight percent (wt%) to about 95 wt% based on the total weight of the formulation.
  • the amount of active agent may range from about 0.05 wt% to about 50 wt%, or from about 0.1 wt% to about 25 wt%.
  • the amount of active agent in the formulation may be measured so as to achieve a desired dose.
  • Formulations containing a subject compound may be presented in unit dose form or in multi-dose containers with an optional preservative to increase shelf life.
  • compositions of the present disclosure may be administered to the patient by any method.
  • both systemic and localized methods of administration are acceptable.
  • selection of a method of administration is influenced by factors, such as the condition being treated, frequency of administration, dosage level, and the wants and needs of the patient. For example, certain methods may be better suited for rapid delivery of high doses of active agent, while other methods may be better suited for slow, steady delivery of active agent.
  • methods of administration that are suitable for delivery of the compounds of the disclosure include parental and transmembrane absorption (including delivery via the digestive and respiratory tracts). Formulations suitable for delivery via these methods are well known in the art.
  • formulations containing the compounds of the present disclosure may be administered parenterally, such as via intravenous, subcutaneous, intraperitoneal, or intramuscular injection, using bolus injection and/or continuous infusion.
  • parenteral administration employs liquid formulations.
  • the compositions may also be administered via the digestive tract, including orally and rectally. Examples of formulations that are appropriate for administration via the digestive tract include tablets, capsules, pastilles, chewing gum, aqueous solutions, and suppositories.
  • the formulations may also be administered via transmucosal administration. Transmucosal delivery includes delivery via the oral (including buccal and sublingual), nasal, vaginal, and rectal mucosal membranes.
  • Formulations suitable for transmucosal deliver are well known in the art and include tablets, chewing gums, mouthwashes, lozenges, suppositories, gels, creams, liquids, and pastes.
  • the formulations may also be administered transdermally. Transdermal delivery may be accomplished using, for example, topically applied creams, liquids, pastes, and gels, among others, as well as what is referred to as transdermal “patches.” [00149]
  • the formulations may also be administered via the respiratory tract. Pulmonary delivery may be accomplished via oral or nasal inhalation, using aerosols, dry powders, and liquid formulations, among others. Aerosol inhalers and imitation cigarettes are examples of pulmonary dosage forms.
  • Liquid formulations include solutions, suspensions, and emulsions.
  • solutions may be aqueous solutions of the active agent and may include propylene glycol and/or polyethylene glycol, among others.
  • Aqueous suspensions can be made by dispersing the finely divided active agent in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other known suspending agents.
  • formulations of solid form which are intended to be converted, shortly before use, to liquid form.
  • Tablets and lozenges may comprise, for example, a flavored base such as compressed lactose, sucrose and acacia or tragacanth and an effective amount of an active agent.
  • Pastilles generally comprise the active agent in an inert base, such as gelatin and glycerine or sucrose and acacia.
  • the subject compounds may inhibit one or more LOX and/or reduce bacteria, e.g., by at least 50 percent (%), or by at least 75%, or by at least 85%, or by at least 95%, or by at least 98%.
  • the compounds are selective inhibitors, and are inhibitors of a subsection of the LOX family of enzymes and/or providing antibacterial activity.
  • the subject compounds may inhibit 5-LOX, or 15-LOX.
  • the subject compounds may inhibit various combinations of 5-LOX and 15-LOX, such as inhibiting 5-LOX, or inhibiting 15-LOX or inhibiting 5-LOX and 15-LOX.
  • the compounds provide antibacterial activity against A. baumannii, K. pneumoniae, P. aeruginosa, E. coli, E. faecalis, S. aureus (including Methicillin-resistant S. aureus), S. marcescens, S. dysenteriae, E. aerogenes, and/or S. paratyphi.
  • Subject compounds are useful in therapies for treating diseases associated with pathogenic lipoxygenase activity, particularly acute and chronic inflammatory diseases, such as asthma, rheumatoid arthritis, inflammatory bowel disease, psoriasis, hereditary ichthyosis, dermatitis, nephritis, atherosclerosis, cardiovascular diseases, neurodegenerative diseases, such as age-related neurodegeneration, neuroinflammation-associated disease, Alzheimer's Disease, ischemia-related disorder, creutzfeldt-jakob disease/prion peptide toxicity, ALS, dementia and Parkinson Disease.
  • Subject compounds are useful in therapies for treating diseases associated with bacterial infections, such as treating an infection from A. baumannii, K.
  • the compounds can be used to treat multiple types of bacterial infections concurrently in the same patient or in different patients.
  • the methods may involve administering a subject compound to a patient in need thereof (e.g., a patient suffering from bacterial infection, and/or a patient suffering from a neurodegenerative disease such as Alzheimer’s Disease, or a patient or a patient at risk for such conditions, or a patient exhibiting symptoms of such conditions, etc.).
  • the compound(s) are used in a method for reducing or eliminating the severity of symptoms associated with a subject disease.
  • the method may involve contacting nervous system cells or cells located in a nervous system, or contacting tissue associated with a nervous system, and such contacting results in one or more of the following: the inhibition of further neurodegeneration; the inhibition of abnormal cell growth and development; the inhibition of growth of non-cell objects in a nervous system; the reduction of neuroinflammation; the reduction in severity of symptoms associated with a neurodegenerative disease; inhibition of further bacterial growth or infection; the reduction in severity of symptoms associated with bacterial infection; among others and in various combinations.
  • the example compounds are used to prepare a composition that is effective in treating a subject disease.
  • the composition may comprise one or more active agents and one or more pharmaceutically acceptable additives. Furthermore, the compositions may be formulated into any suitable dosage form. [00157]
  • treatment of a subject disease involves administering a formulation containing a disclosed compound. As described herein, such formulations may include additives and/or additional active agents, and such formulations may be prepared in any of a variety of dosage forms.
  • treatment of a subject disease using a compound involves determining that the person has a subject disease associated with pathogenic LOX activity and/or bacterial infection. Such determination may be made by any means appropriate for the particular condition, including blood tests and imaging tests.
  • the methods involve measuring a LOX activity (such as 5-LOX, or 15-LOX, and/or various combinations thereof) and/or bacteria activity (such as in a patient prior to treatment with a subject compound, after treatment with a subject compound, or both prior to and after treatment.
  • a LOX activity such as 5-LOX, or 15-LOX, and/or various combinations thereof
  • bacteria activity such as in a patient prior to treatment with a subject compound, after treatment with a subject compound, or both prior to and after treatment.
  • the methods involve measuring a level of a LOX metabolite in a patient.
  • An example metabolite is 5-HETE.
  • measuring enzyme activity or measuring metabolite levels may be carried out using any appropriate sample from the person, such as a body fluid (e.g., blood, urine, etc.).
  • Some embodiments are directed to methods of forming (e.g., synthesizing) any of the above-disclosed compounds, such as those of Formula I, Formula II, and/or Formula III. Specific examples of forming the compounds are further provided below in the Experimental Embodiments. Methods of forming such compounds are not limited to the specific examples provided and may include variations. [00160] Various embodiments are implemented in accordance with the underlying Provisional Application (Ser. No.63/430,432), entitled “Antimicrobial Agents”, filed December 6, 2022, to which benefit is claimed and which is fully incorporated herein by reference for its general and specific teachings. For instance, embodiments herein and/or in the provisional application can be combined in varying degrees (including wholly).
  • the compounds were found to have antimicrobial activity against various bacteria.
  • the inhibitory activity of the compounds against a panel of bacteria was demonstrated in cell-based assays.
  • Such bacteria included: A. baumannii (ATCC AB 1605 multi-drug resistant), A. baumannii (ATCC BAA 1790 multi-drug resistant,) A. baumannii (ATCC BAA 1793 multi-drug resistant), K. pneumoniae (ATCC 43816), P. aeruginosa (ATCC 27853), E. coli (ATCC 25922 pan sensitive), E.
  • Table 1 and Table 2 provide the MIC values for various compounds against bacteria: Table 1
  • the enzyme assay (100 microliter ( ⁇ L)) contained 50 milli-molarity (mM) Tris, pH 7.5, 0.1 mM EDTA, 0.3 mM CaCl2, 20 micro-molarity ( ⁇ M) AA, 100 ⁇ M ATP, 1 ⁇ M DHR123, and recombinant 5-LOX cell lysate (0.5 ⁇ L/100 ⁇ L).
  • Inhibitors (dissolved in DMSO) were plated at 1 ⁇ L into 96-well assay microplates followed by a 40 ⁇ L addition of a solution containing 5-LOX enzyme. Enzyme was pre-incubated with compounds for 15 minutes.
  • the assay was initiated by the addition of a 40 ⁇ L substrate solution containing AA and ATP, and 20 ⁇ L addition of a solution containing DHR123. Enzymatic reaction proceeded for 30 minutes with kinetic reading at 500 nanometer (nm) excitation and 536 nm emission in SpectraMax Paradigm (MolecularDevice). Percent inhibition was calculated for each compound dose for IC50 curve fitting using 4 Parameter Logistic Model or Sigmoidal Dose-Response Model.
  • the enzyme assay (100 ⁇ L) contained 50 mM Tris, pH 7.5, 0.05% Tween-20, 20 ⁇ M AA/LA, 1 ⁇ M DHR123, and 50 nanomolarity (nM) recombinant 15-LOX enzyme.
  • Inhibitors (dissolved in DMSO) were plated at 1 ⁇ L into 96-well assay microplates followed by a 40 ⁇ L addition of a solution containing 15-LOX enzyme. Enzyme was pre-incubated with compounds for 15 minutes. The assay was initiated by the addition of a 40 ⁇ L substrate solution containing AA/LA, and 20 ⁇ L addition of a solution containing DHR123.
  • Enzymatic reaction proceeded for 30 minutes with kinetic reading at 500 nm excitation and 536 nm emission in SpectraMax Paradigm (MolecularDevice). Percent inhibition was calculated for each compound dose for IC50 curve fitting using 4 Parameter Logistic Model or Sigmoidal Dose-Response Model. Inhibitory activity against a panel of LOXs was demonstrated in cell-based assays, e.g., for 5-LOX, a fluorescence-based enzyme assay of human 5- LOX (Anal. Biochem., 364:204.) was used, and for 5-LOX, a colorimetric method to determine platelet 15-LOX activity (Anal. Biochem., 231:354) was used. Table 3 provides results for compounds on 5-LOX and 15-LOX. Table 3: IC50 ( ⁇ M) values for in vitro lipoxygenase inhibition
  • reaction solution was degassed and purged with N 2 for 5-10 minutes and then heated at 90 degrees Celsius ( ° C) overnight.
  • Example 2 [00190] Example Route for Example 2 (SRI-32468): [00191] The synthesis of6-Chloro-N 4 -(2-(6-chloro-3-((4-chlorophenyl)amino)-9H-carbazol-1- yl)ethyl)pyrimidine-2,4-diamine (SRI-32468): 1-(2-aminoethyl)-6-chloro-N-(4-chlorophenyl)-9H- carbazol-3-amine (42 mg, 0.087 mmol), 4,6-dichloropyrimidin-2-amine (29 mg, 0.177 mmol) and Et 3 N (27 mg, 0.267 mmol) in DMF (2 mL) was stirred at 90 °C for overnight.
  • Example 3 [00194] Example Route for Example [00195] The synthesis of 1-(2-(6-Chloro-3-((4-chlorophenyl)amino)-9H-carbazol-1-yl)ethyl)-3- methylguanidine (SRI-32469): 1-(2-aminoethyl)-6-chloro-N-(4-chlorophenyl)-9H-carbazol-3-amine (30 mg, 0.081 mmol), methyl methylcarbamimidothioate hydroiodide (38 mg, 0.164 mmol) and Et 3 N (41 mg, 0.41 mmol) in THF (9 mL) was stirred at room temperature for overnight.
  • Example 4 [00198] Example Route for Example 4 (SRI-32470): [00199] The synthesis of N-(2-(6-Chloro-3-((4-chlorophenyl)amino)-9H-carbazol-1- yl)ethyl)cyanamide (3a): Cyanogen bromide (29 mg, 0.27 mmol) in dichloromethane (1 mL) was added to a solution of 1-(2- aminoethyl)-6-chloro-N-(4-chlorophenyl)-9H-carbazol-3-amine (100 mg, 0.27 mmol) and sodium acetate (111 mg, 1.35 mmol) in methanol (2 mL) drop wise at 0 °C.
  • Example 7 [00212] The synthesis of 1-(Pyrimidin-2-yl)thiourea (11-3): Pyrimidin-2-amine (1.0 g, 10.51 mmol) and benzoyl isothiocyanate (1.89 g, 11.57 mmol) in acetone (20 mL) was heated to reflux for 4 hours. The reaction mixture was cooled down to room temperature and diluted with water. The resulting solid was collected by filtration. The cake was dissolved in methanol (50 mL) and 1 N NaOH (25 mL). After stirring at 85 °C for 1 hour, the reaction was cooled down to room temperature and diluted with water. The resulting solid was collected by filtration.
  • Example 8 [00218] The synthesis of 1-(2-(6-Chloro-3-((4-chlorophenyl)amino)-9H-carbazol-1-yl)ethyl)-3- methoxyguanidine (SRI-32488): A mixture of N-(2-(6-chloro-3-((4-chlorophenyl)amino)-9H- carbazol-1-yl)ethyl)cyanamide (31 mg, 0.078 mmol), O-methylhydroxylamine hydrochloride (131 mg, 1.57 mmol) and potassium carbonate (1.1 mg, 0.0078 mmol) in tert-butanol (2 mL) was stirred at reflux for 2 hours.
  • Example 13 [00265] Example Route for Example 13 (SRI-33110): [00266] The synthesis of tert-Butyl (2-(6-chloro-3-((5-chloropyridin-2-yl)amino)-9-tosyl-9H- carbazol-1-yl)ethyl)carbamate (18-1): tert-butyl (2-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)ethyl)carbamate (300 mg, 0.52 mmol), 5- chloropyridin-2-amine (67 mg, 0.52 mmol), tris(dibenzylideneacetone)dipalladium(0) (91 mg, 0.1 mmol), Xant-Phos (75 mg, 0.13 mmol) and potassium phosphate (331 mg, 1.56 mmol) were dissolved in
  • Example 16 [00291] Example Route for Example 16 (SRI-33114): [00292] The synthesis of tert-Butyl 2-(6-chloro-3-(thiazol-2-ylamino)-9-tosyl-9H-carbazol-1- yl)ethylcarbamate tert-butyl 2-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)ethylcarbamate (135 mg, 0.23 mmol), thiazol-2-amine (24 mg, 0.23 mmol), tris(dibenzylideneacetone)dipalladium(0) (33 mg, 0.045 mmol), tert-butylbrettphos (45 mg, 0.09 mmol), potassium carbonate (65 mg, 0.47 mmol) and acetic acid (1 drop) were dissolved in tert
  • Example 20 [00323] The synthesis of tert-Butyl 4-nitro-1H-pyrazole-1-carboxylate (24-a): To a stirred mixture of 4-nitro-1H-pyrazole (2.1 g, 18.57 mmol) and DMAP (230 mg, 1.88 mmol) in DCM (210 mL) was added di-tert-butyl dicarbonate (4.86 g, 22.27 mmol) and the resulting solution was stirred at room temperature overnight. The reaction solution was washed with 1N HCl, brine and dried over Na 2 SO 4.
  • Example 23 [00349] The synthesis of tert-Butyl (2-(6-chloro-3-((3,4-dichlorobenzyl)amino)-9-tosyl-9H- carbazol-1-yl)ethyl)carbamate (33-1): tert-butyl (2-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1- yl)ethyl)carbamate (125 mg, 0.22 mmol), (3,4-dichlorophenyl)methanamine (115 mg, 0.65 mmol), tris(dibenzylideneacetone)dipalladium(0) (40 mg, 0.044 mmol), tert-butylbrettphos (27 mg, 0.056 mmol), potassium carbonate (90 mg, 0.65 mmol) and acetic acid (1 drop) were dissolved in tert- butanol (5 mL).
  • Example 24 [00357] The synthesis of tert-Butyl (2-(6-chloro-3-((5,6-dichloropyridin-3-yl)amino)-9-tosyl-9H- carbazol-1-yl)ethyl)carbamate (37-1): l - - tert-butyl (2-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)ethyl)carbamate (250 mg, 0.43 mmol), 5,6- dichloropyridin-3-amine (71 mg, 0.43 mmol), tris(dibenzylideneacetone)dipalladium(0) (79 mg, 0.086 mmol), Xant-Phos (62 mg, 0.11 mmol) and potassium phosphate (274 mg, 1.29 mmol) were dissolved in 1,4
  • Example 28 [00395] The synthesis of Ethyl 3,4-dichlorobenzimidate hydrochloride (35-2): A solution of 3,4- dichlorobenzonitrile (1.0 g, 5.81 mmol) and HCl (1 mL, 2M in ethanol) in HCl (10 mL, 4M in 1,4- dioxane) was stirred at room temperature overnight. The reaction solution was concentrated and washed with ethyl acetate to give 811 mg of title compound in 55% yield as a white solid. MS: (ESI) m/z 218.0 (M + H) + .
  • Example 29 [00404] The synthesis of 2-(3,5-Dibromobenzyl)isoindoline-1,3-dione (42-2): A mixture of 1,3-dibromo-5-(bromomethyl)benzene (2 g, 6.08 mmol), potassium 1,3- dioxoisoindolin-2-ide (1.12 g, 6.08 mmol) in DMF (30 mL), the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with water 240 mL and filtered to get product 42-2, the crude product was purified by re-crystallization to give 2.1 g of 42-2 (87% yield) as a white solid.
  • Example 30 The synthesis of tert-Butyl 2-(6,7-dichloro-3-(3,4-dichlorophenylamino)-9H-carbazol-1- yl)ethylcarbamate (45-9): tert-butyl 2-(3-bromo-6,7-dichloro-9-tosyl-9H-carbazol-1- yl)ethylcarbamate (140 mg, 0.23 mmol), 3,4-dichloroaniline (37 mg, 0.23 mmol), tris(dibenzylideneacetone)dipalladium(0) (37 mg, 0.04 mmol), tert-butylbrett-Phos (39 mg, 0.08 mmol), cesium carbonate (223 mg, 0.69 mmol) and acetic acid (1 drop) were dissolved in tert-butanol (5 mL).
  • Example 32 [00429] The synthesis of 2-(3-(3,5-Dibromophenyl)prop-2-yn-1-yl)isoindoline-1,3-dione (43-2): To a solution of 1,3-dibromo-5-iodobenzene (10.0 g, 27.6 mmol) and 2-(prop-2-yn-1-yl)isoindoline- 1,3-dione (5.1 g, 27.6 mmol)in THF (100 mL) was added TEA (5.6 g, 55.2 mmol), CuI (1.1 g, 5.5 mmol) and Pd(PPh 3 ) 2 Cl 2 (3.9 g, 5.5 mmol), the mixture was degassed and purged with N 2 and then heated at 60 ° C for 5 hours.
  • TEA 5.6 g, 55.2 mmol
  • CuI 1.1 g, 5.5 mmol
  • tert-Butyl (3-(6-chloro-3-((3,4-dichlorophenyl)amino)-9H-carbazol-1- yl)propyl)carbamate (43-8): To a solution of tert-butyl (3-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1- yl)propyl)carbamate (180 mg, 0.30 mmol) in t-BuOH (10 mL) was added 3,4-dichloroaniline (49 mg, 0.30 mmol), Pd 2 dba 3 (55 mg, 0.06mmol), t-Bubrettphos (37 mg, 0.08 mmol) and Cs 2 CO 3 (293 mg,0.90 mmol).
  • Example 34 [00449] The synthesis of tert-Butyl (2-(3-bromo-6,7-dichloro-9H-carbazol-1-yl)ethyl)carbamate (32-7b): Activated Mg turnings (834 mg, 34.32 mmol), ammonium chloride (336 mg, 6.24 mmol) and tert-butyl (2-(3-bromo-6,7-dichloro-9-tosyl-9H-carbazol-1-yl)ethyl)carbamate (270 mg, 0.44 mmol) in methanol (20 mL) was stirred at room temperature for 3 hours then quenched with ammonium chloride solution.
  • tert-Butyl (2-(6,7-dichloro-3-(thiazol-2-ylamino)-9H-carbazol-1- yl)ethyl)carbamate (51-1): tert-butyl (2-(3-bromo-6,7-dichloro-9H-carbazol-1-yl)ethyl)carbamate (120 mg, 0.21 mmol), thiazol-2-amine (27 mg, 0.27 mmol), tris(dibenzylideneacetone)dipalladium(0) (38 mg, 0.042 mmol), tert-butylbrett-Phos (26 mg, 0.054 mmol) and cesium carbonate (271 mg, 0.83 mmol) were dissolved in tert-butanol (6 mL).
  • Example 36 The synthesis of tert-Butyl (2-(6,7-dichloro-3-((6-chloropyridazin-3-yl)amino)-9H- carbazol-1-yl)ethyl)carbamate (48-1): To a solution of tert-butyl (2-(3-bromo-6,7-dichloro-9-tosyl- 9H-carbazol-1-yl)ethyl)carbamate (200 mg, 0.33 mmol) in t-BuOH (10 mL) was added 6- chloropyridazin-3-amine (42 mg, 0.33 mmol), Pd 2 dba 3 (55 mg, 0.06mmol), t-Bubrettphos (37 mg, 0.08 mmol) and Cs 2 CO 3 (323 mg, 0.99 mmol).
  • Example 39 The synthesis of 6-(2-(3-Bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)ethyl)-2-oxa-6- azaspiro[3.3]heptane (56-1): To a solution of 2-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)ethan-1- amine (100 mg, 0.21 mmol) in CH 3 CN (20 mL) was added 3,3-bis(bromomethyl)oxetane (51 mg, 0.21 mmol) and K 2 CO 3 (58 mg, 0.42 mmol).
  • Example 40 [00484] Example Route for Example 40 (SRI-33180): [00485] The synthesis of 1-(4-Chlorophenyl)thiourea (57-2): 4-chloroaniline (1.5 g, 10.51 mmol) and benzoyl isothiocyanate (1.89 g, 11.57 mmol) in acetone (20 mL) was heated to reflux for 4 hours. The reaction mixture was cooled down to room temperature and diluted with water. The resulting solid was collected by filtration. The cake was dissolved in methanol (50 mL) and 1 N NaOH (25 mL).
  • Example 41 The synthesis of N-(3'-Bromo-4,4'',5-trichloro-[1,1':4',1''-terphenyl]-2-yl)-4- methylbenzenesulfonamide (55-3): To a solution of 2,4-dibromo-4'-chlorobiphenyl (2 g, 5.8 mmol) in dioxane (20 mL) and H 2 O (2 mL) was added N-(4,5-dichloro-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)-4-methylbenzenesulfonamide (2.8 g, 6.4 mmol), Na 2 CO 3 (1.8 g, 17.3 mmol) and Pd(PPh 3 ) 4 (333.6 mg, 0.3 mmol), the mixture was stirred at 90 o C for 16 hours.
  • the reaction mixture was filtered.
  • the aqueous layer was diluted with water (500 mL) and extracted with ethyl acetate (500 mL x 3), the combined organic layer was washed with saturated brine (400 mL x 2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Example 42 [00507] The synthesis of tert-Butyl 2-(5-acetyl-10,11-dihydro-5H-dibenzo[b,f]azepin-3- ylamino)ethylcarbamate (59-3): The mixture of 1-(3-chloro-10,11-dihydro-5H-dibenzo[b,f]azepin-5- yl)ethanone (2.7 g, 9.94 mmol), tert-butyl 2-aminoethylcarbamate (1.91 g, 11.92 mmol), BrettPhosPalladacycle(790 mg, 0.99 mmol) and Cs 2 CO 3 (6.47 g, 19.87 mmol) in toluene (80 mL) was heated at 110 ° C for 7 hours.
  • the mixture was stirred at 80 o C for 16 hours.
  • the reaction mixture was concentrated under reduced pressure to give a residue.
  • the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2), the combined organic layers were washed with saturated brine (20 mL x 2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Example 46 [00542] The synthesis of tert-Butyl 2-(4-chloro-2-(3,4-dichlorophenyl)-10,11-dihydro-5H- dibenzo[b,f]azepin-3-ylamino)ethylcarbamate (75-1): NCS (58 mg, 0.43 mmol) was added to a solution of tert-butyl 2-(2-(3,4-dichlorophenyl)-10,11-dihydro-5H-dibenzo[b,f]azepin-3- ylamino)ethylcarbamate (215 mg, 0.43 mmol) in DCM (10 mL) at 0 °C.
  • the reaction mixture was filtered to give a filtrate.
  • the filtrate was diluted with water (3 L) and extracted with ethyl acetate(1 L x 3), the combined organic layers were washed with saturated brine (500 mL x 2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • reaction solution was degassed and purged with N 2 for 5-10 minutes and then heated at 90 ° C for 3 hours.
  • Example 50 The synthesis of tert-Butyl 2-(6-chloro-4-(3,4-dichlorophenyl)-9H-carbazol-1- ylamino)ethylcarbamate (84-2): To a solution of tert-butyl 2-(4-bromo-6-chloro-9H-carbazol-1- ylamino)ethylcarbamate (250 mg, 569.8 ⁇ mol) in DME (2 mL) and water (1 mL) was added 3,4- dichlorophenylboronic acid (130.5 mg, 683.8 ⁇ mol), K 2 CO 3 (236.3 mg, 1710 ⁇ mol) and Pd(dppf)Cl 2 (41.7 mg, 57.0 ⁇ mol).
  • Example 58 [00654] The synthesis of 1,6-Dibromo-9H-carbazole (77-2c): To a solution of 1-bromo-9H- carbazole (2 g, 8.1 mmol) in DMF (30 mL) was added NBS (144.67 mg, 8.1 mmol) and stirred at 0 o C for 30 minutes to give a black solution.
  • Example 60 [00672] The synthesis of tert-Butyl (2-(6-chloro-2-((3,4-dichlorophenyl)amino)-9H-carbazol-9- yl)ethyl)carbamate (98-3): The mixture of 6-chloro-N-(3,4-dichlorophenyl)-9H-carbazol-2-amine (100 mg, 0.28 mmol), tert-butyl (2-bromoethyl)carbamate (93 mg, 0.41 mmol) and cesium carbonate (274 mg, 0.84 mmol) in DMF (5 mL) was heated at 50 ° C for 4 days.
  • Example 62 [00686] The synthesis of 6-Chloro-N-phenyl-9H-carbazol-2-amine (97-2): 2-bromo-6-chloro-9H- carbazole (1.0 g, 3.56 mmol), aniline (399 mg, 4.28 mmol), tris(dibenzylideneacetone)dipalladium(0) (163 mg, 0.178 mmol), tert-butylbrett-Phos (173 mg, 0.357 mmol) and cesium carbonate (1.16 g, 3.56 mmol) were dissolved in tert-butanol (20 mL).
  • reaction solution was degassed and purged with N 2 for 5-10 minutes and then heated at 90 ° C for 3 hours.
  • Example 64 [00712] The synthesis of tert-Butyl 2-(2-bromo-6-chloro-9H-carbazol-9-yl)ethylcarbamate (99-1): To a solution of 2-bromo-6-chloro-9H-carbazole (1 g, 3.56 mmol) in DMF (20 mL) was added tert- butyl 2-bromoethylcarbamate (1.2 g, 5.35 mmol) and Cs 2 CO 3 (2.32 g, 7.13 mmol). The mixture was stirred at 50 o C for 12 hours to give a yellow solution.
  • Example 68 [00749] Example Route for Example 68 (SRI-33273): [00750] The synthesis of 6-Chloro-N-(3,4-dichlorobenzyl)-9H-carbazol-2-amine (109-1): To a solution of 2-bromo-6-chloro-9H-carbazole (500 mg, 1.78 mmol) in t-BuOH (5 mL) was added (3,4- dichlorophenyl)methanamine (313.7 mg, 1.78 mmol), Cs 2 CO 3 (1742 mg, 5.4 mmol), t-Bubrettphos (86 mg, 0.18 mmol) and Pd 2 (dba) 3 (163 mg, 0.18 mmol).
  • Example 69 [00759] The synthesis of tert-Butyl 2-(3-bromo-6-chloro-9H-carbazol-9-yl)ethylcarbamate (108- a):The mixture of 3-bromo-6-chloro-9H-carbazole (278 mg, 0.99 mmol), tert-butyl (2- bromoethyl)carbamate (222 mg, 0.99 mmol) and cesium carbonate (646 mg, 1.98 mmol) in DMF (15 mL) was heated at 50 ° C for 16 hours.
  • Example 70 [00767] The synthesis of 6-Bromo-9H-pyrido[3,4-b]indole (116-2): To a solution of 9H- pyrido[3,4-b]indole (500 mg, 2.97 mmol) in DMF (10 mL) was added NBS (529 mg, 2.97 mmol) and stirred at 25 o C for 1 hour.
  • Example 71 [00777] The synthesis of 6-Bromo-9H-pyrido[2,3-b]indole (115-2): NBS (1.48 g, 8.32 mmol, 0.7 eq) was added to a mixture of 9H-pyrido[2,3-b]indole (2.0 g, 11.89 mmol, 1 eq) in dichloromethane (200 mL) at room temperature. After stirring for 16 h, the solid was collected by filtration to give 1.76 g of title compound in 60% yield as a pale brown solid.
  • reaction solution was degassed and purged with N 2 for 5-10 minutes and then heated at 90 ° C for 3 hours.
  • Example 72 [00790] The synthesis of tert-Butyl (2-(6-bromo-3,4-dihydro-1H-carbazol-9(2H)- yl)ethyl)carbamate (112-2): NaH (96 mg, 2.4 mmol, 3.0 eq) was added to a mixture of 6-bromo- 2,3,4,9-tetrahydro-1H-carbazole (200 mg, 0.80 mmol, 1 eq) in DMF (2 mL) at room temperature.
  • reaction solution was degassed and purged with N 2 for 5-10 minutes and then heated at 90 ° C for 3 hours.
  • Example 74 [00811] The synthesis of 2-Bromo-9,9-dimethyl-9,10-dihydroacridine (110-2):To a solution of 9,9-dimethyl-9,10-dihydroacridine (1.26 g, 6.02 mmol) in DMF (20 mL) was added NBS (1.07 g, 6.02 mmol) in portions and stirred at -50 °C for 2 hours. The mixture was cooled to room temperature and quenched with water (40 mL). The product was extracted with ethyl acetate (3x50 mL), dried over Na 2 SO 4 .
  • the product was extracted with ethyl acetate (3x20 mL), dried over Na 2 SO 4 and then purified by Prep-HPLC to give 66 mg title compound in 41% yield as a white solid.
  • Example 77 [00839] The synthesis of 2-(3,4-Dichlorobenzyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (122- 2): To a solution of 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (1 g, 5.81 mmol) in ACN (10 mL) was added 4-(bromomethyl)-1,2-dichlorobenzene (1.67 g, 6.97 mmol) and DIEA (1.13 g, 8.72 mmol). The mixture was stirred at 85 o C for 12 hours.
  • the product was extracted with ethyl acetate (3x20 mL), dried over Na 2 SO 4 and then purified by Prep-HPLC to give 52 mg title compound in 43% yield as a yellow solid.
  • Example 80 [00873] The synthesis of 8-Bromo-5H-pyrido[3,2-b]indole (118-2): NBS (635 mg, 3.57 mmol, 1.0 eq) was added to a mixture of 5H-pyrido[3,2-b]indole (600 mg, 3.57 mmol, 1 eq) in dichloromethane (60 mL) at room temperature. After stirring for 2 h, the solid was collected by filtration to give 693 mg of title compound in 79% yield as a gray solid.
  • reaction solution was degassed and purged with N 2 for 5-10 minutes and then heated at 90 ° C for 3 hours.
  • Example 81 [00886] The synthesis of (121-1): To a solution of 9-(2-aminoethyl)-N-(3,4-dichlorophenyl)- 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-6-amine (80 mg, 0.21 mmol) in ACN (2 mL) was added (Z)-tert-butyl (1H-pyrazol-1-yl)methylenedicarbamate (165.39 mg, 0.53 mmol) and DIEPA (1 mL). The mixture was stirred at 25 o C for 16 hours.
  • Example 83 [00903] Example Route for Example 83 (SRI-33355): [00904] The synthesis of 7-Bromo-2,3,4,9-tetrahydro-1H-carbazole (125-1): To a solution of (3- bromophenyl)hydrazine hydrochloride (4.44 g, 45.24 mmol) in EtOH (60 mL) was added cyclohexanone (10.11 g, 45.24 mmol) and stirred at 80 °C for 16 hours.
  • reaction solution was degassed and purged with N 2 for 5-10 minutes and then heated at 90 ° C for 3 hours.
  • the product was extracted with ethyl acetate (3x20 mL), dried over Na 2 SO 4 and then purified by Prep-HPLC to give 68 mg title compound in 37% yield as an off-white solid.
  • Example 84 [00913] The synthesis of 9-(2-Aminoethyl)-N-(3,4-dichlorophenyl)-2,3,4,9-tetrahydro-1H- carbazol-7-amine (125-4): A solution of tert-butyl 2-(7-(3,4-dichlorophenylamino)-3,4-dihydro-1H- carbazol-9(2H)-yl)ethylcarbamate (300 mg, 0.632 mmol) in TFA (10% in dichloromethane, 20 mL) was stirred at room temperature for 16 hours.
  • the product was extracted with ethyl acetate (3x20 mL), dried over Na 2 SO 4 and then purified by Prep-HPLC to give 68 mg title compound in 23% yield as an off-white solid.
  • reaction solution was degassed and purged with N 2 for 5-10 minutes and then heated at 90 ° C for 3 hours.
  • Example 86 [00931] The synthesis of 6-Bromo-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazole (130-2): To a solution of 4,4-difluorocyclohexanone (1 g, 7.46 mmol) in EtOH (15 mL) was added (4- bromophenyl)hydrazine (1.39 g, 7.46 mmol). The mixture was stirred at 90 o C for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue.
  • the product was extracted with ethyl acetate (3x20 mL), dried over Na 2 SO 4 and then purified by Prep-HPLC to give 141 mg title compound in 34% yield as a white solid.
  • tert-Butyl (2-((2-chloro-7-((3,4-dichlorophenyl)amino)acridin-9- yl)amino)ethyl)carbamate (127-7): tert-butyl (2-((2-bromo-7-chloroacridin-9- yl)amino)ethyl)carbamate (370 mg, 0.82 mmol), 3,4-dichloroaniline (133 mg, 0.82 mmol), tris(dibenzylideneacetone)dipalladium(0) (76 mg, 0.083 mmol), tert-butylbrett-Phos (80 mg, 0.17 mmol) and cesium carbonate (268 mg, 0.82 mmol) were dissolved in tert-butanol (8 mL).

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Abstract

Various embodiments of the present disclosure are directed to compounds having Formula (I), Formula (II), Formula (III), and/or pharmaceutically acceptable salts thereof. The compounds can be suitable for providing antimicrobial activity and/or inhibiting lipoxygenases. In some embodiments, the compounds may be administered to a patient as part of a pharmaceutical formulation.

Description

ANTIMICROBIAL COMPOUNDS GOVERNMENT STATEMENT [0001] This invention was made with Government support under contract number OTA W81XWH-15-9-0001 awarded by the US Army Medical Research Acquisition Activity within the US Army Medical Research and Development Command. The Government has certain rights in the invention. CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This PCT Application claims benefit to U.S. Provisional Application No.63/430,432, filed December 6, 2022, titled “Antimicrobial Agents”, the entirety of which is incorporated herein by reference. BACKGROUND [0003] Antibacterial agents have saved lives and helped the growth of modern medicine over the past half century. However, the emergence of drug resistance is jeopardizing the effectiveness of antibacterial agents and life-saving treatment. There is a worldwide need for new and improved antibacterial agents with novel targets and molecular structures to prevent or mitigate drug resistance. As an example, gram-negative bacteria can produce sepsis and septic shock with a high incident of morbidity and mortality. Antibiotic-resistant organisms are making sepsis more difficult to manage. For example, systematic inflammation secondary to bacterial components is a major cause of organ failure, and there is no early broad-spectrum antibiotic therapy that reduces mortality in severe sepsis. [0004] Lipoxygenases (LOXs) and their catalyzed products, such as inflammatory leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs), are implicated in the pathogenesis of a variety of human diseases, including inflammatory disease, cancer and neurodegenerative diseases. LOX inhibitors are known to be useful for the treatment of all kinds of LOXs-related inflammatory diseases, including neurodegenerative diseases, such as Alzheimer's disease; See, Haeggstrom, Chem. Rev.2011, 111, 5866–589; Manev, H., et al., Prog Neuropsychopharmacol Biol Psychiatry, 2010; Listi, F., et al., J Alzheimers Dis, 2010.19(2): p.551-7; Chu, J. and D. Pratico, Ann Neurol, 2010. SUMMARY [0005] The present invention is directed to overcoming the above-mentioned challenges and others related to compounds, including compounds that provide antimicrobial activity and/or are a LOX inhibitor. [0006] Various embodiments are directed to a compound having Formula I: Formula I wherein: ring A is a 5-7 membered heterocyclic ring or a 5-6 membered heteroaryl ring that is independently substituted with one to three R1 groups, and wherein at least one of the 5-7 members of the heterocyclic ring or at least one of the 5-6 members of the heteroaryl ring is N; ring B is a 5-6 membered heterocyclic ring, a 5-6 membered heteroaryl ring, a 6 membered aromatic ring, or a 6 membered cycloalkyl ring that is unsubstituted or independently substituted with up to four R2 groups, and optionally wherein at least one of the 5-6 members of the heterocyclic ring or at least one of the 5-6 members of the heteroaryl ring is N; ring C is a 6 membered aromatic ring that is unsubstituted or independently substituted with up to four R3 groups; each R1 group independently comprising a H, a halo, C1-6 alkyl, NH(CH2)1-6Ra, (CH2)1-6Ra, (CH2)1-6NH-Ra, NH(CH2)1-6RaRb, CH2NH(CH2)1-6Ra, or a 5-7 membered heterocyclic ring substituted with RaRb; each R2 group independently comprising a H, a halo, C1-6 alkyl, NH(CH2)1-6Ra, NHRa, (CH2)1-6Ra, Ra, or C-(Ra)3; each R3 group independently comprising a H, a halo, C1-6 alkyl, NHRa, NHRaRb, NH(CH2)1-6Ra, O(CH2)1-6Ra, ORa, O(CH2)1-6Ra- (Rb)2, O(CH2)1-6RaRb, (CH2)1-6Ra, (CH2)1-6RaRb, RaRb, or Ra; each Ra and Rb group independently comprising a halo, an amine, an imine, a carboxyl, a carbonyl, a hydroxyl, a thioamide, a nitrile, -O- alkyl, C1-6 alkyl, C-(CH3)3, a 5-6 membered aromatic ring, a 5-6 membered cycloalkyl ring, or a 4-6 membered heterocyclic ring; and a pharmaceutically acceptable salt thereof. [0007] In some aspects, each R1 group is independently selected from the group consisting of: , [0008] In some aspects, each R2 group is independently selected from the group consisting of:
,
[0010] In some aspects, each Ra and Rb group is independently selected from the group consisting of: oxidized forms thereof. [0011] In some aspects, the compound (of Formula I) is selected from the group consisting of:
,
,
,
, , [0012] In some aspects, the compound is configured to provide antimicrobial activity in cells in vitro and in situ. In some aspects, the compound is configured to provide the antimicrobial activity against bacteria selected from the group consisting of: Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Enterococcus faecalis, Staphylococcus aureus, Serratia marcescens, Shigella dysenteriae, Enterobacter aerogenes, Salmonella paratyphi, and a combination thereof. [0013] In some aspects, the compound is compound is configured to provide antimicrobial activity and inhibit a lipoxygenase (LOX) in cells in vitro and in situ. In some aspects, the compound is configured to: provide the antimicrobial activity against bacteria selected from the group consisting of: Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Enterococcus faecalis, Staphylococcus aureus, Serratia marcescens, Shigella dysenteriae, Enterobacter aerogenes, Salmonella paratyphi, and a combination thereof; and/or inhibit the LOX selected from the group consisting of: 5-LOX, 15-LOX, and a combination thereof. [0014] Various embodiments are directed to a compound of Formula II: wherein: ring A is a 5 membered heterocyclic ring or a 5 membered heteroaryl ring that is substituted with one R1 group; ring B is a 6 membered heterocyclic ring, a 6 membered heteroaryl ring, a 6 membered aromatic ring, or a 6 membered cycloalkyl ring that is unsubstituted or independently substituted with up to four R2 groups; ring C is a 6 membered aromatic ring that is unsubstituted or independently substituted with up to four R3 groups; each X independently comprising a C or N; the R1 group comprising a H, a halo, C1-6 alkyl, NH(CH2)1-6Ra, (CH2)1-6Ra, (CH2)1-6NH-Ra, NH(CH2)1- 6RaRb, CH2NH(CH2)1-6Ra, or a 5-7 membered heterocyclic ring substituted with RaRb; each R2 group independently comprising a H, a halo, C1-6 alkyl, NH(CH2)1-6Ra, NHRa, or (CH2)1-6Ra, Ra, or C-(Ra)3; each R3 group independently comprising a H, a halo, C1-6 alkyl, NHRa, NHRaRb, NH(CH2)1-6Ra, O(CH2)1-6Ra, ORa, O(CH2)1-6Ra-(Rb)2, O(CH2)1-6RaRb, (CH2)1-6Ra, (CH2)1-6RaRb, RaRb, or Ra; each Ra and Rb group independently comprising an amine, an imine, a carbonyl, a hydroxyl, a thioamide, a nitrile, -O-alkyl, C1-6 alkyl, a 5-6 membered aromatic ring, a 5-6 membered cycloalkyl ring, or a 4-6 membered heterocyclic ring; and a pharmaceutically acceptable salt thereof. [0015] In some aspects, the R1 group is selected from the group consisting of: , [0016] In some aspects, the R1 group is selected from the group consisting of: [0017] In some aspects, each R2 group is independently selected from the group consisting of: [0018] In some aspects, each R3 group is independently selected from the group consisting of:
. [0019] In some aspects, each Ra and Rb group is independently selected from the group consisting of: oxidized forms thereof. [0020] In some aspects, the compound (of Formula II) is selected from the group consisting of:
,
, , ,
, [0021] In some aspects, the compound is configured to: provide an antimicrobial activity against bacteria selected from the group consisting of: Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Enterococcus faecalis, Staphylococcus aureus, Serratia marcescens, Shigella dysenteriae, Enterobacter aerogenes, Salmonella paratyphi, and a combination thereof; and/or inhibit a LOX in cells in vitro and in situ, the LOX being selected from the group consisting of: 5-LOX, 15-LOX, and a combination thereof. [0022] Various embodiments are directed to a compound of Formula III: Formula III wherein: ring A is a 6 membered heteroaryl ring that is independently substituted with one to three R1 groups; ring B is a 6 membered heterocyclic ring, a 6 membered aromatic ring, or a 6 membered cycloalkyl ring that is unsubstituted or independently substituted with up to four R2 groups; ring C is a 6 membered aromatic ring that is unsubstituted or independently substituted with up to four R3 groups; each X independently comprising a C or N; each R1 group independently comprising a H, a halo, C1-6 alkyl, NH(CH2)1-6Ra, (CH2)1-6Ra, (CH2)1-6NH-Ra, NH(CH2)1-6RaRb, CH2NH(CH2)1-6Ra, or a 5-7 membered heterocyclic ring substituted with RaRb; each R2 group independently comprising a H, a halo, C1-6 alkyl, NH(CH2)1-6Ra, NHRa, (CH2)1-6Ra, Ra, or C-(Ra)3; each R3 group independently comprising a H, a halo, C1-6 alkyl, NHRa, NHRaRb, NH(CH2)1-6Ra, O(CH2)1-6Ra, ORa, O(CH2)1-6Ra- (Rb)2, O(CH2)1-6RaRb, (CH2)1-6Ra, (CH2)1-6RaRb, RaRb, or Ra; each Ra and Rb independently comprising a halo, an amine, an imine, a carboxyl, a carbonyl, a hydroxyl, a thioamide, a nitrile, -O-alkyl, C1-6 alkyl, C-(CH3)3, a 5-6 membered aromatic ring, a 5-6 membered cycloalkyl ring, or a 4-6 membered heterocyclic ring; and a pharmaceutically acceptable salt thereof. [0023] In some aspects, each R1 group is independently selected from the group consisting of: , [0024] In some aspects, each R2 group is independently selected from the group consisting of: , [0025] In some aspects, each R2 group is independently selected from the group consisting of: . [0026] In some aspects, each R3 group is independently selected from the group consisting of:
,
[0027] In some aspects, each R3 group is independently selected from the group consisting of: . [0028] In some aspects, at least one R3 group comprises NH bound to a 6 membered aromatic ring that is substituted with one to three Cl. [0029] In some aspects, each Ra and Rb group is independently selected from the group consisting oxidized forms thereof. [0030] In some aspects, each Ra and Rb group is independently selected from the group consisting of: , , , , , , , , and oxidized forms thereof. [0031] In some aspects, the compound (of Formula III) is selected from the group consisting of: , [0032] In some aspects, the compound is configured to: provide an antimicrobial activity against bacteria selected from the group consisting of: Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Enterococcus faecalis, Staphylococcus aureus, Serratia marcescens, Shigella dysenteriae, Enterobacter aerogenes, and Salmonella paratyphi and a combination thereof; and/or inhibit a LOX in cells in vitro and in situ, the LOX being selected from the group consisting of: 5-LOX, 15-LOX, and a combination thereof. [0033] Embodiments in accordance with the present disclosure include all combinations of the recited particular embodiments. Further embodiments and the full scope of applicability of the invention will become apparent from the detailed description provided hereinafter. However, it should be understood that the detailed description and specific embodiments, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. All publications, patents, and patent applications cited herein, including citations therein, are hereby incorporated by reference in their entirety for all purposes. DETAILED DESCRIPTION [0034] The description below is made with the understanding that the present disclosure is to be considered as an exemplification of the claimed subject matter and is not intended to limit the claims to the specific embodiments described. The headings used throughout this disclosure are provided for convenience and are not to be construed to limit the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading. [0035] There is an urgent need for providing antibacterial agents with novel targets and molecular structures to prevent cross-resistance, such as for gram-negative bacteria. In various embodiments, compounds show broad-spectrum antimicrobial activities against a panel of pathogens, such as Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Enterococcus faecalis, Staphylococcus aureus (including Methicillin-resistant Staphylococcus aureus), Serratia marcescens, Shigella dysenteriae, Enterobacter aerogenes, and Salmonella paratyphi. Such compounds are a class of antimicrobial agents that, in some embodiments, target lipoxygenase (LOX) enzymes and are distinct structurally from prior classes of antibiotics and lack cross-resistance with other antibiotics. In some embodiments, the various compounds inhibit LOX enzymes, such as: 1) 15- LOX, and 2) human 5-LOX, thereby providing reduced inflammation by hindering biosynthesis of harmful inflammatory leukotriene B4 (LTB4), which can complicate some infections, such as in sepsis. In some embodiments, the compounds, which provide antimicrobial activity, have no LOX inhibiting activity. In some embodiments, the dual-activity inhibitors (e.g., LOX inhibiting and antibacterial properties) have the combined properties that can combat multidrug-resistant (MDR) bacteria and module the runaway inflammatory process, such as with sepsis. [0036] In various embodiments, the compounds provide the dual activity providing broad- spectrum bactericidal activity and anti-inflammatory properties. Such compounds may be used combat emerging drug-resistant bacteria threats, limit tissue damage, and/or potential provide superior therapeutic benefits compared to prior bacterial infection treatments. [0037] In some embodiments, the dual-activity compounds can target enzymes involved in bacterial infection and inflammatory diseases. In some embodiments, the dual-activity compounds can inhibit enzymes including, but not limited to LOX, involved in bacterial infections and inflammatory diseases. In some embodiments, the compounds can target any enzyme(s) involved in bacterial infections. In some embodiments, the compounds can target any enzyme(s) involved in inflammatory diseases. [0038] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. A dash at the front or end of a chemical group is a matter of convenience to indicate the point of attachment to a parent moiety; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A line drawn through a line in a chemical structure or a dashed line drawn through a line in a chemical structure indicates a point of attachment of a group. A dashed line within a chemical structure indicates an optional bond. [0039] As used herein and in the appended claims, the singular forms "a" and "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, e.g., reference to "the compound" includes a plurality of such compounds and reference to "the assay" includes reference to one or more assays, and so forth. [0040] The prefix “Cx-y” indicates that the following group has from x (e.g., 1) to y (e.g., 6) carbon atoms, one or more of which, in certain groups (e.g., heteroalkyl, heteroaryl, heteroarylalkyl, etc.), may be replaced with one or more heteroatoms or heteroatomic groups. For example, “C1-6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms. Likewise, the term “x-y membered” rings, wherein x and y are numerical ranges, such as “3-12 membered heterocyclyl”, refers to a ring containing x-y atoms (e.g., 3-12), of which up to half may be heteroatoms, such as N, O, S, P, and the remaining atoms are carbon. Also, certain commonly used alternative chemical names may or may not be used. For example, a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc., may also be referred to as an “alkylene” group or an “alkylenyl” group, or alkylyl group, an “arylene” group or an “arylenyl” group, or arylyl group, respectively. [0041] “Alkyl” refers to any group derived from a linear or branched saturated hydrocarbon. Alkyl groups include, but are not limited to, methyl, ethyl, propyl such as propan-1-yl, propan-2-yl (iso- propyl), butyls such as butan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (iso-butyl), 2-methyl- propan-2-yl (t-butyl), pentyls, hexyls, octyls, and dectyls, among others. Unless otherwise specified, an alkyl group has from 1 to 10 carbon atoms, for example from 1 to 6 carbon atoms, for example from 1 to 4 carbon atoms. [0042] “Alkenyl” refers to any group derived from a straight or branched hydrocarbon with at least one carbon-carbon double bond. Alkenyl groups include, but are not limited to, ethenyl (vinyl), propenyl (allyl), 1-butenyl, and 1,3-butadienyl, among others. Unless otherwise specified, an alkenyl group has from 2 to 10 carbon atoms, for example from 2 to 6 carbon atoms, for example from 2 to 4 carbon atoms. [0043] “Alkynyl” refers to any group derived from a straight or branched hydrocarbon with at least one carbon-carbon triple bond and includes those groups having one triple bond and one double bond. Examples of alkynyl groups include, but are not limited to, ethynyl (—CH≡CH), propargyl (— CH2C≡CH), and (E)-pent-3-en-1-ynyl, among others. Unless otherwise specified, an alkynyl group has from 2 to 10 carbon atoms, for example from 2 to 6 carbon atoms, for example from 2 to 4 carbon atoms. [0044] “Amide” refers to a —(C=O) group bound to a N-RR’, where R and R’ can be any group, such as H. [0045] “Amino” or “amine” refers to —NH2. Amino groups may also be substituted as described herein, such as with alkyl, carbonyl or other amino groups. [0046] “Alkylamino” refers to an amino group substituted with one or two alkyl substituents (e.g., dimethylamino or propylamino). [0047] “Aromatic ring” or “arenes” refers to an aromatic ring of carbon atoms. Unless otherwise specified, an aromatic ring can have between 3 to 20 or more carbon atoms, for example, between 3 to 10 carbon atoms or between 3 to 8 carbon atoms. [0048] “Aryl” refers to any group derived from one or more aromatic rings, that is, a single aromatic ring, a bicyclic or a multicyclic ring system. Aryl groups include, but are not limited to, those groups derived from acenaphthylene, anthracene, azulene, benzene, chrysene, a cyclopentadienyl anion, naphthalene, fluoranthene, fluorene, indane, perylene, phenalene, phenanthrene, and pyrene, among others. [0049] “Arylalkyl” (also “aralkyl”) refers to any combination an aryl group and an alkyl group. Arylalkyl groups include, but are not limited to, those groups derived from benzyl, tolyl, dimethylphenyl, 2-phenylethan-1-yl, and 2-naphthylmethyl, among others. An arylalkyl group comprises from 1 to 30 carbon atoms, for example the alkyl group can comprise from 1 to 10 carbon atoms and the aryl group can comprise from 5 to 20 carbon atoms. [0050] “Carboxyl” refers to —COOH. For example, carboxy groups include any combination of a hydroxyl group (OH) and a carbonyl group C=O. [0051] “Carbonyl” refers to a carbon atom double bonded to an oxygen atom. [0052] “Cycloalkyl” or “cycloalkyl ring” refers to a cyclic alkyl and alkenyl groups. A cycloalkyl group can have one or more cyclic rings and includes fused and bridged groups that are fully saturated or partially unsaturated. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, methylcycloproyl (cyclopropylmethyl), ethylcyclopropyl, and cyclohexenyl, among others. Another example includes C5-7 cycloakenyl. [0053] “Cycloalkyl-aryl” refers to a cycloalkyl ring bonded to an aryl ring. Cycloalkyl is defined above as is the term ‘Aryl’. Examples include, but are not limited to, 2,3-dihydro-1H-indene and 1,2,3,4-tetrahydronaphthalene. [0054] “Halo” and “halogen” refer to fluoro, chloro, bromo, and iodo. [0055] “Haloalkyl” refers to an alkyl wherein one or more hydrogen atoms are each replaced by a halogen. Examples include, but are not limited to, —CH2Cl, —CH2F, —CH2Br, —CFClBr, — CH2CH2Cl, —CH2CH2F, —CF3, —CH2CF3, and —CH2CCl3, among others, as well as alkyl groups, such as perfluoroalkyl in which all hydrogen atoms are replaced by fluorine atoms. [0056] “Hydroxyalkyl” refers to an alkyl wherein one or more hydrogen atoms are each replaced by a hydroxyl group. Examples include, but are not limited to, —CH2OH, —CH2CH2OH, and — C(CH3)2OH, among others. [0057] “Heteroalkyl” refers to an alkyl in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatom or heteroatomic group. Heteroatoms include, but are not limited to, N, P, O, S, etc. Heteroatomic groups include, but are not limited to, —NR—, —O—, —S—, —PH—, —P(O)2—, —S(O)—, and — S(O)2—, among others, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or cycloheteroalkyl. Heteroalkyl groups include, but are not limited to, —OCH3, —CH2OCH3, —SCH3, —CH2SCH3, —NRCH3, —CH2NRCH3, and —CH2OH, among others, where R is H, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. A heteroalkyl group can comprise from 1 to 10 carbon and up to three hetero atoms, e.g., from 1 to 6 carbon and from 1 to 2 hetero atoms. [0058] “Heteroaryl” refers to mono or multicyclic aryl group in which one or more of the aromatic carbon atoms (and associated hydrogen atoms) are independently replaced with the same or different heteroatom or heteroatomic group, as defined above. Multicyclic ring systems are included in heteroaryl and may be attached at the ring with the heteroatom or the aryl ring. Heteroaryl groups include, but are not limited to, groups derived from acridine, benzoimidazole, benzothiophene, benzofuran, benzoxazole, benzothiazole, carbazole, carboline, cinnoline, furan, imidazole, imidazopyridine, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, and xanthene, among others. Heteroaryl groups may have between 3 to 14 members, 3 to 10 members, or 3 to 6 members, among others. [0059] “Heterocycle,” “heterocyclic ring,” and “heterocyclyl” refer to a saturated or partially unsaturated non-aromatic ring or a partially non-aromatic multiple-ring system with at least one heteroatom or heteroatomic group, as defined above. Heterocycles include, but are not limited to, groups derived from azetidine, aziridine, imidazolidine, morpholine, thiomorpholine, tetrahydro-2H- thiopyran, 1-iminotetrahydro-2H-thiopyran 1-oxide, oxirane (epoxide), oxetane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, N-bromopyrrolidine, and N-chloropiperidine, among others. Heterocyclyl groups also include partially unsaturated ring systems containing one or more double bonds, including fused ring systems with one aromatic ring and one non-aromatic ring, but not fully aromatic ring systems. Examples include dihydroquinolines, e.g., 3,4-dihydroquinoline, dihydroisoquinolines, e.g., 1,2-dihydroisoquinoline, dihydroimidazole, tetrahydroimidazole, etc., indoline, isoindoline, isoindolones (e.g., isoindolin-1-one), isatin, dihydrophthalazine, quinolinone, and spiro[cyclopropane-1,1′-isoindolin]-3′-one, among others. Heterocycle groups may have between 3 to 12 members, 3 to 10 members, 3 to 7 members, or 5 to 6 members, among others. Other examples include cyclopente-type rings. [0060] “Hydroxyl” and “hydroxy” are used interchangeably and refer to —OH. “Oxo” refers to =O, or oxide where N-oxide or S-oxide exist. Where tautomeric forms of the compound exist, hydroxyl and oxo groups are interchangeable. [0061] “Imine” refers to —C=N or any group containing a carbon atom double bonded to a nitrogen atom. [0062] “Nitrile” refers to —C≡N or any group containing a carbon atom triple bonded to a nitrogen atom. [0063] “Thioamide” refers to —C(=S)-NRR’, where the R and R’ groups can be any group, such as H or other groups. [0064] It is understood that combinations of chemical groups may be used and will be recognized by persons of ordinary skill in the art. As an example, the group “hydroxyalkyl” refers to a hydroxyl group attached to an alkyl group. A number of such combinations may be readily envisaged. Additional examples of substituent combinations used herein include: C1-6 alkylamiocarbonyl (e.g., CH3CH2NHC(O)—) C1-6 alkoxycarbonyl (e.g., CH3O—C(O)—), 5-7 membered heterocyclyl-C1-6 alkyl (e.g., piperazinyl-CH2—), C1-6 alkylsulfonyl- 5-7 membered heterocyclyl (e.g., CH3S(O)2- morpholinyl-), 5-7 membered heterocyclyl C1-6 alkoxy (e.g., pyrrolidinyl-O—), 5-7 membered heterocyclyloxy, (4-7 membered heterocyclyl)- 4-7 membered heterocyclyl (e.g., oxetanyl- pyrrolidinyl-), C3-6 cycloalkylaminocarbonyl (e.g., cyclopropyl-NH—C(O)—), 5-7 membered heterocyclyl-C2-6 alkynyl (e.g., N-piperazinyl-CH2C≡CCH2—), and C6-10 arylaminocarbonyl (e.g., phenyl-NH—C(O)—). [0065] The present disclosure includes both racemic mixtures of a compound of the disclosed formulas and isolated isomers or any variation thereof. Where more than one chiral center is present in a compound of the present disclosure, some, none, or all of the chiral centers may be enantiomerically enriched. Thus, mixtures of a compound of the disclosed formulas may be racemic with respect to one or more chiral centers and/or enantiomerically enriched with respect to one or more chiral centers. [0066] “Pharmaceutically acceptable salt” refers to a salt of a compound that is pharmaceutically acceptable and that possesses (or can be converted to a form that possesses) the desired pharmacological activity of the parent compound. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, among others; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2- napththalenesulfonic acid, oleic acid, palmitic acid, propionic acid, stearic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, among others, and salts formed when an acidic proton present in the parent compound is replaced by either a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as diethanolamine, triethanolamine, and N-methylglucamine, among others. Also included are ammonium and substituted or quaternized ammonium salts. Representative non-limiting examples of pharmaceutically acceptable salts can be found in S. M. Berge et al., J. Pharma Sci., 66(1), 1-19 (1977), and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, Pa., (2005), at p.732, Table 38-5, both of which are hereby incorporated by reference in their entireties for their teachings. [0067] As used herein and in the claims, “hydrogen” and “H”, “oxygen” and “O”, “carbon” and “C”, “F” and “fluorine”, “Cl” and “chlorine”, “S” and “sulfur”, and “nitrogen” and “N” are interchangeably used, and each respectively refer to a hydrogen atom, an oxygen atom, a carbon atom, a fluorine atom, a chlorine atom, a sulfur atom, and/or a nitrogen atom. As used herein and in the claims, the rings of various compounds are sometimes interchangeably referred to as “ring A” or “A” and “ring B” or “B”, both of which respectively refer to the specifically referenced ring. Similarly, as used herein and in the claims, the various groups of the compounds are sometimes interchangeably referred with or without “atom” or “group” at the end, such as “R1” and R1 group”, both of which respectively refer to the specifically referenced atom or chemical group. [0068] “Subject” and “subjects” refers to humans, domestic animals (e.g., dogs and cats), farm animals (e.g., cattle, horses, sheep, goats and pigs), and laboratory animals (e.g., mice, rats, hamsters, guinea pigs, pigs, pocket pets, rabbits, dogs, and monkeys), among others. [0069] “Treating” and “treatment” of a disease include the following: (1) preventing or reducing the risk of developing the disease, e.g., causing the clinical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease, (2) inhibiting the disease, e.g., arresting or reducing the development of the disease or its clinical symptoms, or (3) relieving the disease, e.g., causing regression of the disease or its clinical symptoms. [0070] “Effective amount” refers to an amount that may be effective to elicit the desired biological, clinical, or medical response, including the amount of a compound that, when administered to a subject for treating a disease, is sufficient to affect such treatment. The effective amount will vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject to be treated. The effective amount can include a range of amounts. [0071] “Antimicrobial” or “antimicrobial agent” refers to a compound which kills, inactivates, or slows the growth of a microbe. Non-limiting example microbes include bacteria, viruses, fungi, and parasites. In some embodiments, the disclosed compounds may be antibacterial agents, which is a compound that kills or prevents growth of bacteria. [0072] The compounds of the invention include solvates, hydrates, tautomers, stereoisomers and salt forms thereof. [0073] Provided are also compounds in which from 1 to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom, or tritiated with a tritium atom, in which n is the number of hydrogen atoms in the molecule. As known in the art, the deuterium atom is a non-radioactive isotope of the hydrogen atom and tritium is a radioactive isotope. Such compounds, particularly deuterated compounds, may increase resistance to metabolism, and thus may be useful for increasing the half-life of the compounds when administered to a mammal. See, e.g., Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium. [0074] The pharmaceutical compositions of compounds of the disclosed formulas may be administered in single or multiple doses by any accepted modes of administration of agents having similar utilities, for example as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer. [0075] In some embodiments, the compounds described herein may be administered orally. Oral administration may be via, for example, capsule or enteric coated tablets. In making the compositions that include at least one compound of Formula I, or a pharmaceutically acceptable salt, is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders. [0076] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propyl hydroxy-benzoates; sweetening agents; and flavoring agents. [0077] In some embodiments, compounds of Formula I have the following structure: Formula I [0078] In some embodiments, ring A is a 5-7 membered heterocyclic ring or a 5-6 membered heteroaryl ring that is independently substituted with one to three R1 groups. In some embodiments, at least one of the 5-7 members of the heterocyclic ring or at least one of the 5-6 members of the heteroaryl ring is N, with the remaining members being C. In some embodiments, one of the 5-7 members of the heterocyclic ring or one of the 5-6 members of the heteroaryl ring is N. In some embodiments, two (or more) of the 5-7 members of the heterocyclic ring or two (or more) of the 5-6 members of the heteroaryl ring are N. In some embodiments, the ring A is independently substituted with three R1 groups, two R1 groups, or one R1 group. [0079] In some embodiments, ring B is a 5-6 membered heterocyclic ring, a 5-6 membered heteroaryl ring, a 6 membered aromatic ring, or a 6 membered cycloalkyl ring that is unsubstituted or independently substituted with up to four R2 groups. In some embodiments, at least one of the 5-6 members of the heterocyclic ring or at least one of the 5-6 members of the heteroaryl ring is N, with the remaining members being C. In some embodiments, one of the 5-6 members of the heterocyclic ring or one of the 5-6 members of the heteroaryl ring is N. In some embodiments, two (or more) of the 5-6 members of the heterocyclic ring or two (or more) of the 5-6 members of the heteroaryl ring are N. In some embodiments, 3 members or 4 members of ring B are N. In some embodiments, ring B is independently substituted with up to three R2 groups. In some embodiments, ring B is independently substituted with four R2 groups, three R2 groups, two R2 groups, one R2 group, or is unsubstituted. [0080] In some embodiments, ring C is a 6 membered aromatic ring that is unsubstituted or independently substituted with up to four R3 groups. In some embodiments, ring C is independently substituted with up to three R3 groups. In some embodiments, ring C is independently substituted with four R3 groups, three R3 groups, two R3 groups, one R3 group, or is unsubstituted. [0081] In some embodiments, each R1 group independently comprises a H, a halo, C1-6 alkyl, NH(CH2)1-6Ra, (CH2)1-6Ra, (CH2)1-6NH-Ra, NH(CH2)1-6RaRb, CH2NH(CH2)1-6Ra, or a 5-7 membered heterocyclic ring substituted with RaRb. In some embodiments, each R1 group independently comprises a H, a halo, CH3, NH(CH2)2Ra, (CH2)2-3Ra, (CH2)2NH-Ra, NH(CH2)2RaRb, CH2NH(CH2)2Ra, or a 5-7 membered heterocyclic ring substituted with RaRb. In some embodiments, at least one R1 is H. In some embodiments, at least one R1 group is a halo, such as Cl. In some embodiments, at least one R1 group is (CH2)2-3-NH-C(=NH)NH2. In some embodiments, at least one R1 group is NH-(CH2)2-NH-C(=NH)NH2, NH-(CH2)2NH2, or NH-(CH2)2NH-CH3. In some embodiments, at least one R1 group is CH2-NH-(CH2)2NH-C(=NH)NH2. In some embodiments, at least one R1 group is (CH2)2NH-2-imidazoline. [0082] In some embodiments, each R1 group is selected from and/or is one of the following structures: , [0083] In some embodiments, each R2 group independently comprises a H, a halo, C1-6 alkyl, NH(CH2)1-6Ra, NHRa, (CH2)1-6Ra, Ra, or C-(Ra)3. In some embodiments, each R2 group independently comprises a H, a halo, NH(CH2)2Ra, NHRa, (CH2)1-2Ra, Ra, or C-(Ra)3. In some embodiments, at least one R2 group is H. In some embodiments, at least one R2 group is a halo, such as Cl and/or F. In some embodiments, at least one R2 group is or includes an imine, such as, but not limited to, NH2-C-(=NH). In some embodiments, at least one R2 group is or includes an aminoalkyl or a hydrocarbon containing an amine and an imine. In some embodiments, at least one R2 group is CH2-dichlorophenyl. In some embodiments, at least one R2 is NH-dichlorophenyl. In some embodiments, at least one R2 group is trifluoromethyl or CF3. [0084] In some embodiments, each R2 group is selected from and/or is one of the following structures: , [0085] In some embodiments, each R3 group independently comprises a H, a halo, C1-6 alkyl, NHRa, NHRaRb, NH(CH2)1-6Ra, O(CH2)1-6Ra, ORa, O(CH2)1-6Ra-(Rb)2, O(CH2)1-6RaRb, (CH2)1-6Ra, (CH2)1-6RaRb, RaRb, or Ra. In some embodiments, each R3 group independently comprises a halo, NHRa, NHRaRb, NH(CH2)1-2Ra, O(CH2)1-3Ra, ORa, O(CH2)2Ra-(Rb)2, O(CH2)2-3RaRb, (CH2)1-3Ra, (CH2)2RaRb, RaRb, or Ra. [0086] In some embodiments, at least one R3 group is CH2CH3. In some embodiments, at least one R3 group is dichlorophenyl or chlorophenyl. In some embodiments, at least one R3 group is NH- aromatic ring, NH-heteroaryl, NH-heterocycle, NH-aryl, NH-fused rings (e.g., heterocylic, aryl, and other rings), such as, but not limited to, NH-phenyl, NH-chlorophenyl, NH-dichlorophenyl, NH- chloroflurophenyl, NH-cyclohexyl, NH-dichlorofluorophenyl, NH-chloropyridine, NH-pyrazole, NH- imidazole, NH-imidazole substituted with CH3, NH-thiazole, NH-dichloropyridine, NH- chloropyridazine, NH-chloropyrimidine, NH-chlorobenzonitrile, and/or NH-dichlorobezothiazole. In some embodiments, at least one R3 group is an O-alkylamine, such as, but not limited to, O- ethylamine, O-propylamine, and/or O-(CH2)2-dimethlyamine. In some embodiments, at least one R3 group is an O-alkyl-aryl, an O-alkyl-aromatic ring, an O-alkyl-heteroaryl, O-alkyl-heterocyclic ring, O-alkyl-cycloalkyl ring, O-heterocyclic ring, or an O-fused rings, such as, but not limited to, O- pyrrolidine, O-CH2-pyrrolidine, O-CH2-azetidine, O-CH2-piperidine, and/or O-(CH2)2-piperazine. In some embodiments, at least one R3 group is an O-aminoalkyl or O-alkyl with an amine and imide and/or a heterocyclic ring, such as, but not limited to, O-(CH2)3-NH-C(=NH)NH2, O-(CH2)3-NH- C(=N-CH3)NH2, O-(CH2)2-NH-C(=NH)NH2, and O-(CH2)2-NH-imiadzole. In some embodiments, at least one R3 group is or includes an amide, an alkylamine, or a hydrocarbon containing at least one amine and imine, such as, but not limited to, CH2-C(=O)NH2, (CH2)2-NH-C(=NH)NH2, (CH2)2-NH- pyramidine which is further substituted with an amine and Cl, (CH2)2-NH-C(=NH)NH-CH3, (CH2)2- NH-C(=NH)NH-OH, (CH2)2-NH-C(=NH)NH-NH2, (CH2)2-NH-C(=NH)NH-C(=NH)NH2, (CH2)2- NH-C(=NH)NH-pyramidine, (CH2)2-NH-C(=NH)NH-O-CH3, CH2-NH-C(=NH)NH2, (CH2)3-NH- C(=NH)NH2, and/or (CH2)2-NH-C(=NH)NH-chlorophenyl. In some embodiments, at least one R3 group is NH-alkyl, NH-alkyl-imine, or NH-imine-aromatic ring or aryl, such as, but not limited to, NH-CH2-phenyl, NH-C(=NH)-chlorophenyl, NH-C(=NH)-dichlorophenyl, NH- dichlorobenzothiazole, NH-CH2-dichlorophenyl, and/or NH-(CH2)2-NHC(=NH)NH2. In some embodiments, at least one R3 group is an alkyl–thioamide, a thiomide-aryl, or an alkyl with an amine and a nitrile, such as, but not limited to, (CH2)2-NH-C(=S)NH2, N-C(=S-NH2)-chlorophenyl, and/or (CH2)2-NH-C(=NH)C(≡N). In some embodiments, at least one R3 group is ethyl. [0087] In some embodiments, each R3 group is selected from and/or is one of the following structures: ,
, [0088] In some embodiments, each Ra and Rb group independently comprise a halo, an amine, an imine, a carboxyl, a carbonyl, a hydroxyl, a thioamide, a nitrile, -O-alkyl, C1-6 alkyl, C-(CH3)3, a 5-6 membered aromatic ring (which is unsubstituted or substituted), a 5-6 membered cycloalkyl ring, or a 4-6 membered heterocyclic ring. In some embodiments, each Ra and Rb group independently comprise a halo, an amine, an imine, a carboxyl, a carbonyl, a hydroxyl, a thioamide, a nitrile, -O-CH3, CH3, C- (CH3)3, a 5-6 membered aromatic ring, such as an aryl, a 5-6 membered cycloalkyl ring, or a 4-6 membered heterocyclic ring. In some embodiments, at least one Ra and/or Rb group is methyl. In some embodiments, at least one Ra group and/or Rb group is an amine. In some embodiments, at least one Ra group and/or Rb group is an imine, alkylamine, or a hydrocarbon containing an amine and an imine, such as, but not limited to, NH-C(=NH)NH2 and/or CH2-C(=NH)NH2. In some embodiments, at least one Ra and/or Rb is or includes a carboxyl, such as C(=O)OH. In some embodiments, at least one Ra group and/or Rb group is or includes a hydroxyl or a hydroxyalkyl, such as, but not limited to, OH or O-CH3. In some embodiments, at least one Ra group and/or Rb group is or includes a carbonyl, such as, but not limited to, C(=O)NH2. In some embodiments, at least one Ra group and/or Rb group is an aromatic ring (which is substituted or unsubstituted), a cycloalkyl ring, or a heterocyclic ring, such as, but not limited to, phenyl, chlorophenyl, dichlorophenyl, dichlorofluorophenyl, chlorofluorophenyl, cyclohexane, imidazoline, imidazoline further substituted with methyl, pyrrolidine, azetidine, piperidine, piperazine, pyrimidine, pyrimidine further substituted with chloro and/or an amine, chloropyridine, pyrazole, thiazole, dichloropyridine, oxetane, and/or chloropyridazine. In some embodiments, at least one Ra group and/or Rb is group C-(CH3)3. In some embodiments, at least one Ra group and/or Rb group is fluro. In some embodiments, at least one Ra group and/or Rb group is or includes a nitrile, such as, but not limited to, C(≡N). In some embodiments, at least one Ra group and/or Rb group is or includes a thioamide, such as, but not limited to, NH-C(=S)NH2. [0089] In some embodiments, each Ra and Rb group is selected from and/or is one of the following structures: , [0090] In some embodiments of Formula I, the compound is selected from: ,
,
,
,
, , salts thereof. [0091] As further described herein, any of the disclosed compounds may be configured to provide antimicrobial activity such that compounds are antimicrobial agents. In some embodiments, the compounds are antibacterial agents. In some embodiments, any of the disclosed compounds may provide the antimicrobial activity against bacteria selected from the group consisting of: Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Enterococcus faecalis, Staphylococcus aureus (including Methicillin-resistant S. aureus), Serratia marcescens, Shigella dysenteriae, Enterobacter aerogenes, Salmonella paratyphi, and a combination thereof. [0092] In some embodiments, any of the disclosed compounds can be configured to inhibit LOX in cells, in vitro and in situ, which may be in addition to or alternative to the antimicrobial activity. For example, any of the disclosed compounds may inhibit 5-LOX and/or 15-LOX in cells in vitro and/or in situ. In some embodiments, any of the disclosure comound may provide antibacterial activated and inhibit LOX activity, and may be referred to as “dual-activity compounds”. In some such embodiments, the compounds can provide the antimicrobial activity against bacteria selected from the group consisting of: Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Enterococcus faecalis, Staphylococcus aureus, Serratia marcescens, Shigella dysenteriae, Enterobacter aerogenes, Salmonella paratyphi, and a combination thereof, and inhibit LOX selected from the group consisting of 5-LOX, 15-LOX, and a combination thereof. [0093] In some embodiments, the compounds disclosed herein have the structure of Formula II, wherein Formula II is: Formula II [0094] In some embodiments, ring A is a 5 membered heterocyclic ring or a 5 membered heteroaryl ring that is substituted with one R1 group. [0095] In some embodiments, ring B is a 6 membered heterocyclic ring, a 6 membered heteroaryl, a 6 membered aromatic ring, or a 6 membered cycloalkyl ring that is unsubstituted or independently substituted with up to four R2 groups. In some embodiments, ring B is independently substituted with up to two R2 groups. In some embodiments, ring B is independently substituted with four R2 groups, three R2 groups, two R2 groups, one R2 group, or is unsubstituted. [0096] In some embodiments, each X is independently a C or N. In some embodiments, two (or more) members of ring B are N. In some embodiments, one member of ring B is N. In some embodiments, three members of ring B are N. In some embodiments, four members of ring B are N. [0097] In some embodiments, ring C is a 6 membered aromatic ring that is unsubstituted or independently substituted with up to four R3 groups. In some embodiments, ring C is independently substituted with up to three R3 groups. In some embodiments, ring C is independently substituted with four R3 groups, three R3 groups, two R3 groups, one R3 group, or is unsubstituted. [0098] In accordance with various embodiments, the R1, R2, R3, Ra, and/or Rb groups of Formula II can include any of the previously described R1, R2, R3, Ra, and/or Rb groups of Formula I. The full details of which are not repeated. [0099] In some embodiments, the R1 group comprises a H, a halo, C1-6 alkyl, NH(CH2)1-6Ra, (CH2)1-6Ra, (CH2)1-6NH-Ra, NH(CH2)1-6RaRb, CH2NH(CH2)1-6Ra, or a 5-7 membered heterocyclic ring substituted with RaRb. In some embodiments, the R1 group is a H or (CH2)2-3Ra. [00100] In some embodiments, the R1 group is selected from and/or is one of the following structures: , [00101] In some embodiments, the R1 group is selected from and/or is one of the following structures: . [00102] In some example, each R2 group independently comprises a H, a halo, C1-6 alkyl, NH(CH2)1-6Ra, NHRa, or (CH2)1-6Ra, Ra, or C-(Ra)3. In some embodiments, each R2 group independently comprises a H, a halo, NH(CH2)2Ra, NHRa, or (CH2)1-2Ra, or a Ra. [00103] In some embodiments, each R2 group is independently selected from and/or is one of the following structures: , or is independently selected from and/or is one of the following structures:
[00104] In some embodiments, each R3 group independently comprises a H, a halo, C1-6 alkyl, NHRa, NHRaRb, NH(CH2)1-6Ra, O(CH2)1-6Ra,ORa, O(CH2)1-6Ra-(Rb)2, O(CH2)1-6RaRb, (CH2)1-6Ra, (CH2)1-6RaRb, RaRb, or Ra. In some embodiments, each R3 group independently comprises a halo, NHRa, NHRaRb, NH(CH2)1-2Ra, O(CH2)1-3Ra,ORa, O(CH2)2Ra-(Rb)2, O(CH2)2-3RaRb, (CH2)1-3Ra, (CH2)2RaRb, RaRb, or Ra. [00105] In some specific embodiments, each R3 group is selected from and/or is one of the
, [00106] In some embodiments, each Ra and Rb group independently comprises an amine, an imine, a carbonyl, a hydroxyl, a thioamide, a nitrile, -O-alkyl, C1-6 alkyl, a 5-6 membered aromatic ring (which is unsubstituted or substituted), a 5-6 membered cycloalkyl ring, or a 4-6 membered heterocyclic ring. [00107] In some embodiments, each Ra and Rb group is selected from and/or is one of the following structures: , oxidized forms thereof, or is selected from and/or is one of the following structures: thereof. [00108] In some embodiments of Formula II, the compound is selected from: C
,
,
,
,
, , , f. [00109] In some embodiments, the compounds disclosed herein have the structure of Formula III, wherein Formula III is: Formula III [00110] In some embodiments, ring A is a 6 membered heteroaryl ring that is independently substituted with one to three R1 groups. In some embodiments, ring A is independently substituted with three R1 groups, two R1 groups, or one R1 group. [00111] In some embodiments, ring B is a 6 membered heterocyclic ring, a 6 membered aromatic ring, or a 6 membered cycloalkyl ring that is unsubstituted or independently substituted with up to four R2 groups. In some embodiments, ring B is independently substituted with up to two R2 groups. In some embodiments, ring B is independently substituted with four R2 groups, three R2 groups, two R2 groups, one R2 group, or is unsubstituted. [00112] In some embodiments, each X independent comprises C or N. In some embodiments, one member or two members of ring B are N. While Formula III includes two X atoms in ring B, in some embodiments, ring B may include additional X atoms, such as illustrated by Formulas I and II. [00113] In some embodiments, ring C is a 6 membered aromatic ring that is unsubstituted or independently substituted with up to four R3 groups. In some embodiments, ring C is independently substituted with one to three R3 groups. In some embodiments, ring C is independently substituted with four R3 groups, three R3 groups, two R3 groups, one R3 group, or is unsubstituted. [00114] In accordance with various embodiments, the R1, R2, R3, Ra, and/or Rb groups of Formula III can include any of the previously described R1, R2, R3, Ra, and/or Rb groups of Formula I. The full details of which are not repeated. [00115] In some embodiments, each R1 group independently comprises a H, a halo, C1-6 alkyl, NH(CH2)1-6Ra, (CH2)1-6Ra, (CH2)1-6NH-Ra, NH(CH2)1-6RaRb, CH2NH(CH2)1-6Ra, or a 5-7 membered heterocyclic ring substituted with RaRb. In some embodiments, each R1 group independently comprises a halo, NH(CH2)2Ra, (CH2)2Ra, NH(CH2)2RaRb, CH2NH(CH2)2Ra, or a 6 membered heterocyclic ring substituted with RaRb. [00116] In some embodiments, each R1 group is independently selected from and/or is one of the following structures: , independently selected from and/or is one of the following structures: . [00117] In some embodiments, each R2 group independently comprises a H, a halo, C1-6 alkyl, NH(CH2)1-6Ra, NHRa, (CH2)1-6Ra, Ra, or C-(Ra)3. In some embodiments, each R2 group independently comprises a halo or C-(Ra)3. [00118] In some embodiments, each R2 group is independently selected from and/or is one of the following structures: , . [00119] In some embodiments, each R2 group is independently selected from and/or is one of the following structures: . [00120] In some embodiments, each R3 group independently comprises a H, a halo, C1-6 alkyl, NHRa, NHRaRb, NH(CH2)1-6Ra, O(CH2)1-6Ra, ORa, O(CH2)1-6Ra-(Rb)2, O(CH2)1-6RaRb, (CH2)1-6Ra, (CH2)1-6RaRb, RaRb, or Ra. In some embodiments, at least one R3 group is NHRa. In some embodiments, at least one R3 group (or the R3 group) is NH bound to a 6 membered aromatic ring that is substituted with one to three Cl. [00121] In some embodiments, each R3 group is independently selected from and/or is one of the following structures: , , [00122] In some embodiments, each R3 group is independently selected from and/or is one of the following structures: . [00123] In some embodiments, each Ra and Rb group independently comprises a halo, an amine, an imine, a carboxyl, a carbonyl, a hydroxyl, a thioamide, a nitrile, -O-alkyl, C1-6 alkyl, C-(CH3)3, a 5- 6 membered aromatic ring, a 5-6 membered cycloalkyl ring, or a 4-6 membered heterocyclic ring. In some embodiments, each Ra and Rb group independently comprises a halo, an amine, an imine, a carboxyl, CH3, C-(CH3)3, or a 6 membered aromatic ring which is unsubstituted or substituted. [00124] In some embodiments, each Ra and Rb group is selected from and/or is one of the following structures: , forms thereof. [00125] In some embodiments, each Ra and Rb group is selected from and/or is one of the following structures: , and oxidized forms thereof. [00126] In some embodiments, a compound having the structure of Formula III can be selected from:
, [00127] In some embodiments, Formula II and/or Formula III can include an implementations of Formula I. [00128] Some embodiments are directed to methods of inhibiting a LOX and/or providing antimicrobial activity in cells determined to be in need thereof, comprising contacting the cells with (or administering to the cells) a compound having structure disclosed in any of the compounds above, where the cells are human cells that are either in vivo or isolated in vitro. In some embodiments, the cells are in situ as part of a person determined to be in need of LOX inhibition, microbe inhibition, or suffering from a disease associated with pathogenic LOX and/or microbe activity, such as a bacterial infection. In some embodiments, the antimicrobial activity is against a bacteria selected from: Acinetobacter baumannii (A. baumannii), Klebsiella pneumoniae (K. pneumoniae), Pseudomonas aeruginosa (P. aeruginosa), Escherichia coli (E. coli), Enterococcus faecalis (E. faecalis), Staphylococcus aureus (S. aureus), Serratia marcescens (S. marcescens), Shigella dysenteriae (S. dysenteriae), Enterobacter aerogenes (E. aerogenes), Salmonella paratyphi (S. paratyphi), and a combination thereof. In some embodiments, the method includes inhibiting LOX of 5-LOX and/or 15- LOX. In some embodiments, the method includes providing antimicrobial activity against bacterial of A. baumannii, K. pneumoniae, P. aeruginosa, E. coli, E. faecalis, S. aureus (including Methicillin- resistant S. aureus), S. marcescens, S. dysenteriae, E. aerogenes, and S. paratyphi, and inhibiting LOX of 5-LOX and/or 15-LOX. [00129] In some embodiments, when inhibiting LOX, the disease can be selected from an acute or chronic inflammatory disease or a neurodegenerative disease. Some of the methods further comprising: (i) measuring a lipoxygenase activity in a sample of the person; (ii) determining a level of a lipoxygenase metabolite in a sample of the person; or (iii) determining the person has the disease. In some of the methods, the disease is: (i) an acute or chronic inflammatory disease that is asthma, rheumatoid arthritis, inflammatory bowel disease, psoriasis, hereditary ichthyosis, dermatitis, nephritis, atherosclerosis, or cardiovascular disease, or (ii) a neurodegenerative disease that is age- related neurodegeneration, amyloid beta- associated disease, Alzheimer's Disease, ischemia-related disorder, creutzfeldt-jakob disease/prion peptide toxicity, ALS, dementia or Parkinson Disease. [00130] Embodiments include pharmaceutical compositions comprising a compound disclosed above for inhibiting LOX activity and/or providing antimicrobial activity, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Further conceived of are pharmaceutical compositions comprising compounds disclosed above for inhibiting lipoxygenase activity and/or inhibiting microbe (e.g., bacteria) activity, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Further embodiments include compositions comprising a compound of Formula I, Formula II, and/or Formula III and a second anti- neurodegenerative disease drug and/or antimicrobial drug. Further embodiments are directed to methods for identifying a LOX inhibitor and/or antimicrobial agent comprising the step of screening for LOX inhibitory activity and/or antimicrobial activity of the compound(s). [00131] As further described herein, subject compounds can be used in pharmaceutically acceptable alternative forms, such as pharmaceutically acceptable salts, and prodrugs (e.g., sulfamates, phosphates, esters, ethers, amides, etc.), among others. Unless otherwise specified, all references herein to compounds according to the formulas are intended to include such alternative forms. Pharmaceutically acceptable and pharmaceutically active combinations of such forms, such as salts of prodrugs, are within the scope of the disclosure. Example salts and prodrugs are provided herein. [00132] In some embodiments, subject compounds are used to prepare a composition that is effective in treating neurodegenerative diseases (also referred to herein as “neurodegenerative conditions”) and/or treating a bacterial infection. Examples of neurodegenerative diseases include neuroinflammation- associated neurodegeneration, Alzheimer's Disease, ischemia-related disorder, creutzfeldt-jakob disease/prion peptide toxicity, ALS, dementia, and Parkinson Disease. In some embodiments, treatment of a neurodegenerative disease involves administering a formulation containing a subject compound. Example bacterial infections include infections from A. baumannii, K. pneumoniae, P. aeruginosa, E. coli, E. faecalis, S. aureus (including Methicillin-resistant S. aureus), S. marcescens, S. dysenteriae, E. aerogenes, and S. paratyphi, as well as combinations thereof. In some embodiments, the composition may comprise one or more antimicrobial agents and one or more pharmaceutically acceptable additives. Furthermore, the compositions may be formulated into any suitable dosage form. [00133] In some embodiments, the subject compositions contain a compound according to Formula I, Formula II, and/or Formula III as the sole active agent; such formulations may include pharmaceutically inactive components, such as carriers. [00134] In some embodiments, the compounds are administered in combination with one or more additional anti-neurodegenerative disease drug(s) and/or antimicrobial drugs. The additional drug may be present with a subject compound in a single formulation, and therefore administered at the same time. Alternatively, the additional drug may be in a separate formulation, and may be administered according to a regimen that is separate from the regimen for administration of the formulation containing a subject compounds. In such embodiments the two regimens may be related; for example, the second formulation is administered along with, or immediately before, or immediately after administration of the first formulation. Examples of additional anti-neurodegenerative disease drugs include acetylcholinesterase inhibitors (e.g., tacrine, rivastigmine, galantamine, donepezil, etc.), N- methyl-D-aspartate (NMDA) receptor antagonists (e.g., memantine), hyperzine A, latrepirdine, and hypothalamic proline-rich peptide 1 (PRP-1), among others. Examples of additional antimicrobial drugs include various antibiotics, such as but not limited to cephalexin, amoxicillin, azithromycin, sulfamethoxazole, trimethoprim, metronidazole, and ciprofloxacin, among others. [00135] In some embodiments, the compounds may be administered as a free base, or in the form of a salt, ester, amide, prodrug, active metabolite, and an analog, among others, provided that the salt, prodrug, active metabolite or analog is pharmaceutically acceptable and pharmacologically active in the present context. Salts, esters, amides, prodrugs, active metabolites, analogs, and other derivatives of the active agents may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, by J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 5th Ed. (New York: Wiley-Interscience, 2001), and Green, Protective Groups in Organic Synthesis, 3rd Ed. (New York: Wiley-Interscience, 1999). [00136] A pharmaceutically acceptable salt may be prepared from any pharmaceutically acceptable organic acid or base, any pharmaceutically acceptable inorganic acid or base, or combinations thereof. [00137] Suitable organic acids for preparing acid addition salts include, e.g., C1-C6 alkyl and C6- C12 aryl carboxylic acids, di-carboxylic acids, and tri-carboxylic acids such as acetic acid, propionic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, glycolic acid, citric acid, pyruvic acid, oxalic acid, malic acid, malonic acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, phthalic acid, and terephthalic acid, and aryl and alkyl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid, among others. Suitable inorganic acids for preparing acid addition salts include, e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, among others. An acid addition salt may be reconverted to the free base by treatment with a suitable base. [00138] Suitable organic bases for preparing basic addition salts include, e.g., primary, secondary and tertiary amines, such as trimethylamine, triethylamine, tripropylamine, N,N- dibenzylethylenediamine, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, glucamine, glucosamine, histidine, and polyamine resins, cyclic amines such as caffeine, N-ethylmorpholine, N- ethylpiperidine, and purine, and salts of amines such as betaine, choline, and procaine, among others. Suitable inorganic bases for preparing basic addition salts include, e.g., salts derived from sodium, potassium, ammonium, calcium, ferric, ferrous, aluminum, lithium, magnesium, or zinc such as sodium hydroxide, potassium hydroxide, calcium carbonate, sodium carbonate, and potassium carbonate, among others. A basic addition salt may be reconverted to the free acid by treatment with a suitable acid. [00139] Prodrugs and active metabolites may be prepared using techniques known to those skilled in the art. Prodrugs are typically prepared by covalent attachment of a moiety that results in a compound that is therapeutically inactive until modified by an individual's metabolic system. For example, a compound according to Formula I, Formula II, and/or Formula III may be in the form of a pharmaceutically acceptable prodrug such as the sulfamate prodrug. [00140] Other derivatives and analogs of the active agents may be prepared using standard techniques known to those skilled in the art of synthetic organic chemistry or may be deduced by reference to the pertinent literature. [00141] Any of the compounds described herein may be the active agent in a subject formulation. Formulations containing the compounds of the disclosure may include 1, 2, 3 or more of the subject compounds, and may also include one or more additional active agents such as analgesics and other antibiotics. By “any of the compounds of the disclosure” is meant any compound selected from a subject compound per se (e.g., as a free base) and salts, prodrugs, etc. thereof. [00142] The amount of active agent in the formulation typically ranges from about 0.05 weight percent (wt%) to about 95 wt% based on the total weight of the formulation. For example, the amount of active agent may range from about 0.05 wt% to about 50 wt%, or from about 0.1 wt% to about 25 wt%. Alternatively, the amount of active agent in the formulation may be measured so as to achieve a desired dose. [00143] Formulations containing a subject compound may be presented in unit dose form or in multi-dose containers with an optional preservative to increase shelf life. [00144] The compositions of the present disclosure may be administered to the patient by any method. In general, both systemic and localized methods of administration are acceptable. It will be obvious to those skilled in the art that the selection of a method of administration is influenced by factors, such as the condition being treated, frequency of administration, dosage level, and the wants and needs of the patient. For example, certain methods may be better suited for rapid delivery of high doses of active agent, while other methods may be better suited for slow, steady delivery of active agent. Examples of methods of administration that are suitable for delivery of the compounds of the disclosure include parental and transmembrane absorption (including delivery via the digestive and respiratory tracts). Formulations suitable for delivery via these methods are well known in the art. [00145] For example, formulations containing the compounds of the present disclosure may be administered parenterally, such as via intravenous, subcutaneous, intraperitoneal, or intramuscular injection, using bolus injection and/or continuous infusion. Generally, parenteral administration employs liquid formulations. [00146] The compositions may also be administered via the digestive tract, including orally and rectally. Examples of formulations that are appropriate for administration via the digestive tract include tablets, capsules, pastilles, chewing gum, aqueous solutions, and suppositories. [00147] The formulations may also be administered via transmucosal administration. Transmucosal delivery includes delivery via the oral (including buccal and sublingual), nasal, vaginal, and rectal mucosal membranes. Formulations suitable for transmucosal deliver are well known in the art and include tablets, chewing gums, mouthwashes, lozenges, suppositories, gels, creams, liquids, and pastes. [00148] The formulations may also be administered transdermally. Transdermal delivery may be accomplished using, for example, topically applied creams, liquids, pastes, and gels, among others, as well as what is referred to as transdermal “patches.” [00149] The formulations may also be administered via the respiratory tract. Pulmonary delivery may be accomplished via oral or nasal inhalation, using aerosols, dry powders, and liquid formulations, among others. Aerosol inhalers and imitation cigarettes are examples of pulmonary dosage forms. [00150] Liquid formulations include solutions, suspensions, and emulsions. For example, solutions may be aqueous solutions of the active agent and may include propylene glycol and/or polyethylene glycol, among others. Aqueous suspensions can be made by dispersing the finely divided active agent in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other known suspending agents. Also included are formulations of solid form which are intended to be converted, shortly before use, to liquid form. [00151] Tablets and lozenges may comprise, for example, a flavored base such as compressed lactose, sucrose and acacia or tragacanth and an effective amount of an active agent. Pastilles generally comprise the active agent in an inert base, such as gelatin and glycerine or sucrose and acacia. [00152] The subject compounds may inhibit one or more LOX and/or reduce bacteria, e.g., by at least 50 percent (%), or by at least 75%, or by at least 85%, or by at least 95%, or by at least 98%. In some embodiments, the compounds are selective inhibitors, and are inhibitors of a subsection of the LOX family of enzymes and/or providing antibacterial activity. In some embodiments, the subject compounds may inhibit 5-LOX, or 15-LOX. In some embodiments, the subject compounds may inhibit various combinations of 5-LOX and 15-LOX, such as inhibiting 5-LOX, or inhibiting 15-LOX or inhibiting 5-LOX and 15-LOX. In some embodiments, the compounds provide antibacterial activity against A. baumannii, K. pneumoniae, P. aeruginosa, E. coli, E. faecalis, S. aureus (including Methicillin-resistant S. aureus), S. marcescens, S. dysenteriae, E. aerogenes, and/or S. paratyphi. [00153] Subject compounds are useful in therapies for treating diseases associated with pathogenic lipoxygenase activity, particularly acute and chronic inflammatory diseases, such as asthma, rheumatoid arthritis, inflammatory bowel disease, psoriasis, hereditary ichthyosis, dermatitis, nephritis, atherosclerosis, cardiovascular diseases, neurodegenerative diseases, such as age-related neurodegeneration, neuroinflammation-associated disease, Alzheimer's Disease, ischemia-related disorder, creutzfeldt-jakob disease/prion peptide toxicity, ALS, dementia and Parkinson Disease. [00154] Subject compounds are useful in therapies for treating diseases associated with bacterial infections, such as treating an infection from A. baumannii, K. pneumoniae, P. aeruginosa, E. coli, E. faecalis, S. aureus (including Methicillin-resistant S. aureus), S. marcescens, S. dysenteriae, E. aerogenes, and/or S. paratyphi. In some embodiments, the compounds can be used to treat multiple types of bacterial infections concurrently in the same patient or in different patients. [00155] For example, the methods may involve administering a subject compound to a patient in need thereof (e.g., a patient suffering from bacterial infection, and/or a patient suffering from a neurodegenerative disease such as Alzheimer’s Disease, or a patient or a patient at risk for such conditions, or a patient exhibiting symptoms of such conditions, etc.). In some embodiments, the compound(s) are used in a method for reducing or eliminating the severity of symptoms associated with a subject disease. For example, the method may involve contacting nervous system cells or cells located in a nervous system, or contacting tissue associated with a nervous system, and such contacting results in one or more of the following: the inhibition of further neurodegeneration; the inhibition of abnormal cell growth and development; the inhibition of growth of non-cell objects in a nervous system; the reduction of neuroinflammation; the reduction in severity of symptoms associated with a neurodegenerative disease; inhibition of further bacterial growth or infection; the reduction in severity of symptoms associated with bacterial infection; among others and in various combinations. [00156] In some embodiments, the example compounds are used to prepare a composition that is effective in treating a subject disease. As described herein, the composition may comprise one or more active agents and one or more pharmaceutically acceptable additives. Furthermore, the compositions may be formulated into any suitable dosage form. [00157] In some embodiments, treatment of a subject disease involves administering a formulation containing a disclosed compound. As described herein, such formulations may include additives and/or additional active agents, and such formulations may be prepared in any of a variety of dosage forms. In some embodiments, treatment of a subject disease using a compound involves determining that the person has a subject disease associated with pathogenic LOX activity and/or bacterial infection. Such determination may be made by any means appropriate for the particular condition, including blood tests and imaging tests. [00158] In some embodiments, the methods involve measuring a LOX activity (such as 5-LOX, or 15-LOX, and/or various combinations thereof) and/or bacteria activity (such as in a patient prior to treatment with a subject compound, after treatment with a subject compound, or both prior to and after treatment. In some embodiments, the methods involve measuring a level of a LOX metabolite in a patient. An example metabolite is 5-HETE. In such methods, measuring enzyme activity or measuring metabolite levels may be carried out using any appropriate sample from the person, such as a body fluid (e.g., blood, urine, etc.). [00159] Some embodiments are directed to methods of forming (e.g., synthesizing) any of the above-disclosed compounds, such as those of Formula I, Formula II, and/or Formula III. Specific examples of forming the compounds are further provided below in the Experimental Embodiments. Methods of forming such compounds are not limited to the specific examples provided and may include variations. [00160] Various embodiments are implemented in accordance with the underlying Provisional Application (Ser. No.63/430,432), entitled “Antimicrobial Agents”, filed December 6, 2022, to which benefit is claimed and which is fully incorporated herein by reference for its general and specific teachings. For instance, embodiments herein and/or in the provisional application can be combined in varying degrees (including wholly). Reference can also be made to the experimental teachings and underlying references provided in the underlying Provisional Application. Embodiments discussed in the Provisional Application are not intended, in any way, to be limiting to the overall technical disclosure, or to any part of the claimed disclosure unless specifically noted. [00161] All patents, patent applications, and publications mentioned herein are hereby incorporated by reference in their entireties. However, where a patent, patent application, or publication containing express definitions is incorporated by reference, those express definitions should be understood to apply to the incorporated patent, patent application, or publication in which they are found, and not to the remainder of the text of this application, in particular the claims. [00162] It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, that the foregoing description and the examples that follow are intended to illustrate and not limit the scope of the invention. It will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the scope of the invention, and further that other aspects, advantages and modifications will be apparent to those skilled in the art to which the invention pertains. EXPERIMENTAL EMBODIMENTS [00163] The compounds disclosed herein were assessed for antimicrobial activity against a panel of bacteria. Such bacteria included A. baumannii, K. pneumoniae, P. aeruginosa, E. coli, E. faecalis, S. aureus, S. marcescens, S. dysenteriae, E. aerogenes, and S. paratyphi. [00164] Anti-bacterial Assay [00165] Broth microdilution assay was used to determine Minimum inhibitory concentration (MIC). A small aliquot (e.g., 10 microliter (µL)) was removed from appropriate dilutions in the 96- well plate used to determine the MIC value with subsequent streaking on agar plates. Five wells were selected, representing the well yielding the MIC value and 2 wells above and below the well that yield the MIC value (microgram (µg)/milliliter (mL)). After 48 hours of incubation at 37 degrees Celsius (oC) with 5% CO2, the agar plates were inspected for the presence or absence of growth. [00166] The compounds were found to have antimicrobial activity against various bacteria. In some experiments, the inhibitory activity of the compounds against a panel of bacteria was demonstrated in cell-based assays. Such bacteria included: A. baumannii (ATCC AB 1605 multi-drug resistant), A. baumannii (ATCC BAA 1790 multi-drug resistant,) A. baumannii (ATCC BAA 1793 multi-drug resistant), K. pneumoniae (ATCC 43816), P. aeruginosa (ATCC 27853), E. coli (ATCC 25922 pan sensitive), E. faecalis (ATCC 51299 vancomycin resistant), E. faecalis (ATCC 29212 pan sensitive), S. aureus (MRSA NRS382 methicillin resistant), S. aureus (ATCC 29213 pan sensitive), S. marcescens (ATCC 14756), S. dysenteriae (ATCC 49345), E. aerogenes (ATCC 29751, ampicillin resistant), S. paratyphi (BAA 1250) , and E. faecalis (ATCC 51575 vancomycin resistant). [00167] Table 1 and Table 2 provide the MIC values for various compounds against bacteria: Table 1
Table 2 [00168] 5-LOX Fluorescent Assay [00169] The enzyme assay (100 microliter (μL)) contained 50 milli-molarity (mM) Tris, pH 7.5, 0.1 mM EDTA, 0.3 mM CaCl2, 20 micro-molarity (μM) AA, 100 μM ATP, 1 μM DHR123, and recombinant 5-LOX cell lysate (0.5 μL/100 μL). Inhibitors (dissolved in DMSO) were plated at 1 μL into 96-well assay microplates followed by a 40 μL addition of a solution containing 5-LOX enzyme. Enzyme was pre-incubated with compounds for 15 minutes. The assay was initiated by the addition of a 40 μL substrate solution containing AA and ATP, and 20 μL addition of a solution containing DHR123. Enzymatic reaction proceeded for 30 minutes with kinetic reading at 500 nanometer (nm) excitation and 536 nm emission in SpectraMax Paradigm (MolecularDevice). Percent inhibition was calculated for each compound dose for IC50 curve fitting using 4 Parameter Logistic Model or Sigmoidal Dose-Response Model. [00170] 15-LOX Fluorescent Assay [00171] The enzyme assay (100 μL) contained 50 mM Tris, pH 7.5, 0.05% Tween-20, 20 μM AA/LA, 1μM DHR123, and 50 nanomolarity (nM) recombinant 15-LOX enzyme. Inhibitors (dissolved in DMSO) were plated at 1 μL into 96-well assay microplates followed by a 40 μL addition of a solution containing 15-LOX enzyme. Enzyme was pre-incubated with compounds for 15 minutes. The assay was initiated by the addition of a 40 μL substrate solution containing AA/LA, and 20 μL addition of a solution containing DHR123. Enzymatic reaction proceeded for 30 minutes with kinetic reading at 500 nm excitation and 536 nm emission in SpectraMax Paradigm (MolecularDevice). Percent inhibition was calculated for each compound dose for IC50 curve fitting using 4 Parameter Logistic Model or Sigmoidal Dose-Response Model. Inhibitory activity against a panel of LOXs was demonstrated in cell-based assays, e.g., for 5-LOX, a fluorescence-based enzyme assay of human 5- LOX (Anal. Biochem., 364:204.) was used, and for 5-LOX, a colorimetric method to determine platelet 15-LOX activity (Anal. Biochem., 231:354) was used. Table 3 provides results for compounds on 5-LOX and 15-LOX. Table 3: IC50 (μM) values for in vitro lipoxygenase inhibition
[00172] General information Examples: All evaporations were carried out in vacuo with a rotary evaporator. Analytical samples were dried in vacuo (1-5 millimeters of mercury (mmHg)) at room temperature. Thin layer chromatography (TLC) was performed on silica gel plates, spots were visualized by ultraviolet (UV) light (214 and 254 nm). Purification by column and flash chromatography was carried out using silica gel (200-300 mesh). Solvent systems are reported as mixtures by volume. All NMR spectra were recorded on a Bruker 400 (400 megaHertz (MHz)) spectrometer.1H chemical shifts are reported in δ values in parts per million (ppm) with the deuterated solvent as the internal standard. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constant (Hz), integration. [00173] Example 1:
[00175] The synthesis of 2-(3,5-Dibromophenyl)acetamide (7-3b): DMF (15 drops) was added to a solution of oxalyl dichloride (8.64 gram (g), 68.04 millimole (mmol)) and 2-(3,5-dibromophenyl)acetic acid (10.0 g, 34.02 mole (mol)) portion-wise. After stirring at room temperature for 2 hours, the mixture was concentrated and the residue was dissolved in DCM (100 mL). The solution was added to a mixture of ammonia solution (25% in water, 50 mL) in DCM (100 mL) drop wise. The resulting mixture was stirred at room temperature overnight. The DCM was removed by vacuum. The aqueous layer was extracted with EtOAc (100 mL × 3). The combined organic phase was dried and concentrated to give a white solid with 64% yield as a white solid. [00176] 1 H NMR (400 MHz, DMSO-d6) ^ 7.71 (t, J = 1.6 Hz, 1H), 7.54 (s, 1H), 7.49 (d, J = 2.0 Hz, 2H), 7.01 (s, 1H), 3.41 (s, 2H). MS: (ESI) m/z 291.7 (M + H) +. [00177] The synthesis of 2-(5-Bromo-5'-chloro-2'-(4-methylphenylsulfonamido)-[1,1'-biphenyl]- 3-yl)acetamide (7-4): To a solution of 2-(3,5-dibromophenyl)acetamide (5.75 g, 19.62 mmol, 4 eq) in 1,4-dioxane and H2O (40 mL, 1,4-dioxane : H2O = 1:1) were added Pd(PPh3)4 (284 mg, 0.25 mmol, 5 mol%), Na2CO3 (1.04 g, 9.81 mmol, 2 eq), and 4-chloro N-Ts-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.0 g, 4.91 mmol, 1.0 eq) under N2. After being stirred at 90 °C for 16 hours, the reaction mixture was cooled to room temperature. EtOAc (1L) was added and the organic layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified column chromatography (petroleum ether, petroleum ether/ethyl acetate = 5/1, 1/1) to give 1.86 g of title compound in 77% yield as a white solid. [00178] 1H NMR (400 MHz, DMSO-d6) ^ 9.66 (s, 1H), 7.37-7.46 (m, 5H), 7.25-7.30 (m, 3H), 7.22 (d, J = 8.8 Hz, 1H), 7.10 (s, 1H), 7.04 (s, 1H), 7.01 (br, 1H), 3.38 (s, 2H), 2.37 (s, 3H). MS: (ESI) m/z 491.9 (M - H)–. [00179] The synthesis of 2-(3-Bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)acetamide (7-5): A solution of PhI(OAc)2 (1.82 g, 5.65 mmol, 1.5 eq) in DCM (20 mL) was added to a mixture of 2-(5- bromo-5'-chloro-2'-(4-methylphenylsulfonamido)-[1,1'-biphenyl]-3-yl)acetamide (1.86 g, 3.77 mmol, 1 eq), Cu(OTf)2 (69 mg, 0.19 mmol, 5 mol%) and TFA (1.29 g, 11.30 mmol, 3 eq) in DCM (40 mL) at reflux. After 10 minutes, the reaction was complete; the reaction mixture was concentrated in vacuo. The residue was purified column chromatography (petroleum ether, petroleum ether/ethyl acetate = 5/1, 1/1) to give 787 mg of title compound in 42% yield as a brown solid. [00180] 1H NMR (400 MHz, DMSO-d6) ^ 8.20 (d, J = 2.0 Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 8.10 (d, J = 9.2 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.57 (dd, J = 9.0, 2.2 Hz, 1H), 7.55 (br, 1H), 7.05-7.11 (m, 4H), 7.01 (br, 1H), 4.07 (s, 2H), 2.19 (s, 3H). MS: (ESI) m/z 491.0 (M + H) +. [00181] The synthesis of tert-Butyl (2-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1- yl)ethyl)carbamate (7-5b): A solution of 2-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)acetamide (500 mg, 1.02 mmol) in borane-tetrahydrofuran complex (1 molarity (M) in THF, 10 ml, 10 mmol) was stirred at room temperature overnight. The reaction mixture was quenched with methanol and then concentrated. The residue was dissolved in DCM, washed with brine, the organic layer was dried (Na2SO4) and the solvent was evaporated. The residue was dissolved in DCM (20 mL), di-tert-butyl dicarbonate (333 mg, 1.53 mmol) and Et3N (6 mg, 0.046 mmol) was added. After stirring at room temperature overnight, the reaction solution was concentrated and purified by column chromatography (petroleum ether, petroleum ether/ethyl acetate = 100/1, 50/1, 20/1) to give 339 mg of title compound in 58% yield as pale brown oil. [00182] 1H NMR (400 MHz, Chloroform-d) ^ 8.10 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 1.6 Hz, 1H), 7.55 (br, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 8.6, 2.2 Hz, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.0 Hz, 2H), 4.74 (br, 1H), 3.55 – 3.65 (m, 2H), 3.45 – 3.51 (m, 2H), 2.24 (s, 3H), 1.43 (s, 9H). MS: (ESI) m/z 575.0 (M - H)- . [00183] The synthesis of tert-Butyl (2-(6-chloro-3-((4-chlorophenyl)amino)-9H-carbazol-1- yl)ethyl)carbamate (7-7b): tert-butyl (2-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)ethyl)carbamate (339 mg, 0.59 mmol), 4- chloroaniline (98 mg, 0.77 mmol), palladium acetate (27 mg, 0.12 mmol), XPhos (70 mg, 0.15 mmol) and cesium carbonate (574 mg, 1.76 mmol) were dissolved in 1,4-dioxane (35 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 degrees Celsius (°C) overnight. The mixture was cooled to room temperature and ethyl acetate was added, filtered through celite. Concentrated and purified on column chromatography (petroleum ether, petroleum ether/ethyl acetate = 20/1, 10/1, 5/1) to give 30 mg of 7-7b (11% yield) as brown oil and 100 mg of 7-7a (27% yield) as brown oil. [00184] 1H NMR (400 MHz, DMSO-d6) 8.54 (s, 1H), 7.99 – 8.04 (m, 2H), 7.46 – 7.51 (m, 2H), 7.28 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 6.94 (br, 1H), 3.25 – 3.35 (m, 4H), 2.20 (s, 3H), 1.33 (s, 9H). MS: (ESI) m/z 468.0 (M - H)-. [00185] The synthesis of 1-(2-Aminoethyl)-6-chloro-N-(4-chlorophenyl)-9H-carbazol-3-amine (7- 7c): A solution of tert-butyl (2-(6-chloro-3-((4-chlorophenyl)amino)-9H-carbazol-1-yl)ethyl)carbamate (10 mg, 0.021 mmol) in TFA (5% in DCM, 1 mL) was stirred at room temperature overnight. The reaction solution was concentrated and used for the next step directly. [00186] The synthesis of (1a): 1-(2-aminoethyl)-6-chloro-N-(4-chlorophenyl)-9H-carbazol-3-amine (9 mg, 0.021 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (7 mg, 0.023 mmol) and Et3N (6 mg, 0.046 mmol) in DMF (1 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water (4 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The residue was purified by Prep-TLC (dichloromethane/petroleum ether = 1/1) to give 10 mg of title compound in 77% yield as a brown solid. MS: (ESI) m/z 611.9 (M + H)+. [00187] The synthesis of 1-(2-(6-Chloro-3-((4-chlorophenyl)amino)-9H-carbazol-1- yl)ethyl)guanidine (SRI-32453): A solution of 1a (30 mg, 0.049 mmol) in TFA (10% in DCM, 3 mL) was stirred at room temperature overnight. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (11 mg, 54%) as a gray solid. [00188] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.37 (s, 1H, formic acid), 8.15 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.21 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 2.0 Hz, 1H), 6.99 (d, J = 8.8 Hz, 2H), 3.51 (t, J = 7.2 Hz, 2H), 3.11 (t, J = 7.0 Hz, 2H). MS: (ESI) m/z 411.9 (M + H)+. [00189] Example 2: [00190] Example Route for Example 2 (SRI-32468): [00191] The synthesis of6-Chloro-N4-(2-(6-chloro-3-((4-chlorophenyl)amino)-9H-carbazol-1- yl)ethyl)pyrimidine-2,4-diamine (SRI-32468): 1-(2-aminoethyl)-6-chloro-N-(4-chlorophenyl)-9H- carbazol-3-amine (42 mg, 0.087 mmol), 4,6-dichloropyrimidin-2-amine (29 mg, 0.177 mmol) and Et3N (27 mg, 0.267 mmol) in DMF (2 mL) was stirred at 90 °C for overnight. The reaction was quenched with water (10 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The residue was purified by Prep-TLC (ethyl acetate /petroleum ether = 3/1) to give 10.7 mg of title compound in 25% yield as an off-white solid. [00192] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.13 (d, J = 2.0 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.17 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 1.6 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 5.81 (br, 1H), 3.56-3.67 (m, 2H), 3.12 (t, J = 6.6 Hz, 2H). MS: (ESI) m/z 496.9 (M + H)+. [00193] Example 3: [00194] Example Route for Example [00195] The synthesis of 1-(2-(6-Chloro-3-((4-chlorophenyl)amino)-9H-carbazol-1-yl)ethyl)-3- methylguanidine (SRI-32469): 1-(2-aminoethyl)-6-chloro-N-(4-chlorophenyl)-9H-carbazol-3-amine (30 mg, 0.081 mmol), methyl methylcarbamimidothioate hydroiodide (38 mg, 0.164 mmol) and Et3N (41 mg, 0.41 mmol) in THF (9 mL) was stirred at room temperature for overnight. The reaction was quenched with water (40 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The residue was purified by Prep-HPLC to give 15.7 mg of title compound in 45% yield as a gray solid. [00196] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.34 (s, 1H, formic acid), 8.13 (d, J = 1.6 Hz, 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.42 (dd, J = 8.8, 2.0 Hz, 1H), 7.23 (d, J = 8.8 Hz, 2H), 7.13 (s, 1H), 7.00 (d, J = 8.8 Hz, 2H), 3.54 (t, J = 6.4 Hz, 2H), 3.13 (t, J = 7.0 Hz, 2H), 2.70 (s, 3H). MS: (ESI) m/z 426.0 (M + H)+. [00197] Example 4: [00198] Example Route for Example 4 (SRI-32470): [00199] The synthesis of N-(2-(6-Chloro-3-((4-chlorophenyl)amino)-9H-carbazol-1- yl)ethyl)cyanamide (3a): Cyanogen bromide (29 mg, 0.27 mmol) in dichloromethane (1 mL) was added to a solution of 1-(2- aminoethyl)-6-chloro-N-(4-chlorophenyl)-9H-carbazol-3-amine (100 mg, 0.27 mmol) and sodium acetate (111 mg, 1.35 mmol) in methanol (2 mL) drop wise at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours and then warmed to room temperature overnight. The solvent was removed in vacuum. The residue was dissolved in water (10 mL). The product was extracted with dichloromethane (3 x 10 mL), dried over Na2SO4, concentrated to give 78 mg of title compound in 73% yield as a brown solid. MS: (ESI) m/z 393.0 (M - H)-. [00200] The synthesis of 1-(2-(6-Chloro-3-((4-chlorophenyl)amino)-9H-carbazol-1-yl)ethyl)-3- hydroxyguanidine (SRI-32470): A mixture of N-(2-(6-chloro-3-((4-chlorophenyl)amino)-9H-carbazol-1-yl)ethyl)cyanamide (30 mg, 0.076 mmol), hydroxylamine hydrochloride (53 mg, 0.76 mmol) and potassium carbonate (53 mg, 0.38 mmol) in methanol (4 mL) was stirred at room temperature overnight. The solid was removed by filtration. The filtrate was acidified with formic acid to pH 5~6. The solvent was removed in vacuum. The residue was purified by Prep-HPLC to give 10.4 mg of title compound in 32% yield as a gray solid. [00201] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.29 (s, 1H, formic acid), 8.06 (d, J = 2.0 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.33 (dd, J = 8.8, 2.0 Hz, 1H), 7.14 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 2.0 Hz, 1H), 6.92 (d, J = 9.2 Hz, 2H), 3.45 (t, J = 7.0 Hz, 2H), 3.05 (t, J = 7.0 Hz, 2H). MS: (ESI) m/z 428.0 (M + H)+. [00202] Example 5: [00203] [00204] The synthesis of N-(2-(6-Chloro-3-((4-chlorophenyl)amino)-9H-carbazol-1- yl)ethyl)hydrazinecarboximidamide (SRI-32485): A mixture of N-(2-(6-chloro-3-((4- chlorophenyl)amino)-9H-carbazol-1-yl)ethyl)cyanamide (20 mg, 0.051 mmol), hydrazine hydrochloride (35 mg, 0.51 mmol) and potassium carbonate (35 mg, 0.25 mmol) in methanol (4 mL) was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was purified by Prep-HPLC to give 2.9 mg of title compound in 14% yield as a gray solid. [00205] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.38 (s, 1H, formic acid), 8.15 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 1.6 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.41 (dd, J = 8.8, 2.0 Hz, 1H), 7.22 (d, J = 8.8 Hz, 2H), 7.11 (s, 1H), 6.99 (d, J = 8.8 Hz, 2H), 3.56 (t, J = 6.8 Hz, 2H), 3.13 (t, J = 6.0 Hz, 2H). MS: (ESI) m/z 427.0 (M + H)+. [00206] Example 6: [00207] [00208] The synthesis of SRI-32486: 1-(2-Aminoethyl)-6-chloro-N-(4-chlorophenyl)-9H- carbazol-3-amine (60 mg, 0.16 mmol), dicyandiamide (16 mg, 0.19 mmol) and chlorotrimethylsilane (124 mg, 1.14 mmol) in acetonitrile (2 mL) was stirred at 130 °C for 1 hour under microwave irradiation. The reaction was concentrated and purified by Prep-HPLC to give 16 mg of title compound in 22% yield as an off-white solid. [00209] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.36 (s, 2H, formic acid), 8.22 (d, J = 2.0 Hz, 1H), 8.16 (d, J = 1.6 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.50 (dd, J = 8.4, 2.0 Hz, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 1.6 Hz, 1H), 3.20-3.28 (m, 4H). MS: (ESI) m/z 454.0 (M + H)+. [00210] Example 7: [00212] The synthesis of 1-(Pyrimidin-2-yl)thiourea (11-3): Pyrimidin-2-amine (1.0 g, 10.51 mmol) and benzoyl isothiocyanate (1.89 g, 11.57 mmol) in acetone (20 mL) was heated to reflux for 4 hours. The reaction mixture was cooled down to room temperature and diluted with water. The resulting solid was collected by filtration. The cake was dissolved in methanol (50 mL) and 1 N NaOH (25 mL). After stirring at 85 °C for 1 hour, the reaction was cooled down to room temperature and diluted with water. The resulting solid was collected by filtration. The cake was dried to give 920 mg of title compound in 56% yield as an off-white solid. MS: (ESI) m/z 155.2 (M + H)+. [00213] The synthesis of methyl pyrimidin-2-ylcarbamimidothioate (11-4): A mixture of compound 1-(pyrimidin-2-yl)thiourea (500 mg, 3.24 mmol) and iodomethane (553 mg, 3.89 mmol) in methanol (10 mL) was stirred at 50 °C overnight. The reaction mixture was cooled down to room temperature and then filtered. The cake was washed with methanol. The filtrate was concentrated and the residue was washed with ethyl acetate to give 730 mg of title compound in 76% yield as an off-white solid. MS: (ESI) m/z 169.2 (M + H)+. [00214] The synthesis of 1-(2-(6-Chloro-3-((4-chlorophenyl)amino)-9H-carbazol-1-yl)ethyl)-3- (pyrimidin-2-yl)guanidine (SRI-32487):
1-(2-Aminoethyl)-6-chloro-N-(4-chlorophenyl)-9H-carbazol-3-amine (35 mg, 0.095 mmol), methyl pyrimidin-2-ylcarbamimidothioate (16 mg, 0.095 mmol) and Et3N (19 mg, 0.19 mmol) in THF (2 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by Prep-HPLC to give 19.4 mg of title compound in 42% yield as an off-white solid. [00215] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.56 (s, 2H, formic acid), 8.36 (s, 1H), 8.15 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.50 (br, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.11-7.18 (m, 4H), 6.95 (d, J = 8.4 Hz, 2H), 3.75 (br, 2H), 3.24 (br, 2H). MS: (ESI) m/z 489.8 (M + H)+. [00216] Example 8: [00218] The synthesis of 1-(2-(6-Chloro-3-((4-chlorophenyl)amino)-9H-carbazol-1-yl)ethyl)-3- methoxyguanidine (SRI-32488): A mixture of N-(2-(6-chloro-3-((4-chlorophenyl)amino)-9H- carbazol-1-yl)ethyl)cyanamide (31 mg, 0.078 mmol), O-methylhydroxylamine hydrochloride (131 mg, 1.57 mmol) and potassium carbonate (1.1 mg, 0.0078 mmol) in tert-butanol (2 mL) was stirred at reflux for 2 hours. The reaction mixture was concentrated. The residue was purified by Prep-HPLC to give 8.3 mg of title compound in 24% yield as a gray solid. [00219] 1H NMR (400 MHz, CDCl3) δ 7.27 (t, J = 8.0 Hz, 1H), 6.86 (dd, J = 8.0, 0.8 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 3.20-3.15 (m, 2H), 3.00-2.95 (m, 2H).1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.30 (s, 1H, formic acid), 8.14 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.40 (dd, J = 8.8, 2.0 Hz, 1H), 7.21 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 2.0 Hz, 1H), 7.00 (d, J = 8.8 Hz, 2H), 3.54 (s, 3H), 3.43 (t, J = 6.8 Hz, 2H), 3.11 (t, J = 7.2 Hz, 2H). MS: (ESI) m/z 442.0 (M + H)+. [00220] Example 9: [00222] The synthesis of 4-Chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (7-2): To a solution of 2-bromo-4-chloroaniline (40 g, 193.73 mmol) in DMSO (400 mL) was added KOAc (57.04 g, 581.20 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (49.20 g, 193.73 mmol) and Pd(dppf)Cl2 (14.18 g, 19.37 mmol) simultaneously and degassed and purged with Argon for 10-15 minutes. The mixture was stirred at 80 oC for 16 hours. The reaction mixture was filtered to give a filtrate. The filtrate was diluted with water (800 mL) and extracted with ethyl acetate (800 mL x 3), the combined organic layers were washed with saturated brine (800 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 25:1) to give 46 g of title compound with 91.97% yield as a yellow solid. [00223] The synthesis of N-(4-Chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4- methylbenzenesulfonamide (7-3): To a solution of the aniline (46.0 g, 181.44 mmol) in pyridine (500 mL) was added 4-methylbenzene- 1-sulfonyl chloride (38.05g, 199.58 mmol,) at 0 °C portion-wise. After being stirred at 25 °C for 16 hours, pyridine was removed by rotary evaporator and the reaction mixture was poured into water. The product was extracted with CH2Cl2 (500 mL, 100 mL), dried over MgSO4, and concentrated in vacuo. The residue was dissolved in minimum volume of CH2Cl2 and stirred for 15 minutes using rotavapor and started to form solids. Hexanes was added to the solution to form solid and let it sit for 2-3 hours. The solids were filtered and dried under high vacuum to give 51 g of title compound with 38.94% yield as a yellow solid. MS: (ESI) m/z 408.2 (M + H)+. [00224] The synthesis of 2-(5-Bromo-5'-chloro-2'-(4-methylphenylsulfonamido)-[1,1'-biphenyl]- 3-yl)acetamide (7-4): To a solution of 2-(3,5-dibromophenyl)acetamide (54.61 g, 186.40 mmol) in 1,4-dioxane and H2O (600 mL, 1,4-dioxane : H2O = 1:1) were added Pd(PPh3)4 (2.69g, 2.33 mmol), Na2CO3 (9.88 g, 93.20 mmol), and 4-chloro N-Ts-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (19 g, 46.60 mmol) under N2. After being stirred at 90 °C for 16 hours, the reaction mixture was cooled to room temperature. EtOAc (1L) was added and the organic layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified column chromatography (petroleum ether, petroleum ether/ethyl acetate = 5/1, 1/1) to give 23 g of title compound in 99.9% yield as a white solid. [00225] 9.66 (s, 1H), 7.37-7.46 (m, 5H), 7.25-7.30 (m, 3H), 7.22 (d, J = 8.8 Hz, 1H), 7.10 (s, 1H), 7.04 (s, 1H), 7.01 (br, 1H), 3.38 (s, 2H), 2.37 (s, 3H). MS: (ESI) m/z 492.9 (M + H)-. [00226] The synthesis of 2-(3-Bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)acetamide (7-5): A solution of PhI(OAc)2 (22.50 g, 69.87 mmol) in DCM (300 mL) was added to a mixture of 2-(5- bromo-5'-chloro-2'-(4-methylphenylsulfonamido)-[1,1'-biphenyl]-3-yl)acetamide (23 g, 46.58 mmol), Cu(OTf)2 (842.32 mg, 2.33 mmol) and TFA (13.56 g, 139.73 mmol) in DCM (100 mL) at reflux. After 10 minutes, the reaction was complete; the reaction mixture was concentrated in vacuo. The residue was purified column chromatography (petroleum ether, petroleum ether/ethyl acetate = 5/1, 1/1) to give 5.1 g of title compound in 22.26% yield as a brown solid. [00227] 1H NMR (400 MHz, DMSO-d6) ^ 8.20 (d, J = 2.0 Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 8.10 (d, J = 9.2 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.57 (dd, J = 9.0, 2.2 Hz, 1H), 7.55 (br, 1H), 7.05-7.11 (m, 4H), 7.01 (br, 1H), 4.07 (s, 2H), 2.19 (s, 3H). MS: (ESI) m/z 491.0 (M + H)+. [00228] The synthesis of tert-Butyl (2-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1- yl)ethyl)carbamate (7-5b): A solution of 2-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)acetamide (5.1 g, 10.37 mmol) in borane-tetrahydrofuran complex (1M in THF, 100 ml, 100 mmol) was stirred at room temperature overnight. The reaction mixture was quenched with methanol and then concentrated. The residue was dissolved in DCM, washed with brine, the organic layer was dried (Na2SO4) and the solvent was evaporated. The residue was dissolved in DCM (20 mL), di-tert-butyl dicarbonate (6.79 g, 31.11 mmol) and Et3N (1.05 g, 10.37 mmol) was added. After stirring at room temperature overnight, the reaction solution was concentrated and purified by column chromatography (petroleum ether, petroleum ether/ethyl acetate = 100/1, 50/1, 20/1) to give 4.58 g of title compound in 76.42% yield as pale brown oil. [00229] 1H NMR (400 MHz, Chloroform-d) ^ 8.10 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 1.6 Hz, 1H), 7.55 (br, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 8.6, 2.2 Hz, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.0 Hz, 2H), 4.74 (br, 1H), 3.55 – 3.65 (m, 2H), 3.45 – 3.51 (m, 2H), 2.24 (s, 3H), 1.43 (s, 9H). MS: (ESI) m/z 575.0 (M - H)-. [00230] The synthesis of tert-Butyl 2-(3-bromo-6-chloro-9H-carbazol-1-yl)ethylcarbamate (7-6): A solution of tert-butyl (2-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)ethyl)carbamate (4.58 g, 7.93 mmol) in THF (100 mL) and TBAF (30 mL) was stirred 60 oC for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (500 mL x 2), the combined organic layers were washed with saturated brine (400 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 10:1) to give 2.71 g of title compound in 80.7% yield as a yellow solid. MS: (ESI) m/z 421.0 (M - H) –. [00231] The synthesis of tert-Butyl (2-(6-chloro-3-((3,4-dichlorophenyl)amino)-9H-carbazol-1- yl)ethyl)carbamate (15-1): To a solution of tert-butyl (2-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)ethyl)carbamate (2.71 g, 6.04 mmol) in t-BuOH (50 mL) was added 3,4-dichloroaniline (1.04 g, 6.04 mmol), Cs2CO3 (5.9 g, 18.12 mmol), t-Bubrettphos (290.82 mg, 0.6 mmol) and Pd2(dba)3 (549.4 mg, 0.6 mmol). The mixture was stirred at 90 oC for 3 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2), the combined organic layers were washed with saturated brine (100 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 0:1) to give 3g of title compound in 92.92% yield as a pale brown solid. MS: (ESI) m/z 502.0 (M - H)-. [00232] The synthesis of 1-(2-Aminoethyl)-6-chloro-N-(3,4-dichlorophenyl)-9H-carbazol-3- amine (15-2): A solution of tert-butyl (2-(6-chloro-3-((3,4-dichlorophenyl)amino)-9H-carbazol-1-yl)ethyl)carbamate (3 g, 5.94 mmol) in TFA (20% in DCM, 60mL) was stirred at room temperature overnight. The reaction solution was concentrated and used for the next step directly. [00233] The synthesis of (15-3): 1-(2-Aminoethyl)-6-chloro-N-(3,4-dichlorophenyl)-9H-carbazol-3-amine (40 mg, 0.08 mmol), tert- butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (23 mg, 0.08 mmol) and Et3N (14 mg, 0.14 mmol) in DMF (2 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water (8 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The residue was purified by Prep-TLC (dichloromethane) to give 26 mg of title compound in 54% yield as a pale brown solid. [00234] To a solution of 1-(2-aminoethyl)-6-chloro-N-(3,4-dichlorophenyl)-9H-carbazol-3-amine (3 g, 7.41 mmol) in DMF (40 mL) was added tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1- yl)methylene)carbamate (3.45 g, 11.12 mmol) and Et3N (2 mL). The mixture was stirred at 25 oC for 2 hours to give a black solution. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 2), the combined organic layers were washed with saturated brine (200 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 0:1) to give 2.5 g of title compound in 52.14% yield as a pale brown solid. MS: (ESI) m/z 645.8 (M + H)+. [00235] The synthesis of 1-(2-(6-Chloro-3-((3,4-dichlorophenyl)amino)-9H-carbazol-1- yl)ethyl)guanidine (SRI-33106): To a solution of 15-3 (2.5 g, 3.86 mmol) in HCl/dioxane (50 mL) and stirred at 25 oC for 16 hours. The reaction mixture was washed with ACN and EA. The mixture was filtered to provide the title compound (1.53 g, 88.63%) as a gray solid. [00236] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.19 (d, J = 2.0 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.41 (dd, J = 2.0, 8.8 Hz, 1H), 7.37 (d, J = 9.2 Hz, 1H), 7.16 (d, J = 2.0 Hz, 1H), 7.07 (d, J = 2.8 Hz, 1H), 6.95 (dd, J = 2.8, 9.2 Hz, 1H), 3.54 (t, J = 7.2 Hz, 2H), 3.15 (t, J = 6.8 Hz, 2H). MS: (ESI) m/z 446.0 (M + H)+. [00237] Example 10: [00238] Example Route for Example 10 (SRI-33107):
[00239] The synthesis of tert-Butyl (2-(3-(benzylamino)-6-chloro-9H-carbazol-1- yl)ethyl)carbamat Activated Mg turnings (314 mg, 12.92 mmol) was added to dry methanol (25 mL), a solution of tert- butyl (2-(3-(benzylamino)-6-chloro-9-tosyl-9H-carbazol-1-yl)ethyl)carbamate (100 mg, 0.17 mmol) in methanol (10 mL) was added following by ammonium chloride (124 mg, 2.32 mmol). The reaction mixture was stirred at room temperature for 3 hours and then quenched with ammonium chloride solution. The product was extracted with ethyl acetate (3x20 mL), dried over Na2SO4. The residue was purified by Prep-TLC (petroleum ether/ethyl acetate = 2/1) to give 33 mg of title compound in 44% yield as a pale brown solid. MS: (ESI) m/z 450.0 (M + H)+. [00240] The synthesis of 1-(2-Aminoethyl)-N-benzyl-6-chloro-9H-carbazol-3-amine (22-2): A solution of tert-butyl (2-(3-(benzylamino)-6-chloro-9H-carbazol-1-yl)ethyl)carbamate (28 mg, 0.062 mmol) in TFA (5% in DCM, 5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and used for the next step directly. [00241] The synthesis of (22-3): 1-(2-Aminoethyl)-N-benzyl-6-chloro-9H-carbazol-3-amine (39 mg, 0.11 mmol), tert-butyl (((tert- butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (34 mg, 0.11 mmol) and Et3N (23 mg, 0.23 mmol) in DMF (2 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water (8 mL). The product was extracted with ethyl acetate (3x10 mL) and dried over Na2SO4. The residue was purified by Prep-TLC (dichloromethane) to give 36 mg of title compound in 55% yield as a pale brown solid. MS: (ESI) m/z 592.0 (M + H)+. [00242] The synthesis of 1-(2-(3-(Benzylamino)-6-chloro-9H-carbazol-1-yl)ethyl)guanidine (SRI- 33107): A solution of 22-3 (36 mg, 0.061 mmol) in TFA (15% in DCM, 5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and purified by Prep-HPLC to provide the title compound 22 (11.3 mg, 47%) as a gray solid. [00243] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.41 (s, 1H, formic acid), 7.97 (d, J = 2.0 Hz, 1H), 7.42-7.47 (m, 3H), 7.28-7.36 (m, 3H), 7.24 (t, J = 7.2 Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H), 6.79 (d, J = 2.0 Hz, 1H), 4.35 (s, 2H), 3.46 (t, J = 7.2 Hz, 2H), 3.03 (t, J = 7.2 Hz, 2H). MS: (ESI) m/z 392.0 (M + H)+. [00244] Example 11: [00245] Example Route for Example 11 ( SRI-33108):
[00246] The synthesis of tert-Butyl (2-(6-chloro-3-((4-chloro-3-fluorophenyl)amino)-9H-carbazol- 1-yl)ethyl)carbamate (16-1): tert-butyl (2-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)ethyl)carbamate (300 mg, 0.52 mmol), 4- chloro-3-fluoroaniline (76 mg, 0.52 mmol), palladium acetate (23 mg, 0.1 mmol), brett-Phos (70 mg, 0.13 mmol) and cesium carbonate (508 mg, 1.56 mmol) were dissolved in 1,4-dioxane (10 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes then heated at 90 °C for 2 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by Prep-TLC (petroleum ether/ethyl acetate = 2/1) to give 35 mg of 16-1 (14% yield) as a pale brown solid. MS: (ESI) m/z 486.0 (M - H)-. [00247] The synthesis of 1-(2-Aminoethyl)-6-chloro-N-(4-chloro-3-fluorophenyl)-9H-carbazol-3- amine (16-2): A solution of tert-butyl (2-(6-chloro-3-((4-chloro-3-fluorophenyl)amino)-9H-carbazol-1- yl)ethyl)carbamate (35 mg, 0.09 mmol) in TFA (5% in DCM, 5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and used for the next step directly. [00248] The synthesis of 16-3: 1-(2-Aminoethyl)-6-chloro-N-(4-chloro-3-fluorophenyl)-9H-carbazol-3-amine (35 mg, 0.09 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (22 mg, 0.09 mmol) and Et3N (14 mg, 0.14 mmol) in DMF (2 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water (8 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The residue was purified by Prep-TLC (dichloromethane) to give 25 mg of title compound in 59% yield as a pale brown solid. MS: (ESI) m/z 630.2 (M + H)+. [00249] The synthesis of 1-(2-(6-Chloro-3-((4-chloro-3-fluorophenyl)amino)-9H-carbazol-1- yl)ethyl)guanidine (SRI-33108): A solution of 16-3 (25 mg, 0.09 mmol) in TFA (15% in DCM, 5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (11.14 mg, 71%) as a black solid. [00250] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.38 (s, 1H, formic acid), 8.17 (s, 1H), 7.80 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 7.2 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.14 (s, 1H), 6.84 (d, J = 12.0 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 3.53 (t, J = 6.8 Hz, 2H), 3.13 (t, J = 6.8 Hz, 2H). MS: (ESI) m/z 429.9 (M + H)+. [00251] Example 12: [00252] Example Route for Example 12 (SRI-33109):
. [00253] The synthesis of 2-(4-Bromo-5'-chloro-2'-((4-methylphenyl)sulfonamido)-[1,1'-biphenyl]- 3-yl)acetamide (14-3): N-(4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methylbenzenesulfonamide (5.0 g, 12.3 mmol), 2-(2,5-dibromophenyl)acetamide (3.6 g, 12.3 mmol), tetrakis(triphenylphosphine)palladium (1.4 g, 1.2 mmol), and sodium carbonate (2.6 g, 24.6 mmol) were dissolved in dioxane/H2O (10:1, 100 mL). The mixture was degassed and purged with N2 for 5- 10 minutes and then heated at 90 °C for 16 hours. The mixture was cooled to room temperature and ethyl acetate (100 mL) was added, washed with water (100 mL) then brine, the organic payer was separated and dried over Na2SO4, concentrated and purified by silica column chromatography (petroleum ether/ethyl acetate = 3/1) to give 3.6 g title compound in 60% yield as a white solid. MS: (ESI) m/z 492.7 (M + H)+. [00254] The synthesis of 2-(2-Bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)acetamide (14-4): To a solution of 2-(2,5-dibromophenyl)acetamide (3.6 g, 7.3 mmol) in DCM (50 mL) was added Cu(OTf)2 (528 mg, 1.5 mmol), PhI(OAc)2 (2.8 g, 8.8 mmol) and TFA (5 mL). The mixture was stirred at reflux for 10 minutes. Cooled to room temperature and water (50 mL) was added, the water phase was extracted with DCM (2 x 50 mL), the organic layers were combined and washed with brine, dried over Na2SO4, concentrated and purified by silica column chromatography (petroleum ether/ethyl acetate = 3/1) to give 680 mg title compound in 19% yield as a white solid. MS: (ESI) m/z 490.9 (M + H)+. [00255] The synthesis of 2-(2-Bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)ethan-1-amine (14-5): To a solution of 2-(2-bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)acetamide (680 mg, 1.39 mmol) in THF (10 mL) was added BH3 (10mL, 1M in THF). The solution was stirred at 40°C for 16 hours. Extracted with DCM (30 mL) and water (50 mL), the water phase was separated and extracted with DCM (2 x 30 mL), the combined organic layers were washed with brine, dried over Na2SO4, concentrated to give 550 mg title compound in 83% yield as a brown solid. MS: (ESI) m/z 476.8 (M + H)+. [00256] The synthesis of tert- Butyl (2-(2-bromo-6-chloro-9-tosyl-9H-carbazol-1- yl)ethyl)carbamate (14-6): To a solution of 2-(2-bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)ethan-1-amine(550 mg, 1.15 mmol) in DCM (10 mL) was added TEA (348 mg, 3.45 mmol) and Boc2O (376 mg, 1.73 mmol) at room temperature. The solution was stirred at room temperature for 16 hours. Extracted with DCM (20 mL) and water (30 mL), the water phase was separated and extracted with DCM (2 x 20 mL), the combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by silica column chromatography (petroleum ether/ethyl acetate = 3/1) to give 620 mg title compound in 93% yield as a white solid. MS: (ESI) m/z 478.8 (M-Boc)+. [00257] The synthesis of tert-Butyl (2-(2-bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)ethyl)(tert- butoxycarbonyl)carbamate (14-7): To a solution of A solution of tert- butyl (2-(2-bromo-6-chloro-9-tosyl-9H-carbazol-1- yl)ethyl)carbamate (620 mg, 1.07 mmol) in dry THF (10 mL) was added NaH (86 mg, 60% in mineral oil, 2.14 mmol) at 0 °C . The mixture was stirred at 0 °C for 30 minutes, then Boc2O (467 mg, 2.14 mmol) was added. The solution was allowed to warm to room temperature and stirred for 4 hours. Quenched with NH4Cl aq., extracted with EA (2 x 30 mL), the combined organic phase was washed with brine, dried over Na2SO4, concentrated and purified by silica column chromatography (petroleum ether/ethyl acetate = 3/1) to give 560 mg title compound in 77% yield as a white solid. MS: (ESI) m/z 476.8 (M -2Boc)+. [00258] The synthesis of tert-Butyl (tert-butoxycarbonyl)(2-(6-chloro-2-((4-chlorophenyl)amino)- 9-tosyl-9H-carbazol-1-yl)ethyl)carbamate (14-8): To a solution of tert-butyl (2-(2-bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)ethyl)(tert- butoxycarbonyl)carbamate (200 mg, 0.30 mmol) in dioxane (5 mL) was added 4-chloroaniline (38 mg, 0.30 mmol), Pd(OAc)2 (13 mg, 0.06 mmol), Brett Phos (43 mg, 0.08 mmol) and Cs2CO3 (293 mg,0.90 mmol). The mixture was stirred under N2 at 90 °C for 2 hours. Cooled to room temperature and filtered, the filtrate was concentrated and purified by prep-TLC (petroleum ether/ethyl acetate = 3/1) to give 40 mg of title compound in 19% yield as a pale brown solid. MS: (ESI) m/z 524.8 (M - 2Boc)+. [00259] The synthesis of tert-Butyl (tert-butoxycarbonyl)(2-(6-chloro-2-((4-chlorophenyl)amino)- 9H-carbazol-1-yl)ethyl)carbamate (14-9): To a solution of tert-butyl (tert-butoxycarbonyl)(2-(6-chloro-2-((4-chlorophenyl)amino)-9-tosyl-9H- carbazol-1-yl)ethyl)carbamate (40 mg, 0.06 mmol) in methanol (5 mL) was added Mg (133 mg, 5.5 mmol), and NH4Cl (32 mg, 0.60 mmol). The mixture was stirred at room temperature for 3 hours. Filtered and the filtrate was concentrated and purified by prep-TLC (DCM/MeOH = 20/1) to give 11 mg of title compound in 35% yield as a white solid. MS: (ESI) m/z 468.0 (M-Boc)+. [00260] The synthesis of 1-(2-Aminoethyl)-6-chloro-N-(4-chlorophenyl)-9H-carbazol-2-amine (14-10): To a solution of tert-butyl (tert-butoxycarbonyl)(2-(6-chloro-2-((4-chlorophenyl)amino)-9H-carbazol- 1-yl)ethyl)carbamate (11 mg, 0.02 mmol) in DCM (2 mL) was added TFA (0.1 mL), the solution was stirred at room temperature overnight. Concentrated to give 12 mg of title compound in 99% yield as a brown solid and used for the next step directly. MS: (ESI) m/z 468.0 (M-Boc)+. [00261] The synthesis of 1-(2-(6-Chloro-2-((4-chlorophenyl)amino)-9H-carbazol-1-yl)ethyl)-N,N’ -tert-butoxycarbonyl-guanidine (14-11): To a solution of 1-(2-aminoethyl)-6-chloro-N-(4-chlorophenyl)-9H-carbazol-2-amine (12 mg, 0.02 mmol) in DMF (2 mL) was added tert-butyl (Z)-(((tert-butoxycarbonyl)amino)(1H-pyrazol-1- yl)methylene)carbamate (12 mg, 0.04 mmol) and DIEA (8 mg, 0.06 mmol), the solution was stirred at room temperature for 2 hours. Extracted with EA (10 mL) and water (20 mL), the organic layer was separated and washed with brine, dried over Na2SO4, concentrated and purified by prep-TLC (DCM/MeOH = 20/1) to give 5.5 mg of title compound in 31% yield as a white solid. MS: (ESI) m/z 612.0 (M+1)+. [00262] The synthesis of 1-(2-(6-chloro-2-((4-chlorophenyl)amino)-9H-carbazol-1- yl)ethyl)guanidine (SRI-33108): To a solution of 1-(2-(6-chloro-2-((4-chlorophenyl)amino)-9H-carbazol-1-yl)ethyl)-N,N’-tert- butoxycarbonyl -guanidine (5.5 mg, 0.01 mmol) in DCM (1 mL) was added TFA (0.1 mL), the solution was stirred at room temperature over night. Concentrated and purified by prep-HPLC to give 3.5 mg of title compound in 94% yield as a gray solid. [00263] 1H NMR (400 MHz, MeOD-d4) ^ 8.53 (br, 1H), 7.97 (d, J = 1.6 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.31 (dd, J = 8.8, 2.0 Hz, 1H), 7.15-7.10 (m, 2H), 7.08 (d, J = 8.4 Hz, 1H), 6.81-6.75 (m, 2H), 3.49 (t, J = 7.6 Hz, 2H), 3.22 (t, J = 8.0 Hz, 2H). MS: (ESI) m/z 412.0 (M + H)+. [00264] Example 13: [00265] Example Route for Example 13 (SRI-33110): [00266] The synthesis of tert-Butyl (2-(6-chloro-3-((5-chloropyridin-2-yl)amino)-9-tosyl-9H- carbazol-1-yl)ethyl)carbamate (18-1): tert-butyl (2-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)ethyl)carbamate (300 mg, 0.52 mmol), 5- chloropyridin-2-amine (67 mg, 0.52 mmol), tris(dibenzylideneacetone)dipalladium(0) (91 mg, 0.1 mmol), Xant-Phos (75 mg, 0.13 mmol) and potassium phosphate (331 mg, 1.56 mmol) were dissolved in 1,4-dioxane (10 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 100 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by Prep-TLC (petroleum ether/ethyl acetate = 2/1) to give 120 mg of 18-1 (39% yield) as a pale brown solid. MS: (ESI) m/z 623.0 (M - H)-. [00267] The synthesis of tert-Butyl (2-(6-chloro-3-((5-chloropyridin-2-yl)amino)-9H-carbazol-1- yl)ethyl)carbamate (18-2): Tetra-n-butylammonium fluoride (1M in THF, 0.1 mL, 0.96 mmol) was slowly added to solution of tert-butyl (2-(6-chloro-3-((5-chloropyridin-2-yl)amino)-9-tosyl-9H-carbazol-1-yl)ethyl)carbamate (120 mg, 0.192 mmol). The reaction was stirred for 1 hour at 70 ºC until the reaction was completed. The reaction quenched with a few drops of water. The product was extracted with DCM and dried over Na2SO4. The organic phase concentrated in vacuo to get crude product. The residue was purified by Prep-TLC (petroleum ether/ethyl acetate = 1/1) to give 35 mg of title compound in 35% yield as a pale brown solid. MS: (ESI) m/z 469.0 (M - H)-. [00268] The synthesis of 1-(2-Aminoethyl)-6-chloro-N-(5-chloropyridin-2-yl)-9H-carbazol-3- amine (18-3): 1-(2-Aminoethyl)-6-chloro-N-(5-chloropyridin-2-yl)-9H-carbazol-3-amine (35 mg, 0.09 mmol), tert- butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (28 mg, 0.09 mmol) and Et3N (19 mg, 0.18 mmol) in DMF (2 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water (8 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The residue was purified by Prep-TLC (dichloromethane) to give 30 mg of title compound in 51% yield as a pale brown solid. MS: (ESI) m/z 613.2 (M + H)+. [00269] The synthesis of (18-4): 1-(2-Aminoethyl)-6-chloro-N-(5-chloropyridin-2-yl)-9H-carbazol-3-amine (35 mg, 0.09 mmol), tert- butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (28 mg, 0.09 mmol) and Et3N (19 mg, 0.18 mmol) in DMF (2 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water (8 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The residue was purified by Prep-TLC (dichloromethane) to give 30 mg of title compound in 51% yield as a pale brown solid. MS: (ESI) m/z 613.2 (M + H)+. [00270] The synthesis of 1-(2-(6-Chloro-3-((5-chloropyridin-2-yl)amino)-9H-carbazol-1- yl)ethyl)guanidine (SRI-33110): A solution of 18-4 (30 mg, 0.05 mmol) in TFA (15% in DCM, 5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (8.54 mg, 36%) as a yellow solid. [00271] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.35 (s, 1H, formic acid), 8.12-8.09 (m, 3H), 7.60 (dd, J = 8.8, 2.8 Hz, 1H), 7.55 (dd, J = 8.4, 2.8 Hz, 1H), 7.44-7.39 (m, 2H), 6.84 (dd, J = 9.2, 4.0 Hz, 1H), 3.55 (t, J = 6.4 Hz, 2H), 3.15 (t, J = 6.0 Hz, 2H). MS: (ESI) m/z 413.3 (M + H)+. [00272] Example 14: [00273] Example Route for Example 14 (SRI-33111):
[00274] The synthesis of tert-Butyl (2-(3-(benzylamino)-6-chloro-9-tosyl-9H-carbazol-1- yl)ethyl)carbamate tert-Butyl (2-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)ethyl)carbamate (100 mg, 0.17 mmol), phenylmethanamine (56 mg, 0.52 mmol), palladium acetate (16 mg, 0.077 mmol), brett-Phos (47 mg, 0.087 mmol) and cesium carbonate (170 mg, 0.52 mmol) were dissolved in 1,4-dioxane (5 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 5 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by Prep-TLC (petroleum ether/ethyl acetate = 3/1) to give 30 mg of 19-1 (50% yield) as a pale brown solid. MS: (ESI) m/z 602.0 (M - H)–. [00275] The synthesis of tert-Butyl (2-(3-amino-6-chloro-9-tosyl-9H-carbazol-1- yl)ethyl)carbamate (19-2): A suspension of tert-butyl (2-(3-(benzylamino)-6-chloro-9-tosyl-9H-carbazol-1-yl)ethyl)carbamate (47 mg, 0.078 mmol) and 25 mg of 10% palladium on carbon in 10 mL of ethyl acetate, the reaction mixture was stirred vigorously under hydrogen pressure (0.8-1.0 atm) for 2 hours at room temperature. The solid was removed by filtration through diatomite and the filtrate was concentrated. The residue was purified by Prep-TLC (petroleum ether/ethyl acetate = 1/1) to give 20 mg of title compound in 50% yield as a pale brown solid. MS: (ESI) m/z 512.0 (M - H)–. [00276] The synthesis of tert-Butyl (2-(6-chloro-3-(cyclohexylamino)-9-tosyl-9H-carbazol-1- yl)ethyl)carbamate A solution of tert-butyl (2-(3-amino-6-chloro-9-tosyl-9H-carbazol-1-yl)ethyl)carbamate (29 mg, 0.056 mmol), cyclohexanone (56 mg, 0.57 mmol), titanium(IV) isopropoxide (160 mg, 0.56 mmol) and sodium cyanoborohydride (120 mg, 0.57 mmol) in DCE (2 mL) was stirred at room temperature overnight. The reaction mixture was filtered through diatomite and the filtrate was concentrated. The residue was purified by Prep-TLC (petroleum ether/ethyl acetate = 3/1) to give 30 mg of title compound in 89% yield as a pale brown solid. MS: (ESI) m/z 594.1 (M - H)-. [00277] The synthesis of tert-Butyl (2-(6-chloro-3-(cyclohexylamino)-9H-carbazol-1- yl)ethyl)carbamate (19-4): Activated Mg turnings (96 mg, 3.95 mmol) was added to dry methanol (10 mL), then a solution of tert-butyl (2-(6-chloro-3-(cyclohexylamino)-9-tosyl-9H-carbazol-1-yl)ethyl)carbamate (30 mg, 0.05 mmol) in methanol (2 mL) was added following by ammonium chloride (38 mg, 0.71 mmol). The reaction mixture was stirred at room temperature for 3 hours then quenched with ammonium chloride solution. The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The residue was purified by Prep-TLC (petroleum ether/ethyl acetate = 2/1) to give 19 mg of title compound in 85% yield as a pale brown solid. MS: (ESI) m/z 442.0 (M + H)+. [00278] The synthesis of 1-(2-Aminoethyl)-6-chloro-N-cyclohexyl-9H-carbazol-3-amine (19-5): A solution of tert-butyl (2-(6-chloro-3-(cyclohexylamino)-9H-carbazol-1-yl)ethyl)carbamate (46 mg, 0.10 mmol) in TFA (5% in DCM, 5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and used to next step directly. [00279] The synthesis of (19-6): 1-(2-Aminoethyl)-6-chloro-N-cyclohexyl-9H-carbazol-3-amine (47 mg, 0.10 mmol), tert-butyl (((tert- butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (32 mg, 0.10 mmol) and Et3N (21 mg, 0.21 mmol) in DMF (2 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water (8 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The residue was purified by Prep-TLC (dichloromethane) to give 30 mg of title compound in 50% yield as a pale brown solid. MS: (ESI) m/z 584.0 (M + H)+. [00280] The synthesis of 1-(2-(6-Chloro-3-(cyclohexylamino)-9H-carbazol-1-yl)ethyl)guanidine (SRI-33111): A solution of 19-6 (40 mg, 0.068 mmol) in TFA (15% in DCM, 5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (27 mg, 72%) as a pale brown solid. [00281] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.34 (s, 1H, formic acid), 8.06 (d, J = 2.0 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 8.8, 2.0 Hz, 1H), 7.24 (d, J = 1.6 Hz, 1H), 6.75 (d, J = 1.2 Hz, 1H), 3.49 (t, J = 7.0 Hz, 2H), 3.22-3.30 (m, 1H), 3.05 (t, J = 7.0 Hz, 2H), 1.95-2.03 (m, 2H), 1.70- 1.78 (m, 2H), 1.59-1.66 (m, 1H), 1.30-1.42 (m, 2H), 1.13-1.25 (m, 3H). MS: (ESI) m/z 384.0 (M + H)+. [00282] Example 15: [00283] Example Route for Example 15 (SRI-33113):
[00284] The synthesis of tert-Butyl 3-((1-(2-((tert-butoxycarbonyl)amino)ethyl)-6-chloro-9-tosyl- 9H-carbazol-3-yl)amino)-1H-pyrazole-1-carboxylate (25-1): To a solution of tert-butyl (2-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)ethyl)carbamate (200 mg, 0.35 mmol) in t-BuOH (20 mL) was added tert-butyl 3-amino-1H-pyrazole-1-carboxylate (63.4 mg, 0.35 mmol), Pd2dba3 (63.5 mg, 0.07 mmol), Brett Phos (42 mg, 0.09 mmol), Cs2CO3 (143.7 mg, 1.04 mmol) and AcOH (0.1 mL). The mixture was stirred under N2 at 100 °C for 2 hours. Cooled to room temperature and filtered, the filtrate was concentrated and purified by prep-TLC (petroleum ether/ethyl acetate = 4/1) to give 110 mg of title compound in 47% yield as a white solid. MS: (ESI) m/z 679.8 (M + H)+. [00285] The synthesis of tert-Butyl 3-((1-(2-((tert-butoxycarbonyl)amino)ethyl)-6-chloro-9H- carbazol-3-yl)amino)-1H-pyrazole-1-carboxylate (25-2): To a solution of tert-butyl 3-((1-(2-((tert-butoxycarbonyl)amino)ethyl)-6-chloro-9-tosyl-9H-carbazol- 3-yl)amino)-1H-pyrazole-1-carboxylate (110 mg, 0.16 mmol) in methanol (10 mL) was added Mg (392 mg, 16 mmol), and NH4Cl (86 mg, 1.6 mmol). The mixture was stirred at room temperature for 3 hours. Filtered and the filtrate was concentrated and purified by prep-TLC (DCM/MeOH = 20/1) to give 55 mg of title compound in 65% yield as a white solid. MS: (ESI) m/z 426.0 (M -Boc)+. [00286] The synthesis of 1-(2-Aminoethyl)-6-chloro-N-(1H-pyrazol-3-yl)-9H-carbazol-3-amine (25-3): To a solution of tert-butyl 3-((1-(2-((tert-butoxycarbonyl)amino)ethyl)-6-chloro-9H-carbazol-3- yl)amino)-1H-pyrazole-1-carboxylate (55 mg, 0.10 mmol) in DCM (5 mL) was added TFA (0.5 mL), the solution was stirred at room temperature overnight. The reaction mixture was concentrated to give 50 mg of title compound in 99% yield as a brown solid, which was used for the next step directly. MS: (ESI) m/z 326.0 (M + H)+. [00287] The synthesis of 1-(2-(3-((1H-Pyrazol-3-yl)amino)-6-chloro-9H-carbazol-1-yl)ethyl) - N,N’ -tert-butoxycarbonyl -guanidine (25-4): To a solution of 1-(2-aminoethyl)-6-chloro-N-(1H-pyrazol-3-yl)-9H-carbazol-3-amine (50 mg, 0.10 mmol) in DMF (3 mL) was added tert-butyl (Z)-(((tert-butoxycarbonyl)amino)(1H-pyrazol-1- yl)methylene)carbamate (52 mg, 0.20 mmol) and DIEA (39 mg, 0.30 mmol), the solution was stirred at room temperature for 2 hour. Extracted with EA (10 mL) and water (20 mL), the organic layer was separated and washed with brine, dried over Na2SO4, concentrated and purified by prep-TLC (DCM/MeOH = 20/1) to give 45 mg of title compound in 79% yield as a white solid. MS: (ESI) m/z poor mass response. [00288] The synthesis of 1-(2-(3-((1H-Pyrazol-3-yl)amino)-6-chloro-9H-carbazol-1- yl)ethyl)guanidine (SRI-33113): To a solution of 1-(2-(3-((1H-pyrazol-3-yl)amino)-6-chloro-9H-carbazol-1-yl)ethyl) -N,N’-tert- butoxycarbonyl -guanidine (20 mg, 0.04 mmol) in DCM (2 mL) was added TFA (0.2 mL), the solution was stirred at room temperature over night. Concentrated and purified by prep-HPLC to give 8.0 mg of title compound in 62% yield as a dark solid. [00289] 1H NMR (400 MHz, DMSO-d6) ^ 11.14 (s, 1H), 7.99 (d, J = 1.6 Hz, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.50 (br, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.33 (dd, J = 8.4, 2.0 Hz, 1H), 7.20 (d, J = 1.6 Hz, 1H), 6.83 (br, 1H), 5.90 (d, J = 2.4 Hz, 1H), 3.87 (br, 6H), 3.48 (q, J = 6.4 Hz, 2H), 3.08 (t, J = 7.6 Hz, 2H). MS: (ESI) m/z 368.0 (M + H)+. [00290] Example 16: [00291] Example Route for Example 16 (SRI-33114): [00292] The synthesis of tert-Butyl 2-(6-chloro-3-(thiazol-2-ylamino)-9-tosyl-9H-carbazol-1- yl)ethylcarbamate tert-butyl 2-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)ethylcarbamate (135 mg, 0.23 mmol), thiazol-2-amine (24 mg, 0.23 mmol), tris(dibenzylideneacetone)dipalladium(0) (33 mg, 0.045 mmol), tert-butylbrettphos (45 mg, 0.09 mmol), potassium carbonate (65 mg, 0.47 mmol) and acetic acid (1 drop) were dissolved in tert-butanol (5 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 100 °C for 2 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by Prep-TLC (petroleum ether/ethyl acetate = 1/1) to give 90 mg title compound in 65% yield as a yellow solid. MS: (ESI) m/z 697.0 (M + H)+. [00293] The synthesis of tert-Butyl 2-(6-chloro-3-(thiazol-2-ylamino)-9H-carbazol-1- yl)ethylcarbamate (27-2): Activated Mg turnings (282 mg, 11.61 mmol)ammonium chloride (113 mg, 2.11 mmol) and tert-butyl 2-(6-chloro-3-(thiazol-2-ylamino)-9-tosyl-9H-carbazol-1-yl)ethylcarbamate (90 mg, 0.15 mmol) in methanol (5 mL) was stirred at room temperature for 3 hours and then quenched with ammonium chloride solution. The product was extracted with ethyl acetate (3x20 mL) and dried over Na2SO4. The residue was purified by Prep-TLC (petroleum ether/ethyl acetate = 1/1) to give 46 mg of title compound in 69% yield as a yellow solid. MS: (ESI) m/z 443.0 (M + H)+. [00294] The synthesis of N-(1-(2-Aminoethyl)-6-chloro-9H-carbazol-3-yl)thiazol-2-amine (27-3): A solution of tert-butyl 2-(6-chloro-3-(thiazol-2-ylamino)-9H-carbazol-1-yl)ethylcarbamate (46 mg, 0.103 mmol) in TFA (5% in DCM, 6 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and used to the next step directly. [00295] The synthesis of (E)-tert-Butyl (tert-butoxycarbonylamino)(2-(6-chloro-3-(thiazol-2- ylamino)-9H-carbazol-1-yl)ethylamino)methylenecarbamate (27-4): N-(1-(2-aminoethyl)-6-chloro-9H-carbazol-3-yl)thiazol-2-amine (36 mg, 0.103 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (32 mg, 0.103 mmol) and Et3N (21 mg, 0.208 mmol) in DMF (5 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water (20 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The residue was purified by Prep-TLC (petroleum ether/ethyl acetate = 2/1) to give 38 mg of title compound in 63% yield as a yellow solid. MS: (ESI) m/z 584.8 (M + H)+. [00296] The synthesis of 1-(2-(6-Chloro-3-(thiazol-2-ylamino)-9H-carbazol-1-yl)ethyl)guanidine (SRI-33114): A solution of (E)-tert-butyl (tert-butoxycarbonylamino)(2-(6-chloro-3-(thiazol-2-ylamino)-9H- carbazol-1-yl)ethylamino)methylenecarbamate (38 mg, 0.065 mmol) in TFA (10% in DCM, 6 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (13 mg, 52%) as a white solid. [00297] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.39 (s, 1H, formic acid), 8.29 (d, J = 2.0 Hz, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 1.6 Hz, 1H), 7.40 (dd, J = 8.4, 2.0 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 3.6 Hz, 1H), 3.50 (t, J = 7.6 Hz, 2H), 3.13 (t, J = 7.6 Hz, 2H). MS: (ESI) m/z 385.0 (M + H)+. [00298] Example 17: l [00300] The synthesis of tert-Butyl (2-(6-chloro-3-((6-chloropyridin-3-yl)amino)-9H-carbazol-1- yl)ethyl)carbamate (17-1): tert-butyl (2-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)ethyl)carbamate (200 mg, 0.34 mmol), 6-chloropyridin-3-amine (44 mg, 0.34 mmol), tris(dibenzylideneacetone)dipalladium (64 mg, 0.068 mmol), Xant-Phos (48 mg, 0.08 mmol) and potassium phosphate (288 mg, 1.36 mmol) were dissolved in 1,4-dioxane (10 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 100 °C for 10 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by Prep-TLC (petroleum ether/ethyl acetate = 2/1) to give 31 mg of 17-1 (19% yield) as a pale brown solid. MS: (ESI) m/z 469.0 (M - H)–. [00301] The synthesis of 1-(2-Aminoethyl)-6-chloro-N-(6-chloropyridin-3-yl)-9H-carbazol-3- amine (17-2): A solution of tert-butyl (2-(6-chloro-3-((6-chloropyridin-3-yl)amino)-9H-carbazol-1- yl)ethyl)carbamate (31 mg, 0.06 mmol) in TFA (5% in DCM, 5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and used for the next step directly. [00302] The synthesis of (17-3): 1-(2-Aminoethyl)-6-chloro-N-(6-chloropyridin-3-yl)-9H- carbazol-3-amine(31 mg, 0.06 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1- yl)methylene)carbamate (18 mg, 0.08 mmol) and Et3N (14 mg, 0.14 mmol) in DMF (2 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water (8 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The residue was purified by Prep- TLC (dichloromethane) to give 36 mg of title compound in 70% yield as a pale brown solid. MS: (ESI) m/z 613.2 (M + H)+. [00303] The synthesis of 1-(2-(6-Chloro-3-((6-chloropyridin-3-yl)amino)-9H-carbazol-1- yl)ethyl)guanidine (SRI-33115): A solution of 17-3 (36 mg, 0.05 mmol) in TFA (15% in DCM, 5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and purified by Prep-HPLC to provide the title compound 17 (17.89 mg, 36%) as a grayish solid. [00304] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.39 (s, 1H, formic acid), 8.17 (d, J = 1.6 Hz, 1H), 8.05 (d, J = 2.8 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.45-7.41 (m, 2H), 7.29 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 1.6 Hz, 1H), 3.53 (t, J = 6.8 Hz, 2H), 3.13 (t, J = 6.8 Hz, 2H). MS: (ESI) m/z 412.9 (M + H)+. [00305] Example 18: [00306] Example Route for Example 18 (SRI-33121):
[00307] The synthesis of tert-Butyl (2-(6-chloro-3-((2,4-dichloro-5-fluorophenyl)amino)-9-tosyl- 9H-carbazol-1-yl)ethyl)carbamate (30-1): To a solution of tert-butyl (2-(3-bromo-6-chloro-9-tosyl- 9H-carbazol-1-yl)ethyl)carbamate (150 mg, 0.26 mmol) in t-BuOH (10 mL) was added 2,4-dichloro- 5-fluoroaniline (46.6 mg, 0.26 mmol), Pd2dba3 (45.7 mg, 0.05 mmol), t-Butyl Brett Phos (31.6 mg, 0.06 mmol), K2CO3 (107.6 mg, 0.78 mmol) and AcOH (0.1 mL). The mixture was stirred under N2 at 100 °C for 2 hours. Cooled to room temperature and filtered, the filtrate was concentrated and purified by prep-TLC (petroleum ether/ethyl acetate = 4/1) to give 70 mg of title compound in 40% yield as a white solid. MS: (ESI) m/z 591.1. [00308] The synthesis of tert-Butyl (2-(6-chloro-3-((2,4-dichloro-5-fluorophenyl)amino)-9H- carbazol-1-yl)ethyl)carbamate (30-2): To a solution of tert-butyl (2-(6-chloro-3-((2,4-dichloro-5- fluorophenyl)amino)-9-tosyl-9H-carbazol-1-yl)ethyl)carbamate (70 mg, 0.10 mmol) in methanol (10 mL) was added Mg (240 mg, 10 mmol), and NH4Cl (5.4 mg, 1.0 mmol). The mixture was stirred at room temperature for 3 hours. Filtered and the filtrate was concentrated and purified by prep-TLC (DCM/MeOH = 20/1) to give 45 mg of title compound in 83% yield as a white solid. MS: (ESI) m/z 523.0(M+H)+. [00309] The synthesis of 1-(2-Aminoethyl)-6-chloro-N-(2,4-dichloro-5-fluorophenyl)-9H- carbazol-3-amine (30-3): To a solution of tert-butyl (2-(6-chloro-3-((2,4-dichloro-5- fluorophenyl)amino)-9H-carbazol-1-yl)ethyl)carbamate (45 mg, 0.10 mmol) in DCM (5 mL) was added TFA (0.25 mL), the solution was stirred at room temperature overnight. The reaction mixture was concentrated to give 40 mg of title compound in 99% yield as a brown solid and used for the next step directly. MS: (ESI) m/z 421.8 (M + H)+. [00310] The synthesis of 1-(2-(6-Chloro-3-((2,4-dichloro-5-fluorophenyl)amino)-9H-carbazol-1- yl)ethyl) -N,N’ -tert-butoxycarbonyl guanidine (30-4): To a solution of 1-(2-aminoethyl)-6-chloro-N- (2,4-dichloro-5-fluorophenyl)-9H-carbazol-3-amine (40 mg, 0.10 mmol) in DMF (5 mL) was added tert-butyl (Z)-(((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (52 mg, 0.20 mmol) and DIEA (39 mg, 0.30 mmol), the solution was stirred at room temperature for 2 hours. Extracted with EA (20 mL) and water (30 mL), the organic layer was separated and washed with brine, dried over Na2SO4, concentrated and purified by prep-TLC (DCM/MeOH = 20/1) to give 40 mg of title compound in 70% yield as a white solid. MS: (ESI) m/z 664.2 (M + H)+. [00311] The synthesis of 1-(2-(6-Chloro-3-((2,4-dichloro-5-fluorophenyl)amino)-9H-carbazol-1- yl)ethyl)guanidine (SRI-33121): To a solution of 1-(2-(6-chloro-3-((2,4-dichloro-5- fluorophenyl)amino)-9H-carbazol-1-yl)ethyl) -N,N’ -tert-butoxycarbonyl guanidine (40 mg, 0.06 mmol) in DCM (5 mL) was added TFA (0.5 mL), the solution was stirred at room temperature over night. Concentrated and purified by prep-HPLC to give 18.0 mg of title compound in 31% yield as a gray solid. [00312] 1H NMR (400 MHz, DMSO-d6) ^ 11.78 (s, 1H), 8.79 (s, 1H), 8.49 (s, 1H), 8.20 (d, J = 2.0 Hz, 1H), 7.93 (d, J = 1.6 Hz, 1H), 7.90 (s, 1H), 7.79 (br, 3H), 7.64 (d, J = 7.2 Hz, 1H), 7.54 (d, J = 7.2 Hz, 1H), 7.40 (dd, J = 8.8, 2.0 Hz, 1H), 7.23 (d, J = 2.0 Hz, 1H), 6.73 (d, J = 12.0 Hz, 1H), 3.47 (t, J = 8.0 Hz, 2H), 3.14 (t, J = 7.6 Hz, 2H). MS: (ESI) m/z 463.8 (M + H)+. [00313] Example 19: [00315] The synthesis of tert-Butyl (2-(6-chloro-3-((2,4-dichlorophenyl)amino)-9-tosyl-9H- carbazol-1-yl)ethyl)carbamate (29-1): tert-butyl (2-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)ethyl)carbamate (150 mg, 0.26 mmol), 2,4- dichloroaniline (42 mg, 0.26 mmol), tris(dibenzylideneacetone)dipalladium(0) (47 mg, 0.051 mmol), tert-butylbrett-Phos (32 mg, 0.064 mmol), potassium carbonate (107 mg, 0.78 mmol) and acetic acid (1 drop) were dissolved in tert-butanol (5 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 100 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by Prep-TLC (dichloromethane/methanol = 20/1) to give 67 mg title compound in 39% yield as a pale brown solid. MS: (ESI) m/z 658.1 (M - H)-. [00316] The synthesis of tert-Butyl (2-(6-chloro-3-((2,4-dichlorophenyl)amino)-9H-carbazol-1- yl)ethyl)carbamate To a solution of 29-1 (67 mg, 0.1 mmol) in THF (5 mL) was added LiAlH4 (9 mg, 0.24 mmol) at 0 °C. After being stirred for 20 minutes at 0 ºC, the reaction was warmed to room temperature and stirred another 16 hours until the reaction was completed. The reaction was cooled back to 0 ºC and quenched with by a few drops of water. The product was extracted with DCM and dried over Na2SO4. The organic phase was concentrated in vacuo to get the crude product, which was further purified by prep-TLC (PE: EA = 4:1) to give 24 mg of title compound in 46% yield as a pale brown solid. MS: (ESI) m/z 502.0 (M - H)-. [00317] The synthesis of 1-(2-Aminoethyl)-6-chloro-N-(2,4-dichlorophenyl)-9H-carbazol-3- amine (29-3): A solution of tert-butyl (2-(6-chloro-3-((2,4-dichlorophenyl)amino)-9H-carbazol-1-yl)ethyl)carbamate (24 mg, 0.048 mmol) in TFA (5% in DCM, 2.5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and used to next step directly. [00318] The synthesis of (29-4): 1-(2-Aminoethyl)-6-chloro-N-(2,4-dichlorophenyl)-9H-carbazol-3-amine (24 mg, 0.048 mmol), tert- butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (14 mg, 0.048mmol) and Et3N (8 mg, 0.088 mmol) in DMF (1 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water (8 mL). The product was extracted with ethyl acetate (3x10 mL) and dried over Na2SO4. The residue was purified by Prep-TLC (dichloromethane/methanol = 17/1) to give 28 mg of title compound in 97% yield as a pale brown solid. MS: (ESI) m/z 646.0 (M + H)+. [00319] The synthesis of 1-(2-(6-Chloro-3-((2,4-dichlorophenyl)amino)-9H-carbazol-1- yl)ethyl)guanidine (SRI-33122): A solution of 29-4 (28 mg, 0.04 mmol) in TFA (15% in DCM, 6 mL) was stirred at room temperature overnight. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (9.4 mg, 48%) as a gray solid. [00320] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.38 (s, 1H, formic acid), 8.15 (d, J = 2.0 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 2.4 Hz, 1H), 7.42 (dd, J = 8.4, 2.0 Hz, 1H), 7.19-7.15 (m, 2H), 6.99 (d, J = 4.4 Hz, 1H), 3.53 (t, J = 6.8 Hz, 2H), 3.13 (t, J = 6.8 Hz, 2H). MS: (ESI) m/z 446.0 (M + H)+. [00321] Example 20: [00323] The synthesis of tert-Butyl 4-nitro-1H-pyrazole-1-carboxylate (24-a): To a stirred mixture of 4-nitro-1H-pyrazole (2.1 g, 18.57 mmol) and DMAP (230 mg, 1.88 mmol) in DCM (210 mL) was added di-tert-butyl dicarbonate (4.86 g, 22.27 mmol) and the resulting solution was stirred at room temperature overnight. The reaction solution was washed with 1N HCl, brine and dried over Na2SO4. The solvent was removed to give 3.7 g of title compound in 93% yield as a white solid. [00324] 1H NMR (400 MHz, Chloroform-d) ^ 8.79 (s, 1H), 8.22 (s, 1H), 1.69 (s, 9H). MS: (ESI) m/z no mass. [00325] The synthesis of tert-Butyl 4-amino-1H-pyrazole-1-carboxylate (24-b): A suspension of tert- butyl 4-nitro-1H-pyrazole-1-carboxylate (3.7 g, 17.36 mmol) and 370 mg of 10% palladium on carbon in 55 ml of methanol, the reaction mixture was stirred vigorously under hydrogen pressure (1.0 atm) overnight at room temperature. The solid was removed by filtration through diatomite and the filtrate was concentrated to give 2.1 g of title compound in 66% yield as a pink solid. MS: (ESI) m/z 184.1 (M + H)+. [00326] The synthesis of tert-Butyl 4-((1-(2-((tert-butoxycarbonyl)amino)ethyl)-6-chloro-9-tosyl- 9H-carbazol-3-yl)amino)-1H-pyrazole-1-carboxylate (24-1): tert-butyl (2-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)ethyl)carbamate (100 mg, 0.17 mmol), tert- butyl 4-amino-1H-pyrazole-1-carboxylate (42 mg, 0.23 mmol), tris(dibenzylideneacetone)dipalladium(0) (32 mg, 0.035 mmol), tert-butylbrett-Phos (21 mg, 0.043 mmol), potassium carbonate (72 mg, 0.52 mmol) and acetic acid (1 drop) were dissolved in tert- butanol (5 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 100 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by Prep-TLC (petroleum ether/ethyl acetate = 1/1, dichloromethane/methanol = 30/1) to give 80 mg title compound in 68% yield as a pale brown solid. MS: (ESI) m/z 678.0 (M - H)-. [00327] The synthesis of tert-Butyl (2-(3-((1H-pyrazol-4-yl)amino)-6-chloro-9H-carbazol-1- yl)ethyl)carbamate (24-2): Activated Mg turnings (223 mg, 9.18 mmol) was added to dry methanol (14 mL), a solution of tert- butyl 4-((1-(2-((tert-butoxycarbonyl)amino)ethyl)-6-chloro-9-tosyl-9H-carbazol-3-yl)amino)-1H- pyrazole-1-carboxylate (80 mg, 0.118 mmol) in methanol (5 mL) was added following by ammonium chloride (89 mg, 1.66 mmol). The reaction mixture was stirred at room temperature for 3 hours then quenched with ammonium chloride solution. The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The residue was purified by Prep-TLC (dichloromethane/methanol = 20/1) to give 42 mg of title compound in 84% yield as a pale brown solid. MS: (ESI) m/z 426.0 (M + H)+. [00328] The synthesis of 1-(2-Aminoethyl)-6-chloro-N-(1H-pyrazol-4-yl)-9H-carbazol-3-amine (24-3): A solution of tert-butyl (2-(3-((1H-pyrazol-4-yl)amino)-6-chloro-9H-carbazol-1-yl)ethyl)carbamate (42 mg, 0.099 mmol) in TFA (5% in DCM, 5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and used to next step directly. [00329] The s 1-(2-Aminoethyl)-6-chloro-N-(1H-pyrazol-4-yl)-9H-carbazol-3-amine (42 mg, 0.099 mmol), tert- butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (31 mg, 0.10 mmol) and Et3N (20 mg, 0.20 mmol) in DMF (2 mL) was stirred at room temperature for 4 hours. The reaction was quenched with water (8 mL). The product was extracted with ethyl acetate (3x10 mL) and dried over Na2SO4. The residue was purified by Prep-TLC (dichloromethane/methanol = 20/1) to give 47 mg of title compound in 84% yield as a pale brown solid. MS: (ESI) m/z 567.9 (M + H)+. [00330] The synthesis of 1-(2-(3-((1H-Pyrazol-4-yl)amino)-6-chloro-9H-carbazol-1- yl)ethyl)guanidine (SRI-33123): - - A solution of 24-4 (47 mg, 0.083 mmol) in TFA (15% in DCM, 5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (15 mg, 49%) as a gray solid.1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.39 (s, 2H, formic acid), 8.08 (d, J = 2.0 Hz, 1H), 7.55-7.66 (m, 2H), 7.49 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.36 (dd, J = 8.8, 2.2 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 3.51 (t, J = 7.2 Hz, 2H), 3.08 (t, J = 7.0 Hz, 2H). MS: (ESI) m/z 368.0 (M + H)+. [00331] Example 21: [00333] The synthesis of tert-Butyl (tert-butoxycarbonyl)(2-(6-chloro-2-((3,4- dichlorophenyl)amino)-9-tosyl-9H-carbazol-1-yl)ethyl)carbamate (31-1): To a solution of tert-butyl (2-(2-bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)ethyl)(tert- butoxycarbonyl)carbamate (150 mg, 0.22 mmol) in dioxane (10 mL) was added 3,4-dichloroaniline (35.7 mg, 0.22 mmol), Pd2dba3 (36.6 mg, 0.04 mmol), Xant Phos (28.9 mg, 0.05 mmol) and K3PO4 (139.9mg, 0.66 mmol). The mixture was stirred under N2 at 100 °C for 12 hours. Cooled to room temperature and filtered, the filtrate was concentrated and purified by prep-TLC (petroleum ether/ethyl acetate = 4/1) to give 20 mg of title compound in 12% yield as a white solid. MS: (ESI) m/z 658.1(M-Boc)+. [00334] The synthesis of tert-Butyl (tert-butoxycarbonyl)(2-(6-chloro-2-((3,4- dichlorophenyl)amino)-9H-carbazol-1-yl)ethyl)carbamate (31-2): To a solution of tert-butyl (tert-butoxycarbonyl)(2-(6-chloro-2-((3,4-dichlorophenyl)amino)-9-tosyl- 9H-carbazol-1-yl)ethyl)carbamate (20 mg, 0.03 mmol) in methanol (10 mL) was added Mg (72 mg, 3 mmol), and NH4Cl (162 mg, 3 mmol). The mixture was stirred at room temperature for 3 hours. Filtered and the filtrate was concentrated and purified by prep-TLC (DCM/MeOH = 20/1) to give 15 mg of title compound in 94% yield as a white solid. MS: (ESI) m/z 604.0(M+H)+. [00335] The synthesis of 1-(2-Aminoethyl)-6-chloro-N-(3,4-dichlorophenyl)-9H-carbazol-2- amine (31-3): To a solution of tert-butyl (tert-butoxycarbonyl)(2-(6-chloro-2-((3,4- dichlorophenyl)amino)-9H-carbazol-1-yl)ethyl)carbamate (15 mg, 0.02 mmol) in DCM (3 mL) was added TFA (0.15 mL), the solution was stirred at room temperature overnight. The reaction mixture was concentrated to give 15 mg of title compound in 99% yield as a brown solid and used for the next step directly. [00336] The synthesis of 1-(2-(6-Chloro-2-((3,4-dichlorophenyl)amino)-9H-carbazol-1- yl)ethyl)guanidine-N,N’ -tert-butoxycarbonyl guanidine (31-4): To a solution of 1-(2-aminoethyl)-6-chloro-N-(3,4-dichlorophenyl)-9H-carbazol-2-amine (15 mg, 0.02 mmol) in DMF (3 mL) was added tert-butyl (Z)-(((tert-butoxycarbonyl)amino)(1H-pyrazol-1- yl)methylene)carbamate (12.4 mg, 0.04 mmol) and DIEA (7.7 mg, 0.06 mmol), the solution was stirred at room temperature for 2 hours. Extracted with EA (10 mL) and water (20 mL), the organic layer was separated and washed with brine, dried over Na2SO4, concentrated and purified by prep- TLC (DCM/MeOH = 20/1) to give 14 mg of title compound in 87% yield as a white solid. MS: (ESI) m/z 558.1. [00337] The synthesis of 1-(2-(6-Chloro-2-((3,4-dichlorophenyl)amino)-9H-carbazol-1- yl)ethyl)guanidine (SRI-33129): l To a solution of 1-(2-(6-chloro-2-((3,4-dichlorophenyl)amino)-9H-carbazol-1-yl)ethyl)guanidine- N,N’-tert-butoxycarbonyl guanidine (14 mg, 0.02 mmol) in DCM (3 mL) was added TFA (0.3 mL), the solution was stirred at room temperature overnight. Concentrated and purified by prep-HPLC to give 6.0 mg of title compound in 62% yield as a gray solid. [00338] 1H NMR (400 MHz, DMSO-d6) ^ 11.73 (s, 1H), 8.67 (br, 1H), 8.51 (s, 1H), 8.15 (s, 1H), 8.14 (d, J = 2.0 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.59 (br, 3H), 7.51 (d, J = 8.8 Hz, 1H), 7.37-7.33 (m, 2H), 7.05 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 2.4 Hz, 1H), 6.78 (dd, J = 8.8, 2.4 Hz, 1H), 3.32 (t, J = 8.4 Hz, 2H), 3.16-3.12 (m, 2H). MS: (ESI) m/z 445.8 (M + H)+. [00339] Example 22: [00341] The synthesis of tert-Butyl (2-(6-chloro-3-((1-methyl-1H-imidazol-2-yl)amino)-9-tosyl- 9H-carbazol-1-yl)ethyl)carbamate (26-1): tert-butyl (2-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1- yl)ethyl)carbamate (100 mg, 0.17 mmol), 1-methyl-1H-imidazol-2-amine (51 mg, 0.53 mmol), tris(dibenzylideneacetone)dipalladium(0) (32 mg, 0.035 mmol), tert-butylbrett-Phos (21 mg, 0.043 mmol), potassium carbonate (72 mg, 0.52 mmol) and acetic acid (1 drop) were dissolved in tert- butanol (5 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 80 °C for 7 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by Prep-TLC (dichloromethane/methanol = 20/1) to give 60 mg title compound in 58% yield as a pale brown solid. MS: (ESI) m/z 592.0 (M - H)-. [00342] The synthesis of tert-Butyl (2-(6-chloro-3-((1-methyl-1H-imidazol-2-yl)amino)-9H- carbazol-1-yl)ethyl)carbamate (26-2): Activated Mg turnings (189 mg, 7.78 mmol) was added to dry methanol (12 mL), then a solution of tert-butyl (2-(6-chloro-3-((1-methyl-1H-imidazol-2-yl)amino)-9- tosyl-9H-carbazol-1-yl)ethyl)carbamate (60 mg, 0.10 mmol) in methanol (4 mL) was added following by ammonium chloride (76 mg, 1.42 mmol). The reaction mixture was stirred at room temperature for 6 hours then quenched with ammonium chloride solution. The product was extracted with ethyl acetate (3x10 mL) and dried over Na2SO4. The residue was purified by Prep-TLC (dichloromethane/methanol = 15/1) to give 34 mg of title compound in 77% yield as a pale brown solid. MS: (ESI) m/z 438.0 (M - H)-. [00343] The synthesis of 1-(2-Aminoethyl)-6-chloro-N-(1-methyl-1H-imidazol-2-yl)-9H- carbazol-3-amine (26-3): A solution of tert-butyl (2-(3-((1H-pyrazol-4-yl)amino)-6-chloro-9H- carbazol-1-yl)ethyl)carbamate (34 mg, 0.077 mmol) in TFA (5% in DCM, 2.5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and used to next step directly. [00344] The synthesis of (26-4): 1-(2-Aminoethyl)-6-chloro-N-(1-methyl-1H-imidazol-2-yl)-9H- carbazol-3-amine (35 mg, 0.103 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1- yl)methylene)carbamate (32 mg, 0.103 mmol) and Et3N (21 mg, 0.207 mmol) in DMF (1 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water (8 mL). The product was extracted with ethyl acetate (3x10 mL) and dried over Na2SO4. The residue was purified by Prep- TLC (dichloromethane/methanol = 17/1) to give 37 mg of title compound in 62% yield as a pale brown solid. MS: (ESI) m/z 582.0 (M + H)+. [00345] The synthesis of 1-(2-(6-Chloro-3-((1-methyl-1H-imidazol-2-yl)amino)-9H-carbazol-1- yl)ethyl)guanidine (SRI-33130): A solution of 26-4 (61 mg, 0.105 mmol) in TFA (15% in DCM, 6 mL) was stirred at room temperature overnight. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (19.1mg, 34%) as a pale brown solid. [00346] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.32 (s, 2H, formic acid), 8.10 (d, J = 2.0 Hz, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.42 (dd, J = 8.4, 2.0 Hz, 1H), 7.29 (d, J = 2.0 Hz, 1H), 6.94 (d, J = 1.6 Hz, 1H), 6.76 (d, J = 1.6 Hz, 1H), 3.51-3.54 (m, 5H), 3.12 (t, J = 7.2 Hz, 2H). MS: (ESI) m/z 382.0 (M + H)+. [00347] Example 23: [00349] The synthesis of tert-Butyl (2-(6-chloro-3-((3,4-dichlorobenzyl)amino)-9-tosyl-9H- carbazol-1-yl)ethyl)carbamate (33-1): tert-butyl (2-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1- yl)ethyl)carbamate (125 mg, 0.22 mmol), (3,4-dichlorophenyl)methanamine (115 mg, 0.65 mmol), tris(dibenzylideneacetone)dipalladium(0) (40 mg, 0.044 mmol), tert-butylbrettphos (27 mg, 0.056 mmol), potassium carbonate (90 mg, 0.65 mmol) and acetic acid (1 drop) were dissolved in tert- butanol (5 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 80 °C for 8 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by Prep-TLC (petroleum ether/ethyl acetate = 2/1) to give 50 mg title compound in 34% yield as a pale brown solid. MS: (ESI) m/z 669.9 (M - H)-. [00350] The synthesis of tert-Butyl (2-(6-chloro-3-((3,4-dichlorobenzyl)amino)-9H-carbazol-1- yl)ethyl)carbamate (33-2): Activated Mg turnings (139 mg, 5.72 mmol), ammonium chloride (56 mg, 1.04 mmol) and tert-butyl (2-(6-chloro-3-((3,4-dichlorobenzyl)amino)-9-tosyl-9H-carbazol-1- yl)ethyl)carbamate (50 mg, 0.074 mmol) in methanol (5 mL) was stirred at room temperature for 3 hours then quenched with ammonium chloride solution. The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The residue was purified by Prep-TLC (petroleum ether/ethyl acetate = 2/1) to give 27 mg of title compound in 70% yield as a pale brown solid. MS: (ESI) m/z 516.0 (M - H)-. [00351] The synthesis of 1-(2-Aminoethyl)-6-chloro-N-(3,4-dichlorobenzyl)-9H-carbazol-3-amine (33-3): A solution of tert-butyl (2-(6-chloro-3-((3,4-dichlorobenzyl)amino)-9H-carbazol-1- yl)ethyl)carbamate (27 mg, 0.052 mmol) in TFA (5% in DCM, 2.5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and used for the next step directly. [00352] The synthesis of (33-4): 1-(2-Aminoethyl)-6-chloro-N-(3,4-dichlorobenzyl)-9H-carbazol- 3-amine (28 mg, 0.067 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1- yl)methylene)carbamate (21 mg, 0.067 mmol) and Et3N (14 mg, 0.138 mmol) in DMF (2 mL) was stirred at room temperature for 4 hours. The reaction was quenched with water (10 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The residue was purified by Prep- TLC (petroleum ether/ethyl acetate = 4/1, dichloromethane/ petroleum ether = 2/1) to give 19 mg of title compound in 43% yield as a pale brown oil. MS: (ESI) m/z 659.8 (M + H)+. [00353] The synthesis of 1-(2-(6-Chloro-3-((3,4-dichlorobenzyl)amino)-9H-carbazol-1- yl)ethyl)guanidine (SRI-33160): A solution of 33-4 (19 mg, 0.029 mmol) in TFA (10% in DCM, 2 mL) was stirred at room temperature for overnight. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (6.1mg, 46%) as a blank solid. [00354] 1H NMR (400 MHz, methanol-d4) ^ 8.52 (s, 1H, formic acid), 7.87 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.34-7.39 (m, 2H), 7.26 (dd, J = 8.4, 2.0 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 6.77 (d, J = 2.0 Hz, 1H), 4.39 (s, 2H), 3.57 (t, J = 7.0 Hz, 2H), 3.12 (t, J = 7.0 Hz, 2H). MS: (ESI) m/z 459.8 (M + H)+. [00355] Example 24: [00357] The synthesis of tert-Butyl (2-(6-chloro-3-((5,6-dichloropyridin-3-yl)amino)-9-tosyl-9H- carbazol-1-yl)ethyl)carbamate (37-1): l - - tert-butyl (2-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)ethyl)carbamate (250 mg, 0.43 mmol), 5,6- dichloropyridin-3-amine (71 mg, 0.43 mmol), tris(dibenzylideneacetone)dipalladium(0) (79 mg, 0.086 mmol), Xant-Phos (62 mg, 0.11 mmol) and potassium phosphate (274 mg, 1.29 mmol) were dissolved in 1,4-dioxane (10 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 100 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by Prep-TLC (petroleum ether/ethyl acetate = 2/1) to give 110 mg of 37-1 (38% yield) as a pale brown solid. MS: (ESI) m/z 656.8 (M - H)-. [00358] The synthesis of tert-Butyl (2-(6-chloro-3-((5,6-dichloropyridin-3-yl)amino)-9H-carbazol- 1-yl)ethyl)carbamate (37-2): Add LiAlH4 (15 mg, 0.17 mmol) to the 37-1 (110 mg, 0.16 mmol) in THF (5 mL) at 0 °C. After being stirred for 20 minutes at 0 ºC, the reaction was warmed to room temperature and stirred another 16 hours by which time all 37-1 had been consumed. The reaction was cooled back to 0 ºC and quenched with ice pieces and a few drops of water. The product was extracted with DCM and dried over Na2SO4. The organic phase concentrated in vacuo to get crude product, and the purified by prep-TLC. (PE: EA=4:1) to give 75 mg of title compound in 88% yield as a pale brown solid. MS: (ESI) m/z 503.0 (M - H)-. [00359] The synthesis of 1-(2-Aminoethyl)-6-chloro-N-(5,6-dichloropyridin-3-yl)-9H-carbazol-3- amine (37-3): A solution of tert-butyl (2-(6-chloro-3-((5,6-dichloropyridin-3-yl)amino)-9H-carbazol-1- yl)ethyl)carbamate (75 mg, 0.15 mmol) in TFA (5% in DCM, 2.5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and used for the next step directly. [00360] The synthesis of (37-4): 1-(2-Aminoethyl)-6-chloro-N-(5,6-dichloropyridin-3-yl)-9H-carbazol-3-amine (60 mg, 0.15 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (46 mg, 0.15 mmol) and Et3N (30 mg, 0.3 mmol) in DMF (1 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water (8 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The residue was purified by Prep-TLC (dichloromethane/methanol = 17/1) to give 80 mg of title compound in 83% yield as a pale brown solid. MS: (ESI) m/z 645.0 (M - H)-. [00361] The synthesis of 1-(2-(6-Chloro-3-((5,6-dichloropyridin-3-yl)amino)-9H-carbazol-1- yl)ethyl)guanidine (SRI-33161): A solution of 37-4 (80 mg, 0.12 mmol) in TFA (15% in DCM, 6 mL) was stirred at room temperature overnight. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (41.14 mg, 74%) as a gray solid. [00362] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.40 (s, 1H, formic acid), 8.20 (s, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.89 (s, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 2.8 Hz, 1H), 7.44 (dd, J = 8.4, 1.6 Hz, 1H), 7.18 (s, 1H), 3.54 (t, J = 7.2 Hz, 2H), 3.15 (t, J = 6.8 Hz, 2H). MS: (ESI) m/z 446.8 (M + H)+. [00363] Example 25: [00364] Example Route for Example 25 (SRI-33162):
[00365] The synthesis of 2-Bromo-4,5-dichloroaniline (32-2): To a stirred solution of 1-bromo- 4,5-dichloro-2-nitrobenzene (14.0 g,40 mmol) in anhydrous ethanol (200 mL) was treated with Zn (21.8 g, 332 mmol), NH4Cl (21.2 g, 400 mmol) and acetic acid (20 mL, 332 mmol). The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate and filtered through celite. The filtrate was concentrated and the residue was dissolved in dichloromethane (200 mL) and washed with saturated NaHCO3 solution followed by brine. The solvent was concentrated and the residue was purified on silica column (200 g) and eluted with 1-50% EtOAc in hexane to give 8.4 g of title compound with 88% yield. MS: (ESI) m/z 237.9 (M-H)-. [00366] The synthesis of 4,5-Dichloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (32- 3): To a stirred solution of 2-bromo-4,5-dichloroaniline (11.5g, 48 mmol) in anhydrous DMSO (140 mL) were added Bis(pinacolato) diborane (18 g, 72 mmol), Pd(dppf)Cl2.CH2Cl2 (1.2 g, 1.4 mmol) and KOAc (12.2 g, 124 mmol) and degassed with Argon for 10-15 minutes. The resulting mixture was heated at 80 oC for 20-22 hours. The solution was cooled to room temperature and water (150 mL) was added. The solid was suspended into DCM (200 mL) and insoluble salts were filtered. The organic layer was dried over Na2SO4 and filtered. The solvent was concentrated and the residue was purified on silica column (100 g) and eluted with 1-20% EtOAc in hexane to give 9.6 g of title compound with 70% yield. MS: (ESI) m/z 204.0 (M-83)–. [00367] The synthesis of N-(4,5-Dichloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)- 4-methylbenzenesulfonamide (32-4): To a solution of the 4,5-dichloro-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)aniline (21.8 g, 75.8 mmol) in pyridine (200 mL) was added p-toluenesulfonyl chloride (15.2 g, 79.9 mmol) at 0 °C portion-wise. After being stirred at 25 °C for 2-3 hours, pyridine was removed by rotary evaporator and the reaction mixture was poured into water. The product was extracted with CH2Cl2 (500 mL, 100 mL), dried over MgSO4 and concentrated in vacuo. The residue was dissolved in minimum volume of CH2Cl2 and stirred for 15 minutes to get the solid. Hexane was added to keep for 2-3 hours at room temperature. The solids were filtered and dried under high vacuum to give 21 g of title compound in 63% yield. MS: (ESI) m/z 358.0 (M-83)–. [00368] The synthesis of 2-(5-Bromo-4',5'-dichloro-2'-(4-methylphenylsulfonamido)-[1,1'- biphenyl]-3-yl)acetamide (32-5): To a solution of 2-(3,5-dibromophenyl)acetamide (5.75 g, 19.62 mmol) in 1,4-dioxane/H2O (20 mL/20 mL) were added Pd(PPh3)4 (284 mg, 0.25 mmol, 5 mol%), Na2CO3 (1.04 g, 9.81 mmol) and N-(4,5-dichloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)-4-methylbenzenesulfonamide (2.2 g, 4.91 mmol) under N2. After being stirred at 90 °C for 14 hours, the reaction mixture was cooled to room temperature EtOAc (1 L) was added and organic layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified column chromatography (petroleum ether/ethyl acetate = 5/1 to 1/1) to give 1.51 g of title compound in 58% yield as a white solid. MS: (ESI) m/z 544.0 (M +NH4)+. [00369] The synthesis of 2-(3-Bromo-6,7-dichloro-9-tosyl-9H-carbazol-1-yl)acetamide (32-6): A solution of PhI(OAc)2 (1.82 g, 5.65 mmol) in DCM (20 mL) was added to a mixture of 2-(5-bromo-5'- chloro-2'-(4-methylphenylsulfonamido)-[1,1'-biphenyl]-3-yl)acetamide (1.98 g, 3.77 mmol), Cu(OTf)2 (69 mg, 0.19 mmol, 5 mol%) and TFA (1.29 g, 11.30 mmol) in DCM (40 mL) at reflux. After 10 mins, the reaction was complete and the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5/1 to 1/1) to give 810 mg of title compound in 41% yield as a brown solid. MS: (ESI) m/z 523.0 (M-H)–. [00370] The synthesis of tert-Butyl (2-(3-bromo-6,7-dichloro-9-tosyl-9H-carbazol-1- yl)ethyl)carbamate (32-7): A solution of 2-(3-bromo-6,7-dichloro-9-tosyl-9H-carbazol-1-yl)acetamide (536 mg, 1.02 mmol) in borane-tetrahydrofuran complex (1M in THF, 10 ml, 10 mmol) was stirred at room temperature overnight. The reaction mixture was quenched with methanol then concentrated. The residue was dissolved in DCM, washed with brine, the organic layer was dried (Na2SO4) and the solvent was evaporated. The residue was dissolved in DCM (20 mL), di-tert-butyl dicarbonate (333 mg, 1.53 mmol) and Et3N (6 mg, 0.046 mmol) was added. After stirring at room temperature overnight, the reaction solution was concentrated and purified by column chromatography (petroleum ether/ethyl acetate = 100/1 to 20/1) to give 311 mg of title compound in 50% yield as pale brown oil. MS: (ESI) m/z 608.8 (M - H)–. [00371] The synthesis of tert-Butyl 2-(6,7-dichloro-3-(4-chlorophenylamino)-9H-carbazol-1- yl)ethylcarbamate (32-9): tert-butyl 2-(3-bromo-6,7-dichloro-9-tosyl-9H-carbazol-1- yl)ethylcarbamate (200 mg, 0.326 mmol), 4-chloroaniline (42 mg, 0.326 mmol), tris(dibenzylideneacetone)dipalladium(0) (60 mg, 0.065 mmol), tert-butylbrett-Phos (63 mg, 0.130 mmol), K2CO3 (135 mg, 0.980 mmol) and 1 drop AcOH were dissolved in tert-butanol (20 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 100 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by CC (petroleum ether/ethyl acetate = 2/1) then purified by Prep-TLC (petroleum ether/ethyl acetate = 2/1) to give 30 mg title compound in 18% yield as a brown solid. MS: (ESI) m/z 502.0 (M - H)–. [00372] The synthesis of 1-(2-Aminoethyl)-6,7-dichloro-N-(4-chlorophenyl)-9H-carbazol-3- amine (32-10): A solution of tert-butyl 2-(6,7-dichloro-3-(4-chlorophenylamino)-9H-carbazol-1- yl)ethylcarbamate (30 mg, 0.059 mmol) in TFA (5% in dichloromethane, 5 mL) was stirred at room temperature for 3 hours. The reaction solution was concentrated and used for the next step directly. MS: (ESI) m/z 403.8 (M + H)+. [00373] The synthesis of (E)-tert-Butyl (tert-butoxycarbonylamino)(2-(6,7-dichloro-3-(4- chlorophenylamino)-9H-carbazol-1-yl)ethylamino)methylenecarbamate (32-11): 1-(2-aminoethyl)- 6,7-dichloro-N-(4-chlorophenyl)-9H-carbazol-3-amine (24 mg, 0.059 mmol), tert-butyl (((tert- butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (18 mg, 0.059 mmol) and Et3N (12 mg, 0.119 mmol) in DMF (5 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water (10 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The residue was purified by Prep-TLC (petroleum ether/ ethyl acetate = 2/1) to give 30 mg of title compound in 78% yield as a yellow solid. MS: (ESI) m/z 645.8 (M + H) +. [00374] The synthesis of 1-(2-(6,7-Dichloro-3-(4-chlorophenylamino)-9H-carbazol-1- yl)ethyl)guanidine (SRI-33162): A solution of (E)-tert-butyl (tert-butoxycarbonylamino)(2-(6,7- dichloro-3-(4-chlorophenylamino)-9H-carbazol-1-yl)ethylamino)methylenecarbamate (30 mg, 0.046 mmol) in TFA (10% in dichloromethane, 5 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and then purified by Prep-HPLC to give 15 mg title compound in 72% yield as a gray solid.1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.46 (s, 0.76H, formic acid), 8.41 (s, 1H), 7.81 (d, J = 1.6 Hz, 1H), 7.69 (s, 1H), 7.18-7.21 (m, 2H), 7.14 (d, J = 1.6 Hz, 1H), 6.98-7.00 (m, 2H), 3.46-3.50 (m, 2H), 3.10 (t, J = 5.8 Hz, 2H). MS: (ESI) m/z 445.8 (M + H)+. [00375] Example 26: [00376] Example Route for Example 26 (SRI-33163):
[00377] The synthesis of tert-Butyl (2-(6-chloro-3-((4,5-dichloropyridin-2-yl)amino)-9-tosyl-9H- carbazol-1-yl)ethyl)carbamate (38-1): To a solution of tert-butyl (2-(3-bromo-6-chloro-9-tosyl-9H- carbazol-1-yl)ethyl)carbamate (200 mg, 0.35 mmol) in dioxane (10 mL) was added 4,5- dichloropyridin-2-amine (55.9 mg, 0.35 mmol), Pd2dba3 (64.0 mg, 0.07 mmol), Xant Phos (43.3 mg, 0.08 mmol) and K3PO4 (222.6 mg, 1.05 mmol). The mixture was stirred under N2 at 90 °C for 3 hours. Cooled to room temperature and filtered, the filtrate was concentrated and purified by prep-TLC (petroleum ether/ethyl acetate = 4/1) to give 110 mg of title compound in 48% yield as a white solid. MS: (ESI) m/z 656.8 (M-H)-. [00378] The synthesis of tert-Butyl (2-(6-chloro-3-((4,5-dichloropyridin-2-yl)amino)-9H-carbazol- 1-yl)ethyl)carbamate (38-2): To a solution of tert-butyl (2-(6-chloro-3-((4,5-dichloropyridin-2- yl)amino)-9-tosyl-9H-carbazol-1-yl)ethyl)carbamate (110 mg, 0.17 mmol) in THF (10 mL) was added LiAlH4 (25.8 mg, 0.68 mmol). The mixture was stirred at room temperature for 16 hours. Quenched with methanol, extracted with EA(20 mL) and water (20 mL), the organic layer was separated and washed with brine, dried over Na2SO4, concentrated and purified by prep-TLC (DCM/MeOH = 20/1) to give 40 mg of title compound in 47% yield as a white solid. MS: (ESI) m/z 504.0(M-H)–. [00379] The synthesis of 1-(2-Aminoethyl)-6-chloro-N-(4,5-dichloropyridin-2-yl)-9H-carbazol-3- amine (38-3): To a solution of tert-butyl (2-(6-chloro-3-((4,5-dichloropyridin-2-yl)amino)-9H- carbazol-1-yl)ethyl)carbamate (40 mg, 0.08 mmol) in DCM (5 mL) was added TFA (0.25 mL), the solution was stirred at room temperature overnight. The reaction mixture was concentrated to give 40 mg of title compound in 99% yield as a brown solid and used for the next step directly. [00380] The synthesis of 1-(2-(6-Chloro-3-((4,5-dichloropyridin-2-yl)amino)-9H-carbazol-1- yl)ethyl) -N,N’ -tert-butoxycarbonyl guanidine (38-4): To a solution of 1-(2-aminoethyl)-6-chloro-N- (4,5-dichloropyridin-2-yl)-9H-carbazol-3-amine (40 mg, 0.08 mmol) in DMF (5 mL) was added tert- butyl (Z)-(((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (50 mg, 0.16 mmol) and DIEA (31 mg, 0.24 mmol), the solution was stirred at room temperature for 2 hours. Extracted with EA (20 mL) and water (30 mL), the organic layer was separated and washed with brine, dried over Na2SO4, concentrated and purified by prep-TLC (DCM/MeOH = 20/1) to give 25 mg of title compound in 49% yield as a white solid. MS: (ESI) m/z 491.2 (M-Boc-56+H)+. [00381] The synthesis of 1-(2-(6-Chloro-3-((4,5-dichloropyridin-2-yl)amino)-9H-carbazol-1- yl)ethyl)guanidine (SRI-33163): To a solution of 1-(2-(6-chloro-3-((4,5-dichloropyridin-2-yl)amino)- 9H-carbazol-1-yl)ethyl) -N,N’ -tert-butoxycarbonyl guanidine (25 mg, 0.04 mmol) in DCM (5 mL) was added TFA (0.5 mL), the solution was stirred at room temperature over night. Concentrated and purified by prep-HPLC to give 10 mg of title compound in 29% yield as a white solid. [00382] 1H NMR (400 MHz, DMSO-d6) ^ 11.60 (s, 1H), 9.30 (s, 1H), 8.54 (br, 1H), 8.50 (s, 1H), 8.28 (s, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.14 (d, J = 2.0 Hz, 1H), 7.68 (br, 3H), 7.51 (d, J = 8.8 Hz, 1H), 7.38 (dd, J = 8.8, 2.0 Hz, 1H), 7.34 (d, J = 1.6 Hz, 1H), 6.97 (s, 1H), 3.47 (t, J = 8.0 Hz, 2H), 3.13 (t, J = 7.6 Hz, 2H). MS: (ESI) m/z 446.8 (M + H)+. [00383] Example 27: [00385] The synthesis of Ethyl 4-chlorobenzimidate hydrochloride (41-2): A solution of 4- dichlorobenzonitrile (3.0 g, 21.81 mmol) and HCl (3 mL, 2M in ethanol) in HCl (30 mL, 4M in 1,4- dioxane) was stirred at room temperature overnight. The reaction solution was concentrated and washed with ethyl acetate to give 3.6 g of title compound in 75% yield as a white solid. MS: (ESI) m/z 184.2 (M + H)+. [00386] The synthesis of 4-Chlorobenzimidamide hydrochloride (41-3): A mixture of ethyl 4- chlorobenzimidate hydrochloride (2.0 g, 9.09 mmol) and ammonium carbonate (4.37 g, 45.43 mmol) in ethanol (30 mL) was stirred at room temperature overnight. The reaction solution was diluted with water (20 mL). The ethanol was removed by vacuum and the solid was collected by filtration to give 1.5 g of title compound in 86% yield as a white solid. MS: (ESI) m/z 155.2 (M + H)+. [00387] The synthesis of tert-Butyl (2-(6-chloro-3-(4-chlorobenzimidamido)-9-tosyl-9H-carbazol- 1-yl)ethyl)carbamate (41-4): tert-butyl (2-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1- yl)ethyl)carbamate (120 mg, 0.21 mmol), 4-chlorobenzimidamide hydrochloride (52 mg, 0.27 mmol), tris(dibenzylideneacetone)dipalladium(0) (38 mg, 0.042 mmol), tert-butylbrett-Phos (26 mg, 0.054 mmol) and cesium carbonate (271 mg, 0.83 mmol) were dissolved in tert-butanol (6 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 1 hour. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by Prep-TLC (petroleum ether/ethyl acetate = 2/1) to give 99 mg title compound in 73% yield as a pale brown solid. MS: (ESI) m/z 649.1 (M - H)–. [00388] The synthesis of tert-Butyl (2-(6-chloro-3-(4-chlorobenzimidamido)-9H-carbazol-1- yl)ethyl)carbamate (41-5): Lithium aluminum hydride (0.46 mL, 1M in THF) was slowly added to tert-butyl (2-(6-chloro-3-(4-chlorobenzimidamido)-9-tosyl-9H-carbazol-1-yl)ethyl)carbamate (126 mg, 0.19 mmol) in THF (5 mL). After being stirred overnight, the reaction was quenched with ice pieces and a few drops of water. The product was extracted with ethyl acetate (3x20 mL), washed with brine, dried over Na2SO4 and concentrated. The residue was purified by Prep-TLC (dichloromethane/methanol = 10/1) to give 40 mg of title compound in 42% yield as a pale brown solid. MS: (ESI) m/z 495.0 (M – H)–. [00389] The synthesis of N-(1-(2-Aminoethyl)-6-chloro-9H-carbazol-3-yl)-4- chlorobenzimidamide (41-6): A solution of tert-butyl (2-(6-chloro-3-(4-chlorobenzimidamido)-9H- carbazol-1-yl)ethyl)carbamate (40 mg, 0.080 mmol) in TFA (5% in DCM, 5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and used for the next step directly. [00390] The synthesis of (41-7): N-(1-(2-Aminoethyl)-6-chloro-9H-carbazol-3-yl)-4- chlorobenzimidamide (40 mg, 0.10 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1- yl)methylene)carbamate (32 mg, 0.10 mmol) and Et3N (21 mg, 0.21 mmol) in DMF (2 mL) was stirred at room temperature for 4 hours. The reaction was quenched with water (10 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The residue was purified by Prep- TLC (dichloromethane/methanol = 15/1) to give 37 mg of title compound in 57% yield as a pale brown solid. MS: (ESI) m/z 638.8 (M + H)+. [00391] The synthesis of 4-Chloro-N-(6-chloro-1-(2-guanidinoethyl)-9H-carbazol-3- yl)benzimidamide (SRI-33167): A solution of 41-7 (37 mg, 0.058 mmol) in TFA (10% in DCM, 5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (21 mg, 83%) as a yellow solid. [00392] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.35 (s, 2H, formic acid), 8.23 (s, 1H), 8.02 (s, 1H), 7.95 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.8 Hz, 1H), 7.48 (dd, J = 8.8, 2.0 Hz, 1H), 7.25 (s, 1H), 3.55 (t, J = 7.2 Hz, 2H), 3.19 (t, J = 6.8 Hz, 2H). MS: (ESI) m/z 439.0 (M + H)+. [00393] Example 28: [00395] The synthesis of Ethyl 3,4-dichlorobenzimidate hydrochloride (35-2): A solution of 3,4- dichlorobenzonitrile (1.0 g, 5.81 mmol) and HCl (1 mL, 2M in ethanol) in HCl (10 mL, 4M in 1,4- dioxane) was stirred at room temperature overnight. The reaction solution was concentrated and washed with ethyl acetate to give 811 mg of title compound in 55% yield as a white solid. MS: (ESI) m/z 218.0 (M + H)+. [00396] The synthesis of 3,4-Dichlorobenzimidamide hydrochloride (35-3): A mixture of ethyl 3,4-dichlorobenzimidate hydrochloride (811 mg, 3.19 mmol) and ammonium carbonate (2.14 g, 22.30 mmol) in ethanol (10 mL) was stirred at room temperature overnight. The reaction solution was diluted with water. The ethanol was removed by vacuum and the solid was collected by filtration to give 394 mg of title compound in 65% yield as a white solid. MS: (ESI) m/z 189.0 (M + H)+. [00397] The synthesis of tert-Butyl (2-(6-chloro-3-(3,4-dichlorobenzimidamido)-9-tosyl-9H- carbazol-1-yl)ethyl)carbamate (35-4): tert-butyl (2-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1- yl)ethyl)carbamate (100 mg, 0.17 mmol), 3,4-dichlorobenzimidamide hydrochloride (51 mg, 0.23 mmol), tris(dibenzylideneacetone)dipalladium(0) (32 mg, 0.035 mmol), tert-butylbrett-Phos (21 mg, 0.043 mmol) and cesium carbonate (226 mg, 0.69 mmol) were dissolved in tert-butanol (5 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 80 °C for 2 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by Prep-TLC (petroleum ether/ethyl acetate = 2/1) to give 58 mg title compound in 49% yield as a pale brown solid. MS: (ESI) m/z 685.2 (M + H)+. [00398] The synthesis of tert-Butyl (2-(6-chloro-3-(3,4-dichlorobenzimidamido)-9H-carbazol-1- yl)ethyl)carbamate (35-5): A mixture of tert-butyl (2-(6-chloro-3-(3,4-dichlorobenzimidamido)-9- tosyl-9H-carbazol-1-yl)ethyl)carbamate (58 mg, 0.085 mmol) and TBAF (1 M in THF, 0.42 mL, 0.42 mmol) in THF (5 mL) was stirred at 60 °C for 3 hours. The mixture was cooled to room temperature and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with brine, dried over Na2SO4 and concentrated. The residue was purified by Prep-TLC (dichloromethane/methanol = 15/1) to give 25 mg of title compound in 56% yield as a pale brown solid. MS: (ESI) m/z 530.8 (M + H)+. [00399] The synthesis of N-(1-(2-Aminoethyl)-6-chloro-9H-carbazol-3-yl)-3,4- dichlorobenzimidamide (35-6): A solution of tert-butyl (2-(6-chloro-3-(3,4-dichlorobenzimidamido)- 9H-carbazol-1-yl)ethyl)carbamate (25 mg, 0.047 mmol) in TFA (5% in DCM, 5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and used for the next step directly. [00400] The synthesis of (35-7): N-(1-(2-aminoethyl)-6-chloro-9H-carbazol-3-yl)-3,4- dichlorobenzimidamide (25 mg, 0.058 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1- yl)methylene)carbamate (18 mg, 0.058 mmol) and Et3N (12 mg, 0.12 mmol) in DMF (1 mL) was stirred at room temperature for 3 hours. The reaction was quenched with water (10 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The residue was purified by Prep- TLC (petroleum ether/ethyl acetate = 2/1, dichloromethane/methanol = 50/1) to give 15 mg of title compound in 38% yield as a pale brown solid. MS: (ESI) m/z 672.7 (M + H)+. [00401] The synthesis of 3,4-Dichloro-N-(6-chloro-1-(2-guanidinoethyl)-9H-carbazol-3- yl)benzimidamide (SRI-33168): A solution of 35-7 (15 mg, 0.022 mmol) in TFA (10% in DCM, 5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (7.4 mg, 70%) as a yellow solid.1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.35 (s, 2H, formic acid), 8.19 (s, 2H), 7.80-7.92 (m, 3H), 7.58 (d, J = 8.4 Hz, 1H), 7.45 (dd, J = 8.4, 2.0 Hz, 1H), 7.10 (s, 1H), 3.55 (t, J = 6.8 Hz, 2H), 3.16 (t, J = 6.6 Hz, 2H). MS: (ESI) m/z 472.8 (M + H)+. [00402] Example 29: [00404] The synthesis of 2-(3,5-Dibromobenzyl)isoindoline-1,3-dione (42-2): A mixture of 1,3-dibromo-5-(bromomethyl)benzene (2 g, 6.08 mmol), potassium 1,3- dioxoisoindolin-2-ide (1.12 g, 6.08 mmol) in DMF (30 mL), the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with water 240 mL and filtered to get product 42-2, the crude product was purified by re-crystallization to give 2.1 g of 42-2 (87% yield) as a white solid. [00405] The synthesis of N-(3'-Bromo-5-chloro-5'-((1,3-dioxoisoindolin-2-yl)methyl)-[1,1'- biphenyl]-2-yl)-4-methylbenzenesulfonamide (42-3): 42-2 (1 g, 2.5 mmol), 7-3 (510 mg, 1.26 mmol), Pd(PPh3)4 (70 mg, 0.06 mmol) and K3PO4 (530 mg, 2.5 mmol) was added in toluene 20 mL. The reaction solution was degassed and purged with N2 for 5- 10 minutes and then heated at 90 °C for 3 hours. The reaction was added 60 mL H2O and extract with DCM and dried over Na2SO4. The organic phase was concentrated in vacuo to get crude product, the crude product was purified by C.C. (PE/EA= 4/1) to give 600 mg of title compound in 40% yield as a pale brown solid. MS: (ESI) m/z 593.0 (M - H)–. [00406] The synthesis of 2-((3-Bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)methyl)isoindoline-1,3- dione (42-4): 42-3 (600 mg, 1.01 mmol), Cu(OTf)2 (18 mg, 0.05 mmol), PhI(OAc)2 (976 mg, 3.03 mmol) and TFA (145 mg, 1.5 mmol) was added in DCM 10 mL. The reaction was stirred 10 minutes at 50 ºC by until 42-3 had been consumed. The reaction was concentrated in vacuo to get crude product, the crude product was purified by C.C. (PE/EA= 2/1) to give 150 mg of title compound in 25% yield as a white solid. MS: (ESI) m/z 592.9 (M + H)+. [00407] The synthesis of 2-(((6-Chloro-3-((3,4-dichlorophenyl)amino)-9H-carbazol-1- yl)methyl)carbamoyl)benzoic acid (42-5): 2-((3-bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)methyl)isoindoline-1,3-dione (150 mg, 0.25 mmol), 3,4-dichloroaniline (42 mg, 0.25 mmol), tris(dibenzylideneacetone)dipalladium(0) (48 mg, 0.051 mmol), tert-butylbrett-Phos (30 mg, 0.06 mmol) and cesium carbonate (63 mg, 0.75 mmol) were dissolved in tert-butanol (10 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by Prep-TLC (petroleum ether/ethyl acetate = 2/1) to give 90 mg title compound in 66% yield as a brown solid. MS: (ESI) m/z 536.0 (M - H)–. [00408] The synthesis of 1-(Aminomethyl)-6-chloro-N-(3,4-dichlorophenyl)-9H-carbazol-3-amine (42-6): A solution of 42-5 (90 mg, 0.16 mmol) and N2H4 (32 mg, 0.83 mmol) in EtOH (5 mL), the reaction mixture was stirred at 80 ºC for 16 hours. The crude product was concentrated and used for the next step directly. MS: (ESI) m/z 388.0 (M – H) –. [00409] The synthesis of (42-7): 1-(Aminomethyl)-6-chloro-N-(3,4-dichlorophenyl)-9H-carbazol-3-amine (65 mg, 0.16 mmol), tert- butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (49 mg, 0.16 mmol) and Et3N (32 mg, 0.32 mmol) in DMF (1 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water (8 mL). The product was extracted with ethyl acetate (3x10 mL) and dried over Na2SO4. The residue was purified by Prep-TLC (dichloromethane/methanol = 20/1) to give 24 mg of title compound in 22% yield as a brown solid. MS: (ESI) m/z 632.0 (M + H)+. [00410] The synthesis of 1-((6-Chloro-3-((3,4-dichlorophenyl)amino)-9H-carbazol-1- yl)methyl)guanidine (SRI-33169): A solution of 42-7 (24 mg, 0.038 mmol) in TFA (15% in DCM, 6 mL) was stirred at room temperature overnight. The reaction solution was concentrated and purified by Prep-HPLC to provide the title compound (5.32 mg, 30%) as a green solid. [00411] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.38 (s, 1H, formic acid), 8.20 (d, J = 1.6 Hz, 1H), 7.87 (d, J = 1.6 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.45 (dd, J = 8.4, 0.4 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.19 (s, 1H), 7.06 (d, J = 2.4 Hz, 1H), 6.93 (dd, J = 9.2, 2.8 Hz, 1H), 4.68 (s, 2H). MS: (ESI) m/z 432.0 (M + H)+. [00412] Example 30: l [00414] The synthesis of tert-Butyl 2-(6,7-dichloro-3-(3,4-dichlorophenylamino)-9H-carbazol-1- yl)ethylcarbamate (45-9): tert-butyl 2-(3-bromo-6,7-dichloro-9-tosyl-9H-carbazol-1- yl)ethylcarbamate (140 mg, 0.23 mmol), 3,4-dichloroaniline (37 mg, 0.23 mmol), tris(dibenzylideneacetone)dipalladium(0) (37 mg, 0.04 mmol), tert-butylbrett-Phos (39 mg, 0.08 mmol), cesium carbonate (223 mg, 0.69 mmol) and acetic acid (1 drop) were dissolved in tert-butanol (5 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 100 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by CC (petroleum ether/ethyl acetate = 5/1) to give 35 mg title compound in 28% yield as a brown solid. MS: (ESI) m/z 536.0 (M - H)–. [00415] The synthesis of 1-(2-Aminoethyl)-6,7-dichloro-N-(3,4-dichlorophenyl)-9H-carbazol-3- amine (45-10): A solution of tert-butyl 2-(6,7-dichloro-3-(3,4-dichlorophenylamino)-9H-carbazol-1- yl)ethylcarbamate (35 mg, 0.065 mmol) in TFA (5% in DCM, 5 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and used for the next step directly. [00416] The synthesis of (E)-tert-Butyl (tert-butoxycarbonylamino)(2-(6,7-dichloro-3-(3,4- dichlorophenylamino)-9H-carbazol-1-yl)ethylamino)methylenecarbamate (45-11): 1-(2-aminoethyl)- 6,7-dichloro-N-(3,4-dichlorophenyl)-9H-carbazol-3-amine (29 mg, 0.065 mmol), tert-butyl (((tert- butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (20 mg, 0.065 mmol) and Et3N (13 mg, 0.129 mmol) in DMF (4 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water (20 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The residue was purified by Prep-TLC (petroleum ether/ethyl acetate = 3/1, petroleum ether/ dichloromethane = 1/2,) to give 25 mg of title compound in 57% yield as a yellow solid. MS: (ESI) m/z 679.6 (M + H)+. [00417] The synthesis of 1-(2-(6,7-Dichloro-3-(3,4-dichlorophenylamino)-9H-carbazol-1- yl)ethyl)guanidine (SRI-33170): A solution of (E)-tert-butyl (tert-butoxycarbonylamino)(2-(6,7- dichloro-3-(3,4-dichlorophenylamino)-9H-carbazol-1-yl)ethylamino)methylenecarbamate (25 mg, 0.037 mmol) in TFA (10% in DCM, 5 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (10 mg, 57%) as a white solid. [00418] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.47 (s, 0.8H, formic acid), 8.46 (d, J = 4.0 Hz, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.71 (s, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 6.93 (dd, J = 8.8, 2.4 Hz, 1H), 3.48-3.50 (m, 2H), 3.12 (t, J = 7.2 Hz, 2H). MS: (ESI) m/z 479.8 (M + H)+. [00419] Example 31: [00421] The synthesis of tert-Butyl (2-(3-bromo-6-chloro-9H-carbazol-1-yl)ethyl)carbamate (40- 1): A mixture of tert-butyl (2-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)ethyl)carbamate (200 mg, 0.34 mmol), t-BuONa (100 mg, 1.04 mmol) in THF (5 mL), the reaction mixture was stirred at 60 ºC for 16 hours and added 10 mL H2O, then extract by EA, the organic phase concentrated in vacuo to get crude product. The crude was purified by prep-TLC.(PE/EA=4/1) to give 180 mg title compound in 96% yield as a pale-yellow oil. MS: (ESI) m/z 421.0 (M - H)–. [00422] The synthesis of tert-Butyl (2-(6-chloro-3-((5-chloropyrimidin-2-yl)amino)-9H-carbazol- 1-yl)ethyl)carbamate (40-2): tert-butyl(2-(3-bromo-6-chloro-9H-carbazol-1-yl)ethyl)carbamate (140 mg, 0.34 mmol), 5- chloropyrimidin-2-amine (44 mg, 0.34 mmol), tris(dibenzylideneacetone)dipalladium(0) (62 mg, 0.068 mmol), tert-butylbrett-Phos (40 mg, 0.084 mmol) and cesium carbonate (332 mg, 1.02 mmol) were dissolved in tert-butanol (10 mL). The reaction solution was degassed and purged with N2 for 5- 10 minutes and then heated at 90 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by Prep-TLC (petroleum ether/ethyl acetate = 2/1) to give 120 mg title compound in 80% yield as a brown solid. MS: (ESI) m/z 470.0 (M - H)–. [00423] The synthesis of 1-(2-Aminoethyl)-6-chloro-N-(5-chloropyrimidin-2-yl)-9H-carbazol-3- amine (40-3): A solution of tert-butyl (2-(6-chloro-3-((5-chloropyrimidin-2-yl)amino)-9H-carbazol-1- yl)ethyl)carbamate (60 mg, 0.14 mmol) in TFA (5% in DCM, 2.5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and used for the next step directly. [00424] The synthesis of (40-4): 1-(2-aminoethyl)-6-chloro-N-(5-chloropyrimidin-2-yl)-9H-carbazol-3-amine (46 mg, 0.12 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (38 mg, 0.12 mmol) and Et3N (24 mg, 0.24 mmol) in DMF (1 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water (8 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The residue was purified by Prep-TLC (dichloromethane/methanol = 17/1) to give 60 mg of title compound in 79% yield as a pale brown solid. MS: (ESI) m/z 614.0 (M + H)+. [00425] The synthesis of 1-(2-(6-Chloro-3-((5-chloropyrimidin-2-yl)amino)-9H-carbazol-1- yl)ethyl)guanidine A solution of 40-4 (60 mg, 0.098 mmol) in TFA (15% in DCM, 6 mL) was stirred at room temperature overnight. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (32.06 mg, 79%) as a yellow solid. [00426] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.48 (s, 2H, formic acid), 8.34 (br., 1H), 8.25 (d, J = 1.6 Hz, 1H), 8.13 (s, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.48 (s, 1H), 7.43 (d, J = 8.8 Hz, 1H), 3.54 (t, J = 6.4 Hz, 2H), 3.15 (t, J = 7.2 Hz, 2H). MS: (ESI) m/z 414.0 (M + H)+. [00427] Example 32: [00429] The synthesis of 2-(3-(3,5-Dibromophenyl)prop-2-yn-1-yl)isoindoline-1,3-dione (43-2): To a solution of 1,3-dibromo-5-iodobenzene (10.0 g, 27.6 mmol) and 2-(prop-2-yn-1-yl)isoindoline- 1,3-dione (5.1 g, 27.6 mmol)in THF (100 mL) was added TEA (5.6 g, 55.2 mmol), CuI (1.1 g, 5.5 mmol) and Pd(PPh3)2Cl2 (3.9 g, 5.5 mmol), the mixture was degassed and purged with N2 and then heated at 60 °C for 5 hours. The mixture was cooled to room temperature and filtered, the filtrate was concentrated and purified by silica column chromatography (petroleum ether/ethyl acetate = 5/1) to give 10.5 g title compound in 89% yield as a white solid. MS: (ESI) m/z 418.0 (M + H)+. [00430] The synthesis of 2-(3-(3,5-Dibromophenyl)propyl)isoindoline-1,3-dione (43-3): To a solution of 2-(3-(3,5-dibromophenyl)prop-2-yn-1-yl)isoindoline-1,3-dione (10.0 g, 23.8 mmol) in MeOH (100 mL) and EtOAc (100 mL) was added RhCl(PPh3)3 (4.4 g, 4.8 mmol), the mixture was stirred under H2 (40 psi) at room temperature for 24 hours. Filtered through celite, the filtrate was concentrated and purified by silica column chromatography (petroleum ether/ethyl acetate = 5/1) to give 9.5 g title compound in 94% yield as a white solid. MS: (ESI) m/z 421.9 (M + H)+. [00431] The synthesis of N-(3'-Bromo-5-chloro-5'-(3-(1,3-dioxoisoindolin-2-yl)propyl)-[1,1'- biphenyl]-2-yl)-4-methylbenzenesulfonamide (43-4): To a solution of 2-(3-(3,5- dibromophenyl)propyl)isoindoline-1,3-dione (2.0 g, 4.8 mmol) and N-(4-chloro-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methylbenzenesulfonamide (967 mg, 2.4 mmol) in toluene (50 mL) was added K3PO4 (2.0 g, 9.6 mmol) and Pd(PPh3)4 (277 mg, 0.24 mmol). The mixture was stirred under N2 at 90°C for 4 hours. Cooled to room temperature and filtered, the filtrate was concentrated and purified by silica column chromatography (petroleum ether/ethyl acetate = 4/1) to give 950 mg title compound in 32% yield as a white solid. MS: (ESI) m/z 623.0 (M + H)+. [00432] The synthesis of 2-(3-(3-Bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)propyl)isoindoline- 1,3-dione (43-5): To a solution of N-(3'-bromo-5-chloro-5'-(3-(1,3-dioxoisoindolin-2-yl)propyl)-[1,1'- biphenyl]-2-yl)-4-methylbenzenesulfonamide (800 mg, 1.29 mmol) in DCM (20 mL) was added Cu(OTf)2 (93 mg, 0.26 mmol), PhI(OAc)2 (499 mg, 1.55 mmol) and TFA (2 mL). The mixture was stirred at reflux for 10 minutes. Cooled to room temperature and water (30 mL) was added, the water phase was extracted with DCM (2 x 20 mL), the organic layers were combined and washed with brine, dried over Na2SO4, concentrated and purified by silica column chromatography (petroleum ether/ethyl acetate = 3/1) to give 380 mg title compound in 47% yield as a white solid. MS: (ESI) m/z no mass response. [00433] The synthesis of 3-(3-Bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)propan-1-amine (43-6): To a solution of 2-(3-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)propyl)isoindoline-1,3-dione (250 mg, 0.40 mmol) in EtOH (50 mL) was added N2H4-H2O (10 mL). The solution was stirred at room temperature for 16 hours. Extracted with DCM and water, the water phase was washed with DCM (2 x 50 mL), combined the organic layers and washed with brine, dried over Na2SO4, concentrated to give 220 mg title compound in 99% yield as a brown solid which was used for the next step directly. [00434] The synthesis of tert-Butyl (3-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1- yl)propyl)carbamate (43-7): To a solution of 3-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)propan-1- amine (220 mg, 0.45 mmol) in DCM (20 mL) was added TEA (136 mg, 1.35 mmol) and Boc2O (118 mg, 0.54 mmol) at room temperature. The solution was stirred at room temperature for 16 hours. Extracted with DCM (20 mL) and water (30 mL), the water phase was separated and extracted with DCM (2 x 20 mL), the combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by silica column chromatography (petroleum ether/ethyl acetate = 3/1) to give 190 mg title compound in 72% yield as a white solid. MS: (ESI) m/z 588.9 (M -1) –. [00435] The synthesis of tert-Butyl (3-(6-chloro-3-((3,4-dichlorophenyl)amino)-9H-carbazol-1- yl)propyl)carbamate (43-8): To a solution of tert-butyl (3-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1- yl)propyl)carbamate (180 mg, 0.30 mmol) in t-BuOH (10 mL) was added 3,4-dichloroaniline (49 mg, 0.30 mmol), Pd2dba3 (55 mg, 0.06mmol), t-Bubrettphos (37 mg, 0.08 mmol) and Cs2CO3 (293 mg,0.90 mmol). The mixture was stirred under N2 at 90 °C for 3 hours. Cooled to room temperature and filtered, the filtrated was concentrated and purified by prep-TLC (petroleum ether/ethyl acetate = 3/1) to give 21 mg of title compound in 13% yield as a white solid. MS: (ESI) m/z 516.0 (M -1)– . [00436] The synthesis of 1-(3-Aminopropyl)-6-chloro-N-(3,4-dichlorophenyl)-9H-carbazol-3- amine (43-9): To a solution of tert-butyl (3-(6-chloro-3-((3,4-dichlorophenyl)amino)-9H-carbazol-1- yl)propyl)carbamate (21 mg, 0.04 mmol) in DCM (2 mL) was added TFA (0.1 mL), the solution was stirred at room temperature overnight. The reaction mixture was concentrated to give 20 mg of title compound in 99% yield as a brown solid and used for the next step directly. [00437] The synthesis of 1-(3-(6-Chloro-3-((3,4-dichlorophenyl)amino)-9H-carbazol-1-yl)propyl) -N,N’ -tert-butoxycarbonyl -guanidine (43-10): To a solution of 1-(3-aminopropyl)-6-chloro-N-(3,4- dichlorophenyl)-9H-carbazol-3-amine (20 mg, 0.04 mmol) in DMF (2 mL) was added tert-butyl (Z)- (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (12 mg, 0.04 mmol) and DIEA (10 mg, 0.08 mmol), the solution was stirred at room temperature for 2 hours. Extracted with EA (10 mL) and water (20 mL), the organic layer was separated and washed with brine, dried over Na2SO4, concentrated and purified by prep-TLC (DCM/MeOH = 20/1) to give 19 mg of title compound in 60% yield as a white solid. MS: (ESI) m/z 662.2 (M+1)+. [00438] The synthesis of 1-(3-(6-Chloro-3-((3,4-dichlorophenyl)amino)-9H-carbazol-1- yl)propyl)guanidine (SRI-33172): To a solution of 1-(3-(6-chloro-3-((3,4-dichlorophenyl)amino)-9H- carbazol-1-yl)propyl)-N,N’-tert-butoxycarbonyl-guanidine (19 mg, 0.03 mmol) in DCM (3 mL) was added TFA (0.3 mL), the solution was stirred at room temperature overnight. The reaction mixture was concentrated and purified by prep-HPLC to give 5.5 mg of title compound in 20% yield as a gray solid. [00439] 1H NMR (400 MHz, MDSO-d6) ^ 11.99 (s, 1H), 8.83 (s, 1H), 8.63 (s, 1H), 8.32 (s, 1H), 8.20 (d, J = 2.0 Hz, 1H), 7.82 (d, J = 1.6 Hz, 1H), 7.51-7.45 (m, 4H), 7.37 (d, J = 2.0 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 1.6 Hz, 1H), 7.02 (d, J = 2.8 Hz, 1H), 6.89 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 3.22-3.18 (m, 2H), 2.95 (t, J = 8.0 Hz, 2H), 1.94-1.88 (m, 2H). MS: (ESI) m/z 461.2 (M + H)+. [00440] Example 33: [00442] The synthesis of tert-Butyl (2-(6,7-dichloro-3-((4-chloro-3-cyanophenyl)amino)-9H- carbazol-1-yl)ethyl)carbamate (50-2): tert-butyl (2-(3-bromo-6,7-dichloro-9H-carbazol-1- yl)ethyl)carbamate (60 mg, 0.13 mmol), 5-amino-2-chlorobenzonitrile (20 mg, 0.13 mmol), tris(dibenzylideneacetone)dipalladium(0) (24 mg, 0.026 mmol), tert-butylbrett-Phos (16 mg, 0.032 mmol) and cesium carbonate (128 mg, 0.39 mmol) were dissolved in tert-butanol (10 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by Prep-TLC (petroleum ether/ethyl acetate = 2/1) to give 50 mg title compound in 72% yield as a brown solid. MS: (ESI) m/z 527.0 (M - H)–. [00443] The synthesis of 5-((1-(2-Aminoethyl)-6,7-dichloro-9H-carbazol-3-yl)amino)-2- chlorobenzonitrile (50-3): A solution of tert-butyl (2-(6,7-dichloro-3-((4-chloro-3- cyanophenyl)amino)-9H-carbazol-1-yl)ethyl)carbamate (50 mg, 0.09 mmol) in TFA (5% in DCM, 5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and used for the next step directly. [00444] The synthesis of (50-4): 5-((1-(2-Aminoethyl)-6,7-dichloro-9H-carbazol-3-yl)amino)-2- chlorobenzonitrile (40 mg, 0.09 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1- yl)methylene)carbamate (30 mg, 0.09 mmol) and Et3N (20 mg, 0.2 mmol) in DMF (2 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water (8 mL). The product was extracted with ethyl acetate (3x10 mL) and dried over Na2SO4. The residue was purified by Prep-TLC (dichloromethane) to give 60 mg of title compound in 98% yield as a pale brown solid. MS: (ESI) m/z 669.0 (M - H)–. [00445] The synthesis of 1-(2-(6,7-Dichloro-3-((4-chloro-3-cyanophenyl)amino)-9H-carbazol-1- yl)ethyl)guanidine (SRI-33173): A solution of 50-4 (60 mg, 0.08 mmol) in TFA (15% in DCM, 5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (19.44 mg, 71%) as a yellow solid. [00446] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.38 (s, 1H, formic acid), 7.85 (s, 1H), 7.78 (s, 1H), 7.47 (d, J = 9.2 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.25 (dd, J = 8.8, 2.8 Hz, 1H), 7.17 (s, 1H), 3.54 (t, J = 6.8 Hz, 2H), 3.13 (t, J = 6.8 Hz, 2H). MS: (ESI) m/z 470.7 (M + H)+. [00447] Example 34: [00449] The synthesis of tert-Butyl (2-(3-bromo-6,7-dichloro-9H-carbazol-1-yl)ethyl)carbamate (32-7b): Activated Mg turnings (834 mg, 34.32 mmol), ammonium chloride (336 mg, 6.24 mmol) and tert-butyl (2-(3-bromo-6,7-dichloro-9-tosyl-9H-carbazol-1-yl)ethyl)carbamate (270 mg, 0.44 mmol) in methanol (20 mL) was stirred at room temperature for 3 hours then quenched with ammonium chloride solution. The product was extracted with ethyl acetate (3 x 10 mL) and dried over Na2SO4. The residue was purified by Prep-TLC (petroleum ether/ethyl acetate = 2/1) to give 122 mg of title compound in 61% yield as a pale brown solid. MS: (ESI) m/z 455.0 (M - H)–. [00450] The synthesis of tert-Butyl (2-(6,7-dichloro-3-(thiazol-2-ylamino)-9H-carbazol-1- yl)ethyl)carbamate (51-1): tert-butyl (2-(3-bromo-6,7-dichloro-9H-carbazol-1-yl)ethyl)carbamate (120 mg, 0.21 mmol), thiazol-2-amine (27 mg, 0.27 mmol), tris(dibenzylideneacetone)dipalladium(0) (38 mg, 0.042 mmol), tert-butylbrett-Phos (26 mg, 0.054 mmol) and cesium carbonate (271 mg, 0.83 mmol) were dissolved in tert-butanol (6 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 1 hour. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by Prep-TLC (petroleum ether/ethyl acetate = 2/1) to give 66 mg title compound in 66% yield as a pale brown solid. MS: (ESI) m/z 475.0 (M - H)–. [00451] The synthesis of N-(1-(2-Aminoethyl)-6,7-dichloro-9H-carbazol-3-yl)thiazol-2-amine (51-2): A solution of tert-butyl (2-(6,7-dichloro-3-(thiazol-2-ylamino)-9H-carbazol-1- yl)ethyl)carbamate (69 mg, 0.14 mmol) in TFA (5% in DCM, 5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and used for the next step directly. [00452] The synthesis of (51-3): N-(1-(2-aminoethyl)-6,7-dichloro-9H-carbazol-3-yl)thiazol-2- amine (56 mg, 0.15 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1- yl)methylene)carbamate (48 mg, 0.15 mmol) and Et3N (31 mg, 0.31 mmol) in DMF (2 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water (10 mL). The product was extracted with ethyl acetate (3x10 mL) and dried over Na2SO4. The residue was purified by Prep- TLC (dichloromethane/methanol = 15/1) to give 46 mg of title compound in 51% yield as a pale brown solid. MS: (ESI) m/z 619.8 (M + H)+. [00453] The synthesis of 1-(2-(6,7-Dichloro-3-(thiazol-2-ylamino)-9H-carbazol-1- yl)ethyl)guanidine (SRI-33174): A solution of 51-3 (46 mg, 0.074 mmol) in TFA (10% in DCM, 5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (25 mg, 81%) as a yellow solid.1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.37 (s, 1H, formic acid), 8.34 (s, 1H), 8.28 (d, J = 2.0 Hz, 1H), 7.75 (s, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.25 (d, J = 4.0 Hz, 1H), 6.85 (d, J = 4.4 Hz, 1H), 3.53 (t, J = 7.2 Hz, 2H), 3.13 (t, J = 6.8 Hz, 2H). MS: (ESI) m/z 418.9 (M + H)+. [00454] Example 35: [00455] Example Route for Example 35 (SRI-33175):
[00456] The synthesis of tert-Butyl (2-(6-chloro-3-((5,6-dichlorobenzo[d]thiazol-2-yl)amino)-9H- carbazol-1-yl)ethyl)carbamate (47-2): tert-butyl (2-(3-bromo-6-chloro-9H-carbazol-1- yl)ethyl)carbamate (100 mg, 0.24 mmol), 5,6-dichlorobenzo[d]thiazol-2-amine (52 mg, 0.24 mmol), tris(dibenzylideneacetone)dipalladium(0) (44 mg, 0.048 mmol), tert-butylbrett-Phos (29 mg, 0.060 mmol), potassium carbonate (98 mg, 0.71 mmol) and acetic acid (2 drop) were dissolved in tert- butanol (5 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 100 °C for 6 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by Prep-TLC (petroleum ether/ethyl acetate = 2/1) to give 42 mg title compound in 32% yield as a brown solid. MS: (ESI) m/z 558.9 (M - H)–. [00457] The synthesis of N-(1-(2-Aminoethyl)-6-chloro-9H-carbazol-3-yl)-5,6- dichlorobenzo[d]thiazol-2-amine (47-3): A solution of tert-butyl (2-(6-chloro-3-((5,6- dichlorobenzo[d]thiazol-2-yl)amino)-9H-carbazol-1-yl)ethyl)carbamate (37 mg, 0.066 mmol) in TFA (5% in DCM, 4 mL) was stirred at room temperature for 6 hours. The reaction solution was concentrated and used for the next step directly. [00458] The synthesis of (47-4): N-(1-(2-aminoethyl)-6-chloro-9H-carbazol-3-yl)-5,6- dichlorobenzo[d]thiazol-2-amine (38 mg, 0.082 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H- pyrazol-1-yl)methylene)carbamate (26 mg, 0.084 mmol) and Et3N (25 mg, 0.25 mmol) in DMF (2 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water (8 mL). The product was extracted with ethyl acetate (3x10 mL) and dried over Na2SO4. The residue was purified by Prep-TLC (petroleum ether/ethyl acetate = 3/1) to give 43 mg of title compound in 74% yield as an off-white solid. MS: (ESI) m/z 702.8 (M + H)+. [00459] The synthesis of 1-(2-(6-Chloro-3-((5,6-dichlorobenzo[d]thiazol-2-yl)amino)-9H- carbazol-1-yl)ethyl)guanidine (SRI-33175): A solution of 47-4 (50 mg, 0.071 mmol) in TFA (10% in DCM, 5 mL) was stirred at room temperature for 2 days. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (27.9 mg, 78% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.43 (d, J = 1.6 Hz, 1H, formic acid), 8.40 (s, 1H), 8.21 (d, J = 2.0 Hz, 1H), 8.06 (s, 1H), 7.83 (s, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 1.6 Hz, 1H), 7.45 (dd, J = 8.4, 2.0 Hz, 1H), 3.56 (t, J = 7.2 Hz, 2H), 3.18 (t, J = 7.2 Hz, 2H). MS: (ESI) m/z 502.8 (M + H)+. [00460] Example 36: [00462] The synthesis of tert-Butyl (2-(6,7-dichloro-3-((6-chloropyridazin-3-yl)amino)-9H- carbazol-1-yl)ethyl)carbamate (48-1): To a solution of tert-butyl (2-(3-bromo-6,7-dichloro-9-tosyl- 9H-carbazol-1-yl)ethyl)carbamate (200 mg, 0.33 mmol) in t-BuOH (10 mL) was added 6- chloropyridazin-3-amine (42 mg, 0.33 mmol), Pd2dba3 (55 mg, 0.06mmol), t-Bubrettphos (37 mg, 0.08 mmol) and Cs2CO3 (323 mg, 0.99 mmol). The mixture was stirred under microwave at 110 °C for 1 hour. Cooled to room temperature and filtered, the filtrate was concentrated and purified by prep- TLC (DCM/MeOH = 10/1) to give 19 mg of title compound in 11% yield as a white solid. MS: (ESI) m/z 504.0 (M -1)–. [00463] The synthesis of 1-(2-Aminoethyl)-6,7-dichloro-N-(6-chloropyridazin-3-yl)-9H-carbazol- 3-amine (48-2): To a solution of tert-butyl (2-(6,7-dichloro-3-((6-chloropyridazin-3-yl)amino)-9H- carbazol-1-yl)ethyl)carbamate (19 mg, 0.04 mmol) in DCM (2 mL) was added TFA (0.1 mL), the solution was stirred at room temperature over night. The reaction mixture was concentrated to give 20 mg of title compound in 99% yield as a brown solid and used for the next step directly. [00464] The synthesis of 1-(2-(6,7-Dichloro-3-((6-chloropyridazin-3-yl)amino)-9H-carbazol-1- yl)ethyl)-N,N’-tert-butoxycarbonyl-guanidine (48-3): To a solution of 1-(2-aminoethyl)-6,7-dichloro- N-(6-chloropyridazin-3-yl)-9H-carbazol-3-amine (20 mg, 0.04 mmol) in DMF (2 mL) was added tert- butyl (Z)-(((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (12 mg, 0.04 mmol) and DIEA (10 mg, 0.08 mmol), the solution was stirred at room temperature for 4 hours. Extracted with EA (10 mL) and water (20 mL), the organic layer was separated and washed with brine, dried over Na2SO4, concentrated and purified by prep-TLC (DCM/MeOH = 20/1) to give 13 mg of title compound in 40% yield as a white solid. [00465] The synthesis of 1-(2-(6,7-Dichloro-3-((6-chloropyridazin-3-yl)amino)-9H-carbazol-1- yl)ethyl)guanidine (SRI-33176): To a solution of 1-(2-(6,7-dichloro-3-((6-chloropyridazin-3- yl)amino)-9H-carbazol-1-yl)ethyl)-N,N’-tert-butoxycarbonyl-guanidine (13 mg, 0.02 mmol) in DCM (2 mL) was added TFA (0.2 mL), the solution was stirred at room temperature overnight. The reaction mixture was concentrated and purified by prep-HPLC to give 6.0 mg of title compound in 67% yield as a yellow solid. [00466] 1H NMR (400 MHz, DMSO-d6) ^ 11.90 (s, 1H), 9.51 (s, 1H), 8.57 (br, 1H), 8.52 (s, 1H), 8.36 (s, 1H), 8.34 (d, J = 1.6 Hz, 1H), 7.72 (s, 1H), 7.70 (br, 3H), 7.53 (d, J = 9.6 Hz, 1H), 7.44 (s, 1H), 7.20 (d, J = 9.6 Hz, 1H), 3.47 (t, J = 6.0 Hz, 2H), 3.13 (t, J = 6.8 Hz, 2H ). MS: (ESI) m/z 447.8 (M + H)+. [00467] Example 37: [00469] The synthesis of N-(2-(6,7-Dichloro-3-(4-chlorophenylamino)-9H-carbazol-1- yl)ethylcarbamothioyl)benzamide (54-2): 1-(2-aminoethyl)-6,7-dichloro-N-(4-chlorophenyl)-9H- carbazol-3-amine (80 mg, 0.20 mmol) and benzoyl isothiocyanate (32 mg, 0.20 mmol) in Me2CO (10 mL) was stirred at 60 °C for 4 hours. After cooling to room temperature, the reaction was quenched with water (20 mL), extracted with ethyl acetate (3x20 mL), dried over Na2SO4 and concentrated to give 50 mg title compound in 45% yield as a yellow solid. MS: (ESI) m/z 565.0 (M - H)–. [00470] The synthesis of 1-(2-(6,7-Dichloro-3-(4-chlorophenylamino)-9H-carbazol-1- yl)ethyl)thiourea (SRI-33177): A solution of N-(2-(6,7-dichloro-3-(4-chlorophenylamino)-9H- carbazol-1-yl)ethylcarbamothioyl)benzamide (40 mg, 0.07 mmol) and LiOH.H2O (24 mg, 0.56 mmol) in THF/H2O(4/1, 7 mL) was stirred at room temperature for 3 hours. The reaction solution was concentrated and then purified by Prep-HPLC twice to give 2.8 mg of title compound in 9% yield as a yellow solid. [00471] 1H NMR (400 MHz, CD3OD) ^ 8.11 (s, 1 H), 7.67 (d, J = 3.2 Hz, 1H), 7.58 (s, 1 H), 7.13- 7.15 (m, 3H), 6.95-6.98 (m, 2H), 3.83-3.85 (m, 2H), 3.13-3.19 (m, 2H). MS: (ESI) m/z 463.0 (M + H)+. [00472] Example 38: [00474] The synthesis of 1-(2-Aminoethyl)-6,7-dichloro-N-(4-chlorophenyl)-9H-carbazol-3- amine (32-10): A solution of tert-butyl 2-(6,7-dichloro-3-(4-chlorophenylamino)-9H-carbazol-1- yl)ethylcarbamate (20 mg, 0.04 mmol) in TFA (5% in dichloromethane, 5 mL) was stirred at room temperature for 3 hours. The reaction solution was concentrated and then the mixture was diluted with water (3 mL), basified with NaOH (10%) to pH=9. The product was extracted with CH2Cl2 (3x5 mL), dried over Na2SO4 and then concentrated to give 16 mg title compound in 99% yield as a yellow solid. MS: (ESI) m/z 404.0 (M + H)+. [00475] The synthesis of SRI-33178: 1-(2-Aminoethyl)-6,7-dichloro-N-(4-chlorophenyl)-9H- carbazol-3-amine (16 mg, 0.04 mmol) and benzoyl isothiocyanate (7 mg, 0.04 mmol) in Me2CO (3 mL) was stirred at 60 °C for 4 hours. After cooling to room temperature, the reaction was filtrated, washed by Me2CO and concentrated to give the compound, which was dissolved in MeOH (3 mL) and NaOH (1 N, 1.5 mL) and stirred at 80° C for 0.5 hours. After cooling to room temperature, the reaction mixture was diluted with water and filtrated, purified by Prep-HPLC and then purified by Prep-TLC (ethyl acetate) to give 1 mg of title compound in 5% yield as a white solid. [00476] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.47 (s, 1 H), 8.14 (s, 1 H), 7.72 (s, 1 H), 7.29- 7.48 (m, 5H), 3.76-3.77 (m, 2H), 3.10-3.12 (m, 2H). MS: (ESI) m/z 522.0 (M + H) +. [00477] Example 39: [00479] The synthesis of 6-(2-(3-Bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)ethyl)-2-oxa-6- azaspiro[3.3]heptane (56-1): To a solution of 2-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)ethan-1- amine (100 mg, 0.21 mmol) in CH3CN (20 mL) was added 3,3-bis(bromomethyl)oxetane (51 mg, 0.21 mmol) and K2CO3 (58 mg, 0.42 mmol). The mixture was stirred at 60 °C for 24 hours. Cooled to room temperature and filtered, the filtrate was concentrated and purified by prep-TLC (DCM/MeOH = 20/1) to give 45 mg of title compound in 38% yield as a white solid. MS: (ESI) m/z 559.0 (M +1)+. [00480] The synthesis of 6-(2-(3-Bromo-6-chloro-9H-carbazol-1-yl)ethyl)-2-oxa-6- azaspiro[3.3]heptane (56-2): To a solution of 6-(2-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1- yl)ethyl)-2-oxa-6-azaspiro[3.3]heptanes (45 mg, 0.08 mmol) in t-BuOH (10 mL) was added t-BuONa (38 mg, 0.40 mmol). The solution was stirred at 60°C for 24 hours. Cooled to room temperature and extracted with DCM (10 mL) and water (10 mL), the water phase was separated and extracted with DCM (2 x 10 mL), the combined organic layers was washed with brine, dried over Na2SO4, concentrated and purified by prep-TLC (DCM/MeOH = 20/1) to give 25 mg of title compound in 40% yield as a white solid. [00481] The synthesis of 1-(2-(2-Oxa-6-azaspiro[3.3]heptan-6-yl)ethyl)-6-chloro-N-(3,4- dichlorophenyl)-9H-carbazol-3-amine (SRI-33179): To a solution of 6-(2-(3-bromo-6-chloro-9H- carbazol-1-yl)ethyl)-2-oxa-6-azaspiro[3.3]heptane (25 mg, 0.06 mmol) in t-BuOH (10 mL) was added 3,4-dichloroaniline (10 mg, 0.06 mmol), Pd2dba3 (9 mg, 0.01mmol), t-Bubrettphos (5 mg, 0.01 mmol) and Cs2CO3 (59 mg, 0.18 mmol). The mixture was stirred under N2 at 90 °C for 2 hours. Cooled to room temperature and filtered, the filtrated was concentrated and purified by prep-HPLC to give 7 mg of title compound in 23% yield as a pale solid. [00482] 1H NMR (400 MHz, MeOD-d4) ^ 7.98 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.33 (dd, J = 8.4, 1.6 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 7.09 (s, 1H), 7.00 (d, J = 2.4 Hz, 1H), 6.84 (dd, J = 8.8, 2.4 Hz, 1H), 4.74-4.71 (m, 4H), 3.66-3.63 (m, 4H ), 3.03-3.18 (m, 4H ). MS: (ESI) m/z 486.2 (M + H) +. [00483] Example 40: [00484] Example Route for Example 40 (SRI-33180): [00485] The synthesis of 1-(4-Chlorophenyl)thiourea (57-2): 4-chloroaniline (1.5 g, 10.51 mmol) and benzoyl isothiocyanate (1.89 g, 11.57 mmol) in acetone (20 mL) was heated to reflux for 4 hours. The reaction mixture was cooled down to room temperature and diluted with water. The resulting solid was collected by filtration. The cake was dissolved in methanol (50 mL) and 1 N NaOH (25 mL). After stirring at 80 °C for 1 hour, the reaction was cooled down to room temperature and diluted with water. The resulting solid was collected by filtration. The cake was dried to give 850 mg of title compound in 43% yield as an off-white solid. MS: (ESI) m/z 187.2 (M + H) +. [00486] The synthesis of Methyl (4-chlorophenyl)carbamimidothioate (57-3): A mixture of compound 1-(4-chlorophenyl)thiourea (602 mg, 3.24 mmol) and iodomethane (553 mg, 3.89 mmol) in methanol (10 mL) was stirred at 50 °C overnight. The reaction mixture was cooled down to room temperature then filtered. The cake was washed with methanol. The filtrate was concentrated and the residue was washed with ethyl acetate to give 560 mg of title compound in 86% yield as an off-white solid. [00487] The synthesis of tert-Butyl (2-(3-bromo-6,7-dichloro-9-tosyl-9H-carbazol-1- yl)ethyl)carbamate (32-8): 4-chloroaniline (153 mg, 1.2 mmol), palladium acetate (31 mg, 0.14 mmol), XPhos (89 mg, 0.14 mmol) and caesium carbonate (381 g, 1.17 mmol) were dissolved in 1,4- dioxane (12 mL). The reaction solution was degassed and purged with Argon for 5-10 minutes then heated to 90 oC. A solution of tert-butyl (2-(3-bromo-6,7-dichloro-9-tosyl-9H-carbazol-1- yl)ethyl)carbamate (570 mg, 0.93 mmol) in 1,4-dioxane (15 mL) was added to the solution over a period of 1.5 hours using syringe pump. The mixture was heated at 90 oC under argon overnight. The mixture was cooled to room temperature and ethyl acetate was added, filtered through celite. Concentrated and purified on silica gel to give 366 mg of title compound in 60% yield. MS: (ESI) m/z 656.9 (M-H) –. [00488] The synthesis of tert-Butyl (2-(6,7-dichloro-3-((4-chlorophenyl)amino)-9H-carbazol-1- yl)ethyl)carbamate (32-9): Activated Mg turnings (834 mg, 34.32 mmol), ammonium chloride (336 mg, 6.24 mmol) and tert-butyl (2-(6,7-dichloro-3-((4-chlorophenyl)amino)-9-tosyl-9H-carbazol-1- yl)ethyl)carbamate (290 mg, 0.44 mmol) in methanol (20 mL) was stirred at room temperature for 3 hours then quenched with ammonium chloride solution. The product was extracted with ethyl acetate (3 x 10 mL) and dried over Na2SO4. The residue was purified by Prep-TLC (petroleum ether/ethyl acetate = 2/1) to give 144 mg of title compound in 65% yield as a pale brown solid. MS: (ESI) m/z 502.0 (M - H). [00489] The synthesis of 1-(2-Aminoethyl)-6,7-dichloro-N-(4-chlorophenyl)-9H-carbazol-3- amine (32-10): A solution of tert-butyl (2-(6,7-dichloro-3-((4-chlorophenyl)amino)-9H-carbazol-1- yl)ethyl)carbamate (70 mg, 0.14 mmol) in TFA (5% in DCM, 5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and used for the next step directly. MS: (ESI) m/z 404.7 (M+H) +. [00490] The synthesis of 1-(4-Chlorophenyl)-3-(2-(6,7-dichloro-3-((4-chlorophenyl)amino)-9H- carbazol-1-yl)ethyl)guanidine (SRI-33180): A mixture of 32-10 (45 mg, 0.11 mmol) and 57-3 (32 mg, 0.16 mmol) in THF (2 mL) was stirred at 110 oC under M.W. for 4 hours. The mixture was cooled to room temperature and concentrated, then purified by Prep-HPLC to provide title compound (21 mg, 34%) as a yellow solid. [00491] 1H NMR (400 MHz, MeOD-d4) ^ 8.52 (s, 0.53H, formic acid), 8.15 (s, 1H), 7.73 (d, J = 1.6 Hz, 1H), 7.59 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.18-7.14 (m, 3H), 7.00-6.97 (m, 4H), 3.73 (t, J = 6.4 Hz, 2H), 3.23 (t, J = 6.4 Hz, 2H). MS: (ESI) m/z 556.1 (M + H) +. [00492] Example 41: [00494] The synthesis of N-(3'-Bromo-4,4'',5-trichloro-[1,1':4',1''-terphenyl]-2-yl)-4- methylbenzenesulfonamide (55-3): To a solution of 2,4-dibromo-4'-chlorobiphenyl (2 g, 5.8 mmol) in dioxane (20 mL) and H2O (2 mL) was added N-(4,5-dichloro-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)-4-methylbenzenesulfonamide (2.8 g, 6.4 mmol), Na2CO3 (1.8 g, 17.3 mmol) and Pd(PPh3)4 (333.6 mg, 0.3 mmol), the mixture was stirred at 90 oC for 16 hours. The reaction mixture was filtered. The aqueous layer was diluted with water (500 mL) and extracted with ethyl acetate (500 mL x 3), the combined organic layer was washed with saturated brine (400 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 10:1) to give 1.2 g of the title compound in 35.7% yield as a yellow solid. [00495] 1H NMR (400 MHz, DMSO-d6) ^ 10.00 (s, 1H), 7.61 (s, 1H), 7.58 (s, 1H), 7.56 (s, 1H), 7.44-7.47(m, 5H), 7.40 (s, 1H), 7.29-7.35 (m, 3H), 7.27 (d, J = 1.2 HZ, 1H), 2.35 (s, 3H). MS: (ESI) m/z 601.0 [m+23]+ . [00496] The synthesis of 3-Bromo-6,7-dichloro-2-(4-chlorophenyl)-9-tosyl-9H-carbazole (55-4): To a solution of 55-3 (1.2 g, 2060 μmol) in DCM (15 mL) was added Cu(OTf)2 (74.6 mg, 206.3 μmol) and TFA (600.4 mg, 6190 μmol), the mixture was stirred at 50 oC for 5 minutes. Then, the solution was added PhI(OAc)2 (664.4 mg, 2060 μmol) and stirred at 50 oC for 10 minutes to give a black solution. The mixture was diluted with water (100 mL) and then extracted with DCM (100 mL x 2). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a black solid. The solid was washed with PE and DCM to give 400 mg of title compound in 33.3% yield as a white solid. [00497] 1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.67 (s, 1H), 8.37(s, 1H), 8.10 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.61 (dd, J = 2.0 Hz, 6.8 Hz, 2H) , 7.54 (dd, J = 2.0 Hz, 6.4 Hz, 2H) , 7.36 (d, J = 8.0 Hz, 2H) , 2.29 (s, 3H). [00498] The synthesis of tert-Butyl 2-(6,7-dichloro-2-(4-chlorophenyl)-9-tosyl-9H-carbazol-3- ylamino)ethylcarbamate (55-5): To a solution of 3-bromo-6,7-dichloro-2-(4-chlorophenyl)-9-tosyl- 9H-carbazole (150mg, 258.8 μmol) in Toluene (2 mL) was added tert-butyl 2-aminoethylcarbamate (45.6 mg, 284.6 μmol), Cs2CO3 (252.9 mg, 776.4 μmol), Xantphos (15 mg, 25.9 μmol) and Pd2(dba)3 (23.7 mg, 25.9 μmol). The mixture was stirred at 110 oC for 3 hours to give a black solution. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (20 mL) and extracted with ethyl acetate(30 mL x 2), the combined organic layers were washed with saturated brine (30 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 85:15) to give 150 mg of title compound in 87.9% yield as a yellow solid. [00499] 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.30 (s, 1H), 7.74 (s, 1H), 7.68 (d, J = 8.4 Hz 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.50-7.53 (m, 2H), 7.32 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 5.6 Hz 1H), 5.01 (s, 1H), 3.15 (s, 4H), 2.27 (s, 3H), 1.34 (s, 9H). MS: (ESI) m/z 658.0 (M + H) +. [00500] The synthesis of tert-Butyl 2-(6,7-dichloro-2-(4-chlorophenyl)-9H-carbazol-3- ylamino)ethylcarbamate (55-6): To a solution of tert-butyl 2-(6,7-dichloro-2-(4-chlorophenyl)-9- tosyl-9H-carbazol-3-ylamino)ethylcarbamate (150 mg, 228 μmol) in THF (2 mL) was added TBFA (0.6 mL) and stirred at 60 oC for 2 hours to give a black solution. The reaction mixture was concentrated under reduced pressure to give a residue. The mixture was diluted with water (50 mL) and extracted with ethyl acetate(50 mL x 2), the combined organic layers were washed with saturated brine (40 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 10:1) to give 120 mg of title compound in 92% yield as a yellow solid. MS: (ESI) m/z 504.0 (M+ H) +. [00501] The synthesis of N1-(6,7-Dichloro-2-(4-chlorophenyl)-9H-carbazol-3-yl)ethane-1,2- diamine (55-7): To a solution of tert-butyl 2-(6,7-dichloro-2-(4-chlorophenyl)-9H-carbazol-3- ylamino)ethylcarbamate (100 mg, 198 mmol) in DCM (2 mL) was added TFA (0.4 mL) and stirred at 25 oC for 2 hours to give a yellow solution. The reaction solution was concentrated and used for the next step directly. MS: (ESI) m/z 404.0 (M+ H) +. [00502] The synthesis of (Z)-tert-Butyl (tert-butoxycarbonylamino)(2-(6,7-dichloro-2-(4- chlorophenyl)-9H-carbazol-3-ylamino)ethylamino)methylenecarbamate (55-8): To a solution of N1- (6,7-dichloro-2-(4-chlorophenyl)-9H-carbazol-3-yl)ethane-1,2-diamine (100 mg, 247.1 μmol) in DMF (1 mL) was added (Z)-tert-butyl (1H-pyrazol-1-yl)methylenedicarbamate (84.4 mg, 271.8 μmol) and Et3N (75 mg, 741.3 μmol). The mixture was stirred at 25 oC for 2 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2), the combined organic layers were washed with saturated brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 0:1) to give 140 mg of title compound in 73% yield as a yellow solid. MS: (ESI) m/z 646.2 (M + H) + [00503] The synthesis of 1-(2-(6,7-Dichloro-2-(4-chlorophenyl)-9H-carbazol-3- ylamino)ethyl)guanidine (SRI-33181): A solution of (Z)-tert-butyl (tert-butoxycarbonylamino)(2-(6,7- dichloro-2-(4-chlorophenyl)-9H-carbazol-3-ylamino)ethylamino)methylenecarbamate (70 mg, 108.2 μmol) in TFA (10% in DCM, 3 mL) was stirred at room temperature overnight. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (5.8 mg, 12%) as a green solid. [00504] 1H NMR (400 MHz, DMSO-d6) ^ 11.17 (s, 1H), 8.70 (s, 1H), 8.40 (s, 1H), 8.48 (s, 2H), 7.63-7.73 (m, 5H), 7.50-7.57 (m, 6H), 7.19 (s, 4H), 3.48-3.50 (m, 4H). MS: (ESI) m/z 446.2 (M + H)+. [00505] Example 42: [00507] The synthesis of tert-Butyl 2-(5-acetyl-10,11-dihydro-5H-dibenzo[b,f]azepin-3- ylamino)ethylcarbamate (59-3): The mixture of 1-(3-chloro-10,11-dihydro-5H-dibenzo[b,f]azepin-5- yl)ethanone (2.7 g, 9.94 mmol), tert-butyl 2-aminoethylcarbamate (1.91 g, 11.92 mmol), BrettPhosPalladacycle(790 mg, 0.99 mmol) and Cs2CO3 (6.47 g, 19.87 mmol) in toluene (80 mL) was heated at 110 °C for 7 hours. The mixture was concentrated and purified by CC (petroleum ether/ethyl acetate = 4/1-2/1) to give 3.4 g title compound in 87% yield as a white solid. MS: (ESI) m/z 396.2 (M + H)+. [00508] The synthesis of N1-(10,11-Dihydro-5H-dibenzo[b,f]azepin-3-yl)ethane-1,2-diamine (59- 4): The mixture of tert-butyl 2-(5-acetyl-10,11-dihydro-5H-dibenzo[b,f]azepin-3- ylamino)ethylcarbamate (500 mg, 1.26 mmol) in HCl/AcOH(1/1, 15 mL) was heated at 120 °C for 16 hours. The reaction was concentrated and diluted with water (3 mL), basified with Na2CO3 (10%) to pH=8. The mixture was filtrated, washed by water to give 300 mg of title compound in 94% yield as a green solid. MS: (ESI) m/z 254.2 (M + H)+. [00509] The synthesis of tert-Butyl 2-(2-iodo-10,11-dihydro-5H-dibenzo[b,f]azepin-3- ylamino)ethylcarbamate (59-5b): NIS (265 mg, 1.18 mmol) was added to a solution of N1-(10,11- dihydro-5H-dibenzo[b,f]azepin-3-yl)ethane-1,2-diamine (300 mg, 1.18 mmol) in DMF (10 mL) portions at 0 °C and stirred at 0 °C for 0.5 hours. Then Et3N (180 mg, 1.78 mmol) and Boc2O (310 mg, 1.42 mmol) was added to the above. After stirring for 16 hours at room temperature, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3x10 mL), dried over Na2SO4. Concentrated and purified by CC (petroleum ether/ethyl acetate = 6/1) to give 350 mg of title compound in 62% yield as a brown solid. MS: (ESI) m/z 480.0 (M + H)+. [00510] The synthesis of tert-Butyl 2-(2-(3,4-dichlorophenyl)-10,11-dihydro-5H- dibenzo[b,f]azepin-3-ylamino)ethylcarbamate (59-6b): tert-butyl 2-(2-iodo-10,11-dihydro-5H- dibenzo[b,f]azepin-3-ylamino)ethylcarbamate (300 mg, 0.626 mmol), 3,4-dichlorophenylboronic acid (132 mg, 0.688 mmol), Pd(dppf)Cl2 (45 mg, 0.062 mmol) and K2CO3 (173 mg, 1.250 mmol) were dissolved in DME/water (3/1, 12 mL). The reaction solution was degassed and purged with N2 for 5- 10 minutes and then heated at 80 °C for 16 hours. The mixture was cooled to room temperature and quenched with water (20 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. Concentrated and purified by CC (petroleum ether/ethyl acetate = 5/1) to give 290 mg of title compound in 93% yield as a white solid. MS: (ESI) m/z 498.3 (M + H)+. [00511] The synthesis of N1-(2-(3,4-Dichlorophenyl)-10,11-dihydro-5H-dibenzo[b,f]azepin-3- yl)ethane-1,2-diamine (59-6): A solution of tert-butyl 2-(2-(3,4-dichlorophenyl)-10,11-dihydro-5H- dibenzo[b,f]azepin-3-ylamino)ethylcarbamate (45 mg, 0.09 mmol) in TFA (5% in DCM, 5 mL) was stirred at room temperature for 3 hours. The reaction solution was concentrated and used for the next step directly. MS: (ESI) m/z 398.2 (M + H)+. [00512] The synthesis of (E)-tert-Butyl (tert-butoxycarbonylamino)(2-(2-(3,4-dichlorophenyl)- 10,11-dihydro-5H-dibenzo[b,f]azepin-3-ylamino)ethylamino)methylenecarbamate (59-7): N1-(2-(3,4- dichlorophenyl)-10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)ethane-1,2-diamine (36 mg, 0.09 mmol), (Z)-tert-butyl (1H-pyrazol-1-yl)methylenedicarbamate (28 mg, 0.09 mmol) and Et3N (19 mg, 0.18 mmol) in DMF (5 mL) was stirred at room temperature for 4 hours. The reaction was quenched with water (10 mL). The product was extracted with ethyl acetate (3x10 mL) and dried over Na2SO4. The residue was purified by Prep-TLC (petroleum ether/ethyl acetate = 5/1) to give 40 mg of title compound in 69% yield as a brown solid. MS: (ESI) m/z 640.2 (M + H)+. [00513] The synthesis of 1-(2-(2-(3,4-Dichlorophenyl)-10,11-dihydro-5H-dibenzo[b,f]azepin-3- ylamino)ethyl)guanidine (SRI-33199): A solution of (E)-tert-butyl (tert-butoxycarbonylamino)(2-(2- (3,4-dichlorophenyl)-10,11-dihydro-5H-dibenzo[b,f]azepin-3- ylamino)ethylamino)methylenecarbamate (40 mg, 0.06 mmol) in TFA (10% in DCM, 5 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by Prep- HPLC to provide the title compound (14 mg, 51%) as a red solid. [00514] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.42 (s, 1H), 8.29 (s, 0.8H), 7.59-7.64 (m, 2H), 7.38 (dd, J = 8.0, 2.0 Hz, 1H), 6.93-7.06 (m, 3H), 6.72 (s, 1H), 6.66-6.70 (m, 1H), 6.39 (s, 1H), 3.23- 3.29 (m, 2H), 3.16-3.19 (m, 2H), 2.86-2.94 (m, 4H). MS: (ESI) m/z 440.2 (M + H)+. [00515] Example 43: [00517] The synthesis of SRI-33200: To a solution of 1-(2-aminoethyl)-6-chloro-N-(3,4- dichlorophenyl)-9H-carbazol-3-amine (20 mg, 0.05 mmol) in t-BuOH (10 mL) was added sodium dicyanamide (23 mg, 0.25 mmol). The mixture was stirred at 80 °C for 15 hours. Cooled to room temperature and filtered, the filtrate was concentrated and purified by prep-HPLC to give 8 mg of title compound in 34% yield as a pale solid. [00518] 1H NMR (400 MHz, DMSO-d6) ^ 11.34 (s, 1H), 8.33 (s, 1H), 8.21 (d, J = 2.0 Hz, 1H), 7.82 (d, J = 1.6 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.09-7.03 (m, 3H), 6.91 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 6.74 (br, 2H), 3.48-3.42 (m, 2H), 3.06 (t, J = 6.8 Hz, 2H ). MS: (ESI) m/z 471.0 (M + H) +. [00519] Example 44: [00521] The synthesis of tert-Butyl 2-(6-chloro-3-(3,4-dichlorophenyl)-9-tosyl-9H-carbazol-1- yl)ethylcarbamate (65-1): To a solution of tert-butyl 2-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1- yl)ethylcarbamate (100 mg, 173.0 μmol) in DME (1 mL) and water (0.5 mL) was added 3,4- dichlorophenylboronic acid (42.9 mg, 225.0 μmol), K2CO3 (71.7 mg, 519.1 μmol) and Pd(dppf)Cl2 (12.8 mg, 17.4 μmol). The mixture was stirred at 80 oC for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2), the combined organic layers were washed with saturated brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography(SiO2, PE/EA=1:0 to 10:1) to give 170 mg of title compound in 95.35% yield as a white solid. [00522] 1H NMR (400 MHz, DMSO-d6) ^ 8.39 (d, J = 1.2 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 8.13 (d, J = 1.6 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.85 (dd, J = 1.6 Hz, 8.4 Hz, 1H), 7.82 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.54 (dd, J = 2.0, 8.8 Hz, 1H), 7.09 (s, 4H), 6.93 (s, 1H) , 3.43 (s, 4H), 2.19 (s, 3H) , 1.26 (s, 9H). [00523] The synthesis of tert-Butyl 2-(6-chloro-3-(3,4-dichlorophenyl)-9H-carbazol-1- yl)ethylcarbamate (65-2): To a solution of tert-butyl 2-(6-chloro-3-(3,4-dichlorophenyl)-9-tosyl-9H- carbazol-1-yl)ethylcarbamate (160 mg, 248.4 μmol) in THF (2 mL) was added TBAF (0.6 mL) and stirred at 60 oC for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The mixture was diluted with water (50 mL) and extracted with ethyl acetate(50 mL x 2), the combined organic layers were washed with saturated brine (40 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography(SiO2, PE/EA=1:0 to 10:1) to give 120 mg of title compound in 92.8% yield as a yellow solid. MS: (ESI) m/z 487.0 (m+1)+ . [00524] The synthesis of 2-(6-Chloro-3-(3,4-dichlorophenyl)-9H-carbazol-1-yl)ethanamine (65- 3): To a solution of tert-butyl 2-(6-chloro-3-(3,4-dichlorophenyl)-9H-carbazol-1-yl)ethylcarbamate (120 mg, 245.0 μmol) in DCM (2 mL) was added TFA (0.4 mL) and stirred at 25 oC for 2 hours to give a yellow solution. The reaction mixture was concentrated under reduced pressure to give 120 mg crude of title compound as a yellow solid. [00525] The synthesis of tert-Butyl (tert-butoxycarbonylamino)(2-(6-chloro-3-(3,4- dichlorophenyl)-9H-carbazol-1-yl)ethylamino)methylenecarbamate (65-4): To a solution of 2-(6- chloro-3-(3,4-dichlorophenyl)-9H-carbazol-1-yl)ethanamine (100 mg, 256.6 μmol) in DMF (1 mL) was added (Z)-tert-butyl (1H-pyrazol-1-yl)methylenedicarbamate (87.6 mg, 282.3 μmol) and Et3N (77.9 mg, 769.8 μmol). The mixture was stirred at 25 oC for 2 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2), the combined organic layers were washed with saturated brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 0:1) to give 100 mg of title compound in 62% yield as a yellow solid. [00526] 1H NMR (400 MHz, DMSO-d6) ^ 11.59 (s, 1H), 11.47 (s, 1H), 8.51 (d, J = 1.6 Hz, 1H), 8.45 (s Hz, 1H), 8.32 (d, J = 2.0 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.79 (dd, J = 2.0, 7.6 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 1.6 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.40 (dd, J = 2.0 Hz, 8.8 Hz, 1H), 3.71-3.73 (m, 2H), 3.23-3.25 (m, 2H), 1.39 (s, 9H), 1.36 (s, 9H). [00527] The synthesis of 1-(2-(6-Chloro-3-(3,4-dichlorophenyl)-9H-carbazol-1-yl)ethyl)guanidine (SRI-33201): To a solution of tert-butyl (tert-butoxycarbonylamino)(2-(6-chloro-3-(3,4- dichlorophenyl)-9H-carbazol-1-yl)ethylamino)methylenecarbamate (100 mg, 158.2 mmol) in DCM (2 mL) was added TFA (0.2 mL) and stirred at 25 oC for 16 hours to give a black solution. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (20.9 mg, 30.6%) as a white solid. [00528] 1H NMR (400 MHz, CD3OD) ^ 8.25 (d, J = 1.6 Hz,1H), 8.15 (d, J = 2.0 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.67 (dd, J = 2.4, 8.4 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.38 (dd, J =2.0, 8.8 Hz, 1H), 3.53 (t, J = 7.2 Hz, 2H), 3.29 (t, J = 7.2 Hz, 2H). MS: (ESI) m/z 433.0 (M + H) +. [00529] Example 45: [00531] The synthesis of N-(3'-Bromo-4,5-dichloro-[1,1'-biphenyl]-2-yl)-4- methylbenzenesulfonamide (68-2a): To a solution of 1-bromo-3-iodobenzene (1.28 g, 4.52 mmol, 2 eq) in 1,4-dioxane and H2O (20 mL, 1,4-dioxane : H2O = 1:1) were added Pd(PPh3)4 (131 mg, 0.11 mmol, 5 mol%), Na2CO3 (480 mg, 4.53 mmol, 2 eq), and N-(4,5-dichloro-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)-4-methylbenzenesulfonamide (1.0 g, 2.26 mmol, 1.0 eq) under N2. After being stirred at 90 °C for 16 h, the reaction mixture was cooled to room temperature. EtOAc (100 mL) was added and organic layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified column chromatography (petroleum ether, petroleum ether/ethyl acetate = 10/1) to give 1.05 g of the title compound in 99% yield as a brown solid. MS: (ESI) m/z 467.8 (M - H)–. [00532] The synthesis of 6-Bromo-2,3-dichloro-9-tosyl-9H-carbazole (68-3a): A solution of PhI(OAc)2 (0.975 g, 3.03 mmol, 1.5 eq) in DCM (50 mL) was added to a mixture of N-(3'-bromo-4,5- dichloro-[1,1'-biphenyl]-2-yl)-4-methylbenzenesulfonamide (0.95 g, 2.02 mmol, 1 eq), Cu(OTf)2 (37 mg, 0.10 mmol, 5 mol%) and TFA (0.69 g, 6.05 mmol, 3 eq) in DCM (100 mL) at reflux. After 1 h, the reaction was complete; the reaction mixture was concentrated in vacuo. The residue was washed with ethyl acetate to give 622 mg of title compound in 66% yield as a brown solid. [00533] 1H NMR (400 MHz, DMSO-d6) ^ 8.61 (s, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.38 (s, 1H), 8.15 (d, J = 9.2 Hz, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.77 (dd, J = 9.2, 2.0 Hz, 1H), 7.34 (d, J = 8.4 Hz, 2H). MS: (ESI) m/z no mass. [00534] The synthesis of tert-Butyl (2-((6,7-dichloro-9-tosyl-9H-carbazol-3- yl)amino)ethyl)carbamate (68-4a): 6-bromo-2,3-dichloro-9-tosyl-9H-carbazole (368 mg, 0.78 mmol), tert-butyl (2-aminoethyl)carbamate (126 mg, 0.79 mmol), tris(dibenzylideneacetone)dipalladium(0) (144 mg, 0.16 mmol), tert-butylbrett-Phos (95 mg, 0.20 mmol) and cesium carbonate (256 mg, 0.79 mmol) were dissolved in tert-butanol (7 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 1 hour. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by CC (petroleum ether/ethyl acetate = 2/1) to give 310 mg title compound in 72% yield as a brown solid. MS: (ESI) m/z 548.0 (M + H)+. [00535] The synthesis of tert-Butyl (2-((6,7-dichloro-9H-carbazol-3-yl)amino)ethyl)carbamate (78-1): A mixture of tert-butyl (2-((6,7-dichloro-9-tosyl-9H-carbazol-3-yl)amino)ethyl)carbamate (120 mg, 0.22 mmol) and TBAF (1 M in THF, 2 mL, 2 mmol) in THF (2 mL) was stirred at 60 °C for 3 hours. The mixture was cooled to room temperature and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with brine, dried over Na2SO4 and concentrated. The residue was purified by Prep-TLC (petroleum ether/ethyl acetate = 1/1) to give 15 mg of title compound in 17% yield as a brown solid. [00536] The synthesis of N1-(6,7-Dichloro-9H-carbazol-3-yl)ethane-1,2-diamine (78-2): A solution of tert-butyl (2-((6,7-dichloro-9H-carbazol-3-yl)amino)ethyl)carbamate (15 mg, 0.038 mmol) in TFA (5% in DCM, 5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and used for the next step directly. [00537] The synthesis of (78-3): N1-(6,7-dichloro-9H-carbazol-3-yl)ethane-1,2-diamine (15 mg, 0.051 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (16 mg, 0.052 mmol) and Et3N (11 mg, 0.11 mmol) in DMF (1 mL) was stirred at room temperature for 3 hours. The reaction was quenched with water (10 mL). The product was extracted with ethyl acetate (3x10 mL) and dried over Na2SO4. The residue was purified by Prep-TLC (petroleum ether/ethyl acetate = 3/1) to give 24 mg of title compound in 88% yield as a pale brown solid. MS: (ESI) m/z 536.2 (M + H) +. [00538] The synthesis of 1-(2-((6,7-Dichloro-9H-carbazol-3-yl)amino)ethyl)guanidine (SRI- 33207): A solution of 78-3 (24 mg, 0.045 mmol) in TFA (10% in DCM, 5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (3.5 mg, 24%) as a pale brown solid. [00539] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.34 (s, 1.5H, formic acid), 8.28 (s, 1H), 7.68 (s, 1H), 7.32-7.37 (m, 2H), 6.93 (dd, J = 8.6, 2.2 Hz, 1H), 3.39 (t, J = 5.4 Hz, 2H), 3.31 (t, J = 5.6 Hz, 2H). MS: (ESI) m/z 336.2 (M + H) +. [00540] Example 46: [00542] The synthesis of tert-Butyl 2-(4-chloro-2-(3,4-dichlorophenyl)-10,11-dihydro-5H- dibenzo[b,f]azepin-3-ylamino)ethylcarbamate (75-1): NCS (58 mg, 0.43 mmol) was added to a solution of tert-butyl 2-(2-(3,4-dichlorophenyl)-10,11-dihydro-5H-dibenzo[b,f]azepin-3- ylamino)ethylcarbamate (215 mg, 0.43 mmol) in DCM (10 mL) at 0 °C. After stirring for 1 hour at 0 °C, the reaction mixture was washed with brine, dried over Na2SO4, concentrated and then purified by CC (petroleum ether/ethyl acetate = 4/1) to give 150 mg of title compound in 65% yield as a yellow solid. MS: (ESI) m/z 532.1 (M + H) +. [00543] The synthesis of N1-(4-Chloro-2-(3,4-dichlorophenyl)-10,11-dihydro-5H- dibenzo[b,f]azepin-3-yl)ethane-1,2-diamine (75-2): A solution of tert-butyl 2-(4-chloro-2-(3,4- dichlorophenyl)-10,11-dihydro-5H-dibenzo[b,f]azepin-3-ylamino)ethylcarbamate (70 mg, 0.13 mmol) in TFA (5% in DCM, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and used for the next step directly. [00544] The synthesis of (E)-tert-Butyl (tert-butoxycarbonylamino)(2-(4-chloro-2-(3,4- dichlorophenyl)-10,11-dihydro-5H-dibenzo[b,f]azepin-3-ylamino)ethylamino)methylenecarbamate (75-3): N1-(4-chloro-2-(3,4-dichlorophenyl)-10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)ethane-1,2- diamine (57 mg, 0.13 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1- yl)methylene)carbamate (41 mg, 0.13 mmol) and Et3N (27 mg, 0.26 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water (20 mL). The product was extracted with ethyl acetate (3x20 mL), dried over Na2SO4. The residue was purified by Prep- TLC (petroleum ether/ethyl acetate = 3/1) to give 70 mg of title compound in 79% yield as a yellow solid. MS: (ESI) m/z 674.2 (M + H) +. [00545] The synthesis of 1-(2-(4-Chloro-2-(3,4-dichlorophenyl)-10,11-dihydro-5H- dibenzo[b,f]azepin-3-ylamino)ethyl)guanidine (SRI-33208): A solution of (E)-tert-butyl (tert- butoxycarbonylamino)(2-(4-chloro-2-(3,4-dichlorophenyl)-10,11-dihydro-5H-dibenzo[b,f]azepin-3- ylamino)ethylamino)methylenecarbamate (70 mg, 0.10 mmol) in TFA (10% in DCM, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by Prep- HPLC to provide title compound (22 mg, 45%) as a white solid. [00546] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.41 (s, 1H, formic acid), 7.70 (d, J = 2.0 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.49 (dd, J = 8.4, 2.0 Hz, 1H), 7.33 (s, 0.5H), 7.19 (dd, J = 8.0, 2.8 Hz, 1H), 7.06-7.11 (m, 2H), 6.92 (s, 1H), 6.79 (t, J = 7.2 Hz, 1H), 3.00-3.03 (m, 6H), 2.74 (t, J = 6.0 Hz, 2H). MS: (ESI) m/z 474.2 (M + H) + [00547] Example 47: 9 [00549] The synthesis of 4-Bromo-3',4'-dichlorobiphenyl-2-amine (68-1): To a solution of 5-bromo-2-iodoaniline (36.50 g, 122.52 mmol) in dioxane (350 mL) and H2O (70 mL) was added 3,4-dichlorophenylboronic acid (23.38 g, 122.52 mmol), Na2CO3 (38.96 g, 367.55 mmol) and Pd(PPh3)4 (7.08 g, 6.13 mmol), the mixture was stirred at 90 °C for 16 hours. The reaction mixture was filtered to give a filtrate. The filtrate was diluted with water (3 L) and extracted with ethyl acetate(1 L x 3), the combined organic layers were washed with saturated brine (500 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 20:1) to give 25.85 g of title compound in 66% yield as pale brown oil. [00550] 1H NMR (400 MHz, DMSO-d6) ^ 7.68 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.37 (dd, J = 2.0, 8.4 Hz, 1H), 6.91-6.95 (m, 2H), 6.74-6.77 (m, 1H), 5.28 (s, 2H). MS: (ESI) m/z 313.9 (m-1)-. [00551] The synthesis of N-(4-Bromo-3',4'-dichlorobiphenyl-2-yl)-4-methylbenzenesulfonamide (68-2): To a solution of 4-bromo-3',4'-dichlorobiphenyl-2-amine (25.85g, 81.54 mmol) in pyridine (260 mL) was added TsCl (16.79 g, 88.07 mmol). The mixture was stirred at room temperature for 16 hours to give a yellow solution. The mixture was concentrated. The residue was diluted with ethyl acetate (500 mL), washed with saturated brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 20:1 to 10:1) to give 34.30 g of title compound in 89 % yield as an off-white solid. MS: (ESI) m/z 467.9 (m-1)- . [00552] The synthesis of 7-Bromo-2,3-dichloro-9-tosyl-9H-carbazole (68-3): To a solution of N-(4-bromo-3',4'-dichlorobiphenyl-2-yl)-4-methylbenzenesulfonamide (9.0 g x 4, 19.10 mmol) in DCM (900 mL x 4) was added Cu(OTf)2 (691 mg x 4, 1.91 mmol) and TFA (6.53 g x 4, 57.30 mmol) was added PhI(OAc)2 (9.23 g x 4, 28.65 mmol) at room temperature to give a black solution. After stirring for 10 minutes, the mixture was concentrated in vacuo. The crude was purified by column chromatography (petroleum ether/ethyl acetate = 5: 1, EA) to give 13.90 g of title compound in 39% yield. [00553] 1H NMR (400 MHz, DMSO-d6) ^ 8.60 (s, 1H), 8.35 (s, 1H), 8.31 (d, J = 1.2 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.68 (dd, J =1.6, 8.4 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 2.29 (s, 3H). [00554] The synthesis of 7-Bromo-2,3-dichloro-9H-carbazole (68-4a): To a solution of 7-bromo-2,3-dichloro-9-tosyl-9H-carbazole (7.7 g, 16.41 mmol) in THF (120 mL x 2) was added TBAF (40 mL x 2) and stirred at 60 °C for 3 hours. The reaction mixture was concentrated the residue was dissolved in ethyl acetate(300 mL x 2), washed with saturated brine (50 mL x 2), dried over Na2SO4, filtered and concentrated. The crude was purified by column chromatography (petroleum ether/ethyl acetate =20:1, 4:1, 1:1) to give 8.77g of title compound in 85% yield as a brown solid. MS: (ESI) m/z 312.0 (M - H) -. [00555] The synthesis of 6,7-Dichloro-N-(4-chlorophenyl)-9H-carbazol-2-amine (68-5): The mixture of 7-bromo-2,3-dichloro-9H-carbazole (7.77 g, 24.66 mmol) 4-chloroaniline (3.15 g, 24.66 mmol), tris(dibenzylideneacetone)dipalladium(0) (1.13 g, 1.23 mmol), tert-butylbrett-Phos (1.20 g, 2.47 mmol) and cesium carbonate (8.03 g, 24.66 mmol) were dissolved in tert-butanol (160 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by CC (petroleum ether/ethyl acetate = 1/1) to give 9.53 g title compound in 100% yield as pale brown oil. [00556] 1H NMR (400 MHz, DMSO-d6) ^ 11.25 (s, 1H), 8.54 (s, 1H), 8.25 (s, 1H), 8.00 (d, J = 4.4 Hz, 1H), 7.61 (s, 1H), 7.30 (d, J = 8.8 Hz, 2H), 7.16-7.17 (m, 2H), 7.15 (s, 1H), 6.93 (dd, J = 2.0, 8.4 Hz,1H). MS: (ESI) m/z 360.7 (M + H) +. [00557] The synthesis of tert-Butyl 2-(2,3-dichloro-7-(4-chlorophenylamino)-9H-carbazol-9- yl)ethylcarbamate (74-1): To a solution of 6,7-dichloro-N-(4-chlorophenyl)-9H-carbazol-2-amine (9.53g, 26.35 mmol) in DMF (100 mL) was added tert-butyl 2-bromoethylcarbamate (7.09 g, 31.62 mmol) and cesium carbonate (25.76 g, 79.05 mmol). The mixture was stirred at 50 °C for 16 hours. The mixture was diluted with water (400 mL) and extracted with ethyl acetate(100 mL x 3), the combined organic layers were washed with saturated brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to give 9.7 g of title compound in 73% yield as an off-white solid. MS: (ESI) m/z 504.0 (M + H) +. [00558] The synthesis of 9-(2-Aminoethyl)-6,7-dichloro-N-(4-chlorophenyl)-9H-carbazol-2- amine (74-2): To a solution of tert-butyl 2-(2,3-dichloro-7-(4-chlorophenylamino)-9H-carbazol-9-yl)ethylcarbamate (9.7 g, 19.21 mmol) in DCM (48 mL) was added TFA (12 mL) and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give 7.78 g crude of title compound as a yellow solid. MS: (ESI) m/z 404.0 (M + H) +. [00559] The synthesis of tert-Butyl (tert-butoxycarbonylamino)(2-(2,3-dichloro-7-(4- chlorophenylamino)-9H-carbazol-9-yl)ethylamino)methylenecarbamate (74-3): To a solution of 9-(2-aminoethyl)-6,7-dichloro-N-(4-chlorophenyl)-9H-carbazol-2-amine (7.78 g, 19.22 mmol) in DMF (40 mL) was added (Z)-tert-butyl (1H-pyrazol-1-yl)methylenedicarbamate (5.97 g, 19.22 mmol) and Et3N (3.89 g, 38.45 mol). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (160 mL) and extracted with ethyl acetate (50 mL x 3), the combined organic layers were washed with saturated brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 10:1) to give 10.5 g of title compound in 84% yield as a white solid. MS: (ESI) m/z 646.2 (M + H) +. [00560] The synthesis of 1-(2-(2,3-Dichloro-7-(4-chlorophenylamino)-9H-carbazol-9- yl)ethyl)guanidine (SRI-33208): The solution of tert-butyl (tert-butoxycarbonylamino)(2-(2,3-dichloro-7-(4-chlorophenylamino)-9H- carbazol-9-yl)ethylamino)methylenecarbamate (10.5 g, 16.23 mmol) in 4M HCl/methanol (500 mL) was stirred at room temperature for 5 days. The reaction solution was concentrated and purified by reverse flash column to provide title compound (7.40 g, 94%) as a pale brown solid. [00561] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.29 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.81 (s , 1H), 7.34 (d, J =9.2 Hz, 1H), 7.20-7.22 (m, 2H), 6.96 (dd, J = 2.0, 8.8 Hz, 1H), 4.40 (t, J = 5.6 Hz, 2H), 3.52-3.61 (m, 2H). MS: (ESI) m/z 446.2 (M + H)+. [00562] Example 48:
[00564] The synthesis of 3-Bromo-6-chloro-9H-carbazole (76-2): NBS (1.77 g, 9.92 mmol, 1 eq) was added to a solution of 3-chloro-9H-carbazole (2.0 g, 9.92 mmol, 1 eq) in dichloromethane (200 mL) at room temperature. After stirring at room temperature for 16 h, the reaction mixture was washed with brine, dried over Na2SO4, concentrated to give 2.29 g of title compound in 82% yield as a pale brown solid. [00565] 1H NMR (400 MHz, DMSO-d6) ^ 11.60 (s, 1H), 8.43 (d, J = 2.0 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 8.6, 1.8 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.43 (dd, J = 8.6, 2.2 Hz, 1H). MS: (ESI) m/z 277.9 (M - H) -. [00566] The synthesis of 6-Chloro-N-(3,4-dichlorophenyl)-9H-carbazol-3-amine (82-2): 3- Bromo-6-chloro-9H-carbazole (1.0 g, 3.56 mmol), 3,4-dichloroaniline (578 mg, 3.57 mmol), tris(dibenzylideneacetone)dipalladium(0) (164 mg, 0.18 mmol), tert-butylbrett-Phos (173 mg, 0.36 mmol) and cesium carbonate (1.16 g, 3.56 mmol) were dissolved in tert-butanol (100 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 80 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by CC (petroleum ether/ethyl acetate = 10/1) to give 736 mg title compound in 57% yield as an off-white solid. MS: (ESI) m/z 359.0 (M - H) -. [00567] The synthesis of 1-Bromo-6-chloro-N-(3,4-dichlorophenyl)-9H-carbazol-3-amine (82-3a): NBS (338 mg, 1.90 mmol, 1 eq) was added to a solution of 6-chloro-N-(3,4-dichlorophenyl)-9H- carbazol-3-amine (686 mg, 1.90 mmol, 1 eq) in dichloromethane (70 mL) at room temperature. After stirring for 16 h, the reaction mixture was washed with brine, dried over Na2SO4, concentrated to give 741 mg of title compound in 89% yield as a white solid. [00568] 1H NMR (400 MHz, DMSO-d6) ^ 11.86 (s, 1H), 8.62 (d, J = 2.0 Hz, 1H), 8.20 (s, 1H), 7.61 (d, J = 1.2 Hz, 1H), 7.59 (d, J = 1.2 Hz, 1H), 7.51 (dd, J = 8.6, 2.2 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 6.79 (d, J = 2.8 Hz, 1H), 6.64 (dd, J = 8.8, 2.4 Hz, 1H). MS: (ESI) m/z 436.8 (M - H) -. [00569] The synthesis of tert-Butyl (2-((6-chloro-3-((3,4-dichlorophenyl)amino)-9H-carbazol-1- yl)amino)ethyl)carbamate (80-2): 1-bromo-6-chloro-N-(3,4-dichlorophenyl)-9H-carbazol-3-amine (100 mg, 0.23 mmol), tert-butyl (2-aminoethyl)carbamate (37 mg, 0.23 mmol), tris(dibenzylideneacetone)dipalladium(0) (42 mg, 0.046 mmol), tert-butylbrett-Phos (28 mg, 0.058 mmol) and cesium carbonate (74 mg, 0.23 mmol) were dissolved in tert-butanol (4 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes then heated at 90 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by Prep-TLC (dichloromethane) to give 10 mg title compound in 8% yield as a brown solid. MS: (ESI) m/z 519.2 (M + H)+. [00570] The synthesis of N1-(2-Aminoethyl)-6-chloro-N3-(3,4-dichlorophenyl)-9H-carbazole-1,3- diamine (80-3): A solution of tert-butyl (2-((6-chloro-3-((3,4-dichlorophenyl)amino)-9H-carbazol-1- yl)amino)ethyl)carbamate (12 mg, 0.023 mmol) in TFA (5% in dichloromethane, 5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and used for the next step directly. [00571] The synthesis of (80-4): N1-(2-Aminoethyl)-6-chloro-N3-(3,4-dichlorophenyl)-9H- carbazole-1,3-diamine (12 mg, 0.029 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1- yl)methylene)carbamate (9 mg, 0.029 mmol) and Et3N (6 mg, 0.059 mmol) in DMF (2 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water (10 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The residue was purified by Prep- TLC (petroleum ether/ethyl acetate = 3/1) to give 9 mg of title compound in 48% yield as pale brown oil. MS: (ESI) m/z 661.2 (M + H)+. [00572] The synthesis of 1-(2-((6-Chloro-3-((3,4-dichlorophenyl)amino)-9H-carbazol-1- yl)amino)ethyl)guanidine (SRI-33218): A solution of 80-4 (9 mg, 0.014 mmol) in TFA (10% in dichloromethane, 5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (2.1 mg, 33%) as a white solid. [00573] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.39 (s, 1.2H, formic acid), 8.04 (d, J = 1.6 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.43 (dd, J = 8.8, 2.0 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 6.66 (d, J = 2.4 Hz, 1H), 6.60 (dd, J = 8.8, 2.4 Hz, 1H), 3.29 (d, J = 5.2 Hz, 2H), 3.25 (d, J = 4.8 Hz, 2H). MS: (ESI) m/z 461.3 (M + H) +. [00574] Example 49: [00575] Example Route for Example 49 (SRI-33219):
[00576] The synthesis of tert-Butyl 2-(6-bromo-9H-carbazol-3-ylamino)ethylcarbamate (76-2b): 3,6-dibromo-9H-carbazole (650 mg, 2.00 mmol), tert-butyl 2-aminoethylcarbamate (320 mg, 2.00 mmol), tris(dibenzylideneacetone)dipalladium(0) (183 mg, 0.20 mmol), tert-butylbrett-Phos (194 mg, 0.40 mmol) and cesium carbonate (1.30 g, 4.00 mmol) were dissolved in tert-butanol (100 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by CC (petroleum ether/ethyl acetate = 5/1) to give 200 mg title compound in 25% yield as a yellow solid. MS: (ESI) m/z .404.2 (M + H) +. [00577] The synthesis of tert-Butyl 2-(6-(3,4-dichlorophenylamino)-9H-carbazol-3- ylamino)ethylcarbamate (76-3a): tert-butyl 2-(6-bromo-9H-carbazol-3-ylamino)ethylcarbamate (180 mg, 0.45 mmol), 3,4-dichloroaniline (72 mg, 0.45 mmol), tris(dibenzylideneacetone)dipalladium(0) (82 mg, 0.09 mmol), tert-butylbrett-Phos (87 mg, 0.18 mmol) and cesium carbonate ( 290 mg, 0.89 mmol) were dissolved in tert-butanol (100 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by CC (petroleum ether/ethyl acetate = 2/1) to give 100 mg title compound in 46% yield a yellow solid. MS: (ESI) m/z 485.2 (M + H)+. [00578] The synthesis of N3-(2-Aminoethyl)-N6-(3,4-dichlorophenyl)-9H-carbazole-3,6-diamine (76-4a): A solution of tert-butyl 2-(6-(3,4-dichlorophenylamino)-9H-carbazol-3- ylamino)ethylcarbamate (100 mg, 0.21 mmol) in TFA (5% in DCM, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and used for the next step directly. [00579] The synthesis of (Z)-tert-Butyl (tert-butoxycarbonylamino)(2-(6-(3,4- dichlorophenylamino)-9H-carbazol-3-ylamino)ethylamino)methylenecarbamate (76-5a): N3-(2- aminoethyl)-N6-(3,4-dichlorophenyl)-9H-carbazole-3,6-diamine (81 mg, 0.21 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (64 mg, 0.21 mmol) and Et3N (42 mg, 0.41 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water (20 mL). The product was extracted with ethyl acetate (3x20 mL), dried over Na2SO4. The residue was purified by CC (petroleum ether/ethyl acetate = 3/1) to give 110 mg of title compound in 85% yield as a yellow solid. MS: (ESI) m/z 627.2 (M + H)+. [00580] The synthesis of 1-(2-(6-(3,4-Dichlorophenylamino)-9H-carbazol-3- ylamino)ethyl)guanidine (SRI-33219): A solution of (Z)-tert-butyl (tert-butoxycarbonylamino)(2-(6- (3,4-dichlorophenylamino)-9H-carbazol-3-ylamino)ethylamino)methylenecarbamate (70 mg, 0.11 mmol) in TFA (10% in DCM, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (14 mg, 29%) as a white solid. [00581] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.41 (s, 1H, formic acid), 7.79 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.27-7.31 (m, 2H), 7.14 (dd, J = 8.4, 1.6 Hz, 1H), 6.97 (d, J = 2.4 Hz, 1H), 6.84-6.88 (m, 2H), 3.36-3.37 (m, 2H), 3.28-3.29 (m, 2H). MS: (ESI) m/z 427.2 (M + H)+. [00582] Example 50: [00584] The synthesis of tert-Butyl 2-(6-chloro-4-(3,4-dichlorophenyl)-9H-carbazol-1- ylamino)ethylcarbamate (84-2): To a solution of tert-butyl 2-(4-bromo-6-chloro-9H-carbazol-1- ylamino)ethylcarbamate (250 mg, 569.8 μmol) in DME (2 mL) and water (1 mL) was added 3,4- dichlorophenylboronic acid (130.5 mg, 683.8 μmol), K2CO3 (236.3 mg, 1710 μmol) and Pd(dppf)Cl2 (41.7 mg, 57.0 μmol). The mixture was stirred at 80 oC for 16 hours to give a black solution. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2), the combined organic layers were washed with saturated brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 10:1) to give 130 mg of title compound in 43.2% yield as a white solid. MS: (ESI) m/z 504.2 (m-1)-. [00585] The synthesis of N1-(6-Chloro-4-(3,4-dichlorophenyl)-9H-carbazol-1-yl)ethane-1,2- diamine (84-3): To a solution of tert-butyl 2-(6-chloro-4-(3,4-dichlorophenyl)-9H-carbazol-1- ylamino)ethylcarbamate (130 mg, 257.5 mmol) in DCM (2 mL) was added TFA (0.2 mL) and stirred at 25 oC for 16 hours. The reaction mixture was concentrated under reduced pressure to give 130 mg crude of the title compound as yellow oil. MS: (ESI) m/z 404.0 (M - H) -. [00586] The synthesis of (Z)-tert-Butyl (tert-butoxycarbonylamino)(2-(6-chloro-4-(3,4- dichlorophenyl)-9H-carbazol-1-ylamino)ethylamino)methylenecarbamate (84-4): To a solution of N1- (6-chloro-4-(3,4-dichlorophenyl)-9H-carbazol-1-yl)ethane-1,2-diamine (130 mg, 321.2 μmol) in DMF (2 mL) was added (Z)-tert-butyl (1H-pyrazol-1-yl)methylenedicarbamate (109.7 mg, 353.3 μmol) and Et3N (97.5 mg, 963.6 μmol). The mixture was stirred at 25 oC for 2 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2), the combined organic layers were washed with saturated brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 10:1) to give 30 mg of title compound in 14.4% yield as a white solid. MS: (ESI) m/z 646.0 (M + H)+. [00587] The synthesis of 1-(2-(6-Chloro-4-(3,4-dichlorophenyl)-9H-carbazol-1- ylamino)ethyl)guanidine (SRI-33220): To a solution of (Z)-tert-butyl (tert-butoxycarbonylamino)(2- (6-chloro-4-(3,4-dichlorophenyl)-9H-carbazol-1-ylamino)ethylamino)methylenecarbamate (30 mg, 46.4 mmol) in DCM (2 mL) was added TFA (0.2 mL) and stirred at 25 oC for 16 hours. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (5.48 mg 26.5%) as a white solid. [00588] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 7.79 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 9.2 Hz, 1H), 7.54 (dd, J = 2.0, 8.0 Hz, 1H), 7.36-7.39 (m, 2H), 6.97 (d, J = 7.6 Hz, 2H), 6.75 (d, J = 8.0 Hz, 1H), 3.47 (s, 4H). MS: (ESI) m/z 446.0 (M + H) +. [00589] Example 51: [00590] Example Route for Example 51 (SRI-33221):
[00591] The synthesis of tert-Butyl (2-(3-chloro-6-((3,4-dichlorophenyl)amino)-9H-carbazol-9- yl)ethyl)carbamate (85-1): The mixture of 6-chloro-N-(3,4-dichlorophenyl)-9H-carbazol-3-amine (400 mg, 1.11 mmol, 1 eq), tert-butyl (2-bromoethyl)carbamate (298 mg, 1.33 mmol) and cesium carbonate (1.08 g, 3.32 mmol) in DMF (4 mL), was heated at 50 °C for 8 hours. The mixture was cooled to room temperature and quenched with water (40 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. Concentrated and purified by CC (petroleum ether/ethyl acetate = 3/1) to give 132 mg title compound in 24% yield as pale brown oil. MS: (ESI) m/z 502.0 (M - H) -. [00592] The synthesis of 9-(2-Aminoethyl)-6-chloro-N-(3,4-dichlorophenyl)-9H-carbazol-3- amine (85-2): A solution of tert-butyl (2-(3-chloro-6-((3,4-dichlorophenyl)amino)-9H-carbazol-9- yl)ethyl)carbamate (132 mg, 0.26 mmol) in TFA (5% in dichloromethane, 5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and used for the next step directly. [00593] The synthesis of (85-3): 9-(2-Aminoethyl)-6-chloro-N-(3,4-dichlorophenyl)-9H-carbazol- 3-amine (132 mg, 0.326 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1- yl)methylene)carbamate (102 mg, 0.329 mmol) and Et3N (66 mg, 0.652 mmol) in DMF (2 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water (20 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The residue was purified by Prep- TLC (petroleum ether/ dichloromethane = 1/1) to give 170 mg of title compound in 81% yield as a brown solid. MS: (ESI) m/z 646.2 (M + H)+. [00594] The synthesis of 1-(2-(3-Chloro-6-((3,4-dichlorophenyl)amino)-9H-carbazol-9- yl)ethyl)guanidine (SRI-33221): A solution of 85-3 (170 mg, 0.26 mmol) in TFA (10% in dichloromethane, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (66.2 mg, 56%) as an off-white solid. [00595] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.30 (s, 0.54 H, formic acid), 8.23 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 1.6 Hz, 1H), 7.58 (dd, J = 8.4, 6.4 Hz, 2H), 7.49 (dd, J = 8.8, 2.0 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.35 (dd, J = 8.8, 2.0 Hz, 1H), 7.07 (d, J = 2.4 Hz, 1H), 6.95 (dd, J = 8.8, 2.8 Hz, 1H), 4.51 (t, J = 5.2 Hz, 2H), 3.65 (t, J = 5.2 Hz, 2H). MS: (ESI) m/z 446.2 (M + H) +. [00596] Example 52: [00598] The synthesis of 3-Bromo-6-chloro-9H-carbazole (76-2): NBS (1.77 g, 9.92 mmol, 1 eq) was added to a solution of 3-chloro-9H-carbazole (2.0 g, 9.92 mmol, 1 eq) in DCM (200 mL) at room temperature. After stirring for 16 h, the reaction mixture was washed with brine, dried over Na2SO4, concentrated to give 2.29 g of title compound in 82% yield as a pale brown solid. [00599] 1H NMR (400 MHz, DMSO-d6) ^ 11.60 (s, 1H), 8.43 (d, J = 2.0 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 8.6, 1.8 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.43 (dd, J = 8.6, 2.2 Hz, 1H). MS: (ESI) m/z 277.9 (M - H)-. [00600] The synthesis of 3-Chloro-6-(3,4-dichlorophenyl)-9H-carbazole (79-2a): 3-bromo-6- chloro-9H-carbazole (2.78 g, 10.00 mmol), 3,4-dichlorophenylboronic acid (1.90 g, 10.00 mmol), Pd(PPh3)4 (578 mg, 0.50 mmol) and K2CO3 (2.76 g, 20.00 mmol) were dissolved in DME/water (3/1, 400 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 80 °C for 16 hours. The mixture was cooled to room temperature and quenched with water (600 mL). The product was extracted with ethyl acetate (3x300 mL), dried over Na2SO4. Concentrated and purified by CC (petroleum ether/ethyl acetate = 4/1) to give 2.60 g title compound in 75% yield as a white solid. MS: (ESI) m/z 344.0 (M - H)-. [00601] The synthesis of tert-Butyl 2-(3-chloro-6-(3,4-dichlorophenyl)-9H-carbazol-9- yl)ethylcarbamate (86-1): The mixture of 3-chloro-6-(3,4-dichlorophenyl)-9H-carbazole (345 mg, 1.00 mmol, 1 eq), tert-butyl 2-bromoethylcarbamate (336 mg, 1.50 mmol) and Cs2CO3 (975 mg, 3.00 mmol) in DMF (10 mL) was heated at 50 °C for 8 hours. The mixture was cooled to room temperature and quenched with water (40 mL). The product was extracted with ethyl acetate (3x20 mL), dried over Na2SO4. Concentrated and purified by CC (petroleum ether/ethyl acetate = 6/1) to give 280 mg title compound in 57% yield as a white solid. MS: (ESI) m/z 433.0 (M -56 + H)+. [00602] The synthesis of 2-(3-Chloro-6-(3,4-dichlorophenyl)-9H-carbazol-9-yl)ethanamine (86- 2): A solution of tert-butyl 2-(3-chloro-6-(3,4-dichlorophenyl)-9H-carbazol-9-yl)ethylcarbamate (244 mg, 0.50 mmol) in TFA (5% in DCM, 15 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and used for the next step directly. [00603] The synthesis of (Z)-tert-Butyl (tert-butoxycarbonylamino)(2-(3-chloro-6-(3,4- dichlorophenyl)-9H-carbazol-9-yl)ethylamino)methylenecarbama (86-3): 2-(3-chloro-6-(3,4- dichlorophenyl)-9H-carbazol-9-yl)ethanamine (194 mg, 0.50 mmol), (Z)-tert-butyl (1H-pyrazol-1- yl)methylenedicarbamate (156 mg, 0.50 mmol) and Et3N (101 mg, 1.00 mmol) in DMF (10 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water (30 mL). The product was extracted with ethyl acetate (3x20 mL), dried over Na2SO4. The residue was purified by CC (petroleum ether/ethyl acetate = 5/1) to give 180 mg of title compound in 57% yield as a white solid. MS: (ESI) m/z 631.2 (M + H)+. [00604] The synthesis of 1-(2-(3-Chloro-6-(3,4-dichlorophenyl)-9H-carbazol-9-yl)ethyl)guanidine (SRI-33240): A solution of (Z)-tert-butyl (tert-butoxycarbonylamino)(2-(3-chloro-6-(3,4- dichlorophenyl)-9H-carbazol-9-yl)ethylamino)methylenecarbamate (180 mg, 0.28 mmol) in TFA (10% in DCM, 20 mL) was stirred at room temperature overnight. The reaction solution was concentrated and purified by Prep-HPLC to provide the title compound (100 mg, 81%) as a white solid. [00605] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.70 (d, J = 1.6 Hz, 1H), 8.43 (s, 0.2H, formic acid), 8.40 (d, J = 2.0 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.89 (dd, J = 8.8, 1.6 Hz, 1H), 7.82 (dd, J = 8.4, 2.0 Hz, 1H),7.70-7.75 (m, 2H), 7.65 (d, J = 8.8 Hz, 1H), 7.51 (dd, J = 8.8, 2.0 Hz, 1H), 4.55 (t, J = 7.2 Hz, 2H), 3.64 (d, J = 6.0 Hz, 2H). MS: (ESI) m/z 431.2 (M + H) +. [00606] Example 53: [00607] Example Route for Example 53 (SRI-33241):
[00608] The synthesis of 2-Bromo-6-chloro-9H-carbazole (82-2a): To a solution of 2-bromo-9H- carbazole (1 g, 4.1 mmol) in DMF (15 mL) was added NCS (813.9 mg, 6.1 mmol) and stirred at 0 oC for 4 hours to give a black solution. The reaction mixture was filtered to give a filtrate. The filtrate was diluted with water (100 mL) and extracted with ethyl acetate(100 mL x 3), the combined organic layers were washed with saturated brine (100 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 10:1) to give 800 mg of title compound in 70.2% yield as a yellow solid. MS: (ESI) m/z 278.0 (M - H)-. [00609] The synthesis of tert-Butyl 2-(6-chloro-9H-carbazol-2-ylamino)ethylcarbamate (82-3b): To a solution of 2-bromo-6-chloro-9H-carbazole (400 mg, 1425.8 μmol) in t-BuOH (5 mL) was added tert-butyl 2-aminoethylcarbamate (251.2 mg, 1568.4 μmol), Cs2CO3 (1393.6 mg, 4280 μmol), t- Bubrettphos (69.2 mg, 142.6 μmol) and Pd2(dba)3 (130.6 mg, 342.6 μmol). The mixture was stirred at 90 oC for 3 hours. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 10:1) to give 250 mg of title compound in 48.7 % yield as a white solid. [00610] 1H NMR(400 MHz, DMSO-d6): δ 10.93 (s, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 8.8 Hz,1H), 7.29 (d, J = 8.8 Hz, 1H), 7.14 (dd, J = 8.4, 2.0 Hz, 1H), 6.92-6.94 (m, 1H), 6.49-6.51 (m, 2H), 5.85-5.87 (m, 1H), 3.14 (s, 4H), 1.35 (s, 9H). MS: (ESI) m/z 358.2 (m-1)-. [00611] The synthesis of tert-Butyl 2-(3-bromo-6-chloro-9H-carbazol-2-ylamino)ethylcarbamate (82-4a): To a solution of tert-butyl 2-(6-chloro-9H-carbazol-2-ylamino)ethylcarbamate (250 mg, 694.7 μmol) in DCM (4 mL) was added NBS (123.7 mg, 694.7 μmol) and stirred at 0 oC for 1 hour. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 10:1) to give 120 mg of title compound in 39.4% yield as a white solid. [00612] 1H NMR(400 MHz, DMSO-d6): δ 11.12 (s, 1H), 8.24 (s, 1H), 8.01 (d, J = 2.0 Hz,1H), 7.34 (d, J = 8.8 Hz, 1H), 7.21 (dd, J = 2.0, 8.4 Hz, 1H), 7.10-7-12 (m, 1H), 6.66 (s, 1H), 5.41 (s, 1H), 3.24 (s, 4H) 1.35 (s, 9H). MS: (ESI) m/z 436.0 (M - H)-. [00613] The synthesis of tert-Butyl 2-(6-chloro-3-(3,4-dichlorophenyl)-9H-carbazol-2- ylamino)ethylcarbamate (88-1): The synthesis of To a solution of tert-butyl 2-(3-bromo-6-chloro-9H- carbazol-2-ylamino)ethylcarbamate (50 mg, 114.0 μmol) in DME (2 mL) and water (1 mL) was added 3,4-dichlorophenylboronic acid (26.1 mg, 136.8 μmol), K2CO3 (47.3 mg, 341.9 μmol) and Pd(dppf)Cl2 (8.3 mg, 11.4 μmol). The mixture was stirred at 90 oC for 16 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2), the combined organic layers were washed with saturated brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 10:1) to give 50 mg of title compound in 86.9% yield as a white solid. MS: (ESI) m/z 502.0 (M - H)-. [00614] The synthesis of N1-(6-Chloro-3-(3,4-dichlorophenyl)-9H-carbazol-2-yl)ethane-1,2- diamine (88-2): The synthesis of To a solution of tert-butyl 2-(6-chloro-3-(3,4-dichlorophenyl)-9H- carbazol-2-ylamino)ethylcarbamate (50 mg, 99.04 mmol) in DCM (2 mL) was added TFA (0.2 mL) and stirred at 25 oC for 1 hour. The reaction mixture was concentrated under reduced pressure to give 50 mg crude of title compound as a yellow solid. MS: (ESI) m/z 402.0 (M + H)+. [00615] The synthesis of (E)-tert-Butyl (tert-butoxycarbonylamino)(2-(6-chloro-3-(3,4- dichlorophenyl)-9H-carbazol-2-ylamino)ethylamino)methylenecarbamate (88-3): To a solution of N1- (6-chloro-3-(3,4-dichlorophenyl)-9H-carbazol-2-yl)ethane-1,2-diamine (50 mg, 123.5 μmol) in DMF (2 mL) was added (Z)-tert-butyl (1H-pyrazol-1-yl)methylenedicarbamate (42.2 mg, 135.9 μmol) and Et3N (37.5 mg, 370.6 μmol). The mixture was stirred at 25 oC for 2 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate(20 mL x 2), the combined organic layers were washed with saturated brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 10:1) to give 50 mg of title compound in 62.5% yield as a white solid. MS: (ESI) m/z 646.2 (M + H)+. [00616] The synthesis of 1-(2-(6-Chloro-3-(3,4-dichlorophenyl)-9H-carbazol-2- ylamino)ethyl)guanidine (SRI-33241): To a solution of (E)-tert-butyl (tert-butoxycarbonylamino)(2- (6-chloro-3-(3,4-dichlorophenyl)-9H-carbazol-2-ylamino)ethylamino)methylenecarbamate(50 mg, 77.3 mmol) in DCM (2 mL) was added TFA (0.2 mL) and stirred at 25 oC for 48 hours. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (16.14 mg, 46.75%) as a white solid. [00617] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 7.99 (d, J = 2.0 Hz, 1H), 7.83 (s, 1H), 7.71 (d, J = 6.8 Hz, 1H), 7.70 (s, 1H), 7.48 (dd, J = 2.4, 8.4 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.23 (dd, J = 2.0, 8.4 Hz, 1H), 6.70 (s, 1H), 3.30-3.34 (m, 4H). MS: (ESI) m/z 446.2 (M + H) +. [00618] Example 54: [00620] The synthesis of tert-Butyl 2-(6-chloro-1-(3,4-dichlorophenyl)-9H-carbazol-2- ylamino)ethylcarbamate (90-1): To a solution of tert-butyl 2-(1-bromo-6-chloro-9H-carbazol-2- ylamino)ethylcarbamate (100 mg, 227.9 μmol) in DME (2 mL) and water (1 mL) was added 3,4- dichlorophenylboronic acid (52.2 mg, 273.5 μmol), K2CO3 (94.5 mg, 683.8 μmol) and Pd(dppf)Cl2 (16.6 mg, 22.8 μmol). The mixture was stirred at 80 oC for 16 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate(20 mL x 2), the combined organic layers were washed with saturated brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 10:1) to give 100 mg of title compound in 86.9% yield as a white solid. MS: (ESI) m/z 504.0 (M + H)+. [00621] The synthesis of N1-(6-Chloro-1-(3,4-dichlorophenyl)-9H-carbazol-2-yl)ethane-1,2- diamine (90-2): To a solution of tert-butyl tert-butyl 2-(6-chloro-1-(3,4-dichlorophenyl)-9H-carbazol- 2-ylamino)ethylcarbamate (100 mg, 198.08 mmol) in DCM (2 mL) was added TFA (0.2 mL) and stirred at 25 oC for 1 hour. The reaction mixture was concentrated under reduced pressure to give 100 mg crude of title compound as a yellow solid. [00622] The synthesis of (E)-tert-Butyl (tert-butoxycarbonylamino)(2-(6-chloro-1-(3,4- dichlorophenyl)-9H-carbazol-2-ylamino)ethylamino)methylenecarbamate (90-3): To a solution of N1- (6-chloro-1-(3,4-dichlorophenyl)-9H-carbazol-2-yl)ethane-1,2-diamine (100 mg, 247.1 μmol) in DMF (2 mL) was added (Z)-tert-butyl (1H-pyrazol-1-yl)methylenedicarbamate (84.4 mg, 271.8 μmol) and Et3N (75.0 mg, 741.3 μmol). The mixture was stirred at 25 oC for 2 hours to give a black solution. The mixture was diluted with water (20 mL) and extracted with ethyl acetate(20 mL x 2), the combined organic layers were washed with saturated brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 10:1) to give 120 mg of title compound in 75.0% yield as a white solid. MS: (ESI) m/z 646.2 (M + H)+. [00623] The synthesis of 1-(2-(6-Chloro-1-(3,4-dichlorophenyl)-9H-carbazol-2- ylamino)ethyl)guanidine (SRI-33242): To a solution of (E)-tert-butyl (tert-butoxycarbonylamino)(2- (6-chloro-1-(3,4-dichlorophenyl)-9H-carbazol-2-ylamino)ethylamino)methylenecarbamate (120 mg, 185.5 mmol) in DCM (2 mL) was added TFA (0.2 mL) and stirred at 25 oC for 48 hours. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (35.78 mg, 43.18%) as a white solid. [00624] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 7.99-8.00 (d, J = 2.0 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.18 (dd, J = 2.4, 8.8 Hz, 1H), 6.73 (d, J = 8.8 Hz, 2H), 3.27-3.31 (m, 4H). MS: (ESI) m/z 446.0 (M + H) +. [00625] Example 55: [00627] The synthesis of 3-Chloro-6-(3,4-dichlorophenyl)-9H-carbazole (79-1): To a solution of 3-bromo-6-chloro-9H-carbazole (650 mg, 2.31 mmol) in DME and H2O (20 mL, 1,4-DME : H2O = 3:1) were added Pd(dppf)Cl2 (131 mg, 0.17 mmol,), K2CO3 (957 mg, 6.93 mmol) and (3,4- dichlorophenyl)boronic acid (440 mg, 2.31 mmol) under N2. After being stirred at 80 °C for 16 h, the reaction mixture was cooled to room temperature. EtOAc (100 mL) was added and organic layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified column chromatography (petroleum ether, petroleum ether/ethyl acetate = 8/1) to give 500 mg of title compound in 62% yield as a white solid. MS: (ESI) m/z 345.0 (M - H)-. [00628] The synthesis of 1-Bromo-6-chloro-3-(3,4-dichlorophenyl)-9H-carbazole (79-2): NBS (256 mg, 1.44 mmol) was added to a solution of 1-bromo-6-chloro-3-(3,4-dichlorophenyl)-9H- carbazole (500 mg, 1.44 mmol) in dichloromethane (20 mL) at 0 ºC. After stirring for 2 h, the reaction mixture was washed with brine, dried over Na2SO4, concentrated and purified by C.C (PE/EA 1/1) to give 280 mg of title compound in 45% yield as a brown solid. MS: (ESI) m/z 421.9 (M - H)–. [00629] The synthesis of tert-Butyl (2-((6-chloro-3-(3,4-dichlorophenyl)-9H-carbazol-1- yl)amino)ethyl)carbamate (79-3): 1-bromo-6-chloro-3-(3,4-dichlorophenyl)-9H-carbazole (280 mg, 0.65 mmol), tert-butyl (2-aminoethyl)carbamate (126 mg, 0.78 mmol), tris(dibenzylideneacetone)dipalladium(0) (118 mg, 0.13 mmol), tert-butylbrett-Phos (78 mg, 0.16 mmol) and cesium carbonate (635 mg, 1.95 mmol) were dissolved in tert-butanol (20 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by Prep-TLC (dichloromethane) to give 130 mg title compound in 39% yield as a brown solid. MS: (ESI) m/z 502.0 (M - H)-. [00630] The synthesis of N1-(6-Chloro-3-(3,4-dichlorophenyl)-9H-carbazol-1-yl)ethane-1,2- diamine (79-4): A solution of tert-butyl (2-((6-chloro-3-(3,4-dichlorophenyl)-9H-carbazol-1- yl)amino)ethyl)carbamate (130 mg, 0.25 mmol) in TFA (5% in dichloromethane, 5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and used for next step directly. [00631] The synthesis of (79-5): N1-(6-chloro-3-(3,4-dichlorophenyl)-9H-carbazol-1-yl)ethane- 1,2-diamine (104 mg, 0.25 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1- yl)methylene)carbamate (80 mg, 0.25 mmol) and Et3N (50 mg, 0.5 mmol) in DMF (5 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water (10 mL). The product was extracted with ethyl acetate (3 x 10 mL) and dried over Na2SO4. The residue was purified by Prep- TLC (petroleum ether/ethyl acetate = 3/1) to give 140 mg of title compound in 84% yield as a brown solid. MS: (ESI) m/z 646.2 (M + H)+. [00632] The synthesis of 1-(2-((6-Chloro-3-(3,4-dichlorophenyl)-9H-carbazol-1- yl)amino)ethyl)guanidine (SRI-33249): A solution of 79-5 (140 mg, 0.22 mmol) in TFA (10% in dichloromethane, 10 mL) was stirred at room temperature overnight. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (30.16 mg, 32%) as a white solid. [00633] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.29 (s, 1H), 8.23 (d, J = 2.4 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.87 (d, J = 0.8 Hz, 1H), 7.77 (dd, J = 8.4, 2.0 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.43 (dd, J = 8.4, 2.0 Hz, 1H), 6.93 (s, 1H), 3.56-3.54 (m, 2H), 3.51-3.49 (m, 2H). MS: (ESI) m/z 446.0 (M + H)+. [00634] Example 56: [00636] The synthesis of tert-Butyl 2-(6-chloro-3-(3,5-dichloropyridin-4-ylamino)-9H-carbazol-1- yl)ethylcarbamate (89-1): tert-butyl 2-(3-bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)ethylcarbamate (336 mg, 0.58 mmol), 3,5-dichloropyridin-4-amine (95 mg, 0.58 mmol), tris(dibenzylideneacetone)dipalladium(0) (110 mg, 0.12 mmol), XantPhos (87 mg, 0.15 mmol) and K3PO4 (370 mg, 1.74 mmol) were dissolved in dioxane (15 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 100 °C for 7 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by Prep-TLC (petroleum ether/ethyl acetate = 3/1) to give 59 mg title compound in 20% yield as a yellow solid. MS: (ESI) m/z .505.2 (M + H)+. [00637] The synthesis of 1-(2-Aminoethyl)-6-chloro-N-(3,5-dichloropyridin-4-yl)-9H-carbazol-3- amine (89-2): A solution of tert-butyl 2-(6-chloro-3-(3,5-dichloropyridin-4-ylamino)-9H-carbazol-1- yl)ethylcarbamate (59 mg, 0.117 mmol) in TFA (5% in DCM, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and used for the next step directly. [00638] The synthesis of (E)-tert-Butyl (tert-butoxycarbonylamino)(2-(6-chloro-3-(3,5- dichloropyridin-4-ylamino)-9H-carbazol-1-yl)ethylamino)methylenecarbamate (89-3): 1-(2- aminoethyl)-6-chloro-N-(3,5-dichloropyridin-4-yl)-9H-carbazol-3-amine (47 mg, 0.117 mmol), tert- butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (37 mg, 0.117 mmol) and Et3N (24 mg, 0.233 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water (20 mL). The product was extracted with ethyl acetate (3x20 mL) and dried over Na2SO4. The residue was purified by Prep-TLC (petroleum ether/ethyl acetate = 3/1) to give 45 mg of title compound in 60% yield as a yellow solid. MS: (ESI) m/z 647.2 (M + H) +. [00639] The synthesis of 1-(2-(6-Chloro-3-(3,5-dichloropyridin-4-ylamino)-9H-carbazol-1- yl)ethyl)guanidine (SRI-33250): A solution of (E)-tert-butyl (tert-butoxycarbonylamino)(2-(6-chloro- 3-(3,5-dichloropyridin-4-ylamino)-9H-carbazol-1-yl)ethylamino)methylenecarbamate (45 mg, 0.07 mmol) in TFA (10% in DCM, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (12 mg, 37%) as a white solid. [00640] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.45 (s, 1H, formic acid), 8.37 (s, 2H), 8.16 (d, J = 2.4 Hz, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.05 (d, J = 2.0 Hz, 1H), 3.46 (t, J = 8.0 Hz, 2H), 3.11 (t, J = 8.0 Hz, 2H). MS: (ESI) m/z 447.2 (M + H) +. [00641] Example 57: [00643] The synthesis of 6-Chloro-2-(3,4-dichlorophenyl)-9H-carbazole (81-2): The mixture of 2- bromo-6-chloro-9H-carbazole (1.0 g, 3.92 mmol, 1 eq), (3,4-dichlorophenyl)boronic acid (749 mg, 3.93 mmol) and potassium carbonate (813 mg, 5.88 mmol) in DME (15 mL), water (5 mL) was heated at 80 °C for 16 hours. The mixture was cooled to room temperature. Concentrated and purified by CC (petroleum ether/ethyl acetate = 20/1, 10/1, 5/1) to give 900 mg title compound in 66% yield as an off-white solid. [00644] 1H NMR (400 MHz, DMSO-d6) ^ 11.54 (s, 1H), 8.23-8.29 (m, 2H), 8.03 (d, J = 2.0 Hz, 1H), 7.79 (d, J = 1.2 Hz, 1H), 7.72-7.78 (m, 2H), 7.54 (d, J = 8.4 Hz, 1H), 7.53 (dd, J = 8.0, 1.6 Hz, 1H), 7.42 (dd, J = 8.6, 2.2 Hz, 1H). MS: (ESI) m/z 344.0 (M - H)-. [00645] The synthesis of tert-Butyl (2-(6-chloro-2-(3,4-dichlorophenyl)-9H-carbazol-9- yl)ethyl)carbamate (91-2): The mixture of 6-chloro-2-(3,4-dichlorophenyl)-9H-carbazole (200 mg, 0.577 mmol, 1 eq), tert-butyl (2-bromoethyl)carbamate (156 mg, 0.696 mmol) and cesium carbonate (564 mg, 1.73 mmol) in DMF (2 mL) was heated at 50 °C for 16 hours. The mixture was cooled to room temperature and quenched with water (40 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The solvent was removed to give 217 mg title compound in 77% yield as an off-white solid. [00646] 1H NMR (400 MHz, DMSO-d6) ^ 8.29 (d, J = 2.0 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H), 7.97 (s, 1H), 7.83 (dd, J = 8.4, 2.0 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.47 (dd, J = 8.4, 2.0 Hz, 1H), 6.96 (t, J = 5.8 Hz, 1H), 4.52 (t, J = 4.2 Hz, 2H), 3.33-3.40 (m, 2H), 1.11 (s, 9H). MS: (ESI) m/z 487.0 (M - H)-. [00647] The synthesis of 2-(6-Chloro-2-(3,4-dichlorophenyl)-9H-carbazol-9-yl)ethanamine (91- 3): A solution of tert-butyl (2-(6-chloro-2-(3,4-dichlorophenyl)-9H-carbazol-9-yl)ethyl)carbamate (217 mg, 0.44 mmol) in TFA (10% in dichloromethane, 10 mL) was stirred at room temperature for overnight. The reaction solution was concentrated and used for the next step directly. [00648] The synthesis of (91-4): 2-(6-Chloro-2-(3,4-dichlorophenyl)-9H-carbazol-9- yl)ethanamine (223 mg, 0.57 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1- yl)methylene)carbamate (178 mg, 0.57 mmol) and Et3N (116 mg, 1.15 mmol) in DMF (2 mL) was stirred at room temperature for 3 hours. The reaction was quenched with water (20 mL). The product was extracted with ethyl acetate (3x10 mL) and dried over Na2SO4. The residue was purified by Prep- TLC (petroleum ether/ ethyl acetate = 4/1) to give 264 mg of title compound in 73% yield as a white solid. [00649] 1H NMR (400 MHz, DMSO-d6) ^ 11.30 (s, 1H), 8.50 (t, J = 5.8 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.25 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 2.4 Hz, 1H), 7.98 (s, 1H), 7.82 (dd, J = 8.4, 2.0 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.56 (dd, J = 8.2, 1.4 Hz, 1H), 7.42 (dd, J = 8.8, 2.0 Hz, 1H), 4.64 (t, J = 6.4 Hz, 2H), 3.71 (q, J = 6.0 Hz, 2H), 1.36 (s, 9H), 1.34 (s, 9H). MS: (ESI) m/z 631.2 (M + H) +. [00650] The synthesis of 1-(2-(6-Chloro-2-(3,4-dichlorophenyl)-9H-carbazol-9-yl)ethyl)guanidine (SRI-33253): A solution of 91-4 (264 mg, 0.418 mmol) in TFA (15% in dichloromethane, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (157.1 mg, 87%) as a white solid. [00651] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.32 (s, 0.24 H, formic acid), 8.29 (d, J = 8.0 Hz, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.09 (d, J = 2.4 Hz, 1H), 7.89 (d, J = 0.8 Hz, 1H), 7.83 (dd, J = 8.4, 2.0 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.59 (dd, J = 8.4, 1.6 Hz, 1H), 7.52 (dd, J = 8.4, 1.6 Hz, 1H), 4.60 (t, J = 5.2 Hz, 2H), 3.69 (t, J = 5.2 Hz, 2H). MS: (ESI) m/z 431.2 (M + H) +. [00652] Example 58: [00654] The synthesis of 1,6-Dibromo-9H-carbazole (77-2c): To a solution of 1-bromo-9H- carbazole (2 g, 8.1 mmol) in DMF (30 mL) was added NBS (144.67 mg, 8.1 mmol) and stirred at 0 oC for 30 minutes to give a black solution. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (300 mL x 2), the combined organic layers were washed with saturated brine (300 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 10:1) to give 2 g of title compound in 75.7% yield as a white solid. [00655] 1H NMR (400 MHz, DMSO-d6) ^ 11.63 (s, 1H), 8.42 (d, J = 1.6 Hz, 1H), 8.21 (d, J = 7.6 Hz, 1H), 7.65 (dd, J = 8.0 Hz, 1H), 7.58 (dd, J = 2.0, 8.8 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.14 (t, J =8.0 Hz, 1H). MS: (ESI) m/z 323.9 (M + H)+. [00656] The synthesis of 8-Bromo-N-(3,4-dichlorophenyl)-9H-carbazol-3-amine (77-3c): To a solution of 1,6-dibromo-9H-carbazole (1 g, 3.08 mmol) in t-BuOH (15 mL) was added 3,4- dichloroaniline (498.5 mg, 3.08 μmol), Cs2CO3 (2.0 g, 6.15 mmol), t-Bubrettphos (150.3 mg, 0.31 mmol) and Pd2(dba)3 (283.9 mg, 0.31 μmol). The mixture was stirred at 80 oC for 3 hours to give a black solution. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2), the combined organic layers were washed with saturated brine (40 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC to give 100 mg of title compound in 8% yield as a white solid. [00657] 1H NMR (400 MHz, DMSO-d6) ^ 11.39 (s, 1H), 8.38 (s, 1H), 8.14 (d, J = 7.6 Hz, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.60 (dd, J = 1.2, 8.0 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.26 (dd, J = 2.4, 8.8 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.89 (dd, J =2.8, 9.2 Hz, 1H). MS: (ESI) m/z 403.0 (m-1)-. [00658] The synthesis of tert-Butyl 2-(6-(3,4-dichlorophenylamino)-9H-carbazol-1- ylamino)ethylcarbamate (77-4): To a solution of 8-bromo-N-(3,4-dichlorophenyl)-9H-carbazol-3- amine (95 mg, 233.93 μmol) in t-BuOH (1 mL) was added tert-butyl 2-aminoethylcarbamate (51.2 mg, 257.32 μmol), Cs2CO3 (228.66 mg, 701.79 μmol), t-Bubrettphos (11.3 mg, 23.4 μmol) and Pd2(dba)3 (21.4 mg, 23.4 μmol). The mixture was stirred at 90 oC for 3 hours to give a black solution. The mixture was diluted with water (50 mL) and extracted with ethyl acetate(50 mL x 2), the combined organic layers were washed with saturated brine (40 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 10:1) to give 70 mg of title compound in 61.65 % yield as a white solid. MS: (ESI) m/z 483.2 (M - H)-. [00659] The synthesis of N1-(2-Aminoethyl)-N6-(3,4-dichlorophenyl)-9H-carbazole-1,6-diamine (77-5): To a solution of tert-butyl 2-(6-(3,4-dichlorophenylamino)-9H-carbazol-1- ylamino)ethylcarbamate (70 mg, 144.21 mmol) in DCM (2 mL) was added TFA (0.2 mL) and stirred at 25 oC for 16 hours to give a black solution. The reaction mixture was concentrated under reduced pressure to give 70 mg crude of title compound as yellow oil. MS: (ESI) m/z 383.0 (M + H)+. [00660] The synthesis of (Z)-tert-Butyl (tert-butoxycarbonylamino)(2-(6-(3,4- dichlorophenylamino)-9H-carbazol-1-ylamino)ethylamino)methylenecarbamate (77-6): To a solution of N1-(2-aminoethyl)-N6-(3,4-dichlorophenyl)-9H-carbazole-1,6-diamine (70 mg, 181.7 μmol) in DMF (2 mL) was added (Z)-tert-butyl (1H-pyrazol-1-yl)methylenedicarbamate (62.0 mg, 199.9 μmol) and Et3N (55.2 mg, 545.0 μmol). The mixture was stirred at 25 oC for 2 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2), the combined organic layers were washed with saturated brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 10:1) to give 25 mg of title compound in 21.9% yield as a white solid. MS: (ESI) m/z 625.0 (M - H)+. [00661] The synthesis of 1-(2-(6-(3,4-Dichlorophenylamino)-9H-carbazol-1- ylamino)ethyl)guanidine (SRI-33254): To a solution of (Z)-tert-butyl (tert-butoxycarbonylamino)(2- (6-(3,4-dichlorophenylamino)-9H-carbazol-1-ylamino)ethylamino)methylenecarbamate (25 mg, 39.8 μmol) in DCM (2 mL) was added TFA (0.2 mL) and stirred at 25 oC for 16 hours. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound Target 77 (7.9 mg, 46.41%) as a white solid. [00662] , 7.79 (d, J = 2.4 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.18 (dd, J = 2.0, 8.4 Hz, 1H), 6.98-7.02 (m, 2H), 6.87 (dd, J = 2.4, 8.4 Hz, 1H), 6.62 (d, J = 7.2 Hz, 1H), 3.41-3.57 (m, 4H). MS: (ESI) m/z 427.2 (M + H)+. [00663] Example 59: [00665] The synthesis of tert-Butyl (2-(2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-6-chloro- 3-(3,4-dichlorophenyl)-9H-carbazol-9-yl)ethyl)carbamate (95-1): To a solution of tert-butyl 2-(6- chloro-3-(3,4-dichlorophenyl)-9H-carbazol-2-ylamino)ethylcarbamate (170 mg, 337.3 μmol) in DMF (4 mL) was added tert-butyl 2-bromoethylcarbamate (90.1 mg, 404.1μmol) and Cs2CO3 (329.8 mg, 1009.8 μmol). The mixture was stirred at 50 oC for 12 hours to give a yellow solution. The mixture was diluted with water (20 mL) and extracted with ethyl acetate(20 mL x 2), the combined organic layers were washed with saturated brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 10:1) to give 180 mg of title compound in 82.5% yield. MS: (ESI) m/z 647.3 (M + H)+. [00666] The synthesis of N1-(9-(2-Aminoethyl)-6-chloro-3-(3,4-dichlorophenyl)-9H-carbazol-2- yl)ethane-1,2-diamine (95-2):To a solution of 95-1(180 mg, 277.7 mmol) in DCM (2 mL) was added TFA (0.2 mL) and stirred at 25 oC for 16 hours. The reaction mixture was concentrated under reduced pressure to give 180 mg crude of title compound as a yellow solid. MS: (ESI) m/z 447.2 (M + H) +. [00667] The synthesis of (95-3): To a solution of N1-(9-(2-aminoethyl)-6-chloro-3-(3,4- dichlorophenyl)-9H-carbazol-2-yl)ethane-1,2-diamine (180 mg, 402.0 μmol) in DMF (2 mL) was added (Z)-tert-butyl (1H-pyrazol-1-yl)methylenedicarbamate (274.5 mg, 884.4 μmol) and Et3N (122 mg, 1210 μmol). The mixture was stirred at 25 oC for 2 hours to give a black solution. The mixture was diluted with water (20 mL) and extracted with ethyl acetate(20 mL x 2), the combined organic layers were washed with saturated brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 10:1) to give 100 mg of title compound in 26.26% yield as a white solid. MS: (ESI) m/z 931.2 (M + H) +. [00668] The synthesis of 1-(2-((6-Chloro-3-(3,4-dichlorophenyl)-9-(2-guanidinoethyl)-9H- carbazol-2-yl)amino)ethyl)guanidine (SRI-33255): To a solution of 95-3 (100 mg, 107.3 mmol) in DCM (2 mL) was added TFA (0.2 mL) and stirred at 25 oC for 16 hours. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (24.86 mg, 43.58%) as a white solid. [00669] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.42 (s, 2H, formic acid), 8.03 (d, J = 2.4 Hz, 1H), 7.85 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.45-7.50 (m, 2H), 7.30 (dd, J = 2.0, 8.8 Hz, 1H), 6.75 (s, 1H), 4.46 (s, 2H) , 3.62 (s, 2H) , 3.37 (s, 4H). MS: (ESI) m/z 531.0 (M + H)+. [00670] Example 60: [00672] The synthesis of tert-Butyl (2-(6-chloro-2-((3,4-dichlorophenyl)amino)-9H-carbazol-9- yl)ethyl)carbamate (98-3): The mixture of 6-chloro-N-(3,4-dichlorophenyl)-9H-carbazol-2-amine (100 mg, 0.28 mmol), tert-butyl (2-bromoethyl)carbamate (93 mg, 0.41 mmol) and cesium carbonate (274 mg, 0.84 mmol) in DMF (5 mL) was heated at 50 °C for 4 days. The mixture was cooled to room temperature and quenched with water (40 mL). The product was extracted with ethyl acetate (3 x 10 mL) and dried over Na2SO4. The solvent was removed to give 50 mg title compound in 35% yield as a brown solid. MS: (ESI) m/z 502.0 (M - H) -. [00673] The synthesis of 9-(2-Aminoethyl)-6-chloro-N-(3,4-dichlorophenyl)-9H-carbazol-2- amine (98-4): A solution of tert-butyl (2-(6-chloro-2-((3,4-dichlorophenyl)amino)-9H-carbazol-9- yl)ethyl)carbamate (50 mg, 0.1 mmol) in TFA (10% in dichloromethane, 10 mL) was stirred at room temperature overnight. The reaction solution was concentrated and used for the next step directly. [00674] The synthesis of (98-5): 9-(2-Aminoethyl)-6-chloro-N-(3,4-dichlorophenyl)-9H-carbazol- 2-amine (40 mg, 0.1 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1- yl)methylene)carbamate (30 mg, 0.1 mmol) and Et3N (20 mg, 0.2 mmol) in DMF (2 mL) was stirred at room temperature for 3 hours. The reaction was quenched with water (20 mL). The product was extracted with ethyl acetate (3x10 mL) and dried over Na2SO4. The residue was purified by Prep-TLC (petroleum ether/ ethyl acetate = 4/1) to give 48 mg of title compound in 75% yield as a brown solid. MS: (ESI) m/z 646.2 (M + H) +. [00675] The synthesis of 1-(2-(6-Chloro-2-((3,4-dichlorophenyl)amino)-9H-carbazol-9- yl)ethyl)guanidine (SRI-33256): A solution of 98-5 (48 mg, 0.07 mmol) in TFA (15% in dichloromethane, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (21.37 mg, 32%) as a white solid. [00676] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.38 (s, 1H, formic acid), 8.12 (d, J = 2.0 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.37 (dd, J = 8.8, 2.4 Hz, 1H), 7.28 (d, J = 2.8 Hz, 1H), 7.25 (d, J = 1.6 Hz, 1H), 7.18 (dd, J = 8.8, 2.8 Hz, 1H), 7.00 (dd, J = 8.4, 2.0 Hz, 1H), 4.43 (t, J = 6.0 Hz, 2H), 3.61 (t, J = 5.6 Hz, 2H). MS: (ESI) m/z 446.0 (M + H) +. [00677] Example 61: [00678] Example Route for Example 61 (SRI-33257):
[00679] The synthesis of tert-Butyl 3-(6-chloro-2-(3,4-dichlorophenylamino)-9H-carbazol-9- yl)propylcarbamate (100-1): The mixture of 6-chloro-N-(3,4-dichlorophenyl)-9H-carbazol-2-amine (180 mg, 0.498 mmol), tert-butyl 3-bromopropylcarbamate (237 mg, 0.995 mmol) and cesium carbonate (324 mg, 0.995 mmol) in DMF (6 mL) was heated at 90 °C for 16 hours. The mixture was cooled to room temperature and quenched with water (12 mL). The product was extracted with ethyl acetate (3x15 mL), dried over Na2SO4. The solvent was removed and the crude was purified by CC (petroleum ether/ethyl acetate = 4/1-2/1) to give 240 mg title compound in 93% yield as a white solid. MS: (ESI) m/z 516.0 (M - H) -. [00680] The synthesis of 9-(3-Aminopropyl)-6-chloro-N-(3,4-dichlorophenyl)-9H-carbazol-2- amine (100-2): A solution of tert-butyl 3-(6-chloro-2-(3,4-dichlorophenylamino)-9H-carbazol-9- yl)propylcarbamate (240 mg, 0.463 mmol) in TFA (10% in dichloromethane, 20 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and used for the next step directly. MS: (ESI) m/z 418.2 (M + H)+. [00681] The synthesis of (Z)-tert-Butyl (tert-butoxycarbonylamino)(3-(6-chloro-2-(3,4- dichlorophenylamino)-9H-carbazol-9-yl)propylamino)methylenecarbamate (100-3): 9-(3- aminopropyl)-6-chloro-N-(3,4-dichlorophenyl)-9H-carbazol-2-amine (194 mg, 0.463 mmol), tert- butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (144 mg, 0.463 mmol) and Et3N (94 mg, 0.925 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water (10 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The residue was purified by CC (petroleum ether/ ethyl acetate = 4/1) to give 240 mg of title compound in 78% yield as brown oil. MS: (ESI) m/z 660.2 (M + H) +. [00682] The synthesis of 1-(3-(6-Chloro-2-(3,4-dichlorophenylamino)-9H-carbazol-9- yl)propyl)guanidine (SRI-33257): A solution of (Z)-tert-butyl (tert-butoxycarbonylamino)(3-(6- chloro-2-(3,4-dichlorophenylamino)-9H-carbazol-9-yl)propylamino)methylenecarbamate (600 mg, 0.945 mmol) in TFA (10% in dichloromethane, 40 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and then purified by Prep-HPLC to give 120 mg title compound in 72% yield as a pale solid. [00683] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.29 (s, 0.5 H, formic acid), 8.09 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.33 (dd, J = 8.8, 2.4 Hz, 1H), 7.23-7.25 (m, 2H), 7.09 (dd, J = 8.8, 2.8 Hz, 1H), 6.94 (dd, J = 8.4, 2.0 Hz, 1H), 4.31 (t, J = 6.8 Hz, 2H), 3.07 (t, J = 6.8 Hz, 2H), 1.90-1.93 (m, 2H). MS: (ESI) m/z 460.2 (M + H) +. [00684] Example 62: [00686] The synthesis of 6-Chloro-N-phenyl-9H-carbazol-2-amine (97-2): 2-bromo-6-chloro-9H- carbazole (1.0 g, 3.56 mmol), aniline (399 mg, 4.28 mmol), tris(dibenzylideneacetone)dipalladium(0) (163 mg, 0.178 mmol), tert-butylbrett-Phos (173 mg, 0.357 mmol) and cesium carbonate (1.16 g, 3.56 mmol) were dissolved in tert-butanol (20 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by CC (petroleum ether/ethyl acetate = 20/1, 10/1, 5/1) to give 736 mg title compound in 66% yield as an off-white solid. [00687] 1H NMR (400 MHz, DMSO-d6) ^ 11.11 (s, 1H), 8.36 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.22-7.30 (m, 3H), 7.14-7.19 (m, 3H), 6.90 (dd, J = 8.4, 2.0 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H). MS: (ESI) m/z 291.2 (M - H) -. [00688] The synthesis of 3-Bromo-6-chloro-N-phenyl-9H-carbazol-2-amine (97-3): NBS (402 mg, 2.26 mmol, 1 eq) was added to a solution of 6-chloro-N-phenyl-9H-carbazol-2-amine (660 mg, 2.25 mmol, 1 eq) in dichloromethane (150 mL) at -20 °C. The reaction mixture was warmed to room temperature and stirred for 3 hours. The solvent was removed and the crude was purified by CC (petroleum ether/ethyl acetate = 10/1) to give 763 mg (a mixture of 97-3 and 97-3-by) title compound in 91% yield as a pale brown solid. MS: (ESI) m/z 369.0 (M - H) -. [00689] The synthesis of 6-Chloro-3-(3,4-dichlorophenyl)-N-phenyl-9H-carbazol-2-amine (97-4): The mixture of 3-bromo-6-chloro-N-phenyl-9H-carbazol-2-amine (763 mg, 2.05 mmol, 1 eq), (3,4- dichlorophenyl)boronic acid (392 mg, 2.05 mmol) and potassium carbonate (426 mg, 3.08 mmol) in DME (30 mL), water (10 mL) was heated at 80 °C for 16 hours. The mixture was cooled to room temperature. Concentrated and purified by CC (petroleum ether/ethyl acetate = 10/1) to give 455 mg 97-4 in 51% yield as a brown solid, 321 mg 97-4-by in 36% yield as a brown solid. [00690] 1H NMR (400 MHz, DMSO-d6) ^ 11.28 (s, 1H), 8.17 (d, J = 2.0 Hz, 1H), 8.15 (s, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.50 (dd, J = 8.2, 2.2 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.35 (s, 1H), 7.31 (dd, J = 8.6, 2.2 Hz, 1H), 7.16 (dd, J = 8.4, 7.6 Hz, 2H), 6.94 (d, J = 7.6 Hz, 2H), 6.75 (t, J = 7.2 Hz, 1H). MS: (ESI) m/z 435.0 (M - H) -. [00691] 1H NMR (400 MHz, DMSO-d6) ^ 10.86 (s, 1H), 8.13 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.38-7.42 (m, 3H), 7.29 (dd, J = 8.6, 2.2 Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H), 7.13 (dd, J = 8.4, 7.6 Hz, 2H), 6.89 (d, J = 7.6 Hz, 2H), 6.72 (t, J = 7.2 Hz, 1H). MS: (ESI) m/z 435.0 (M - H) -. [00692] The synthesis of tert-Butyl (2-(6-chloro-3-(3,4-dichlorophenyl)-2-(phenylamino)-9H- carbazol-9-yl)ethyl)carbamate (97-5): The mixture of 6-chloro-3-(3,4-dichlorophenyl)-N-phenyl-9H- carbazol-2-amine (200 mg, 0.457 mmol, 1 eq), tert-butyl (2-bromoethyl)carbamate (123 mg, 0.549 mmol) and cesium carbonate (447 mg, 1.37 mmol) in DMF (2 mL) was heated at 50 °C for 16 hours. The mixture was cooled to room temperature and quenched with water (40 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The solvent was removed and the crude was purified by CC (petroleum ether/ethyl acetate = 5/1) to give 197 mg title compound in 74% yield as a pale brown solid. [00693] 1H NMR (400 MHz, DMSO-d6) ^ 8.19-8.22 (m, 2H), 7.72 (d, J = 2.0 Hz, 1H), 7.67 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.43-7.49 (m, 2H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.13 (t, J = 7.8 Hz, 2H), 6.94 (d, J = 8.0 Hz, 2H), 6.89 (t, J = 5.8 Hz, 1H), 6.71 (t, J = 7.2 Hz, 1H), 4.34 (t, J = 5.4 Hz, 2H), 3.25-3.31 (m, 2H), 1.20 (s, 9H). MS: (ESI) m/z 578.0 (M - H) -. [00694] The synthesis of 9-(2-Aminoethyl)-6-chloro-3-(3,4-dichlorophenyl)-N-phenyl-9H- carbazol-2-amine (97-6): A solution of tert-butyl (2-(6-chloro-3-(3,4-dichlorophenyl)-2- (phenylamino)-9H-carbazol-9-yl)ethyl)carbamate (197 mg, 0.339 mmol) in TFA (10% in dichloromethane, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and used for the next step directly. [00695] The synthesis of (97-7): 9-(2-Aminoethyl)-6-chloro-3-(3,4-dichlorophenyl)-N-phenyl-9H- carbazol-2-amine (202 mg, 0.42 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1- yl)methylene)carbamate (131 mg, 0.42 mmol) and Et3N (85 mg, 0.84 mmol) in DMF (2 mL) was stirred at room temperature for 3 hours. The reaction was quenched with water (20 mL). The product was extracted with ethyl acetate (3x10 mL) and dried over Na2SO4. The residue was purified by Prep- TLC (petroleum ether/ ethyl acetate = 5/1) to give 212 mg of title compound in 70% yield as a pale brown solid. [00696] 1H NMR (400 MHz, DMSO-d6) ^ 11.37 (s, 1H), 8.49 (t, J = 5.8 Hz, 1H), 8.19-8.22 (m, 2H), 7.78 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.61 (s, 1H), 7.52 (s, 1H), 7.45 (dd, J = 8.2, 2.2 Hz, 1H), 7.32 (dd, J = 8.8, 2.0 Hz, 1H), 7.14 (t, J = 8.0 Hz, 2H), 6.96 (d, J = 8.0 Hz, 2H), 6.71 (t, J = 7.4 Hz, 1H), 4.44 (t, J = 6.6 Hz, 2H), 3.60-3.69 (m, 2H), 1.42 (s, 9H), 1.39 (s, 9H). MS: (ESI) m/z 722.2 (M + H) +. [00697] The synthesis of 1-(2-(6-Chloro-3-(3,4-dichlorophenyl)-2-(phenylamino)-9H-carbazol-9- yl)ethyl)guanidine (SRI-33258): A solution of 97-7 (212 mg, 0.293 mmol) in TFA (15% in dichloromethane, 15 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by Prep-HPLC to give 149.8 mg title compound in 97% yield as an off- white solid. [00698] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.39 (s, 0.09 H, formic acid), 8.21 (d, J = 2.0 Hz, 1H), 8.18 (s, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.49 (dd, J = 8.4, 2.0 Hz, 1H), 7.44 (dd, J = 8.8, 2.0 Hz, 1H), 7.42 (s, 1H), 7.18 (t, J = 8.0 Hz, 2H), 6.91 (d, J = 8.0 Hz, 2H), 6.78 (t, J = 7.2 Hz, 1H), 4.42 (t, J = 5.2 Hz, 2H), 3.62 (t, J = 5.4 Hz, 2H). MS: (ESI) m/z 522.2 (M + H) +. [00699] Example 63: [00700] Example Route for Example 63 (SRI-33259):
[00701] The synthesis of 6-Chloro-N-(3,4-dichlorophenyl)-9H-carbazol-2-amine (92-2): 2- Bromo-6-chloro-9H-carbazole (1.5 g, 5.34 mmol), 3,4-dichloroaniline (693 mg, 4.27 mmol), tris(dibenzylideneacetone)dipalladium(0) (300 mg, 0.32 mmol), tert-butylbrett-Phos (647 mg, 1.33 mmol) and cesium carbonate (3.47 g, 10.68 mmol) were dissolved in tert-butanol (30 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by Prep-TLC (petroleum ether/ethyl acetate = 2/1) to give 900 mg title compound in 46% yield as a brown oil. MS: (ESI) m/z 359.0 (M - H) -. [00702] The synthesis of 3-Bromo-6-chloro-N-(3,4-dichlorophenyl)-9H-carbazol-2-amine (92-3): NBS (265 mg, 1.49 mmol) was added to a solution of 6-chloro-N-(3,4-dichlorophenyl)-9H-carbazol- 2-amine (600 mg, 1.65 mmol) in dichloromethane (20 mL) at -20ºC- 0ºC. After stirring for 2 h, the reaction mixture was washed with brine, dried over Na2SO4, concentrated and purified by C.C (PE/EA 1/1) to give 500 mg of title compound in 68% yield as a brown solid. MS: (ESI) m/z 436.0 (M - H) –. [00703] The synthesis of 6-Chloro-N-(3,4-dichlorophenyl)-3-vinyl-9H-carbazol-2-amine (92-4): To a solution of 3-bromo-6-chloro-N-(3,4-dichlorophenyl)-9H-carbazol-2-amine (500 mg, 1.12 mmol) in DME and H2O (20 mL, 1,4-DME : H2O = 10:1) were added Pd(dppf)Cl2 (100 mg, 0.13 mmol), K2CO3 (232 mg, 1.68 mmol), and potassium vinyltrifluoroborate (152 mg, 1.12 mmol) under N2. After being stirred at 80 °C for 3 h, the reaction mixture was cooled to room temperature. EtOAc (100 mL) was added and organic layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified column chromatography (petroleum ether, petroleum ether/ethyl acetate = 2/1) to give 400 mg of title compound in 90% yield as a white solid. MS: (ESI) m/z 385.0 (M - H) -. [00704] The synthesis of tert-Butyl (2-(6-chloro-2-((3,4-dichlorophenyl)amino)-3-vinyl-9H- carbazol-9-yl)ethyl)carbamate (92-5): The mixture of 6-chloro-N-(3,4-dichlorophenyl)-3-vinyl-9H- carbazol-2-amine (300 mg, 0.77 mmol), tert-butyl (2-bromoethyl)carbamate (260 mg, 1.16 mmol) and potassium carbonate (212 mg, 1.54 mmol) in DMF (10 mL) was heated at 55 °C for 2 days. The mixture was cooled to room temperature and quenched with water (40 mL). The product was extracted with ethyl acetate (3x10 mL) and dried over Na2SO4. The solvent was removed to give 230 mg title compound in 56% yield as a brown solid. MS: (ESI) m/z 528.1 (M - H) -. [00705] The synthesis of tert-Butyl (2-(6-chloro-2-((3,4-dichlorophenyl)amino)-3-ethyl-9H- carbazol-9-yl)ethyl)carbamate (92-6): A suspension of tert-butyl (2-(6-chloro-2-((3,4- dichlorophenyl)amino)-3-vinyl-9H-carbazol-9-yl)ethyl)carbamate (100 mg, 0.18 mmol) and 25 mg of 10 percent palladium on carbon ethyl acetate (10 mL) is stirred vigorously under a low hydrogen pressure for 4 hours at room temperature. The solid was removed by filtration through diatomite and the filtrate was concentrated. The residue was purified by Prep-TLC (petroleum ether/ethyl acetate = 1/1) to give 90 mg of title compound in 89% yield as a pale brown oil. MS: (ESI) m/z 530.2 (M - H)-. [00706] The synthesis of 9-(2-Aminoethyl)-6-chloro-N-(3,4-dichlorophenyl)-3-ethyl-9H-carbazol- 2-amine (92-7): A solution of tert-butyl (2-(6-chloro-2-((3,4-dichlorophenyl)amino)-3-ethyl-9H- carbazol-9-yl)ethyl)carbamate (100 mg, 0.19 mmol) in TFA (5% in DCM, 5 mL) was stirred at room temperature overnight. The reaction solution was concentrated and used for the next step directly. [00707] The synthesis of (92-8): 9-(2-Aminoethyl)-6-chloro-N-(3,4-dichlorophenyl)-3-ethyl-9H- carbazol-2-amine (80 mg, 0.19 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1- yl)methylene)carbamate (57 mg, 0.19 mmol) and Et3N (38 mg, 0.38 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water (20 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The residue was purified by Prep- TLC (petroleum ether/ ethyl acetate = 1/1) to give 99 mg of title compound in 79% yield as a yellow solid. MS: (ESI) m/z 674.2 (M + H) +. [00708] The synthesis of 1-(2-(6-Chloro-2-((3,4-dichlorophenyl)amino)-3-ethyl-9H-carbazol-9- yl)ethyl)guanidine (SRI-33259): A solution of 92-8 (99 mg, 0.147 mmol) in TFA (15% in dichloromethane, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (39.4 mg, 56%) as a yellow solid. [00709] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.39 (s, 0.5H, formic acid), 8.19 (d, J = 2.0 Hz, 1H), 8.11 (s, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.43 (dd, J = 8.8, 2.4 Hz, 1H), 7.40 (s, 1H), 7.37 (d, J = 3.2 Hz, 1H), 7.00 (d, J = 2.8 Hz, 1H), 6.87 (dd, J = 8.8, 2.8 Hz, 1H), 4.41 (t, J = 5.2 Hz, 2H), 3.58 (t, J = 5.2 Hz, 2H), 2.71 (q, J = 7.6 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H). MS: (ESI) m/z 476.2 (M + H) +. [00710] Example 64: [00712] The synthesis of tert-Butyl 2-(2-bromo-6-chloro-9H-carbazol-9-yl)ethylcarbamate (99-1): To a solution of 2-bromo-6-chloro-9H-carbazole (1 g, 3.56 mmol) in DMF (20 mL) was added tert- butyl 2-bromoethylcarbamate (1.2 g, 5.35 mmol) and Cs2CO3 (2.32 g, 7.13 mmol). The mixture was stirred at 50 oC for 12 hours to give a yellow solution. The mixture was diluted with water (100 mL) and extracted with ethyl acetate(100 mL x 2), the combined organic layers were washed with saturated brine (100 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 10:1) to give 1.3 g of title compound in 86.07% yield as a white solid. [00713] 1H NMR (400 MHz, DMSO-d6) ^ 8.29 (d, J = 2.0 Hz, 2H), 8.14 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 1.2 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.48 (dd, J = 2.0, 8.8 Hz, 1H), 7.35 (dd, J = 1.6, 8.4 Hz, 1H), 6.91 (t, J = 6.0 Hz, 1H), 4.41 (t, J = 5.6 Hz, 2H), 3.28-3.34 (m, 2H) , 1.21 (s, 9H). MS: (ESI) m/z 421.0 (M - H) -. [00714] The synthesis of tert-Butyl 2-(6-chloro-2-(4,5-dichloropyridin-2-ylamino)-9H-carbazol-9- yl)ethylcarbamate (99-2): To a solution of tert-butyl 2-(2-bromo-6-chloro-9H-carbazol-9- yl)ethylcarbamate (300 mg, 708.0 μmol) in dioxane (20 mL) was added 4,5-dichloropyridin-2-amine (581.0 mg, 708.0 μmol), K3PO4 (450.9 mg, 2120 mmol), Xantphos (40.9 mg, 70.8 μmol) and Pd2(dba)3 (64.8 mg, 70.8 μmol). The mixture was stirred at 110 oC for 3 hours. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (300 mL x 2), the combined organic layers were washed with saturated brine (300 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 10:1) to give 220 mg of title compound in 61.4% yield as a white solid. MS: (ESI) m/z 503.0 (M - H)–. [00715] The synthesis of 9-(2-Aminoethyl)-6-chloro-N-(4,5-dichloropyridin-2-yl)-9H-carbazol-2- amine (99-3): To a solution of tert-butyl 2-(6-chloro-2-(4,5-dichloropyridin-2-ylamino)-9H-carbazol- 9-yl)ethylcarbamate (220 mg, 434.9 mmol) in DCM (2 mL) was added TFA (0.2 mL) and stirred at 25 oC for 16 hours. The reaction mixture was concentrated under reduced pressure to give 220 mg crude of title compound as a yellow solid. MS: (ESI) m/z 405.0 (M + H) +. [00716] The synthesis of (Z)-tert-Butyl (tert-butoxycarbonylamino)(2-(6-chloro-2-(4,5- dichloropyridin-2-ylamino)-9H-carbazol-9-yl)ethylamino)methylenecarbamate (99-4): To a solution of 9-(2-aminoethyl)-6-chloro-N-(4,5-dichloropyridin-2-yl)-9H-carbazol-2-amine (1220 mg, 402.0 μmol) in DMF (2 mL) was added (Z)-tert-butyl (1H-pyrazol-1-yl)methylenedicarbamate (274.5 mg, 884.4 μmol) and Et3N (122 mg, 1210 μmol). The mixture was stirred at 25 oC for 2 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2), the combined organic layers were washed with saturated brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 10:1) to give 200 mg of title compound in 59.9% yield as a white solid. MS: (ESI) m/z 647.2 (M + H) +. [00717] The synthesis of 1-(2-(6-Chloro-2-(4,5-dichloropyridin-2-ylamino)-9H-carbazol-9- yl)ethyl)guanidine (SRI-33260): To a solution of (Z)-tert-butyl (tert-butoxycarbonylamino)(2-(6- chloro-2-(4,5-dichloropyridin-2-ylamino)-9H-carbazol-9-yl)ethylamino)methylenecarbamate (200 mg, 308.7 mmol) in DCM (2 mL) was added TFA (0.2 mL) and stirred at 25 oC for 16 hours. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (70.56 mg, 51.06%) as a white solid. [00718] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.39 (s, 1H), 8.14 (d, J = 2.0 Hz, 1H), 8.07-8.11 (m, 2H), 7.57 (d, J = 8.8 Hz, 1H), 7.38 (dd, J = 1.6, 8.4 Hz, 1H), 7.29 (dd, J = 1.6, 8.4 Hz, 1H), 7.14 (s, 1H), 4.44 (t, J = 5.6 Hz, 2H) , 3.56 (m, 2H). MS: (ESI) m/z 447.0 (M + H) +. [00719] Example 65: [00720] Example Route for Example 65 (SRI-33261):
[00721] The synthesis of tert-Butyl (2-(6-chloro-1-(3,4-dichlorophenyl)-2-(phenylamino)-9H- carbazol-9-yl)ethyl)carbamate (103-2): The mixture of 6-chloro-1-(3,4-dichlorophenyl)-N-phenyl-9H- carbazol-2-amine (200 mg, 0.457 mmol, 1 eq), tert-butyl (2-bromoethyl)carbamate (123 mg, 0.549 mmol) and cesium carbonate (447 mg, 1.37 mmol) in DMF (2 mL) was heated at 50 °C for 30 hours. The mixture was cooled to room temperature and quenched with water (40 mL). The product was extracted with ethyl acetate (3x10 mL) and dried over Na2SO4. The solvent was removed and the crude was purified by CC (petroleum ether/ethyl acetate = 10/1) to give 220 mg title compound in 83% yield an off-white solid. [00722] 1H NMR (400 MHz, DMSO-d6) ^ 8.17 (d, J = 2.0 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 1.6 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.34-7.40 (m, 2H), 7.15 (d, J = 8.4 Hz, 1H), 7.13 (t, J = 7.8 Hz, 2H), 6.84-6.90 (m, 3H), 6.68-6.77 (m, 2H), 3.61-3.85 (m, 2H), 2.77- 2.85 (m, 2H), 1.21 (s, 9H). MS: (ESI) m/z 578.0 (M - H) -. [00723] The synthesis of 9-(2-Aminoethyl)-6-chloro-1-(3,4-dichlorophenyl)-N-phenyl-9H- carbazol-2-amine (103-3): A solution of tert-butyl (2-(6-chloro-1-(3,4-dichlorophenyl)-2- (phenylamino)-9H-carbazol-9-yl)ethyl)carbamate (220 mg, 0.379 mmol) in TFA (15% in dichloromethane, 10 mL) was stirred at room temperature for 3 hours. The reaction solution was concentrated and used for the next step directly. [00724] The synthesis of (103-4): 9-(2-Aminoethyl)-6-chloro-1-(3,4-dichlorophenyl)-N-phenyl- 9H-carbazol-2-amine (183 mg, 0.38 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1- yl)methylene)carbamate (119 mg, 0.38 mmol) and Et3N (77 mg, 0.76 mmol) in DMF (2 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water (20 mL). The product was extracted with ethyl acetate (3x10 mL) and dried over Na2SO4. The residue was purified by Prep- TLC (petroleum ether/ ethyl acetate = 10/1) to give 263 mg of title compound in 96% yield as a yellow solid. [00725] 1H NMR (400 MHz, DMSO-d6) ^ 11.20 (s, 1H), 8.15 (d, J = 2.0 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.99 (t, J = 6.0 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.42 (dd, J = 8.0, 2.0 Hz, 1H), 7.27 (dd, J = 8.8, 2.0 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 7.14 (t, J = 7.8 Hz, 2H), 6.87-6.92 (m, 3H), 6.75 (t, J = 7.2 Hz, 1H), 3.76-3.88 (m, 2H), 3.20-3.32 (m, 2H), 1.42 (s, 9H), 1.36 (s, 9H). MS: (ESI) m/z 722.3 (M + H) +. [00726] The synthesis of 1-(2-(6-Chloro-1-(3,4-dichlorophenyl)-2-(phenylamino)-9H-carbazol-9- yl)ethyl)guanidine (SRI-33261): A solution of 103-4 (263 mg, 0.364 mmol) in TFA (15% in dichloromethane, 15 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by Prep-HPLC to give 79 mg of title compound in 42% yield as an off- white solid. [00727] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.32 (s, 0.74 H, formic acid), 8.15-8.20 (m, 2H), 7.72 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.38-7.48 (m, 3H), 7.15-7.23 (m, 3H), 6.88 (d, J = 7.6 Hz, 2H), 6.81 (t, J = 7.2 Hz, 1H), 3.76-3.92 (m, 2H), 3.05-3.11 (m, 2H). MS: (ESI) m/z 522.2 (M + H) +. [00728] Example 66: [00730] The synthesis of 1,6-Dibromo-3-chloro-9H-carbazole (101-1): To a solution of 1,6-dibromo-9H-carbazole (1.5 g, 4.62 mmol) in DMF (15 mL) was added NCS (616.3 mg, 4.62 mmol) and the reaction was stirred at 50 oC for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA= 1:0 to 10:1) to give 1.0 g of title compound in 60.8% yield as a colorless solid. [00731] 1H NMR (400 MHz, DMSO-d6): δ 11.81 (s, 1H), 8.48 (d, J = 1.6 Hz, 1H), 8.38 (d, J = 1.6 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.61 (dd, J = 8.8, 2.0 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H). MS: (ESI) m/z 355.9 (M - H) -. [00732] The synthesis of tert-Butyl 2-(6-bromo-3-chloro-9H-carbazol-1-ylamino)ethylcarbamate (101-2b): To a solution of 1,6-dibromo-3-chloro-9H-carbazole (750 mg, 2.09 mmol) in t-BuOH (10 mL) was added tert-butyl 2-aminoethylcarbamate (334.3 mg, 2.09 mmol), Cs2CO3 (2.04 mg, 6.26 mmol), t- Bubrettphos (101.8 mg, 0.21 mmol) and Pd2(dba)3 (192.3 mg, 0.21 mmol). The mixture was stirred at 90 oC for 3 hours. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 2), the combined organic layers were washed with saturated brine (200 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA= 1:0 to 10:1) to give 240 mg of title compound in 26.22 % yield as a white solid. [00733] 1H NMR (400 MHz, DMSO-d6): δ 11.13 (s, 1H), 8.30 (d, J = 1.2 Hz, 1H), 7.46-7.52 (m, 3H), 6.97 (t, J = 5.2 Hz, 1H), 6.57 (s, 1H), 3.27-3.30 (m, 2H), 3.20-3.23 (m, 2H), 1.39 (s, 9H). MS: (ESI) m/z 436.0 (m-1)-. [00734] The synthesis of tert-Butyl 2-(3-chloro-6-(3,4-dichlorophenylamino)-9H-carbazol-1- ylamino)ethyl To a solution of tert-butyl 2-(6-bromo-3-chloro-9H-carbazol-1-ylamino)ethylcarbamate (190 mg, 0.43 mmol) in t-BuOH (3 mL) was added 3,4-dichloroaniline (70.2 mg, 0.43 mmol), Cs2CO3 (423.3 mg, 1.30 mmol), t-Bubrettphos (21 mg, 43.3 μmol) and Pd2(dba)3 (39.6 mg, 43.3 μmol). The mixture was stirred at 90 oC for 3 hours. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 2), the combined organic layers were washed with saturated brine (30 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA= 1:0 to 10:1) to give 40 mg of title compound in 17.77% yield as a white solid. [00735] 1H NMR (400 MHz, DMSO-d6): δ 10.90 (s, 1H), 8.32 (s, 1H), 7.82 (d, J = 1.6 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 1.6 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.18 (dd, J = 2.0, 8.8 Hz, 1H), 6.96-6.99 (m, 2H), 6.87 (dd, J = 2.4, 8.8 Hz, 1H), 6.53 (d, J = 1.6 Hz, 1H), 3.27-3.3 (m, 2H), 3.20-3.23 (m, 2H), 1.39 (s, 9H). [00736] The synthesis of N1-(2-Aminoethyl)-3-chloro-N6-(3,4-dichlorophenyl)-9H-carbazole-1,6- diamine (101-4): To a solution of tert-butyl 2-(3-chloro-6-(3,4-dichlorophenylamino)-9H-carbazol-1- ylamino)ethylcarbamate(40 mg, 76.95 mmol) in DCM (1 mL) was added TFA (0.2 mL) and stirred at 25 oC for 1 hour. The reaction mixture was concentrated under reduced pressure to give 40 mg crude of title compound as a yellow solid. MS: (ESI) m/z 419.0 (M + H)+. [00737] The synthesis of (Z)-tert-Butyl (tert-butoxycarbonylamino)(2-(3-chloro-6-(3,4- dichlorophenylamino)-9H-carbazol-1-ylamino)ethylamino)methylenecarbamate (101-5): To a solution of N1-(2-aminoethyl)-3-chloro-N6-(3,4-dichlorophenyl)-9H-carbazole-1,6-diamine (40 mg, 95.3 μmol) in DMF (1 mL) was added (Z)-tert-butyl (1H-pyrazol-1-yl)methylenedicarbamate (32.53 mg, 104.8 μmol) and Et3N (28.9 mg, 285.9 μmol). The mixture was stirred at 25 oC for 2 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2), the combined organic layers were washed with saturated brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA= 1:0 to 10:1) to give 40 mg of title compound in 63.4% yield as a white solid. MS: (ESI) m/z 661.1 (M + H) +. [00738] The synthesis of 1-(2-(3-Chloro-6-(3,4-dichlorophenylamino)-9H-carbazol-1- ylamino)ethyl)guanidine (SRI-33262): To a solution of (Z)-tert-butyl (tert-butoxycarbonylamino)(2-(3-chloro-6-(3,4-dichlorophenylamino)- 9H-carbazol-1-ylamino)ethylamino)methylenecarbamate (40 mg, 60.42 mmol) in DCM (2 mL) was added TFA (0.2 mL) and stirred at 25 oC for 16 hours. The reaction solution was concentrated and purified by Prep-HPLC to provide the title compound (18.82 mg, 67.45%) as a white solid. [00739] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 7.83 (d, J = 2.0 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.21 (dd, J = 2.0, 8.4 Hz, 1H), 7.02 (d, J = 2.8 Hz, 1H), 6.90 (dd, J = 2.8, 9.2 Hz, 1H), 6.58 (d, J = 2.0 Hz, 1H), 3.42-3.44 (m, 4H). MS: (ESI) m/z 461.0 (M + H)+. [00740] Example 67: [00742] The synthesis of N3,N6-Bis(3,4-dichlorophenyl)-9H-carbazole-3,6-diamine (104-2): 3,6- dibromo-9H-carbazole (1.30 g, 4.00 mmol), 3,4-dichloroaniline (1.30 g, 8.00 mmol), tris(dibenzylideneacetone)dipalladium(0) (732 mg, 0.80 mmol), tert-butylbrett-Phos (774 mg, 1.60 mmol) and cesium carbonate (5.21 g, 16.00 mmol) were dissolved in tert-butanol (60 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 6 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by CC (petroleum ether/ethyl acetate = 8/1) to give 1.20 g title compound in 62% yield as a pale brown solid. MS: (ESI) m/z 486.0 (M + H) +. [00743] The synthesis of tert-Butyl 2-(3,6-bis(3,4-dichlorophenylamino)-9H-carbazol-9- yl)ethylcarbamate (104-3): The mixture of N3,N6-bis(3,4-dichlorophenyl)-9H-carbazole-3,6-diamine (244 mg, 0.50 mmol), tert-butyl (2-bromoethyl)carbamate (135 mg, 0.60 mmol) and cesium carbonate (326 mg, 1.00 mmol) in DMF (10 mL) was heated at 90 °C for 5 hours. The mixture was cooled to room temperature and quenched with water (20 mL), extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The residue was purified by Prep-TLC (petroleum ether/ ethyl acetate = 3/2). The mixture was filtrated, washed by water and then concentrated to give 60 mg of title compound in 19% yield as a brown solid. MS: (ESI) m/z 629.0 (M + H) +. [00744] The synthesis of 9-(2-Aminoethyl)-N3,N6-bis(3,4-dichlorophenyl)-9H-carbazole-3,6- diamine (104-4): A solution of tert-butyl 2-(3,6-bis(3,4-dichlorophenylamino)-9H-carbazol-9- yl)ethylcarbamate (60 mg, 0.095 mmol) in TFA (10% in dichloromethane, 5 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and used for the next step directly. [00745] The synthesis of tert-Butyl (2-(3,6-bis(3,4-dichlorophenylamino)-9H-carbazol-9- yl)ethylamino)(tert-butoxycarbonylamino)methylenecarbamate (104-5): 9-(2-aminoethyl)-N3,N6- bis(3,4-dichlorophenyl)-9H-carbazole-3,6-diamine (51 mg, 0.095 mmol), tert-butyl (((tert- butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (30 mg, 0.095 mmol) and Et3N (30 mg, 0.190 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water (10 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The residue was purified by Prep-TLC (petroleum ether/ ethyl acetate = 4/1) to give 40 mg of title compound in 73% yield as brown oil. MS: (ESI) m/z 771.0 (M + H) +. [00746] The synthesis of 1-(2-(3,6-Bis(3,4-dichlorophenylamino)-9H-carbazol-9- yl)ethyl)guanidine (SRI-33263): A solution of tert-butyl (2-(3,6-bis(3,4-dichlorophenylamino)-9H- carbazol-9-yl)ethylamino)(tert-butoxycarbonylamino)methylenecarbamate (40 mg, 0.052 mmol) in TFA (10% in dichloromethane, 5 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and then purified by Prep-HPLC to give 13 mg the title compound in 44% yield as a pale blue solid. [00747] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.43 (s, 0.76H, formic acid), 7.93 (s, 2H), 7.57 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.8 Hz, 2H), 7.27 (dd, J = 8.8, 2.0 Hz, 2H), 7.03 (d, J = 2.8 Hz, 2H), 6.89 (dd, J = 8.8, 2.4 Hz, 2H), 4.48 (t, J = 5.2 Hz, 2H), 3.55-3.57 (m, 2H). MS: (ESI) m/z 571.0 (M + H) +. [00748] Example 68: [00749] Example Route for Example 68 (SRI-33273): [00750] The synthesis of 6-Chloro-N-(3,4-dichlorobenzyl)-9H-carbazol-2-amine (109-1): To a solution of 2-bromo-6-chloro-9H-carbazole (500 mg, 1.78 mmol) in t-BuOH (5 mL) was added (3,4- dichlorophenyl)methanamine (313.7 mg, 1.78 mmol), Cs2CO3 (1742 mg, 5.4 mmol), t-Bubrettphos (86 mg, 0.18 mmol) and Pd2(dba)3 (163 mg, 0.18 mmol). The mixture was stirred at 90 oC for 3 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2), the combined organic layers were washed with saturated brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA = 1:0 to 10:1) to give 245 mg of title compound in 36.3% yield as a white solid. [00751] 1H NMR (400 MHz, DMSO-d6) ^ 10.91 (s, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.14 (dd, J = 2.4, 8.4 Hz, 1H), 6.60-6.63 (m, 1H), 6.56 (d, J = 8.8 Hz, 1H) , 6.41 (d, J = 2.0 Hz, 1H). MS: (ESI) m/z 373.0 (M - H)-. [00752] The synthesis of tert-Butyl 2-(6-chloro-2-(3,4-dichlorobenzylamino)-9H-carbazol-9- yl)ethylcarbamate (109-2): To a solution of 6-chloro-N-(3,4-dichlorobenzyl)-9H-carbazol-2-amine (230 mg, 0.61 mmol) in DMF (5 mL) was added tert-butyl 2-bromoethylcarbamate (137.2 mg, 0.61 mmol) and Cs2CO3 (598.4 mg, 1.84 mmol). The mixture was stirred at 50 oC for 12 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2), the combined organic layers were washed with saturated brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA = 1:0 to 10:1) to give 150 mg of title compound in 47.22% yield as a white solid. MS: (ESI) m/z 516.0 (M - H) -. [00753] The synthesis of 9-(2-Aminoethyl)-6-chloro-N-(3,4-dichlorobenzyl)-9H-carbazol-2-amine (109-3): To a solution of tert-butyl 2-(6-chloro-2-(3,4-dichlorobenzylamino)-9H-carbazol-9- yl)ethylcarbamate (150 mg, 0.29 mmol) in DCM (2 mL) was added TFA (0.4 mL) and stirred at 25 oC for 1 hour. The reaction mixture was concentrated under reduced pressure to give 150 mg crude of title compound as a yellow solid. MS: (ESI) m/z 418.0 (M + H) +. [00754] The synthesis of tert-Butyl (tert-butoxycarbonylamino)(2-(6-chloro-2-(3,4- dichlorobenzylamino)-9H-carbazol-9-yl)ethylamino)methylenecarbamate (109-4): To a solution of 9- (2-aminoethyl)-6-chloro-N-(3,4-dichlorobenzyl)-9H-carbazol-2-amine (150 mg, 0.36 mmol) in DMF (2 mL) was added (Z)-tert-butyl (1H-pyrazol-1-yl)methylenedicarbamate (133.4 mg, 0.43 mmol) and Et3N (1 mL). The mixture was stirred at 25 oC for 16 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate(20 mL x 2), the combined organic layers were washed with saturated brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA= 1:0 to 10:1) to give 150 mg of title compound in 63.35% yield as a white solid. MS: (ESI) m/z 660.2(M + H) +. [00755] The synthesis of 1-(2-(6-Chloro-2-(3,4-dichlorobenzylamino)-9H-carbazol-9- yl)ethyl)guanidine (SRI-33273): To a solution of tert-butyl (tert-butoxycarbonylamino)(2-(6-chloro-2- (3,4-dichlorobenzylamino)-9H-carbazol-9-yl)ethylamino)methylenecarbamate (150 mg, 0.23 mmol) in DCM (2 mL) was added TFA (0.2 mL) and stirred at 25 oC for 48 hours. The reaction solution was concentrated and purified by Prep-HPLC to provide the title compound (47.42 mg, 45%) as a white solid. [00756] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 7.94 (d, J = 2.0 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 1.6 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.43 (dd, J = 1.6, 8.4 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 7.23 (dd, J = 2.0, 8.8 Hz, 1H), 6.60 (dd, J = 1.6, 8.4 Hz, 1H), 6.54 (s, 1H) , 4.41 (s, 2H) , 4.29-4.32 (m, 2H) , 3.51-3.54 (m, 2H). MS: (ESI) m/z 460.2 (M + H) +. [00757] Example 69: [00759] The synthesis of tert-Butyl 2-(3-bromo-6-chloro-9H-carbazol-9-yl)ethylcarbamate (108- a):The mixture of 3-bromo-6-chloro-9H-carbazole (278 mg, 0.99 mmol), tert-butyl (2- bromoethyl)carbamate (222 mg, 0.99 mmol) and cesium carbonate (646 mg, 1.98 mmol) in DMF (15 mL) was heated at 50 °C for 16 hours. The mixture was cooled to room temperature and quenched with water (30 mL). The mixture was filtrated, washed by water and then concentrated to give 342 mg of title compound in 81% yield as a brown solid. MS: (ESI) m/z 367.0 (M -56+ H) +. [00760] The synthesis of tert-Butyl 2-(3-chloro-6-(3,4-dichlorobenzylamino)-9H-carbazol-9- yl)ethylcarbamate (108-2): tert-butyl 2-(3-bromo-6-chloro-9H-carbazol-9-yl)ethylcarbamate (342 mg, 0.807 mmol), (3,4-dichlorophenyl)methanamine (142 mg, 0.807 mmol), tris(dibenzylideneacetone)dipalladium(0) (74 mg, 0.081 mmol), tert-butylbrett-Phos (78 mg, 0.161 mmol) and cesium carbonate (526 mg, 1.61 mmol) were dissolved in tert-butanol (30 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 2 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by Prep-TLC (petroleum ether/ethyl acetate = 3/1) to give 200 mg title compound in 48% yield as a yellow solid. MS: (ESI) m/z 518.1 (M + H) +. [00761] The synthesis of 9-(2-Aminoethyl)-6-chloro-N-(3,4-dichlorobenzyl)-9H-carbazol-3-amine (108-3): A solution of tert-butyl 2-(3-chloro-6-(3,4-dichlorobenzylamino)-9H-carbazol-9- yl)ethylcarbamate (200 mg, 0.385 mmol) in TFA (10% in dichloromethane, 15 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and used for the next step directly. MS: (ESI) m/z 418.0 (M + H) +. [00762] The synthesis of tert-Butyl (tert-butoxycarbonylamino)(2-(3-chloro-6-(3,4- dichlorobenzylamino)-9H-carbazol-9-yl)ethylamino)methylenecarbamate (108-4): 9-(2-aminoethyl)- 6-chloro-N-(3,4-dichlorobenzyl)-9H-carbazol-3-amine (161 mg, 0.385 mmol), tert-butyl (((tert- butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (120 mg, 0.385 mmol) and Et3N (78 mg, 0.771 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water (10 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The residue was purified by CC (petroleum ether/ ethyl acetate = 4/1) to give 200 mg of title compound in 78% yield as a white solid. MS: (ESI) m/z 660.0 (M + H) +. [00763] The synthesis of 1-(2-(3-Chloro-6-(3,4-dichlorobenzylamino)-9H-carbazol-9- yl)ethyl)guanidine (SRI-33274): A solution of tert-butyl (tert-butoxycarbonylamino)(2-(3-chloro-6- (3,4-dichlorobenzylamino)-9H-carbazol-9-yl)ethylamino)methylenecarbamate (200 mg, 0.303 mmol) in TFA (10% in dichloromethane, 15 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and then purified by Prep-HPLC to give 84 mg title compound in 60% yield as a pale green solid. [00764] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.07 (d, J = 2.0 Hz, 1 H), 7.68 (d, J = 1.6 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.45 (dd, J = 8.4, 2.0 Hz, 1H), 7.37 (d, J = 1.6 Hz, 1H), 7.35 (d, J = 1.6 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 6.92 (dd, J = 8.0, 2.0 Hz, 1H), 4.38-4.40 (m, 4H) , 3.54 (t, J = 5.6 Hz, 2H). MS: (ESI) m/z 460.3 (M + H)+. [00765] Example 70: [00767] The synthesis of 6-Bromo-9H-pyrido[3,4-b]indole (116-2): To a solution of 9H- pyrido[3,4-b]indole (500 mg, 2.97 mmol) in DMF (10 mL) was added NBS (529 mg, 2.97 mmol) and stirred at 25 oC for 1 hour. The mixture was diluted with water (100 mL) and extracted with ethyl acetate(100 mL x 2), the combined organic layers were washed with saturated brine (100 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA = 1:0 to 3:1) to give 340 mg of title compound in 46.29% yield as a white solid. [00768] 1H NMR (400 MHz, DMSO-d6) ^ 11.80 (s, 1H), 8.94 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.37 (d, J = 5.2 Hz, 1H), 8.17 (d, J = 5.2 Hz, 1H), 7.67 (dd, J = 2.0, 8.4 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H). MS: (ESI) m/z 245.0 (M - H) -. [00769] The synthesis of N-(3,4-Dichlorophenyl)-9H-pyrido[3,4-b]indol-6-amine (116-3): 6- bromo-9H-pyrido[3,4-b]indole (320 mg, 1.30 mmol), 3,4-dichloroaniline (32.8 mg, 1.3 mmol), Pd2(dba)3 (119 mg, 0.13 mmol), t-Bubrettphos (63 mg, 0.13 mmol) and Cs2CO3 (1.27 g, 3.9 mmol) were dissolved in t-BuOH (10 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by CC (petroleum ether/ethyl acetate = 3/2) to give 230 mg title compound in 54.11% yield as a brown solid. MS: (ESI) m/z 326.2 (M - H)-. [00770] The synthesis of tert-Butyl 2-(6-(3,4-dichlorophenylamino)-9H-pyrido[3,4-b]indol-9- yl)ethylcarbamate (116-4): The mixture of N-(3,4-dichlorophenyl)-9H-pyrido[3,4-b]indol-6-amine (210 mg, 0.64 mmol), tert-butyl (2-bromoethyl)carbamate (143.39 mg, 0.64 mmol) and Cs2CO3 (625.4 mg, 1.92 mmol) in DMF (3 mL) was heated at 50 °C for 16 hours. The mixture was cooled to room temperature and quenched with water (30 mL). The product was extracted with ethyl acetate (3x10 mL) and dried over Na2SO4. The solvent was removed and the crude was purified by CC (petroleum ether/ethyl acetate = 1/1) to give 150 mg title compound in 49.7% yield as a white solid. MS: (ESI) m/z 469.2 (M - H)-. [00771] The synthesis of 9-(2-Aminoethyl)-N-(3,4-dichlorophenyl)-9H-pyrido[3,4-b]indol-6- amine (116-5): A solution of tert-butyl 2-(6-(3,4-dichlorophenylamino)-9H-pyrido[3,4-b]indol-9- yl)ethylcarbamate (150 mg, 0.29 mmol) in TFA (20% in dichloromethane, 10 mL) was stirred at room temperature for 1 hour. The reaction solution was concentrated and used for the next step directly. [00772] The synthesis of (Z)-tert-Butyl (tert-butoxycarbonylamino)(2-(6-(3,4- dichlorophenylamino)-9H-pyrido[3,4-b]indol-9-yl)ethylamino)methylenecarbamate (116-6): 9-(2- aminoethyl)-N-(3,4-dichlorophenyl)-9H-pyrido[3,4-b]indol-6-amine (150 mg, 0.41 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (150.5 mg, 0.49 mmol) and Et3N (1 mL) in DMF (2 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water (10 mL). The product was extracted with ethyl acetate (3 x 10 mL), dried over Na2SO4. The residue was purified by CC (petroleum ether/ethyl acetate = 2/1) to give 130 mg of title compound in 52.44% yield as a pale brown solid. MS: (ESI) m/z 613.2 (M + H) +. [00773] The synthesis of 1-(2-(6-(3,4-Dichlorophenylamino)-9H-pyrido[3,4-b]indol-9- yl)ethyl)guanidine (SRI-33284): A solution of (Z)-tert-butyl (tert-butoxycarbonylamino)(2-(6-(3,4- dichlorophenylamino)-9H-pyrido[3,4-b]indol-9-yl)ethylamino)methylenecarbamate (130 mg, 0.21 mmol) in TFA (15% in dichloromethane, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (50.46 mg, 57.62%) as a yellow solid. [00774] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 9.28 (s, 1H), 8.73 (d, J = 6.0 Hz, 1H), 8.51 (d, J = 6.4 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 7.83 (d, J = 9.2 Hz, 1H), 7.66 (dd, J = 2.0, 8.8 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 2.8 Hz, 1H), 7.07 (dd, J = 2.8, 8.8 Hz, 1H), 4.73 (t, J = 4.8 Hz, 2H), 3.72 (t, J = 4.8 Hz, 2H). MS: (ESI) m/z 413.4 (M + H) +. [00775] Example 71: [00777] The synthesis of 6-Bromo-9H-pyrido[2,3-b]indole (115-2): NBS (1.48 g, 8.32 mmol, 0.7 eq) was added to a mixture of 9H-pyrido[2,3-b]indole (2.0 g, 11.89 mmol, 1 eq) in dichloromethane (200 mL) at room temperature. After stirring for 16 h, the solid was collected by filtration to give 1.76 g of title compound in 60% yield as a pale brown solid. [00778] 1H NMR (400 MHz, DMSO-d6) ^ 11.98 (s, 1H), 8.57 (dd, J = 7.8, 2.6 Hz, 1H), 8.46 (dd, J = 5.0, 1.4 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H), 7.58 (dd, J = 8.4, 2.0 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.24 (dd, J = 7.8, 4.6 Hz, 1H). MS: (ESI) m/z 245.0 (M - H) -. [00779] The synthesis of N-(3,4-Dichlorophenyl)-9H-pyrido[2,3-b]indol-6-amine (115-3): 6- bromo-9H-pyrido[2,3-b]indole (600 mg, 2.43 mmol), 3,4-dichloroaniline (394 mg, 2.43 mmol), tris(dibenzylideneacetone)dipalladium(0) (112 mg, 0.12 mmol), tert-butylbrett-Phos (118 mg, 0.23 mmol) and cesium carbonate (792 mg, 2.43 mmol) were dissolved in tert-butanol (10 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by CC (petroleum ether/ethyl acetate = 3/2) to give 450 mg title compound in 56% yield as a brown solid. [00780] 1H NMR (400 MHz, DMSO-d6) ^ 11.75 (s, 1H), 8.51 (dd, J = 7.6, 1.2 Hz, 1H), 8.41 (dd, J = 4.8, 1.6 Hz, 1H), 8.38 (s, 1H), 7.97 (d, J = 1.6 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.27 (dd, J = 8.6, 2.2 Hz, 1H), 7.18 (dd, J = 7.8, 4.6 Hz, 1H), 7.04 (d, J = 2.8 Hz, 1H), 6.90 (dd, J = 8.8, 2.4 Hz, 1H). MS: (ESI) m/z 328.2 (M + H) +. [00781] The synthesis of tert-Butyl (2-(6-((3,4-dichlorophenyl)amino)-9H-pyrido[2,3-b]indol-9- yl)ethyl)carbamate (115-4): The mixture of N-(3,4-dichlorophenyl)-9H-pyrido[2,3-b]indol-6-amine (250 mg, 0.76 mmol), tert-butyl (2-bromoethyl)carbamate (205 mg, 0.91 mmol) and cesium carbonate (745 mg, 2.29 mmol) in DMF (3 mL) was heated at 50 °C for 16 hours. The mixture was cooled to room temperature and quenched with water (30 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The solvent was removed and the crude was purified by CC (petroleum ether/ethyl acetate = 1/1) to give 317 mg title compound in 88% yield as a brown solid. [00782] 1H NMR (400 MHz, DMSO-d6) ^ 8.54 (dd, J = 7.6, 1.2 Hz, 1H), 8.45 (dd, J = 5.0, 1.4 Hz, 1H), 8.42 (s, 1H), 7.99 (d, J = 1.6 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.33 (dd, J = 8.8, 2.0 Hz, 1H), 7.22 (dd, J = 7.4, 5.0 Hz, 1H), 7.04 (d, J = 2.4 Hz, 1H), 6.97 (t, J = 5.8 Hz, 1H), 6.90 (dd, J = 8.8, 2.4 Hz, 1H), 4.48 (t, J = 6.0 Hz, 2H), 3.34-3.39 (m, 2H), 1.29 (s, 9H). MS: (ESI) m/z 471.2 (M + H) +. [00783] The synthesis of 9-(2-Aminoethyl)-N-(3,4-dichlorophenyl)-9H-pyrido[2,3-b]indol-6- amine (115-5): A solution of tert-butyl (2-(6-((3,4-dichlorophenyl)amino)-9H-pyrido[2,3-b]indol-9- yl)ethyl)carbamate (317 mg, 0.67 mmol) in TFA (20% in dichloromethane, 10 mL) was stirred at room temperature for 1 hour. The reaction solution was concentrated and used for the next step directly. [00784] The synthesis of (115-6): 9-(2-Aminoethyl)-N-(3,4-dichlorophenyl)-9H-pyrido[2,3- b]indol-6-amine (250 mg, 0.67 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1- yl)methylene)carbamate (209 mg, 0.67 mmol) and Et3N (137 mg, 1.35 mmol) in DMF (2 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water (10 mL). The product was extracted with ethyl acetate (3 x 10 mL), dried over Na2SO4. The residue was purified by CC (petroleum ether/ethyl acetate = 2/1) to give 332 mg of title compound in 80% yield as a pale brown solid. [00785] 1H NMR (400 MHz, DMSO-d6) ^ 11.38 (s, 1H), 8.49-8.55 (m, 2H), 8.43 (dd, J = 5.0, 1.4 Hz, 1H), 8.41 (s, 1H), 7.98 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.28 (dd, J = 8.6, 2.2 Hz, 1H), 7.20 (dd, J = 7.6, 4.8 Hz, 1H), 7.05 (d, J = 2.8 Hz, 1H), 6.90 (dd, J = 8.0, 2.6 Hz, 1H), 4.63 (t, J = 6.2 Hz, 2H), 3.72 (q, J = 6.0 Hz, 2H), 1.42 (s, 9H), 1.39 (s, 9H). MS: (ESI) m/z 613.2 (M + H) +. [00786] The synthesis of 1-(2-(6-((3,4-Dichlorophenyl)amino)-9H-pyrido[2,3-b]indol-9- yl)ethyl)guanidine (SRI-33291): A solution of 115-6 (332 mg, 0.54 mmol) in TFA (15% in dichloromethane, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (201 mg, 90%) as a yellow solid. [00787] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.54 (dd, J = 7.8, 1.4 Hz, 1H), 8.48 (dd, J = 4.8, 1.2 Hz, 1H), 7.98 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.36 (dd, J = 8.4, 2.0 Hz, 1H), 7.28 (dd, J = 7.6, 4.8 Hz, 1H), 7.07 (d, J = 2.4 Hz, 1H), 6.96 (dd, J = 8.8, 2.8 Hz, 1H), 4.56 (t, J = 6.4 Hz, 2H), 3.53 (t, J = 6.4 Hz, 2H). MS: (ESI) m/z 413.2 (M + H) +. [00788] Example 72: [00790] The synthesis of tert-Butyl (2-(6-bromo-3,4-dihydro-1H-carbazol-9(2H)- yl)ethyl)carbamate (112-2): NaH (96 mg, 2.4 mmol, 3.0 eq) was added to a mixture of 6-bromo- 2,3,4,9-tetrahydro-1H-carbazole (200 mg, 0.80 mmol, 1 eq) in DMF (2 mL) at room temperature. After stirring for 15 minutes, tert-butyl (2-bromoethyl)carbamate (180 mg, 0.80 mmol) was added. The mixture was stirred for 4 hours and quenched with water (10 mL). The product was extracted with ethyl acetate (3 x 20 mL), dried over Na2SO4. The solvent was removed and the crude was purified by Prep-TLC (petroleum ether/ethyl acetate = 5/1) to give 165 mg title compound in 52% yield as pale brown oil. [00791] 1H NMR (400 MHz, DMSO-d6) ^ 7.51 (d, J = 1.6 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 7.15 (dd, J = 8.6, 1.8 Hz, 1H), 6.94 (t, J = 6.0 Hz, 1H), 4.07 (t, J = 6.2 Hz, 2H), 3.15 (q, J = 6.0 Hz, 2H), 2.66-2.72 (m, 2H), 2.56-2.62 (m, 2H), 1.72-1.89 (m, 4H), 1.34 (s, 9H). MS: (ESI) m/z 393.2 (M + H)+. [00792] The synthesis of tert-Butyl (2-(6-((3,4-dichlorophenyl)amino)-3,4-dihydro-1H-carbazol- 9(2H)-yl)ethyl)carbamate (112-3): tert-butyl (2-(6-bromo-3,4-dihydro-1H-carbazol-9(2H)- yl)ethyl)carbamate (165 mg, 0.42 mmol), 3,4-dichloroaniline (68 mg, 0.42 mmol), tris(dibenzylideneacetone)dipalladium(0) (39 mg, 0.043 mmol), tert-butylbrett-Phos (41 mg, 0.085 mmol) and cesium carbonate (410 mg, 1.26 mmol) were dissolved in tert-butanol (4 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by Prep-TLC (petroleum ether/ethyl acetate = 4/1, dichloromethane) to give 101 mg title compound in 51% yield as an off-white solid. [00793] 1H NMR (400 MHz, DMSO-d6) ^ 8.16 (s, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 1.6 Hz, 1H), 6.97 (t, J = 5.6 Hz, 1H), 6.92 (d, J = 2.8 Hz, 1H), 6.87 (dd, J = 8.6, 1.8 Hz, 1H), 6.78 (dd, J = 8.8, 2.4 Hz, 1H), 4.07 (t, J = 6.4 Hz, 2H), 3.16 (q, J = 6.0 Hz, 2H), 2.65- 2.72 (m, 2H), 2.53-2.61 (m, 2H), 1.73-1.89 (m, 4H), 1.37 (s, 9H). MS: (ESI) m/z 472.2 (M - H) -. [00794] The synthesis of 9-(2-Aminoethyl)-N-(3,4-dichlorophenyl)-2,3,4,9-tetrahydro-1H- carbazol-6-amine (112-4): The mixture of tert-butyl (2-(6-((3,4-dichlorophenyl)amino)-3,4-dihydro- 1H-carbazol-9(2H)-yl)ethyl)carbamate (101 mg, 0.21 mmol) in TFA (10% in dichloromethane, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and used for the next step directly. [00795] The synthesis of (112-5): 9-(2-Aminoethyl)-N-(3,4-dichlorophenyl)-2,3,4,9-tetrahydro- 1H-carbazol-6-amine (80 mg, 0.21 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1- yl)methylene)carbamate (67 mg, 0.22 mmol) and Et3N (65 mg, 0.64 mmol) in DMF (2 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water (10 mL). The product was extracted with ethyl acetate (3 x 10 mL) and dried over Na2SO4. The residue was purified by CC (petroleum ether/ethyl acetate = 5/1, dichloromethane) to give 130 mg of title compound in 99% yield as a white solid. [00796] 1H NMR (400 MHz, DMSO-d6) ^ 11.42 (s, 1H), 8.48 (t, J = 5.8 Hz, 1H), 8.15 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.09 (d, J = 1.6 Hz, 1H), 6.94 (d, J = 2.8 Hz, 1H), 6.85 (dd, J = 8.6, 1.8 Hz, 1H), 6.79 (dd, J = 8.8, 2.4 Hz, 1H), 4.16 (t, J = 6.8 Hz, 2H), 3.52 (q, J = 6.8 Hz, 2H), 2.70-2.76 (m, 2H), 2.54-2.60 (m, 2H), 1.73-1.90 (m, 4H), 1.46 (s, 9H), 1.43 (s, 9H). MS: (ESI) m/z 616.3 (M + H) +. [00797] The synthesis of 1-(2-(6-((3,4-Dichlorophenyl)amino)-3,4-dihydro-1H-carbazol-9(2H)- yl)ethyl)guanidine (SRI-33292): A solution of 112-5 (130 mg, 0.21 mmol) in TFA (15% in dichloromethane, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and basified with NaOH (10%). The product was extracted with ethyl acetate (3 x 10 mL), dried over Na2SO4, concentrated. The residue was purified by Prep-HPLC to provide the title compound (35.7 mg, 41%) as an off-white solid. [00798] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.38 (s, 1H, formic acid), 7.36 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 1.6 Hz, 1H), 6.95 (d, J = 2.4 Hz, 1H), 6.91 (dd, J = 8.6, 1.8 Hz, 1H), 6.83 (dd, J = 9.0, 2.6 Hz, 1H), 4.16 (t, J = 5.6 Hz, 2H), 3.48 (t, J = 5.6 Hz, 2H), 2.65-2.71 (m, 2H), 2.55-2.61 (m, 2H), 1.74-1.91 (m, 4H). MS: (ESI) m/z 416.4 (M + H) +. [00799] Example 73: [00801] The synthesis of 2-Bromoacridin-9(10H)-one (119-2): To a solution of acridin-9(10H)- one (3.9 g, 20.08 mmol) in DMF (60 mL) was added NBS (3.57 g, 20.08 mmol) in portions and stirred at room temperature for 16 hours. The reaction mixture was filtrated, washed by ethyl acetate and then concentrated to give 4.50 g of title compound in 82% yield as a yellow solid. MS: (ESI) m/z 274.0 (M + H) +. [00802] The synthesis of 2-Bromo-9-chloroacridine (119-3): A solution of 2-bromoacridin- 9(10H)-one (15.50 g, 56.55 mmol) in SOCl2 (80 mL) was stirred at 80 °C for 4 hours. The reaction solution was concentrated and then the mixture was diluted with water (500 mL), basified with 2N NaOH to pH=7. The product was extracted with ethyl acetate (3x500 mL), dried over Na2SO4 and then concentrated to give 10.00 g of title compound in 60% yield as a yellow solid. MS: (ESI) m/z 292.0 (M + H) +. [00803] The synthesis of 9-Chloro-N-(3,4-dichlorophenyl)acridin-2-amine (119-4a): 3-bromo-6- chloro-9H-carbazole (10.00 g, 34.18 mmol), 3,4-dichloroaniline (5.54 g, 34.18 mmol), tris(dibenzylideneacetone)dipalladium(0) (1.56 g, 1.71 mmol), tert-butylbrett-Phos (1.66 g, 3.42 mmol) and cesium carbonate (11.14 g, 34.18 mmol) were dissolved in tert-butanol (120 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by CC (petroleum ether/ethyl acetate = 1/1) to give 5.30 g title compound in 42% yield as a yellow solid. MS: (ESI) m/z 373.0 (M + H) +. [00804] The synthesis of tert-Butyl 2-(2-(3,4-dichlorophenylamino)acridin-9- ylamino)ethylcarbamate (119-5a): A solution of -chloro-N-(3,4-dichlorophenyl)acridin-2-amine (3.40 g, 9.10 mmol) in tert-butyl 2-aminoethylcarbamate (25 mL) was stirred at 100 °C for 5 hours. Concentrated and purified by CC (petroleum ether/ethyl acetate = 1/1- ethyl acetate) to give 2.36 g title compound in 52% yield as a yellow solid. MS: (ESI) m/z 497.2 (M + H) +. [00805] The synthesis of N9-(2-Aminoethyl)-N2-(3,4-dichlorophenyl)acridine-2,9-diamine (119- 6): A solution of tert-butyl 2-(2-(3,4-dichlorophenylamino)acridin-9-ylamino)ethylcarbamate (800 mg, 0.61 mmol) in TFA (10 in dichloromethane, 50 mL) was stirred at room temperature for 16 h, the reaction solution was concentrated and used for next step directly. [00806] The synthesis of (Z)-tert-Butyl (tert-butoxycarbonylamino)(2-(2-(3,4- dichlorophenylamino)acridin-9-ylamino)ethylamino)methylenecarbamate (119-7): N9-(2-aminoethyl)- N2-(3,4-dichlorophenyl)acridine-2,9-diamine (800 mg, 1.61 mmol), tert-butyl (((tert- butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (500 mg, 1.61 mmol) and Et3N (325 mg, 3.22 mmol) in DMF (15 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water (30 mL). The product was extracted with ethyl acetate (3x30 mL), dried over Na2SO4. The residue was purified by CC (petroleum ether/ethyl acetate = 1/1- ethyl acetate) to give 0.86 g title compound in 83% yield as a brown solid. [00807] The synthesis of 1-(2-(2-(3,4-Dichlorophenylamino)acridin-9-ylamino)ethyl)guanidine (SRI-33302):A solution of (Z)-tert-butyl (tert-butoxycarbonylamino)(2-(2-(3,4- dichlorophenylamino)acridin-9-ylamino)ethylamino)methylenecarbamate (860 mg, 1.34 mmol) in HCl/dioxane (4 N, 60 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with CH3CN(60 mL) and filtrated, washed by CH3CN, ethyl acetate and then concentrated to give 635 mg of the title compound in 98% yield as a red solid. [00808] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.47 (d, J = 8.0 Hz, 1H), 8.10 (s, 1 H), 7.84-7.96 (m, 3H), 7.80 (d, J = 7.6 Hz, 1H), 7.51-7.52 (m, 2H), 7.35 (d, J = 2.4 Hz, 1H), 7.18 (dd, J = 8.0, 1.6 Hz, 1H), 4.21-4.22 (m, 2H), 3.64 (t, J = 5.6 Hz, 2H). MS: (ESI) m/z 439.0 (M + H) +. [00809] Example 74: [00811] The synthesis of 2-Bromo-9,9-dimethyl-9,10-dihydroacridine (110-2):To a solution of 9,9-dimethyl-9,10-dihydroacridine (1.26 g, 6.02 mmol) in DMF (20 mL) was added NBS (1.07 g, 6.02 mmol) in portions and stirred at -50 °C for 2 hours. The mixture was cooled to room temperature and quenched with water (40 mL). The product was extracted with ethyl acetate (3x50 mL), dried over Na2SO4. The solvent was removed and the crude was purified by CC (petroleum ether/ethyl acetate = 10/1-8/1) to give 600 mg title compound in 35% yield as a white solid. [00812] 1H NMR (400 MHz, DMSO-d6) ^ 9.02 (s, 1 H), 7.45 (d, J = 2.0 Hz, 1H), 7.34 (d, J = 7.2 Hz, 1H), 7.21 (dd, J = 8.4, 2.0 Hz, 1H), 7.05-7.08 (m, 1H), 6.73-6.84 (m, 3H), 1.48 (s, 6H). MS: (ESI) m/z 286.1 (M - H) -. [00813] The synthesis of tert-Butyl 2-(2-bromo-9,9-dimethylacridin-10(9H)-yl)ethylcarbamate (110-3a): To a solution of 7-bromo-1,2,3,4-tetrahydrocyclopenta[b]indole (810 mg, 2.81 mmol) in DMF (20 mL) was added NaH (60%, 366 mg, 8.43 mmol) in a portion and stirred at room temperature for 0.5 hours. Then tert-butyl 2-bromoethylcarbamate (630 mg, 2.81 mmol) was added to above. The mixture was stirred at room temperature for 16 hours and quenched with water (60 mL). The product was extracted with ethyl acetate (3x50 mL), dried over Na2SO4. The solvent was removed and the crude was purified by CC (petroleum ether/ethyl acetate = 10/1-8/1) to give 590 mg title compound in 49% yield as a yellow solid. MS: (ESI) m/z 431.2 (M + H)+. [00814] The synthesis of tert-Butyl 2-(2-(3,4-dichlorophenylamino)-9,9-dimethylacridin-10(9H)- yl)ethylcarbamate (110-4): The synthesis of tert-butyl 2-(2-bromo-9,9-dimethylacridin-10(9H)- yl)ethylcarbamate (590 mg, 1.37 mmol), 3,4-dichloroaniline (222 mg, 1.37 mmol), tris(dibenzylideneacetone)dipalladium(0) (125 mg, 0.137 mmol), tert-butylbrett-Phos (133 mg, 0.274 mmol) and cesium carbonate (891 mg, 2.74 mmol) were dissolved in tert-butanol (30 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by CC (petroleum ether/ethyl acetate = 8/1) to give 510 mg title compound in 73% yield as a yellow solid. MS: (ESI) m/z 512.3 (M + H)+. [00815] The synthesis of 10-(2-Aminoethyl)-N-(3,4-dichlorophenyl)-9,9-dimethyl-9,10- dihydroacridin-2-amine (110-5): A solution of tert-butyl 2-(2-(3,4-dichlorophenylamino)-9,9- dimethylacridin-10(9H)-yl)ethylcarbamate (510 mg, 0.995 mmol) in TFA (10% in dichloromethane, 30 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and used for the next step directly. MS: (ESI) m/z 412.2 (M + H)+. [00816] The synthesis of (Z)-tert-Butyl (tert-butoxycarbonylamino)(2-(2-(3,4- dichlorophenylamino)-9,9-dimethylacridin-10(9H)-yl)ethylamino)methylenecarbamate (110-6): 10- (2-aminoethyl)-N-(3,4-dichlorophenyl)-9,9-dimethyl-9,10-dihydroacridin-2-amine (410 mg, 0.995 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (309 mg, 0.995 mmol) and Et3N (202 mg, 1.99 mmol) in DMF (15 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water (40 mL). The product was extracted with ethyl acetate (3x20 mL), dried over Na2SO4. The residue was purified by CC (petroleum ether/ ethyl acetate = 8/1) to give 530 mg of title compound in 81% yield as a yellow solid. MS: (ESI) m/z 654.2 (M + H) +. [00817] The synthesis of 1-(2-(2-(3,4-Dichlorophenylamino)-9,9-dimethylacridin-10(9H)- yl)ethyl)guanidine (SRI-33303): A solution of (Z)-tert-butyl (tert-butoxycarbonylamino)(2-(2-(3,4- dichlorophenylamino)-9,9-dimethylacridin-10(9H)-yl)ethylamino)methylenecarbamate (530 mg, 0.809 mmol) in TFA (15% in dichloromethane, 30 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated then purified by Prep-HPLC to give 125 mg title compound in 34% yield as a gray solid. [00818] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.42 (s, 1.26 H), 7.42 (dd, J = 7.6, 1.2 Hz, 1H), 7.36 (d, J = 9.2 Hz, 1H), 7.20-7.24 (m, 1H), 7.03 (d, J = 2.4 Hz, 1H), 7.08-7.10 (m, 2H), 7.02-7.05 (m, 2H), 6.96 (t, J = 7.6 Hz, 1H), 6.86 (dd, J = 8.8, 2.8 Hz, 1H), 4.13 (t, J = 6.8 Hz, 2H), 3.48-3.51 (m, 2H), 1.46 (s, 6H). MS: (ESI) m/z 454.3 (M + H)+. [00819] Example 75: [00821] The synthesis of tert-Butyl 2-(6-bromo-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)- yl)ethylcarbamate (120-1): To a solution of 6-bromo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (200 mg, 0.80 mmol) in ACN (10 mL) was added tert-butyl 2-bromoethylcarbamate (214.2 mg, 0.96 mmol) and DIEA (154.4 mg, 1.20 mmol). The mixture was stirred at 85 oC for 12 hours. The residue was purified by CC (petroleum ether/ethyl acetate = 3:1) to give 150 mg of the title compound in 47.77% yield as a yellow solid. [00822] 1H NMR (400 MHz, DMSO-d6) ^ 10.98 (s, 1H), 7.52 (d, J = 2.0 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.10 (dd, J = 2.0, 8.4 Hz, 1H), 6.74 (t, J = 5.6 Hz, 1H), 3.62 (s, 2H), 3.11-3.17 (m, 2H), 2.76 (t, J = 4.4 Hz, 2H), 2.64-2.67 (m, 2H), 2.58 (t, J = 6.8 Hz, 2H), 1.37 (s, 9H). MS: (ESI) m/z 392.0 (M - H) -. [00823] The synthesis of tert-Butyl 2-(6-(3,4-dichlorophenylamino)-3,4-dihydro-1H-pyrido[3,4- b]indol-2(9H)-yl)ethylcarbamate (120-2): To a solution of tert-butyl 2-(6-bromo-3,4-dihydro-1H- pyrido[3,4-b]indol-2(9H)-yl)ethylcarbamate (150 mg, 0.61 mmol) in t-BuOH (2 mL) was added 3,4- dichloroaniline (98.4 mg, 0.61 mmol), Cs2CO3 (593.4 mg, 1.83 mmol), t-Bubrettphos (29.4 mg, 0.06 mmol) and Pd2(dba)3 (55.5 mg, 0.06 mmol). The mixture was stirred at 90 oC for 3 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate(20 mL x 2), the combined organic layers were washed with saturated brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 2:1) to give 90 mg of title compound in 49.76% yield as a white solid. MS: (ESI) m/z 473.2 (M - H)-. [00824] The synthesis of 2-(2-Aminoethyl)-N-(3,4-dichlorophenyl)-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indol-6-amine (120-3): A solution of tert-butyl 2-(6-(3,4-dichlorophenylamino)-3,4- dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)ethylcarbamate (90 mg, 0.29 mmol) in TFA (20% in dichloromethane, 10 mL) was stirred at room temperature for 1 hour. The reaction solution was concentrated and used for the next step directly. MS: (ESI) m/z 375.2 (M + H)-. [00825] The synthesis of tert-Butyl (tert-butoxycarbonylamino)(2-(6-(3,4-dichlorophenylamino)- 3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)ethylamino)methylenecarbamate (120-4): 2-(2- aminoethyl)-N-(3,4-dichlorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-6-amine (90 mg, 0.24 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (81.87 mg, 0.26 mmol) and Et3N (1 mL) in DMF (2 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water (10 mL). The product was extracted with ethyl acetate (3 x 10 mL) and dried over Na2SO4. The residue was purified by CC (petroleum ether/ethyl acetate = 2/1) to give 80 mg of title compound in 54.02% yield as a yellow solid. MS: (ESI) m/z 617.3 (M + H)+. [00826] The synthesis of 1-(2-(6-(3,4-Dichlorophenylamino)-3,4-dihydro-1H-pyrido[3,4-b]indol- 2(9H)-yl)ethyl)guanidine (SRI-33304): A solution of tert-butyl (tert-butoxycarbonylamino)(2-(6-(3,4- dichlorophenylamino)-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)ethylamino)methylenecarbamate (80 mg, 0.13 mmol) in TFA (15% in dichloromethane, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (18.44 mg, 34.1%) as a yellow solid. [00827] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.20 (s, 1H), 7.28-7.33 (m, 2H), 7.13 (d, J = 1.6 Hz, 1H), 6.94 (d, J = 2.8 Hz, 1H), 6.86 (dd, J =2.0, 8.8 Hz, 1H), 6.81 (dd, J =2.8, 8.8 Hz, 1H), 3.68 (s, 2H), 3.33 (t, J = 5.6 Hz, 2H), 2.84 (t, J = 5.6 Hz, 2H), 2.73 (t, J = 5.6 Hz, 2H), 2.68-2.69 (m, 2H). MS: (ESI) m/z 417.0 (M + H)+. [00828] Example 76: [00830] The synthesis of 7-Bromo-1,2,3,4-tetrahydrocyclopenta[b]indole (113-2): To a solution of (4-bromophenyl)hydrazine hydrochloride (2.22 g, 9.93 mmol) in EtOH (50 mL) was added cyclopentanone (836 mg, 9.93 mmol) and stirred at 80 °C for 16 hours. The reaction solution was concentrated and purified by CC (petroleum ether/ethyl acetate = 8/1) to give 1.25 g title compound in 53% yield as a yellow solid. MS: (ESI) m/z 234.0 (M -H)–. [00831] The synthesis of tert-Butyl 2-(7-bromo-2,3-dihydrocyclopenta[b]indol-4(1H)- yl)ethylcarbamate (113-3): To a solution of 7-bromo-1,2,3,4-tetrahydrocyclopenta[b]indole (470 mg, 1.99 mmol) in DMF (20 mL) was added NaH (60%, 239 mg, 5.97 mmol) in portion and stirred at room temperature for 0.5 hours. Then tert-butyl 2-bromoethylcarbamate (446 mg, 1.99 mmol) was added to above. The mixture was stirred at room temperature for 16 hours and quenched with water (60 mL). The product was extracted with ethyl acetate (3x50 mL), dried over Na2SO4. The solvent was removed and the crude was purified by CC (petroleum ether/ethyl acetate = 10/1-5/1) to give 220 mg title compound in 29% yield as a yellow solid. MS: (ESI) m/z 379.2 (M + H)+. [00832] The synthesis of tert-Butyl 2-(7-(3,4-dichlorophenylamino)-2,3- dihydrocyclopenta[b]indol-4(1H)-yl)ethylcarbamate (113-4): tert-butyl 2-(7-bromo-2,3- dihydrocyclopenta[b]indol-4(1H)-yl)ethylcarbamate (220 mg, 0.58 mmol), 3,4-dichloroaniline (94 mg, 0.58 mmol), tris(dibenzylideneacetone)dipalladium(0) (53 mg, 0.06 mmol), tert-butylbrett-Phos (58 mg, 0.12 mmol) and cesium carbonate (1.16 g, 3.78 mmol) were dissolved in tert-butanol (15 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by CC (petroleum ether/ethyl acetate = 8/1) to give 200 mg title compound in 75% yield as a yellow solid. MS: (ESI) m/z 460.2 (M + H)+. [00833] The synthesis of 4-(2-Aminoethyl)-N-(3,4-dichlorophenyl)-1,2,3,4- tetrahydrocyclopenta[b]indol-7-amine (113-5): A solution of tert-butyl 2-(7-(3,4- dichlorophenylamino)-2,3-dihydrocyclopenta[b]indol-4(1H)-yl)ethylcarbamate (200 mg, 0.43 mmol) in TFA (10% in dichloromethane, 20 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and used for the next step directly. MS: (ESI) m/z 360.2 (M + H)+. [00834] The synthesis of (E)-tert-Butyl (tert-butoxycarbonylamino)(2-(7-(3,4- dichlorophenylamino)-2,3-dihydrocyclopenta[b]indol-4(1H)-yl)ethylamino)methylenecarbamate (113-6): 4-(2-aminoethyl)-N-(3,4-dichlorophenyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-7-amine (157 mg, 0.43 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (135 mg, 0.43 mmol) and Et3N (88 mg, 0.87 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water (10 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The residue was purified by CC (petroleum ether/ ethyl acetate = 8/1) to give 244 mg of title compound in 93% yield as a yellow solid. MS: (ESI) m/z 602.2 (M + H)+. [00835] The synthesis of 1-(2-(7-(3,4-Dichlorophenylamino)-2,3-dihydrocyclopenta[b]indol- 4(1H)-yl)ethyl)guanidine (SRI-33311): A solution of (E)-tert-butyl (tert-butoxycarbonylamino)(2-(7- (3,4-dichlorophenylamino)-2,3-dihydrocyclopenta[b]indol-4(1H)-yl)ethylamino)methylenecarbamate (244 mg, 0.41 mmol) in TFA (10% in dichloromethane, 40 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and then the mixture was diluted with water (30 mL), basified with NaOH (10%) to pH=7. The product was extracted with ethyl acetate (3x20 mL), dried over Na2SO4 and then purified by Prep-HPLC to give 66 mg title compound in 41% yield as a white solid. [00836] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.42 (s, 1 H, formic acid), 7.32-7.38 (m, 2H), 7.09 (d, J = 2.0 Hz, 1H), 6.96 (d, J = 2.8 Hz, 1H), 6.82-6.89 (m, 2H), 4.17 (t, J = 5.6 Hz, 2H) , 3.50 (t, J = 5.6 Hz, 2H), 2.84 (t, J = 6.4 Hz, 2H), 2.73 (t, J = 6.8 Hz, 2H), 2.45-2.54 (m, 2H). MS: (ESI) m/z 402.2 (M + H)+. [00837] Example 77: [00839] The synthesis of 2-(3,4-Dichlorobenzyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (122- 2): To a solution of 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (1 g, 5.81 mmol) in ACN (10 mL) was added 4-(bromomethyl)-1,2-dichlorobenzene (1.67 g, 6.97 mmol) and DIEA (1.13 g, 8.72 mmol). The mixture was stirred at 85 oC for 12 hours. The residue was purified by CC (petroleum ether/ethyl acetate = 3:1) to give 1.6 g of the title compound in 83.19% yield as a yellow solid. [00840] 1H NMR (400 MHz, DMSO-d6) ^ 10.66 (s, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.39 (dd, J = 2.0, 8.0 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 6.98-7.02 (m, 1H), 6.91-6.96 (m, 1H), 3.74 (s, 2H), 3.58 (s, 2H), 2.79-2.82 (m, 2H), 2.68-2.71 (m, 2H). MS: (ESI) m/z 329.0 (M - H)-. [00841] The synthesis of tert-Butyl 2-(2-(3,4-dichlorobenzyl)-3,4-dihydro-1H-pyrido[3,4-b]indol- 9(2H)-yl)ethylcarbamate (122-3): To a solution of 2-(3,4-dichlorobenzyl)-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indole (1.6 g, 4.83 mmol) in DMF (20 mL) was added tert-butyl 2-bromoethylcarbamate (1.3 g, 5.80 mmol) and NaH (386.4 mg, 0.97 mmol). The mixture was stirred at 70 oC for 12 hours. The reaction mixture was quenched by addition saturated NH4Cl solution to adjust pH = 6-7, and extracted with EA (300 mL x2), the combined organic layers were washed with saturated brine (300 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA = 1:0 to 3:1) to give 600 mg of title compound in 26.18% yield as a yellow solid. MS: (ESI) m/z 472.2 (M - H)-. [00842] The synthesis of 2-(2-(3,4-Dichlorobenzyl)-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)- yl)ethanamine (122-4): A solution of tert-butyl 2-(2-(3,4-dichlorobenzyl)-3,4-dihydro-1H-pyrido[3,4- b]indol-9(2H)-yl)ethylcarbamate (600 mg, 1.26 mmol) in TFA (20% in dichloromethane, 10 mL) was stirred at room temperature for 2 hours. The reaction solution was concentrated and used for the next step directly. MS: (ESI) m/z 374.2 (M + H)-. [00843] The synthesis of (Z)-tert-Butyl (tert-butoxycarbonylamino)(2-(2-(3,4-dichlorobenzyl)-3,4- dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)ethylamino)methylenecarbamate (122-5): 2-(2-(3,4- dichlorobenzyl)-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)ethanamine (300 mg, 0.80 mmol mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (298.49 mg, 0.96 mmol) and Et3N (1 mL) in DMF (5 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water (50 mL). The product was extracted with ethyl acetate (3 x 50 mL), dried over Na2SO4. The residue was purified by CC (petroleum ether/ethyl acetate = 2/1) to give 300 mg of title compound in 60.71% yield as a yellow solid. MS: (ESI) m/z 616.2 (M + H)+. [00844] The synthesis of 1-(2-(2-(3,4-Dichlorobenzyl)-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)- yl)ethyl)guanidine (SRI-33312): A solution of (Z)-tert-butyl (tert-butoxycarbonylamino)(2-(2-(3,4- dichlorobenzyl)-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)ethylamino)methylenecarbamate (300 mg, 0.49 mmol) in TFA (15% in dichloromethane, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (114.01 mg, 56.28%) as a white solid. [00845] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 7.64 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.39-7.42 (m, 3H), 7.08-7.12 (m, 1H), 7.00-7.04 (m, 1H), 4.11 (t, J =6.0 Hz, 2H), 3.77 (s, 2H), 3.72 (s, 2H), 3.42 (t, J = 5.6 Hz, 2H), 2.75-2.78 (m, 2H), 2.69-2.70 (m, 2H). MS: (ESI) m/z 416.2 (M + H) +. [00846] Example 78: [00848] The synthesis of 2-Oxopiperidine-3-carboxylic acid (114-2): To a solution of ethyl 2- oxopiperidine-3-carboxylate (5 g, 29.21 mmol) in H2O (60 mL) was added KOH (6.88 g, 122.67 mmol) and stirred at 25 oC for 16 hours. The mixture was extracted with CHCl3/i-PrOH (85/15) (100 mL x 2), the combined organic layers were washed with saturated brine (100 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give 3 g crude of title compound in 71.76% yield as a white solid. [00849] The synthesis of 6-Bromo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one (114-3): To a solution of 2-oxopiperidine-3-carboxylic acid (2.5 g, 17.47 mmol) in HOAc (30 mL) was added 4- bromobenzene-1-diazonium chloride (3.54 g, 19.21 mmol) and stirred at 90 oC for 16 hours. The brown solid was removed by filtration, then washed with 100 mL H2O and 100 mL Na2CO3 (a.q.) to give 1.7 g of title compound in 36.72% yield as a light yellow solid. MS: (ESI) m/z 263.0 (M - H) . [00850] The synthesis of 6-Bromo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (114-4): To a solution of 6-bromo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one (1.2 g, 4.53 mmol) in dioxane (20 mL) was added LiAlH4 (515.4 mg, 13.58 mmol) and stirred at 105 oC for 2 hours. The reaction mixture was quenched by addition water (10 mL), 15% NaOH (10 mL) and water (30 mL). The mixture was filtered to give filtrate. The filtrate was concentrated to give 1 g crude of title compound in 62.10% yield as a white solid. MS: (ESI) m/z 249.0 (M - H)-. [00851] The synthesis of tert-Butyl 6-bromo-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)- carboxylate (114-5): To a solution of 6-bromo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (1 g, 3.98 mmol) in DCM (20 mL) was added Na2CO3 (844.12 mg, 7.96 mmol) and di-tert-butyl dicarbonate(1.3 g, 5.97 mmol). The mixture stirred at 25 oC for 3 hours. The product was extracted with ethyl acetate (3 x 10 mL), dried over Na2SO4. The residue was purified by CC (petroleum ether/ethyl acetate = 10/1) to give 800 mg of the title compound in 57.2% yield as a white solid. [00852] 1H NMR (400 MHz, DMSO-d6) ^ 11.07 (s, 1H), 7.57 (s, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 3.67 (t, J = 5.2 Hz, 2H), 2.66 (t, J = 5.2 Hz, 1H), 1.43 (s, 9H). MS: (ESI) m/z 349.0 (M - H) -. [00853] The synthesis of tert-Butyl 6-bromo-9-(2-(tert-butoxycarbonylamino)ethyl)-3,4-dihydro- 1H-pyrido[3,4-b]indole-2(9H)-carboxylate (114-6): To a solution of tert-butyl 6-bromo-3,4-dihydro- 1H-pyrido[3,4-b]indole-2(9H)-carboxylate (600 mg, 1.71 mmol) in DMF (10 mL) was added tert- butyl 2-bromoethylcarbamate (459.37 mg, 2.05 mmol) and NaH (60%, 136.65 mg, 3.42 mmol). The mixture was stirred at 70 oC for 16 hours. The reaction mixture was quenched by addition saturated NH4Cl solution (300 mL) to adjust pH = 6 - 7 and extracted with EA (300 mL x2). The combined organic layers were washed with saturated brine (300 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA = 1:0 to 3:1) to give 380 mg of title compound in 44.99% yield as a yellow solid. [00854] 1H NMR (400 MHz, DMSO-d6) ^ 7.60 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 6.96 (t, J = 6.0 Hz, 1H), 4.07 (t, J = 6.0 Hz, 2H), 3.64 (t, J = 5.2 Hz, 2H), 3.15-3.19 (m, 2H), 2.67 (s, 2H), 1.44 (s, 9H), 1.33 (s, 9H). MS: (ESI) m/z 492.2 (M - H)-. [00855] The synthesis of tert-Butyl 9-(2-(tert-butoxycarbonylamino)ethyl)-6-(3,4- dichlorophenylamino)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (114-7):To a solution of tert-butyl 6-bromo-9-(2-(tert-butoxycarbonylamino)ethyl)-3,4-dihydro-1H-pyrido[3,4-b]indole- 2(9H)-carboxylate (360 mg, 0.73 mmol) in t-BuOH (5 mL) was added 3,4-dichloroaniline (117.97 mg, 0.73 mmol), Cs2CO3 (711.71 mg, 2.18 mmol), t-Bubrettphos (35.29 mg, 72.81 μmol) and Pd2(dba)3 (66.67 mg, 72.81 μmol). The mixture was stirred at 90 oC for 3 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2), the combined organic layers were washed with saturated brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA = 1:0 to 2:1) to give 340 mg of title compound in 81.1% yield as a white solid. [00856] 1H NMR (400 MHz, DMSO-d6) ^ 8.19 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 7.16 (s, 1H), 6.99 (t, J = 5.6 Hz, 1H), 6.91-6.94 (m, 2H), 6.80 (dd, J = 2.4, 8.8 Hz, 1H), 4.59 (s, 2H), 4.07 (t, J = 6.0 Hz, 2H), 3.65 (t, J = 5.6 Hz, 2H), 3.17-3.21 (m, 2H), 2.65 (s, 2H), 1.45 (s, 19H), 1.35 (s, 9H). MS: (ESI) m/z 573.2 (M - H)-. [00857] The synthesis of 9-(2-Aminoethyl)-N-(3,4-dichlorophenyl)-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indol-6-amine (114-8): A solution of tert-butyl 9-(2-(tert-butoxycarbonylamino)ethyl)-6- (3,4-dichlorophenylamino)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (340 mg, 0.59 mmol) in TFA (20% in dichloromethane, 10 mL) was stirred at room temperature for 2 hours. The reaction solution was concentrated and used for the next step directly. [00858] The synthesis of (Z)-tert-Butyl (tert-butoxycarbonylamino)(2-(6-(3,4- dichlorophenylamino)-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)ethylamino)methylenecarbamate (114-9): 9-(2-aminoethyl)-N-(3,4-dichlorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-6-amine (100 mg, 0.27 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (82.7 mg, 0.27 mmol) and Et3N (1 mL) in DMF (2 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water (10 mL). The product was extracted with ethyl acetate (3 x 10 mL), dried over Na2SO4. The residue was purified by CC (petroleum ether/ethyl acetate = 2/1) to give 30 mg of title compound in 18.23% yield as a yellow solid. MS: (ESI) m/z 617.2 (M + H)+. [00859] The synthesis of 1-(2-(6-(3,4-Dichlorophenylamino)-3,4-dihydro-1H-pyrido[3,4-b]indol- 9(2H)-yl)ethyl)guanidine (SRI-33336): A solution of (Z)-tert-butyl (tert-butoxycarbonylamino)(2-(6- (3,4-dichlorophenylamino)-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)- yl)ethylamino)methylenecarbamate (30 mg, 48.58 μmol) in TFA (15% in dichloromethane, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (9.69 mg, 47.8%) as a yellow solid. [00860] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 7.43 (d, J = 8.8 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.21 (d, J = 1.6 Hz, 1H), 6.96-6.99 (m, 2H), 6.85 (dd, J =2.8, 8.8 Hz, 1H), 4.14-4.20 (m, 4H), 3.48 (t, J = 6.0 Hz, 2H), 3.22 (t, J = 5.2 Hz, 2H), 2.78 (t, J = 5.2 Hz, 2H). MS: (ESI) m/z 417.2 (M + H) +. [00861] Example 79: [00863] The synthesis of 8-Bromo-5H-pyrido[4,3-b]indole (117-2): NBS (619 mg, 3.50 mmol, 1 eq) was added to a solution of 5H-pyrido[4,3-b]indole (588 mg, 3.50 mmol, 1 eq) in DMF (15 mL) at room temperature. After stirring for 16 h, the reaction mixture was quenched with water (30 mL). The product was extracted with ethyl acetate (3x30 mL), dried over Na2SO4. Concentrated and purified by CC (petroleum ether/ethyl acetate = 5/1) to give 560 mg title compound in 65% yield as a white solid. [00864] 1H NMR (400 MHz, DMSO-d6) ^ 11.87 (s, 1H), 9.39 (s, 1H), 8.50 (d, J = 1.6 Hz, 1H), 8.45 (d, J = 5.6 Hz, 1H), 7.60 (dd, J = 8.8, 2.0 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.49 (dd, J = 5.6, 0.8 Hz, 1H). MS: (ESI) m/z 247.2 (M + H)+. [00865] The synthesis of N-(3,4-Dichlorophenyl)-5H-pyrido[4,3-b]indol-8-amine (117-3): 8- bromo-5H-pyrido[4,3-b]indole (490 mg, 1.98 mmol), 3,4-dichloroaniline (322 mg, 1.98 mmol), tris(dibenzylideneacetone)dipalladium(0) (183 mg, 0.20 mmol), tert-butylbrett-Phos (194 mg, 0.40 mmol) and cesium carbonate (1.29 g, 3.27 mmol) were dissolved in tert-butanol (30 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by CC (petroleum ether/ethyl acetate = 1/1- ethyl acetate) to give 340 mg title compound in 52% yield as a yellow solid. MS: (ESI) m/z 328.2 (M + H)+. [00866] The synthesis of tert-Butyl 2-(8-(3,4-dichlorophenylamino)-5H-pyrido[4,3-b]indol-5- yl)ethylcarbamate (117-4): The mixture of N-(3,4-dichlorophenyl)-5H-pyrido[4,3-b]indol-8-amine (343 mg, 1.05 mmol), tert-butyl 2-bromoethylcarbamate (258 mg, 1.15 mmol) and Cs2CO3 (684 mg, 2.09 mmol) in DMF (10 mL) was heated at 50 °C for 16 hours. The mixture was cooled to room temperature and quenched with water (20 mL). The product was extracted with ethyl acetate (3x20 mL), dried over Na2SO4. Concentrated and purified by CC (petroleum ether/ethyl acetate = 1/1- ethyl acetate) to give 244 mg title compound in 50% yield as a yellow solid. MS: (ESI) m/z 471.2 (M + H)+. [00867] The synthesis of 5-(2-Aminoethyl)-N-(3,4-dichlorophenyl)-5H-pyrido[4,3-b]indol-8- amine (117-5): A solution of tert-butyl 2-(8-(3,4-dichlorophenylamino)-5H-pyrido[4,3-b]indol-5- yl)ethylcarbamate (244 mg, 0.52 mmol) in TFA (10% in DCM, 15 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and used for the next step directly. [00868] The synthesis of (Z)-tert-Butyl (tert-butoxycarbonylamino)(2-(8-(3,4- dichlorophenylamino)-5H-pyrido[4,3-b]indol-5-yl)ethylamino)methylenecarbamate (117-6): 5-(2- aminoethyl)-N-(3,4-dichlorophenyl)-5H-pyrido[4,3-b]indol-8-amine (192 mg, 0.52 mmol), (Z)-tert- butyl (1H-pyrazol-1-yl)methylenedicarbamate (161 mg, 0.52 mmol) and Et3N (105 mg, 1.04 mmol) in DMF (6 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water (20 mL). The product was extracted with ethyl acetate (3x20 mL), dried over Na2SO4. The residue was purified by CC (ethyl acetate) to give 200 mg of title compound in 63% yield as a yellow solid. MS: (ESI) m/z 613.2 (M + H)+. [00869] The synthesis of 1-(2-(8-(3,4-Dichlorophenylamino)-5H-pyrido[4,3-b]indol-5- yl)ethyl)guanidine (SRI-33337): A solution of (Z)-tert-butyl (tert-butoxycarbonylamino)(2-(8-(3,4- dichlorophenylamino)-5H-pyrido[4,3-b]indol-5-yl)ethylamino)methylenecarbamate (180 mg, 0.29 mmol) in TFA (15% in DCM, 20 mL) was stirred at room temperature for overnight. The reaction solution was concentrated and then the mixture was diluted with water (30 mL), basified with NaOH (10%) to pH=7. The product was extracted with ethyl acetate (3x20 mL), dried over Na2SO4 and then purified by Prep-HPLC to give 52 mg title compound in 43% yield as a yellow solid. [00870] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 9.34 (s, 1H), 8.46 (d, J = 6.0 Hz, 1H), 8.30 (s, 2H), 8.06 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 6.0 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.35 (dd, J = 8.8, 2.4 Hz, 1H), 7.69 (d, J = 2.8 Hz, 1H), 6.96 (dd, J = 8.8, 5.6 Hz, 1H), 4.51 (t, J = 5.6 Hz, 2H), 3.62 (t, J = 5.6 Hz, 2H). MS: (ESI) m/z 413.0 (M + H)+. [00871] Example 80: [00873] The synthesis of 8-Bromo-5H-pyrido[3,2-b]indole (118-2): NBS (635 mg, 3.57 mmol, 1.0 eq) was added to a mixture of 5H-pyrido[3,2-b]indole (600 mg, 3.57 mmol, 1 eq) in dichloromethane (60 mL) at room temperature. After stirring for 2 h, the solid was collected by filtration to give 693 mg of title compound in 79% yield as a gray solid. [00874] 1H NMR (400 MHz, DMSO-d6) ^ 11.72 (s, 1H), 8.52 (d, J = 4.4 Hz, 1H), 8.32 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.65 (dd, J = 8.6, 1.8 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.48 (dd, J = 8.2, 4.6 Hz, 1H). MS: (ESI) m/z 245.0 (M - H)-. [00875] The synthesis of N-(3,4-Dichlorophenyl)-5H-pyrido[3,2-b]indol-8-amine (118-3): 8- bromo-5H-pyrido[3,2-b]indole (693 mg, 2.80 mmol), 3,4-dichloroaniline (455 mg, 2.81 mmol), tris(dibenzylideneacetone)dipalladium(0) (129 mg, 0.14 mmol), tert-butylbrett-Phos (136 mg, 0.28 mmol) and cesium carbonate (1.37 g, 4.21 mmol) were dissolved in tert-butanol (15 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by CC (petroleum ether/ethyl acetate = 2/1) to give 393 mg title compound in 43% yield as a pale brown solid. [00876] 1H NMR (400 MHz, DMSO-d6) ^ 11.38 (s, 1H), 8.44 (s, 1H), 8.43 (d, J = 4.4 Hz, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.35-7.40 (m, 2H), 7.33 (dd, J = 8.4, 2.0 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 6.93 (dd, J = 8.8, 2.8 Hz, 1H). MS: (ESI) m/z 326.0 (M - H)-. [00877] The synthesis of tert-Butyl (2-(8-((3,4-dichlorophenyl)amino)-5H-pyrido[3,2-b]indol-5- yl)ethyl)carbamate (118-4): The mixture of N-(3,4-dichlorophenyl)-5H-pyrido[3,2-b]indol-8-amine (393 mg, 1.20 mmol), tert-butyl (2-bromoethyl)carbamate (322 mg, 1.44 mmol) and cesium carbonate (1.17 g, 3.59 mmol) in DMF (2 mL) was heated at 50 °C for 16 hours. The mixture was cooled to room temperature and quenched with water (10 mL). The product was extracted with ethyl acetate (3 x 10 mL) and dried over Na2SO4. The solvent was removed and the crude was purified by CC (petroleum ether/ethyl acetate = 2/1) to give 339 mg title compound in 60% yield as a pale brown solid. [00878] 1H NMR (400 MHz, DMSO-d6) ^ 8.48 (s, 1H), 8.44 (d, J = 4.4 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.91 (d, J = 1.6 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.43 (dd, J = 8.2, 4.6 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.37 (dd, J = 8.4, 2.0 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 6.90-6.95 (m, 2H), 4.45 (t, J = 5.4 Hz, 2H), 3.30-3.36(m, 2H), 1.25 (s, 9H). MS: (ESI) m/z 469.0 (M - H)-. [00879] The synthesis of 5-(2-Aminoethyl)-N-(3,4-dichlorophenyl)-5H-pyrido[3,2-b]indol-8- amine (118-5): A solution of tert-butyl (2-(8-((3,4-dichlorophenyl)amino)-5H-pyrido[3,2-b]indol-5- yl)ethyl)carbamate (339 mg, 0.72 mmol) in TFA (10% in dichloromethane, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and used for the next step directly. [00880] The synthesis of (118-6): 5-(2-aminoethyl)-N-(3,4-dichlorophenyl)-5H-pyrido[3,2- b]indol-8-amine (267 mg, 0.72 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1- yl)methylene)carbamate (224 mg, 0.72 mmol) and Et3N (146 mg, 1.44 mmol) in DMF (2 mL) was stirred at room temperature for 1 hour. The reaction was quenched with water (10 mL). The product was extracted with ethyl acetate (3 x 10 mL), dried over Na2SO4. The residue was purified by CC (petroleum ether/ethyl acetate = 1/1) to give 268 mg of title compound in 61% yield as a yellow solid. [00881] 1H NMR (400 MHz, DMSO-d6) ^ 11.37 (s, 1H), 8.54 (t, J = 6.0 Hz, 1H), 8.47 (s, 1H), 8.45 (dd, J = 4.6, 1.0 Hz, 1H), 8.11 (dd, J = 8.4, 1.2 Hz, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.41 (dd, J = 8.4, 4.4 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.35 (dd, J = 8.8, 2.0 Hz, 1H), 7.10 (d, J = 2.8 Hz, 1H), 6.94 (dd, J = 8.8, 2.8 Hz, 1H), 4.55 (t, J = 6.6 Hz, 2H), 3.66 (q, J = 6.4 Hz, 2H), 1.45 (s, 9H), 1.42 (s, 9H). MS: (ESI) m/z 613.2 (M + H)+. [00882] The synthesis of 1-(2-(8-((3,4-Dichlorophenyl)amino)-5H-pyrido[3,2-b]indol-5- yl)ethyl)guanidine (SRI-33338): A solution of 118-6 (248 mg, 0.40 mmol) in TFA (15% in dichloromethane, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and basified with NaOH (10%). The product was extracted with dichloromethane (3 x 10 mL), dried over Na2SO4 concentrated. The residue was purified by Prep-HPLC to provide title compound (150 mg, 90%) as a yellow solid. [00883] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.47 (d, J = 4.0 Hz, 1H), 8.30 (s, 1.7 H, formic acid), 8.04 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.53 (dd, J = 8.4, 4.8 Hz, 1H), 7.44 (dd, J = 8.8, 2.0 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.12 (d, J = 2.8 Hz, 1H), 6.98 (dd, J = 8.8, 2.4 Hz, 1H), 4.54 (t, J = 5.2 Hz, 2H), 3.67 (t, J = 5.2 Hz, 2H). MS: (ESI) m/z 413.3 (M + H) +. [00884] Example 81: [00886] The synthesis of (121-1): To a solution of 9-(2-aminoethyl)-N-(3,4-dichlorophenyl)- 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-6-amine (80 mg, 0.21 mmol) in ACN (2 mL) was added (Z)-tert-butyl (1H-pyrazol-1-yl)methylenedicarbamate (165.39 mg, 0.53 mmol) and DIEPA (1 mL). The mixture was stirred at 25 oC for 16 hours. The residue was purified by CC (petroleum ether/ethyl acetate = 3:1) to give 70 mg of title compound in 38.19% yield as a white solid. MS: (ESI) m/z 859.2 (M + H)+. [00887] The synthesis of 6-(3,4-Dichlorophenylamino)-9-(2-guanidinoethyl)-3,4-dihydro-1H- pyrido[3,4-b]indole-2(9H)-carboximidamide (SRI-33339): A solution of 121-1 (70 mg, 81.41 μmol) in TFA (15% in dichloromethane, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (10.8 mg, 28.8%) as a white solid. [00888] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 7.44 (d, J = 8.8 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.23 (d, J = 2.0 Hz, 1H), 6.97-7.00 (m, 2H), 6.86 (dd, J = 2.8, 8.8 Hz, 1H), 4.73 (s, 2H), 4.18 (t, J = 5.2 Hz, 2H), 3.75-3.77 (m, 2H), 3.51 (t, J = 5.6 Hz, 2H), 2.79 (s, 2H). MS: (ESI) m/z 459.3 (M + H)+. [00889] [00890] Example 82: [00891] Example Route for Example 82 (SRI-33342):
[00892] The synthesis of 6-Chloro-4,9-dihydro-1H-carbazol-3(2H)-one (123-2): A mixture of compound (4-chlorophenyl)hydrazine (1.2 g, 8.42 mmol, 1.0 eq) and 1,4-dioxaspiro[4.5]decan-8-one (1.31 g, 8.42 mmol, 1 eq) in toluene (30 mL) was heated to reflux for 1 hour. The reaction mixture was concentrated and dissolved in toluene (30 mL), added ZnCl2 (1.15 g, 8.42 mmol, 1 eq). After reflux for 16 h, the reaction mixture was concentrated. The residue was dissolved in acetone (30 mL), added TFA (2 mL), reflux for 16 hours. The solvent was removed and the crude was purified by CC (petroleum ether/ethyl acetate = 2/1) to give 466 mg title compound in 25% yield as an off-white solid. [00893] 1H NMR (400 MHz, DMSO-d6) ^ 11.16 (s, 1H), 7.40 (d, J = 1.6 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.04 (dd, J = 8.6, 1.8 Hz, 1H), 3.49 (s, 2H), 3.11 (t, J = 7.0 Hz, 2H), 2.70 (t, J = 6.8 Hz, 2H). MS: (ESI) m/z 220.3 (M + H)+. [00894] The synthesis of 6-Chloro-N-(3,4-dichlorophenyl)-2,3,4,9-tetrahydro-1H-carbazol-3- amine (123-3): A mixture of 6-chloro-4,9-dihydro-1H-carbazol-3(2H)-one (333 mg, 1.52 mmol) and 3,4-dichloroaniline (491 mg, 3.03 mmol) in dichloromethane ( 5 mL) was stirred at room temperature for 4 hours. Sodium triacetoxyborohydride (482 mg, 2.27 mmol) was added. The reaction solution was stirred at room temperature for 16 hours and then concentrated. The residue was purified by CC (petroleum ether/dichloromethane = 2/1) to give 258 mg title compound in 47% yield as a brown solid. [00895] 1H NMR (400 MHz, DMSO-d6) ^ 10.96 (s, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 6.98 (dd, J = 8.4, 2.0 Hz, 1H), 6.85 (d, J = 2.8 Hz, 1H), 6.65 (dd, J = 9.0, 2.6 Hz, 1H), 6.18 (d, J = 8.0 Hz, 1H), 3.71-3.81 (m, 1H), 3.03 (dd, J = 15.2, 4.8 Hz, 1H), 2.77-2.93 (m, 2H), 2.40-2.50 (m, 1H), 2.06-2.14 (m, 1H), 1.70-1.81 (m, 1H). MS: (ESI) m/z 365.0 (M + H)+. [00896] The synthesis of tert-Butyl (2-(6-chloro-3-((3,4-dichlorophenyl)amino)-3,4-dihydro-1H- carbazol-9(2H)-yl)ethyl)carbamate (123-4): The mixture of 6-chloro-N-(3,4-dichlorophenyl)-2,3,4,9- tetrahydro-1H-carbazol-3-amine (258 mg, 0.71 mmol), tert-butyl (2-bromoethyl)carbamate (238 mg, 1.06 mmol) and cesium carbonate (690 mg, 2.12 mmol) in DMF (2 mL) was heated at 90 °C for 16 hours. The mixture was cooled to room temperature and quenched with water (10 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The solvent was removed and the crude was purified by CC (petroleum ether/ethyl acetate = 4/1) to give 256 mg title compound in 71% yield as a pale brown solid. MS: (ESI) m/z 508.2 (M + H)+. [00897] The synthesis of 9-(2-Aminoethyl)-6-chloro-N-(3,4-dichlorophenyl)-2,3,4,9-tetrahydro- 1H-carbazol-3-amine (123-5): The mixture of tert-butyl (2-(6-chloro-3-((3,4-dichlorophenyl)amino)- 3,4-dihydro-1H-carbazol-9(2H)-yl)ethyl)carbamate (256 mg, 0.50 mmol) in TFA (10% in dichloromethane, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and used for the next step directly. [00898] The synthesis of (123-6): 9-(2-Aminoethyl)-6-chloro-N-(3,4-dichlorophenyl)-2,3,4,9- tetrahydro-1H-carbazol-3-amine (245 mg, 0.60 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H- pyrazol-1-yl)methylene)carbamate (186 mg, 0.60 mmol) and Et3N (122 mg, 1.21 mmol) in DMF (3 mL) was stirred at room temperature for 5 hours. The reaction was quenched with water (30 mL). The product was extracted with ethyl acetate (3 x 10 mL), dried over Na2SO4. The residue was purified by CC (petroleum ether/ethyl acetate = 9/1) to give 340 mg of title compound in 87% yield as a brown solid. [00899] 1H NMR (400 MHz, DMSO-d6) ^ 7.38 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 7.01 (dd, J = 8.4, 2.0 Hz, 1H), 6.80 (d, J = 2.8 Hz, 1H), 6.61 (dd, J = 8.8, 2.8 Hz, 1H), 4.18-4.30 (m, 2H), 3.60-3.80 (m, 3H), 3.08 (dd, J = 15.4, 5.0 Hz, 1H), 2.89 (t, J = 5.8 Hz, 2H), 2.54 (dd, J = 15.0, 8.2 Hz, 1H), 2.19-2.28 (m, 1H), 1.81-1.94 (m, 1H), 1.46 (s, 9H), 1.44 (s, 9H). MS: (ESI) m/z 550.2 (M + H)+. [00900] The synthesis of 1-(2-(6-Chloro-3-((3,4-dichlorophenyl)amino)-3,4-dihydro-1H-carbazol- 9(2H)-yl)ethyl)guanidine (SRI-33342): A solution of 123-6 (340 mg, 0.52 mmol) in TFA (15% in dichloromethane, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and basified with NaOH (10%). The product was extracted with ethyl acetate (3 x 10 mL), dried over Na2SO4, concentrated. The residue was purified by Prep-HPLC to provide title compound (167 mg, 71%) as a white solid. [00901] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.39 (s, 1.4H, formic acid), 7.37 (d, J = 2.0 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.18 (d, J = 8.8 Hz, 1H), 7.08 (dd, J = 8.6, 1.8 Hz, 1H), 6.79 (d, J = 2.8 Hz, 1H), 6.60 (dd, J = 8.8, 2.8 Hz, 1H), 4.19-4.31 (m, 2H), 3.71-3.81 (m, 1H), 3.57 (t, J = 5.6 Hz, 2H), 3.10 (dd, J = 15.2, 5.2 Hz, 1H), 2.88 (t, J = 5.6 Hz, 2H), 2.56 (dd, J = 15.2, 8.4 Hz, 1H), 2.25-2.31 (m, 1H), 1.83-1.94 (m, 1H). MS: (ESI) m/z 450.0 (M + H)+. [00902] Example 83: [00903] Example Route for Example 83 (SRI-33355): [00904] The synthesis of 7-Bromo-2,3,4,9-tetrahydro-1H-carbazole (125-1): To a solution of (3- bromophenyl)hydrazine hydrochloride (4.44 g, 45.24 mmol) in EtOH (60 mL) was added cyclohexanone (10.11 g, 45.24 mmol) and stirred at 80 °C for 16 hours. The reaction solution was concentrated and purified by CC (petroleum ether/ethyl acetate = 10/1) to give 1.75 g title compound in 35% yield as an off-white solid. MS: (ESI) m/z 248.3 (M -H)–. [00905] The synthesis of tert-Butyl 2-(7-bromo-3,4-dihydro-1H-carbazol-9(2H)-yl)ethylcarbamate (125-2): The mixture of 7-bromo-2,3,4,9-tetrahydro-1H-carbazole (1.75 g, 7.00 mmol), tert-butyl (2- bromoethyl)carbamate (1.57 g, .00 mmol) and cesium carbonate (4.56 g, 13.99 mmol) in DMF (50 mL) was heated at 90 °C for 16 hours. The mixture was cooled to room temperature and quenched with water (200 mL). The product was extracted with ethyl acetate (3 x 50 mL) and dried over Na2SO4. The solvent was removed and the crude was purified by CC (petroleum ether/ethyl acetate = 10/1) to give 1.0 g title compound in 36% yield as a white solid. MS: (ESI) m/z 391.3 (M - H)-. [00906] The synthesis of tert-Butyl 2-(7-(3,4-dichlorophenylamino)-3,4-dihydro-1H-carbazol- 9(2H)-yl)ethylcarbamate (125-3): tert-butyl 2-(7-bromo-3,4-dihydro-1H-carbazol-9(2H)- yl)ethylcarbamate (1.0 g, 2.54 mmol), 3,4-dichloroaniline (412 mg, 2.54 mmol), tris(dibenzylideneacetone)dipalladium(0) (294 mg, 0.254 mmol), tert-butylbrett-Phos (246 mg, 0.508 mmol) and cesium carbonate (1.66 g, 5.08 mmol) were dissolved in tert-butanol (60 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by CC (petroleum ether/ethyl acetate = 10/1-5/1) to give 1.0 g title compound in 83% yield as yellow oil. [00907] The synthesis of 9-(2-Aminoethyl)-N-(3,4-dichlorophenyl)-2,3,4,9-tetrahydro-1H- carbazol-7-amine (125-4): A solution of tert-butyl 2-(7-(3,4-dichlorophenylamino)-3,4-dihydro-1H- carbazol-9(2H)-yl)ethylcarbamate (447 mg, 0.942 mmol) in TFA (10% in dichloromethane, 30 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and used for the next step directly. MS: (ESI) m/z 374.2 (M + H)+. [00908] The synthesis of (E)-tert-Butyl (tert-butoxycarbonylamino)(2-(7-(3,4- dichlorophenylamino)-3,4-dihydro-1H-carbazol-9(2H)-yl)ethylamino)methylenecarbamate (125-5): 9-(2-aminoethyl)-N-(3,4-dichlorophenyl)-2,3,4,9-tetrahydro-1H-carbazol-7-amine (353 mg, 0.942 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (292 mg, 0.942 mmol) and Et3N (191 mg, 1.88 mmol) in DMF (15 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water (40 mL). The product was extracted with ethyl acetate (3x20 mL) and dried over Na2SO4. The residue was purified by CC (petroleum ether/ ethyl acetate = 10/1) to give 540 mg of title compound in 93% yield as a yellow solid. MS: (ESI) m/z 616.2 (M + H)+. [00909] The synthesis of 1-(2-(7-(3,4-Dichlorophenylamino)-3,4-dihydro-1H-carbazol-9(2H)- yl)ethyl)guanidine (SRI-33355): A solution of (E)-tert-butyl (tert-butoxycarbonylamino)(2-(7-(3,4- dichlorophenylamino)-3,4-dihydro-1H-carbazol-9(2H)-yl)ethylamino)methylenecarbamate (270 mg, 0.468 mmol) in TFA (20% in dichloromethane, 15 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and then the mixture was diluted with water (30 mL), basified with NaOH (10%) to pH=7. The product was extracted with ethyl acetate (3x20 mL), dried over Na2SO4 and then purified by Prep-HPLC to give 68 mg title compound in 37% yield as an off-white solid. [00910] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.40 (s, 1.16 H, formic acid), 7.33-7.36 (m, 2H), 7.16 (d, J = 1.6 Hz, 1H), 7.04 (d, J = 2.8 Hz, 1H), 6.92 (dd, J = 8.8, 2.4 Hz, 1H), 6.82 (dd, J = 8.8, 2.4 Hz, 1H), 4.10 (t, J = 6.0 Hz, 2H) , 3.42 (t, J = 6.0 Hz, 2H), 2.67-2.69 (m, 2H), 2.61-2.62 (m, 2H), 1.85-1.87 (m, 2H), 1.78-1.79 (m, 2H). MS: (ESI) m/z 522.2 (M + H)+. [00911] Example 84: [00913] The synthesis of 9-(2-Aminoethyl)-N-(3,4-dichlorophenyl)-2,3,4,9-tetrahydro-1H- carbazol-7-amine (125-4): A solution of tert-butyl 2-(7-(3,4-dichlorophenylamino)-3,4-dihydro-1H- carbazol-9(2H)-yl)ethylcarbamate (300 mg, 0.632 mmol) in TFA (10% in dichloromethane, 20 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and used for the next step directly. MS: (ESI) m/z 374.2 (M + H)+. [00914] The synthesis of N-(3,4-Dichlorophenyl)-9-(2-(4,5-dihydro-1H-imidazol-2- ylamino)ethyl)-2,3,4,9-tetrahydro-1H-carbazol-7-amine (SRI-33356): 9-(2-aminoethyl)-N-(3,4- dichlorophenyl)-2,3,4,9-tetrahydro-1H-carbazol-7-amine (237 mg, 0.632 mmol), 2-(methylthio)-4,5- dihydro-1H-imidazole hydroiodide (309 mg, 1.26 mmol) and Et3N (320 mg, 3.16 mmol) in THF/H2O (20/1, 21 mL) was stirred at 70 °C for 16 hours. The reaction solution was concentrated and then the mixture was diluted with water (30 mL), basified with NaOH (10%) to pH=7. The product was extracted with ethyl acetate (3x20 mL), dried over Na2SO4 and then purified by Prep-HPLC to give 68 mg title compound in 23% yield as an off-white solid. [00915] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.42 (s, 1.08 H, formic acid), 7.36 (d, J = 2.0 Hz, 1H), 7.33 (d, J = 1.6 Hz, 1H), 7.15 (d, J = 1.6 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 6.92 (dd, J = 8.8, 2.8 Hz, 1H), 6.82 (dd, J = 8.0, 1.6 Hz, 1H), 4.12 (t, J = 6.0 Hz, 2H) , 3.47 (s, 4 H), 3.42 (t, J = 6.0 Hz, 2H), 2.66-2.69 (m, 2H), 2.61-2.62 (m, 2H), 1.85-1.87 (m, 2H), 1.77-1.80 (m, 2H). MS: (ESI) m/z 442.2 (M + H)+. [00916] Example 85: [00918] The synthesis of 6-Bromo-3-chloro-9H-pyrido[2,3-b]indole (129-3): NCS (325 mg, 2.43 mmol, 1.0 eq) was added to a mixture of 6-bromo-9H-pyrido[2,3-b]indole (600 mg, 2.43 mmol, 1 eq) in DMF (12 mL) at room temperature. After stirring for 2 d, the solid was collected by filtration to give 609 mg of title compound in 89% yield as an off-white solid. [00919] 1H NMR (400 MHz, DMSO-d6) ^ 12.19 (s, 1H), 8.76 (d, J = 2.4 Hz, 1H), 8.48 (d, J = 2.0 Hz, 1H), 8.47 (d, J = 2.4 Hz, 1H), 7.63 (dd, J = 8.6, 1.8 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H). MS: (ESI) m/z 281.1 (M + H)+. [00920] The synthesis of 3-Chloro-N-(3,4-dichlorophenyl)-9H-pyrido[2,3-b]indol-6-amine (129- 4): 6-bromo-3-chloro-9H-pyrido[2,3-b]indole (609 mg, 2.16 mmol), 3,4-dichloroaniline (351 mg, 2.17 mmol), tris(dibenzylideneacetone)dipalladium(0) (99 mg, 0.11 mmol), tert-butylbrett-Phos (105 mg, 0.22 mmol) and cesium carbonate (705 mg, 2.16 mmol) were dissolved in tert-butanol (12 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by CC (petroleum ether/ethyl acetate = 3/1) to give 310 mg title compound in 40% yield as an off-white solid. [00921] 1H NMR (400 MHz, DMSO-d6) ^ 11.94 (s, 1H), 8.72 (d, J = 2.4 Hz, 1H), 8.41 (s, 1H), 8.40 (d, J = 2.4 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 9.2 Hz, 1H), 7.30 (dd, J = 8.6, 2.2 Hz, 1H), 7.06 (d, J = 2.8 Hz, 1H), 6.92 (dd, J = 8.8, 2.8 Hz, 1H). MS: (ESI) m/z 362.2 (M + H)+. [00922] The synthesis of tert-Butyl (2-(3-chloro-6-((3,4-dichlorophenyl)amino)-9H-pyrido[2,3- b]indol-9-yl)ethyl)carbamate (129-5): The mixture of 3-chloro-N-(3,4-dichlorophenyl)-9H- pyrido[2,3-b]indol-6-amine (311 mg, 0.86 mmol), tert-butyl (2-bromoethyl)carbamate (231 mg, 1.03 mmol) and cesium carbonate (838 mg, 2.57 mmol) in DMF (3 mL) was heated at 50 °C for 16 hours. The mixture was cooled to room temperature and quenched with water (30 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The solvent was removed and the crude was purified by CC (petroleum ether/ethyl acetate = 3/1) to give 394 mg title compound in 91% yield as a yellow solid. [00923] 1H NMR (400 MHz, DMSO-d6) ^ 8.75 (d, J = 2.4 Hz, 1H), 8.46 (s, 1H), 8.45 (d, J = 2.4 Hz, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.36 (dd, J = 8.4, 2.0 Hz, 1H), 7.05 (d, J = 2.8 Hz, 1H), 6.89-6.95 (m, 2H), 4.46 (t, J = 5.8 Hz, 2H), 3.33-3.39(m, 2H), 1.25 (s, 9H). MS: (ESI) m/z 505.0 (M + H)+. [00924] The synthesis of 9-(2-Aminoethyl)-3-chloro-N-(3,4-dichlorophenyl)-9H-pyrido[2,3- b]indol-6-amine (129-6): A solution of tert-butyl (2-(3-chloro-6-((3,4-dichlorophenyl)amino)-9H- pyrido[2,3-b]indol-9-yl)ethyl)carbamate (394 mg, 0.78 mmol) in TFA (10% in dichloromethane, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and used for the next step directly. [00925] The synthesis of (129-7): 9-(2-Aminoethyl)-3-chloro-N-(3,4-dichlorophenyl)-9H- pyrido[2,3-b]indol-6-amine (316 mg, 0.78 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H- pyrazol-1-yl)methylene)carbamate (242 mg, 0.78 mmol) and Et3N (158 mg, 1.56 mmol) in DMF (3 mL) was stirred at room temperature for 4 hours. The reaction was quenched with water (30 mL). The product was extracted with ethyl acetate (3 x 10 mL), dried over Na2SO4. The residue was purified by CC (petroleum ether/ethyl acetate = 3/1) to give 489 mg of title compound in 97% yield as a yellow solid. [00926] 1H NMR (400 MHz, DMSO-d6) ^ 11.29 (s, 1H), 8.72 (d, J = 2.4 Hz, 1H), 8.45 (t, J = 6.0 Hz, 1H), 8.43 (s, 1H), 8.42 (d, J = 2.4 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.28 (dd, J = 8.4, 2.0 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 6.90 (dd, J = 9.0, 2.6 Hz, 1H), 4.61 (t, J = 5.8 Hz, 2H), 3.72 (q, J = 5.8 Hz, 2H), 1.40 (s, 9H), 1.35 (s, 9H). MS: (ESI) m/z 647.0 (M + H)+. [00927] The synthesis of 1-(2-(3-Chloro-6-((3,4-dichlorophenyl)amino)-9H-pyrido[2,3-b]indol-9- yl)ethyl)guanidine (SRI-33357): A solution of 129-7 (489 mg, 0.75 mmol) in TFA (15% in dichloromethane, 15 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and basified with NaOH (10%). The product was extracted with dichloromethane (3 x 10 mL), dried over Na2SO4 concentrated. The residue was purified by Prep-HPLC to provide title compound (259 mg, 77%) as a yellow solid. [00928] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.67 (d, J = 2.4 Hz, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.40 (s, 0.67 H, formic acid), 8.02 (d, J = 2.0 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.41 (dd, J = 8.8, 2.0 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 2.8 Hz, 1H), 6.98 (dd, J = 9.0, 2.6 Hz, 1H), 4.59 (t, J = 5.4 Hz, 2H), 3.67 (t, J = 5.4 Hz, 2H). MS: (ESI) m/z 447.2 (M + H) +. [00929] Example 86: [00931] The synthesis of 6-Bromo-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazole (130-2): To a solution of 4,4-difluorocyclohexanone (1 g, 7.46 mmol) in EtOH (15 mL) was added (4- bromophenyl)hydrazine (1.39 g, 7.46 mmol). The mixture was stirred at 90 oC for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by CC (petroleum ether/ethyl acetate = 10:1) to give 1 g of title compound in 46.88% yield as a white solid. [00932] 1H NMR (400 MHz, DMSO-d6) ^ 11.15 (s, 1H), 7.58 (d, J = 1.6 Hz, 1H), 7.25 (d, J = 8.8 Hz, 1H), 7.14 (dd, J = 1.6, 8.4 Hz, 1H), 3.20 (t, J = 14.4 Hz, 2H), 2.92 (t, J = 8.4 Hz, 2H), 2.29-2.36 (m, 2H). MS: (ESI) m/z 284.0 (M - H)-. [00933] The synthesis of N-(3,4-Dichlorophenyl)-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6- amine (130-3): To a solution of 6-bromo-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazole (500 mg, 1.75 mmol) in t-BuOH (10 mL) was added 3,4-dichloroaniline (283.13 mg, 1.75 mmol), Cs2CO3 (1.71 g, 5.24 mmol), t-Bubrettphos (84.82 mg, 0.18 mmol) and Pd2(dba)3 (160.25 mg, 0.18 mmol). The mixture was stirred at 90 oC for 3 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate(50 mL x 2), the combined organic layers were washed with saturated brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 3:1) to give 650 mg of title compound in 97.39% yield as a white solid. MS: (ESI) m/z 365.0 (M - H)-. [00934] The synthesis of tert-Butyl 2-(6-(3,4-dichlorophenylamino)-3,3-difluoro-3,4-dihydro-1H- carbazol-9(2H)-yl)ethylcarbamate (130-4):To a solution of N-(3,4-dichlorophenyl)-3,3-difluoro- 2,3,4,9-tetrahydro-1H-carbazol-6-amine (600 mg, 1.63 mmol) in DMF (1 mL) was added tert-butyl 2- bromoethylcarbamate (366.15 mg, 1.63 mmol) and NaH (130.70 mg, 3.27 mmol). The mixture was stirred at 70 oC for 16 hours. The reaction mixture was quenched by addition saturated NH4Cl solution to adjust pH = 6 - 7, and extracted with EA (300 mL x2), the combined organic layers were washed with saturated brine (300 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA = 1:0 to 3:1) to give 230 mg of title compound in 27.58% yield as a yellow solid. MS: (ESI) m/z 508.2 (M - H) -. [00935] The synthesis of 9-(2-Aminoethyl)-N-(3,4-dichlorophenyl)-3,3-difluoro-2,3,4,9- tetrahydro-1H-carbazol-6-amine (130-5): A solution of tert-butyl 2-(6-(3,4-dichlorophenylamino)-3,3- difluoro-3,4-dihydro-1H-carbazol-9(2H)-yl)ethylcarbamate (230 mg, 0.45 mmol) in TFA (20% in dichloromethane, 10 mL) was stirred at room temperature for 2 hours. The reaction solution was concentrated and used for the next step directly. MS: (ESI) m/z 410.2 (M + H)–. [00936] The synthesis of tert-Butyl (tert-butoxycarbonylamino)(2-(6-(3,4-dichlorophenylamino)- 3,3-difluoro-3,4-dihydro-1H-carbazol-9(2H)-yl)ethylamino)methylenecarbamate (130-6): 9-(2- Aminoethyl)-N-(3,4-dichlorophenyl)-3,3-difluoro-2,3,4,9-tetrahydro-1H-carbazol-6-amine (230 mg, 0.56 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (173.98 mg, 0.56 mmol) and Et3N (1 mL) in DMF (5 mL) was stirred at room temperature for 1 hours. The reaction was quenched with water (50 mL). The product was extracted with ethyl acetate (3 x 50 mL), dried over Na2SO4. The residue was purified by CC (petroleum ether/ethyl acetate = 2/1) to give 300 mg of title compound in 82.01% yield as a yellow solid. MS: (ESI) m/z 652.2 (M + H)+. [00937] The synthesis of 1-(2-(6-(3,4-Dichlorophenylamino)-3,3-difluoro-3,4-dihydro-1H- carbazol-9(2H)-yl)ethyl)guanidine (SRI-33358): A solution of tert-butyl (tert- butoxycarbonylamino)(2-(6-(3,4-dichlorophenylamino)-3,3-difluoro-3,4-dihydro-1H-carbazol-9(2H)- yl)ethylamino)methylenecarbamate (300 mg, 0.46 mmol) in TFA (15% in dichloromethane, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (31.37 mg, 15.09%) as a white solid. [00938] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.42 (s, 1H, formic acid), 7.41 (d, J = 8.8 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 1.6 Hz, 1H), 6.95-6.97 (m, 2H), 6.85 (dd, J = 2.8, 8.8 Hz, 2H), 4.18-4.19 (m, 2H), 3.48-3.51 (m, 2H), 3.20 (t, J = 14 Hz, 2H), 2.90-2.95 (m, 2H), 2.33-2.38 (m, 2H). MS: (ESI) m/z 452.2 (M + H)+. [00939] Example 87: [00941] The synthesis of 6-Bromo-8-fluoro-2,3,4,9-tetrahydro-1H-carbazole (128-2):To a solution of (4-bromo-2-fluorophenyl)hydrazine hydrochloride (2.4 g, 9.94 mmol) in EtOH (60 mL) was added cyclohexanone (975 mg, 9.94 mmol) and stirred at 80 °C for 16 hours. The reaction solution was concentrated and purified by CC (petroleum ether/ethyl acetate = 10/1) to give 2.0 g title compound in 75% yield as a yellow solid. MS: (ESI) m/z 266.0 (M -H)–. [00942] The synthesis of tert-Butyl 2-(6-bromo-8-fluoro-3,4-dihydro-1H-carbazol-9(2H)- yl)ethylcarbamate (128-3): The mixture of 6-bromo-8-fluoro-2,3,4,9-tetrahydro-1H-carbazole (1.34 g, 5.00 mmol), tert-butyl (2-bromoethyl)carbamate (2.24 g, 10.00 mmol) and cesium carbonate (1.36 g, 10.00 mmol) in DMF (50 mL) was heated at 90 °C for 16 hours. The mixture was cooled to room temperature and quenched with water (200 mL). The product was extracted with ethyl acetate (3 x 50 mL) and dried over Na2SO4. The solvent was removed and the crude was purified by CC (petroleum ether/ethyl acetate = 10/1) to give 1.9 g title compound in 93% yield as a white solid. MS: (ESI) m/z 409.2 (M - H)-. [00943] The synthesis of tert-Butyl 2-(6-(3,4-dichlorophenylamino)-8-fluoro-3,4-dihydro-1H- carbazol-9(2H)-yl)ethylcarbamate (128-4): tert-butyl 2-(6-bromo-8-fluoro-3,4-dihydro-1H-carbazol- 9(2H)-yl)ethylcarbamate (820 mg, 1.99 mmol), 3,4-dichloroaniline (323 mg, 1.99 mmol), tris(dibenzylideneacetone)dipalladium(0) (294 mg, 0.254 mmol), tert-butylbrett-Phos (246 mg, 0.508 mmol) and cesium carbonate (1.30 g, 3.99 mmol) were dissolved in tert-butanol (30 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by CC (petroleum ether/ethyl acetate = 8/1) to give 900 mg title compound in 91% yield as brown oil. MS: (ESI) m/z 492.2 (M + H)+. [00944] The synthesis of 9-(2-Aminoethyl)-N-(3,4-dichlorophenyl)-8-fluoro-2,3,4,9-tetrahydro- 1H-carbazol-6-amine (128-5): A solution of tert-butyl 2-(6-(3,4-dichlorophenylamino)-8-fluoro-3,4- dihydro-1H-carbazol-9(2H)-yl)ethylcarbamate (492 mg, 0.999 mmol) in TFA (10% in dichloromethane, 30 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and used for the next step directly. MS: (ESI) m/z 392.2 (M + H)+. [00945] The synthesis of (E)-tert-Butyl (tert-butoxycarbonylamino)(2-(6-(3-chlorophenylamino)- 8-fluoro-3,4-dihydro-1H-carbazol-9(2H)-yl)ethylamino)methylenecarbamate (128-6): 9-(2- aminoethyl)-N-(3,4-dichlorophenyl)-8-fluoro-2,3,4,9-tetrahydro-1H-carbazol-6-amine (392 mg, 0.999 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (310 mg, 0.999 mmol) and Et3N (202 mg, 2.00 mmol) in DMF (15 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water (40 mL). The product was extracted with ethyl acetate (3x20 mL), dried over Na2SO4. The residue was purified by CC (petroleum ether/ ethyl acetate = 10/1) to give 580 mg of title compound in 97% yield as a white solid. MS: (ESI) m/z 634.2 (M + H)+. [00946] The synthesis of 1-(2-(6-(3,4-Dichlorophenylamino)-8-fluoro-3,4-dihydro-1H-carbazol- 9(2H)-yl)ethyl)guanidine (SRI-33364): A solution of (E)-tert-butyl (tert-butoxycarbonylamino)(2-(6- (3-chlorophenylamino)-8-fluoro-3,4-dihydro-1H-carbazol-9(2H)-yl)ethylamino)methylenecarbamate (600 mg, 0.945 mmol) in TFA (20% in dichloromethane, 40 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and then the mixture was diluted with water (30 mL), basified with NaOH (10%) to pH=7. The product was extracted with ethyl acetate (3x20 mL), dried over Na2SO4 and then purified by Prep-HPLC to give 141 mg title compound in 34% yield as a white solid.
[00950] The synthesis of 2-Chloroacridin-9(10H)-one (127-2):NCS (3.42 g, 25.61 mmol, 1.0 eq) was added to a mixture of acridin-9(10H)-one (5.0 g, 25.61 mmol, 1 eq) in DMF (100 mL) at room temperature. After stirring for 16 hours, the solid was collected by filtration to give 3.82 g of title compound in 65% yield as a yellow solid. MS: (ESI) m/z 230.3 (M + H)+. [00951] The synthesis of 2-Bromo-7-chloroacridin-9(10H)-one (127-3): NBS (3.48 g, 19.55 mmol, 1.0 eq) was added to a mixture of 2-chloroacridin-9(10H)-one (4.5 g, 19.55 mmol, 1 eq) in DMF (100 mL) at room temperature. After stirring for 16 hours, the solid was collected by filtration to give 4.4 g of title compound in 73% yield as a yellow solid. MS: (ESI) m/z 308.0 (M + H) +. [00952] The synthesis of 2-Bromo-7,9-dichloroacridine (127-4): A mixture of 2-bromo-7- chloroacridin-9(10H)-one (4.4 g, 14.26 mmol, 1.0 eq) in SOCl2 (100 mL) was heated to reflux for 24 hours. The reaction mixture was concentrated. The residue was neutralized with NaHCO3 solution. The solid was collected by filtration to give 3.7 g of title compound in 79% yield as a yellow solid. MS: (ESI) m/z 326.0 (M + H)+. [00953] The synthesis of N1-(2-Bromo-7-chloroacridin-9-yl)ethane-1,2-diamine (127-5): A mixture of 2-bromo-7,9-dichloroacridine (1.1 g, 3.36 mmol, 1.0 eq) in ethylenediamine (11 mL) was heated to 120 °C for 4 hours. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate (1000 mL), washed with water, brine, dried and concentrated. The residue washed with ethyl acetate to give 582 mg of title compound in 49% yield as a brown solid. MS: (ESI) m/z 350.4 (M + H) +. [00954] The synthesis of tert-Butyl (2-((2-bromo-7-chloroacridin-9-yl)amino)ethyl)carbamate (127-6): A mixture of N1-(2-bromo-7-chloroacridin-9-yl)ethane-1,2-diamine (582 mg, 1.66 mmol, 1.0 eq), Boc2O (544 mg, 2.49 mmol, 1.5 eq) and Et3N (336 mg, 3.32 mmol, 2.0 eq) in dichloromethane (10 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated. The residue was purified by CC (petroleum ether/ethyl acetate = 3/2) to give 370 mg of title compound in 49% yield as a yellow solid. MS: (ESI) m/z 450.0 (M + H)+. [00955] The synthesis of tert-Butyl (2-((2-chloro-7-((3,4-dichlorophenyl)amino)acridin-9- yl)amino)ethyl)carbamate (127-7): tert-butyl (2-((2-bromo-7-chloroacridin-9- yl)amino)ethyl)carbamate (370 mg, 0.82 mmol), 3,4-dichloroaniline (133 mg, 0.82 mmol), tris(dibenzylideneacetone)dipalladium(0) (76 mg, 0.083 mmol), tert-butylbrett-Phos (80 mg, 0.17 mmol) and cesium carbonate (268 mg, 0.82 mmol) were dissolved in tert-butanol (8 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by CC (petroleum ether/ethyl acetate = 1/3) to give 310 mg title compound in 30% yield as a brown solid. MS: (ESI) m/z 531.0 (M + H)+. [00956] The synthesis of N9-(2-Aminoethyl)-7-chloro-N2-(3,4-dichlorophenyl)acridine-2,9- diamine (SRI-33380): A solution of tert-butyl (2-((2-chloro-7-((3,4-dichlorophenyl)amino)acridin-9- yl)amino)ethyl)carbamate (132 mg, 0.25 mmol) in TFA (10% in dichloromethane, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated. The residue was dissolved in ethyl acetate and basified with Na2CO3 solution, washed with brine, dried and concentrated. The residue was purified by Prep-HPLC to provide title compound (60 mg, 56%) as a red solid. [00957] 1H NMR (400 MHz, DMSO-d6) ^ 8.92 (s, 1H), 8.38 (d, J = 2.0 Hz, 1H), 8.35 (s, 2H), 7.85 (d, J = 2.4 Hz, 1H), 7.71 (d, J = 9.2 Hz, 1H), 7.69 (d, J = 9.2 Hz, 1H), 7.56 (dd, J = 9.0, 2.2 Hz, 1H), 7.49 (dd, J = 9.2, 2.4 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.29 (d, J = 2.8 Hz, 1H), 7.11 (dd, J = 8.8, 2.8 Hz, 1H), 3.90 (t, J = 6.0 Hz, 2H), 3.10 (q, J = 6.2 Hz, 2H). MS: (ESI) m/z 431.0 (M + H)+. [00958] The synthesis of (127-9): N9-(2-Aminoethyl)-7-chloro-N2-(3,4-dichlorophenyl)acridine- 2,9-diamine (95 mg, 0.22 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1- yl)methylene)carbamate (69 mg, 0.22 mmol) and Et3N (45 mg, 0.44 mmol) in DMF (2 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water (10 mL). The product was extracted with ethyl acetate (3 x 10 mL), dried over Na2SO4 and concentrated in vacuum. The residue was purified by CC (petroleum ether/ethyl acetate = 1/3) to give 110 mg of title compound in 74% yield as brown oil. MS: (ESI) m/z 673.1 (M + H) +. [00959] The synthesis of 1-(2-((2-Chloro-7-((3,4-dichlorophenyl)amino)acridin-9- yl)amino)ethyl)guanidine (SRI-33379): A solution of 127-9 (489 mg, 0.75 mmol) in TFA (15% in dichloromethane, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and basified with NaOH (10%). The product was extracted with dichloromethane (3 x 10 mL), dried over Na2SO4 and concentrated. The residue was purified by Prep-HPLC to provide title compound (33.9 mg, 44%) as a red solid. [00960] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.36 (d, J = 2.0 Hz, 1H), 8.32 (s, 2H), 7.85-7.83 (m, 3H), 7.68 (dd, J = 9.2, 2.4 Hz, 1H), 7.59 (dd, J = 9.2, 2.4 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.35 (d, J = 2.8 Hz, 1H), 7.16 (dd, J = 8.8, 2.8 Hz, 1H), 3.92 (t, J = 6.0 Hz, 2H), 3.50 (t, J = 5.8 Hz, 2H). MS: (ESI) m/z 473.0 (M + H)+. [00961] Example 90: [00963] The synthesis of N1-(2-Bromo-7-chloroacridin-9-yl)-N2-methylethane-1,2-diamine (132- 1): A solution of 2-bromo-7,9-dichloroacridine (1.00 g, 3.06 mmol) in N1-methylethane-1,2-diamine (10 mL) was stirred at 120 °C for 4 hours. Concentrated and purified by CC (petroleum ether/ethyl acetate = 1/1- ethyl acetate) to give 0.70 g title compound in 63% yield as a yellow solid. MS: (ESI) m/z 364.2 (M + H)+. [00964] The synthesis of tert-Butyl 2-(2-bromo-7-chloroacridin-9- ylamino)ethyl(methyl)carbamate (132-2): N1-(2-bromo-7-chloroacridin-9-yl)-N2-methylethane-1,2- diamine (646 mg, 1.77 mmol), Boc2O (386 mg, 1.77 mmol) and Et3N (358 mg, 3.54 mmol) in DCM (20 mL) was stirred at room temperature for 16 hours. Concentrated and purified by CC (petroleum ether/ethyl acetate = 1/1) to give 0.70 g title compound in 85% yield as a yellow solid. MS: (ESI) m/z 464.0 (M + H)+. [00965] The synthesis of tert-Butyl 2-(2-chloro-7-(3,4-dichlorophenylamino)acridin-9- ylamino)ethyl(methyl)carbamate (132-3): tert-butyl 2-(2-bromo-7-chloroacridin-9- ylamino)ethyl(methyl)carbamate (696 mg, 1.50 mmol), 3,4-dichloroaniline (243 mg, 1.50 mmol), tris(dibenzylideneacetone)dipalladium(0) (173 mg, 0.15 mmol), tert-butylbrett-Phos (145 mg, 0.30 mmol) and cesium carbonate (976 mg, 3.00 mmol) were dissolved in tert-butanol (30 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by CC (petroleum ether/ethyl acetate = 1/1) then Prep-HPLC to give 260 mg title compound in 32% yield as a yellow solid. MS: (ESI) m/z 545.1 (M + H)+. [00966] The synthesis of 7-Chloro-N2-(3,4-dichlorophenyl)-N9-(2-(methylamino)ethyl)acridine- 2,9-diamine (SRI-33400): A solution of tert-butyl 2-(2-chloro-7-(3,4-dichlorophenylamino)acridin-9- ylamino)ethyl(methyl)carbamate (30 mg, 0.055 mmol) in HCl/dioxane (4 N, 5 mL) was stirred at room temperature for 16 hours. Then the solution was concentrated to give 5.31 mg of title compound in 22% yield as a red solid. [00967] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.73 (s, 1 H), 8.04 (s, 1 H),7.88-8.00 (m, 4H), 7.54 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 2.4 Hz, 1H),7.29 (dd, J = 8.8, 2.4 Hz, 1H), 4.44 (t, J = 4.8 Hz, 2H) , 3.49 (t, J = 5.6 Hz, 2H) , 2.63 (s, 3 H). MS: (ESI) m/z 445.0 (M + H)+. [00968] Example 91: [00970] The synthesis of 7-Bromo-1,2,3,4-tetrahydroacridin-9(10H)-one (134-2): To a solution of 2-amino-5-bromobenzoic acid (4.30 g, 19.90 mmol) in toluene (80 mL) was added cyclohexanone (5.86 g, 59.71 mmol) and stirred at 110 °C for 16 hours. The reaction solution was concentrated and then the mixture was diluted with water (50 mL), basified with Na2CO3 aqueous to pH=7. The product was extracted with ethyl acetate (3x50 mL), dried over Na2SO4, then concentrated and filtrated to give 330 mg of title compound in 6% yield as a gray solid. MS: (ESI) m/z 276.0 (M -H)–. [00971] The synthesis of 7-Bromo-9-chloro-1,2,3,4-tetrahydroacridine (134-3): A solution of 7- bromo-1,2,3,4-tetrahydroacridin-9(10H)-one (410 mg, 1.47 mmol) in POCl3 (5 mL) was stirred at 110 °C for 6 hours. The reaction solution was concentrated and then the mixture was diluted with water (20 mL), basified with Na2CO3 aqueous to pH=7. The product was extracted with ethyl acetate (3x20 mL), dried over Na2SO4, then concentrated and purified by CC (petroleum ether/ethyl acetate = 8/1- 4/1) to give 215 mg title compound in 49% yield as a yellow solid. MS: (ESI) m/z 296.0 (M + H) +. [00972] The synthesis of 9-Chloro-N-(3,4-dichlorophenyl)-5,6,7,8-tetrahydroacridin-2-amine (134-4): 7-Bromo-9-chloro-1,2,3,4-tetrahydroacridine (215 mg, 0.725 mmol), 3,4-dichloroaniline (178 mg, 0.725 mmol), tris(dibenzylideneacetone)dipalladium(0) (83 mg, 0.072 mmol), tert- butylbrett-Phos (70 mg, 0.144 mmol) and cesium carbonate (473 mg, 1.45 mmol) were dissolved in tert-butanol (10 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by CC (petroleum ether/ethyl acetate = 1/1) to give 200 mg title compound in 73% yield as a yellow solid. MS: (ESI) m/z 377.0 (M + H) +. [00973] The synthesis of tert-Butyl 2-(7-(3,4-dichlorophenylamino)-1,2,3,4-tetrahydroacridin-9- ylamino)ethylcarbamate (134-4a): 9-Chloro-N-(3,4-dichlorophenyl)-5,6,7,8-tetrahydroacridin-2- amine (178 mg, 0.471 mmol), tert-butyl 2-aminoethylcarbamate (76 mg, 0.471 mmol), tris(dibenzylideneacetone)dipalladium(0) (54 mg, 0.047 mmol), tert-butylbrett-Phos (46 mg, 0.094 mmol) and cesium carbonate (307 mg, 0.942 mmol) were dissolved in tert-butanol (10 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 6 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by CC (petroleum ether/ethyl acetate = 2/1) to give 50 mg title compound in 21% yield as a yellow solid. MS: (ESI) m/z 501.2 (M + H)+. [00974] The synthesis of 6-Chloro-3-(3,4-dichlorophenyl)-N-phenyl-9H-carbazol-2-amine (134- 5): A solution of tert-butyl 2-(7-(3,4-dichlorophenylamino)-1,2,3,4-tetrahydroacridin-9- ylamino)ethylcarbamate (50 mg, 0.100 mmol) in TFA (10% in dichloromethane, 8 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and used for the next step directly. MS: (ESI) m/z 401.3 (M + H)+. [00975] The synthesis of (Z)-tert-Butyl (tert-butoxycarbonylamino)(2-(7-(3,4- dichlorophenylamino)-1,2,3,4-tetrahydroacridin-9-ylamino)ethylamino)methylenecarbamate (134-6): 6-chloro-3-(3,4-dichlorophenyl)-N-phenyl-9H-carbazol-2-amine (40 mg, 0.100 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (31 mg, 0.100 mmol) and Et3N (21 mg, 0.199 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water (20 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The residue was purified by CC (petroleum ether/ ethyl acetate = 2/1) to give 50 mg of title compound in 78% yield as a yellow solid. MS: (ESI) m/z 643.2 (M + H)+. [00976] The synthesis of 1-(2-(7-(3,4-Dichlorophenylamino)-1,2,3,4-tetrahydroacridin-9- ylamino)ethyl)guanidine (SRI-33401): A solution of (Z)-tert-butyl (tert-butoxycarbonylamino)(2-(7- (3,4-dichlorophenylamino)-1,2,3,4-tetrahydroacridin-9-ylamino)ethylamino)methylenecarbamate (50 mg, 0.078 mmol) in TFA (10% in dichloromethane, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and then diluted with water (20 mL), basified with Na2CO3 aqueous to pH=7. The product was extracted with ethyl acetate (3x20 mL), dried over Na2SO4, then concentrated and purified by Prep-HPLC to give 3 mg of title compound in 9% yield as a red solid. [00980] The synthesis of 2-((4-Bromophenyl)amino)nicotinic acid (139-2): 2-aminonicotinic acid (2.0 g, 14.48 mmol), 1,4-dibromobenzene (13.66 mg, 57.92 mmol), tris(dibenzylideneacetone)dipalladium(0) (663 mg, 0.724 mmol), tert-butylbrett-Phos (702 mg, 1.45 mmol) and cesium carbonate (9.44 g, 28.96 mmol) were dissolved in tert-butanol (100 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 2 days. The mixture was cooled to room temperature and methanol was added, filtered through diatomite. The filtrate was concentrated and washed with ethyl acetate. The solid was removed by filtration. The filtrate was concentrated and dissolved in water, extracted with petroleum ether. The aqueous layer was acidified with 2 N HCl to pH 2-3. The resulting solid was collected by filtration to give 2.16 g title compound in 51% yield as a yellow solid. [00981] 1H NMR (400 MHz, DMSO-d6) ^ 13.71 (s, 1H), 10.55 (s, 1H), 8.41 (dd, J = 4.8, 2.0 Hz, 1H), 8.27 (dd, J = 7.6, 2.0 Hz, 1H), 7.73 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 9.2 Hz, 2H), 6.91 (dd, J = 7.6, 4.8 Hz, 1H). MS: (ESI) m/z 291.0 (M - H)-. [00982] The synthesis of 7-Bromobenzo[b][1,8]naphthyridin-5(10H)-one (139-3): A mixture of 2-((4-bromophenyl)amino)nicotinic acid (2.0 g, 6.82 mmol, 1.0 eq) and PPA (20.0 g) was heated to 120 °C for 3.5 hours. The reaction mixture was diluted with water, basified with NaHCO3 solution. The resulting solid was collected by filtration to give 1.8 g of the title compound in 96% yield as a gray solid. [00983] 1H NMR (400 MHz, DMSO-d6) ^ 12.43 (s, 1H), 8.83 (dd, J = 4.6, 2.2 Hz, 1H), 8.58 (dd, J = 8.0, 2.0 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H), 7.92 (dd, J = 8.8, 2.4 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.37 (dd, J = 7.8, 4.6 Hz, 1H). MS: (ESI) m/z 275.2 (M + H)+. [00984] The synthesis of 7-Bromo-5-chlorobenzo[b][1,8]naphthyridine (139-4): A mixture of 7-bromobenzo[b][1,8]naphthyridin-5(10H)-one (1.0 g, 3.64 mmol, 1.0 eq) in SOCl2 (20 mL) was heated to reflux for 3 hours. The reaction mixture was concentrated. The residue was diluted with water, basified with NaHCO3 solution. The product was extracted with ethyl acetate (3 x 200 mL), dried over Na2SO4 and concentrated in vacuum. The crude was used for the next step directly. MS: (ESI) m/z 293.0 (M + H)+. [00985] The synthesis of N1-(7-Bromobenzo[b][1,8]naphthyridin-5-yl)ethane-1,2-diamine (139- 5): A mixture of 7-bromo-5-chlorobenzo[b][1,8]naphthyridine (1.07 g, 3.65 mmol, 1.0 eq) in ethylenediamine (10 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate (1500 mL), washed with water, brine, dried and concentrated. The crude was used for the next step directly. MS: (ESI) m/z 317.0 (M + H)+. [00986] The synthesis of tert-Butyl (2-((7-bromobenzo[b][1,8]naphthyridin-5- yl)amino)ethyl)carbamate (139-6): A mixture of N1-(7-bromobenzo[b][1,8]naphthyridin-5-yl)ethane-1,2-diamine (800 mg, 2.52 mmol, 1.0 eq), Boc2O (606 mg, 2.78 mmol, 1.1 eq) and Et3N (255 mg, 2.52 mmol, 1.0 eq) in tetrahydrofuran (100 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated. The residue was purified by CC (ethyl acetate) to give 230 mg of title compound in 22% yield as a yellow solid. MS: (ESI) m/z 417.2 (M + H)+. [00987] The synthesis of tert-Butyl (2-((7-((3,4-dichlorophenyl)amino)benzo[b][1,8]naphthyridin- 5-yl)amino)ethyl)carbamate (139-7): tert-Butyl (2-((7-bromobenzo[b][1,8]naphthyridin-5-yl)amino)ethyl)carbamate (340 mg, 0.82 mmol), 3,4-dichloroaniline (132 mg, 0.82 mmol), tris(dibenzylideneacetone)dipalladium(0) (38 mg, 0.042 mmol), tert-butylbrett-Phos (40 mg, 0.083 mmol) and cesium carbonate (266 mg, 0.82 mmol) were dissolved in tert-butanol (30 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by CC (dichloromethane /methanol = 8/1) to give 380 mg title compound in 94% yield as a red solid. MS: (ESI) m/z 531.0 (M + H)+. [00988] The synthesis of N5-(2-Aminoethyl)-N7-(3,4-dichlorophenyl)benzo[b][1,8]naphthyridine- 5,7-diamine (139-8): A solution of tert-butyl (2-((7-((3,4-dichlorophenyl)amino)benzo[b][1,8]naphthyridin-5- yl)amino)ethyl)carbamate (380 mg, 0.76 mmol) in TFA (10% in dichloromethane, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated. The crude was used for the next step directly. MS: (ESI) m/z 398.3 (M + H)+. [00989] The synthesis of (139-9): N5-(2-Aminoethyl)-N7-(3,4-dichlorophenyl)benzo[b][1,8]naphthyridine-5,7-diamine (303 mg, 0.76 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (236 mg, 0.76 mmol) and Et3N (154 mg, 1.52 mmol) in DMF (6 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water (60 mL). The product was extracted with ethyl acetate (3 x 20 mL), dried over Na2SO4. The residue was purified by CC (ethyl acetate) to give 230 mg of title compound in 47% yield as a brown solid. MS: (ESI) m/z 640.2 (M + H)+. [00990] The synthesis of 1-(2-((7-((3,4-Dichlorophenyl)amino)benzo[b][1,8]naphthyridin-5- yl)amino)ethyl)guanidine (SRI-33422): A solution of 139-9 (40 mg, 0.0468 mmol) in HCl (4M in 1,4-dioxane, 3 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated to provide title compound (24 mg, 81%) as a red solid. [00991] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.99 (s, 1H), 8.85 (d, J = 3.6 Hz, 1H), 8.10 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.49-7.60 (m, 2H), 7.35 (d, J = 2.4 Hz, 1H), 7.18 (dd, J = 8.8, 2.4 Hz, 1H), 4.21-4.26 (m, 2H), 3.66 (t, J = 5.6 Hz, 2H). MS: (ESI) m/z 440.1 (M + H)+. [00992] Example 93: [00994] The synthesis of 1-(2-(4-Bromophenylamino)phenyl)ethanone (141-1): To a solution of 1-bromo-4-iodobenzene (5 g, 17.67 mmol) in Bu2O (50 mL) was added 1-(2-aminophenyl)ethanone (2.39 g, 17.67 mmol) , K2CO3 (4.89g, 35.35 mmol) and Cu (112.31 mg, 1.77 mmol). The mixture was stirred at 142 oC for 16 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate(100 mL x 2), the combined organic layers were washed with saturated brine (100 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 4:1) to give 3.4 g of title compound in 66.30% yield as a yellow solid. MS: (ESI) m/z 288.0 (M - H)-. [00995] The synthesis of 2-Bromo-9-methylacridine (141-2): Add 96% H2SO4 (1.5 mL) to 1-(2- (4-bromophenylamino)phenyl)ethanone (3.4 g, 11.72 mmol) in CH3COOH (30 mL). The reaction mixture was stirred 10 minutes at 110 °C. Cool the reaction mixture to room temperature. Add water (50 mL) to the reaction mixture. Basify the mixture using 25% NH3 ^H2O. Extract the mixture using EA (3 × 200 mL). The residue was purified by column chromatography (SiO2, PE/EA = 1:0 to 4:1) to give 2.6 g of title compound in 81.53 % yield as a yellow solid. MS: (ESI) m/z 272.0(M + H)+. [00996] The synthesis of 2-Bromo-9-(bromomethyl)acridine (141-3): To a solution of 2-bromo-9- methylacridine (200 mg, 0.74 mmol) in CCl4 (4 mL) was added NBS (156.96 mg, 0.88 mmol), BPO (18.2 mg, 73.5 μmol). The mixture was stirred at 80 oC for 3 hours. The organic compounds were extracted in DCM and washed two times with aqueous NaHCO3 and dried over anhydrous Na2SO4. The organic solvent was then removed under reduced pressure to give 220 mg of title compound in 85.28% yield as a yellow solid. MS: (ESI) m/z 350.0 (M + H)+. [00997] The synthesis of tert-Butyl 2-((2-bromoacridin-9-yl)methylamino)ethylcarbamate (141-4): A solution of 2-bromo-9-(bromomethyl)acridine (200 mg, 0.57 mmol) in tert-butyl 2- aminoethylcarbamate (2 mL) was stirred at 40 oC for 16 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 0:1) to give 150 mg of title compound in 61.18% yield as a yellow solid. MS: (ESI) m/z 430.2 (M + H)+. [00998] The synthesis of tert-Butyl 2-((2-(3,4-dichlorophenylamino)acridin-9- yl)methylamino)ethylcarbamate (141-5): To a solution of tert-butyl 2-((2-bromoacridin-9- yl)methylamino)ethylcarbamate (200 mg, 0.46 mmol) in t-BuOH (3 mL) was added 3,4- dichloroaniline (75.3 mg, 0.46 mmol), Cs2CO3 (454.28 mg, 1.39 mmol), t-Bubrettphos (22.5 mg, 46.48 μmol) and Pd2(dba)3 (42.6 mg, 46.48 μmol). The mixture was stirred at 90 oC for 3 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate(20 mL x 2), the combined organic layers were washed with saturated brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 0:1) to give 150 mg of title compound in 63.11% yield as a yellow solid. MS: (ESI) m/z 511.0 (M + H)+. [00999] The synthesis of N1-((2-(3,4-Dichlorophenylamino)acridin-9-yl)methyl)ethane-1,2- diamine (141-6): A solution of tert-butyl 2-((2-(3,4-dichlorophenylamino)acridin-9- yl)methylamino)ethylcarbamate (150 mg, 0.29 mmol) in TFA (20% in dichloromethane, 10 mL) was stirred at room temperature for 2 hours. The reaction solution was concentrated and used for the next step directly. [001000] The synthesis of (E)-tert-Butyl 1-(2-(3,4-dichlorophenylamino)acridin-9-yl)-10,10- dimethyl-8-oxo-9-oxa-2,5,7-triazaundecan-6-ylidenecarbamate (141-7): N1-((2-(3,4- Dichlorophenylamino)acridin-9-yl)methyl)ethane-1,2-diamine (150 mg, 0.36 mmol), tert-butyl (((tert- butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (169.76 mg, 0.55 mmol) and Et3N (1 mL) in DMF (5 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water (50 mL). The product was extracted with ethyl acetate (3 x 50 mL), dried over Na2SO4. The residue was purified by CC (petroleum ether/ethyl acetate = 2/1) to give 35 mg of title compound in 14.68% yield as a yellow solid. MS: (ESI) m/z 653.2 (M + H)+. [001001] The synthesis of 1-(2-((2-(3,4-dichlorophenylamino)acridin-9- yl)methylamino)ethyl)guanidine (SRI-33423): A solution of (E)-tert-butyl 1-(2-(3,4- dichlorophenylamino)acridin-9-yl)-10,10-dimethyl-8-oxo-9-oxa-2,5,7-triazaundecan-6- ylidenecarbamate (35 mg, 53.55 μmol) in TFA (15% in dichloromethane, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (24.26 mg, 99.93%) as a white solid. [001002] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.70 (d, J = 8.8 Hz, 1H), 8.31-8.34 (m, 2H), 7.90-7.99 (m, 3H), 7.78-7.82 (m, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.52 (dd, J = 2.8, 8.8 Hz, 1H), 5.26 (s, 2H), 3.65-6.69 (m, 2H). MS: (ESI) m/z 453.2 (M + H)+. [001003] Example 94: To a solution of (2-aminophenyl)(4-bromophenyl)methanone (2 g, 7.24 mmol) in DMSO (20 mL) was added t-BuOK (2.44 g, 21.72 mmol). The mixture was stirred at room temperature for 6 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate(50 mL x 2), the combined organic layers were washed with saturated brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give 1.8 g of title compound in 90.66% yield as a yellow solid. MS: (ESI) m/z 274.1 (M + H)+. [001006] The synthesis of 3-Bromo-9-chloroacridine (136-3): A solution of 3-bromoacridin-9(10H)-one (1.8mg, 7.56 mmol) in SOCl2 (20 mL) was stirred at 90 oC for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was used saturated Na2CO3 to adjust the pH = 7 - 8. The mixture was filtered and concentrated under reduced pressure to give 1.6 g of title compound in 83.3% yield as a yellow solid. MS: (ESI) m/z 292.0(M + H)+. [001007] The synthesis of tert-Butyl 2-(3-bromoacridin-9-ylamino)ethylcarbamate (136-4): A solution of 3-bromo-9-chloroacridine (500 mg, 1.71 mmol) in tert-butyl 2-aminoethylcarbamate (3 mL) and stirred at 40oC for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 3:1) to give 320 mg of title compound in 44.98% yield as a white solid. MS: (ESI) m/z 416.0 (M + H)+. [001008] The synthesis of tert-Butyl 2-(3-(3,4-dichlorophenylamino)acridin-9- ylamino)ethylcarbamate (136-5): To a solution of tert-butyl 2-(3-bromoacridin-9-ylamino)ethylcarbamate (300 mg, 0.72 mmol) in t- BuOH (5 mL) was added 3,4-dichloroaniline (116.75 mg, 0.72 mmol), Cs2CO3 (704.37 mg, 2.16 mmol), t-Bubrettphos (34.9 mg, 72.06 μmol) and Pd2(dba)3 (65.98 mg, 72.06 μmol). The mixture was stirred at 90 oC for 3 hours. The reaction mixture was filtered to give filtrate. The filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE/EA = 1:0 to 0:1) to give 130 mg of title compound in 36.27% yield as a white solid. MS: (ESI) m/z 497.1 (M + H)+. [001009] The synthesis of N9-(2-Aminoethyl)-N3-(3,4-dichlorophenyl)acridine-3,9-diamine (136- 6): A solution of tert-butyl 2-(3-(3,4-dichlorophenylamino)acridin-9-ylamino)ethylcarbamate (130 mg, 0.26 mmol) in TFA (20% in dichloromethane, 10 mL) was stirred at room temperature for 2 hours. The reaction solution was concentrated and used for the next step directly. [001010] The synthesis of (136-7): N9-(2-Aminoethyl)-N3-(3,4-dichlorophenyl)acridine-3,9-diamine (130 mg, 0.33 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (152.32 mg, 0.49 mmol) and Et3N (1 mL) in DMF (5 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water (50 mL). The product was extracted with ethyl acetate (3 x 50 mL), dried over Na2SO4. The residue was purified by CC (petroleum ether/ethyl acetate = 2/1) to give 30 mg of title compound in 14.34% yield as a yellow solid. MS: (ESI) m/z 639.2 (M + H)+. [001011] The synthesis of 1-(2-(3-(3,4-Dichlorophenylamino)acridin-9-ylamino)ethyl)guanidine (SRI-33424): A solution of 136-7 (30 mg, 46.91 μmol) in TFA (15% in dichloromethane, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by Prep-HPLC to provide title compound (14.54 mg, 70.56%) as a white solid. [001012] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.53 (d, J = 8.8 Hz, 1H), 8.38 (d, J = 9.2 Hz, 1H), 7.91 (t, J = 7.6 Hz, 1H), 7.67-7.74 (m, 2H), 7.58 (d, J = 1.6 Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H), 7.36 (d, J = 8.8 Hz, 1H), 7.28 (s, 1H), 7.18 (d, J = 8.4 Hz, 2H), 4.18 (d, J = 4.0 Hz, 2H), 3.76 (d, J = 6.0 Hz, 2H). MS: (ESI) m/z 439.3 (M + H)+. [001013] Example 95: [001014] Example Route for Example 95 (SRI-33442):
[001015] The synthesis of Methyl 3-(phenylamino)picolinate (138-2): Methyl 3-aminopicolinate (1.0 g, 6.57 mmol), bromobenzene (2.06 g, 13.14 mmol), tris(dibenzylideneacetone)dipalladium(0) (301 mg, 0.33 mmol), tert-butylbrett-Phos (319 mg, 0.66 mmol) and cesium carbonate (2.14 g, 6.57 mmol) were dissolved in tert-butanol (20 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by CC (petroleum ether/ethyl acetate = 3/1) to give 1.18 g title compound in 79% yield as a pale brown solid. [001016] 1H NMR (400 MHz, DMSO-d6) ^ 9.19 (s, 1H), 8.07 (dd, J = 4.2, 1.4 Hz, 1H), 7.63 (dd, J = 8.6, 1.4 Hz, 1H), 7.42 (dd, J = 8.4, 4.0 Hz, 1H), 7.38 (dd, J = 8.4, 7.2 Hz, 2H), 7.26 (dd, J = 8.4, 0.8 Hz, 2H), 7.10-7.15 (m, 1H), 3.87 (s, 3H). MS: (ESI) m/z 229.2 (M + H)+. [001017] The synthesis of methyl 3-((4-bromophenyl)amino)picolinate (138-3): NBS (889 mg, 4.99 mmol, 1.0 eq) was added to a mixture of methyl 3-(phenylamino)picolinate (1.14 g, 4.99 mmol, 1 eq) in dichloromethane (120 mL) at -78 °C. The reaction mixture was warmed to room temperature and stirred for 16 hours. The solvent was removed and the crude was purified by CC (petroleum ether/ethyl acetate = 3/2) to give 1.50 g title compound in 98% yield as an off-white solid. [001018] 1H NMR (400 MHz, DMSO-d6) 9.12 (s, 1H), 8.11 (dd, J = 4.4, 1.2 Hz, 1H), 7.66 (dd, J = 8.8, 1.6 Hz, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.44 (dd, J = 8.6, 4.6 Hz, 1H), 7.21 (d, J = 8.8 Hz, 2H), 3.87 (s, 3H). MS: (ESI) m/z 307.0 (M + H)+. [001019] The synthesis of 3-((4-Bromophenyl)amino)picolinic acid (138-4): A mixture of compound methyl 3-((4-bromophenyl)amino)picolinate (1.50 g, 4.88 mmol, 1.0 eq) and LiOH.H2O (410 mg, 9.77 mmol, 2.0 eq) in tetrahydrofuran/methanol/water (1:1:1, 90 mL) was stirred at room temperature for 16 hours. The solvent was removed and the aqueous layer was acidified with 2N HCl to pH = 2~3. The resulting solid was collected by filtration to give 1.40 g title compound in 98% yield as a yellow solid. [001020] 1H NMR (400 MHz, DMSO-d6) 9.91 (s, 1H), 8.08 (d, J = 3.6 Hz, 1H), 7.76 (dd, J = 8.8, 1.2 Hz, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.50 (dd, J = 8.6, 4.6 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H). MS: (ESI) m/z 293.2 (M + H)+. [001021] The synthesis of 8-Bromobenzo[b][1,5]naphthyridin-10(5H)-one (138-5): A mixture of 3-((4-bromophenyl)amino)picolinic acid (1.44 g, 4.91 mmol, 1.0 eq) and PPA (15.0 g) was heated to 120 °C for 24 hours. The reaction mixture was diluted with water, basified with NaHCO3 solution. The resulting solid was collected by filtration to give 1.3 g of title compound in 96% yield as a brown solid. [001022] 1H NMR (400 MHz, DMSO-d6) ^ 12.01 (s, 1H), 8.64 (dd, J = 4.0, 1.6 Hz, 1H), 8.34 (d, J = 2.4 Hz, 1H), 7.99 (dd, J = 8.4, 1.2 Hz, 1H), 7.89 (dd, J = 8.8, 2.4 Hz, 1H), 7.74 (dd, J = 8.6, 4.6 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H). MS: (ESI) m/z 275.2 (M + H)+. [001023] The synthesis of 8-Bromo-10-chlorobenzo[b][1,5]naphthyridine (138-6): A mixture of 8-bromobenzo[b][1,5]naphthyridin-10(5H)-one (1.2 g, 4.36 mmol, 1.0 eq) in SOCl2 (50 mL) was heated to reflux for 6 hours. The reaction mixture was concentrated. The residue was diluted with water, basified with NaHCO3 solution. The product was extracted with ethyl acetate (3 x 200 mL), dried over Na2SO4 and concentrated in vacuum. The crude was used for the next step directly. [001024] 1H NMR (400 MHz, DMSO-d6) ^ 9.25 (dd, J = 3.6, 1.6 Hz, 1H), 8.63 (d, J = 2.0 Hz, 1H), 8.61 (dd, J = 8.6, 1.4 Hz, 1H), 8.19 (d, J = 9.2 Hz, 1H), 8.09 (dd, J = 9.0, 2.2 Hz, 1H), 7.98 (dd, J = 8.8, 4.0 Hz, 1H). MS: (ESI) m/z 293.0 (M + H)+. [001025] The synthesis of tert-Butyl (2-((8-bromobenzo[b][1,5]naphthyridin-10- yl)amino)ethyl)carbamate (138-7): A mixture of compound 8-bromo-10-chlorobenzo[b][1,5]naphthyridine (800 mg, 2.73 mmol, 1.0 eq) in tert-butyl (2-aminoethyl)carbamate (8 mL) was stirred at 50 °C for 16 hours. The reaction mixture was purified by CC (petroleum ether/ethyl acetate = 2/3) to give 809 mg of title compound in 71% yield as a yellow solid. [001026] 1H NMR (400 MHz, DMSO-d6) ^ 8.72 (dd, J = 3.6, 1.6 Hz, 1H), 8.65 (s, 1H), 8.17 (dd, J = 8.8, 1.6 Hz, 1H), 8.03 (t, J = 5.4 Hz, 1H), 7.74-7.80 (m, 2H), 7.67 (dd, J = 8.8, 3.6 Hz, 1H) 7.06 (t, J = 5.4 Hz, 1H), 4.22-4.30 (m, 2H), 3.33-3.42 (m, 2H), 1.34 (s, 9H). MS: (ESI) m/z 417.2 (M + H) +. [001027] The synthesis of tert-Butyl (2-((8-((3,4- dichlorophenyl)amino)benzo[b][1,5]naphthyridin-10-yl)amino)ethyl)carbamate (138-8): tert-butyl (2-((8-bromobenzo[b][1,5]naphthyridin-10-yl)amino)ethyl)carbamate (300 mg, 0.72 mmol), 3,4-dichloroaniline (117 mg, 0.72 mmol), tris(dibenzylideneacetone)dipalladium(0) (66 mg, 0.072 mmol), tert-butylbrett-Phos (70 mg, 0.14 mmol) and cesium carbonate (235 mg, 0.72 mmol) were dissolved in tert-butanol (6 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 16 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by CC (ethyl acetate) to give 220 mg title compound in 61% yield as a pale brown solid. [001028] 1H NMR (400 MHz, DMSO-d6) ^ 8.78 (s, 1H), 8.71 (dd, J = 3.6, 1.2 Hz, 1H), 8.19 (dd, J = 8.8, 1.6 Hz, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.87 (d, J = 9.2 Hz, 1H), 7.64 (t, J = 5.6 Hz, 1H), 7.62 (dd, J = 8.8, 4.0 Hz, 1H), 7.53 (dd, J = 9.4, 2.2 Hz, 1H) 7.47 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 2.8 Hz, 1H), 7.15 (dd, J = 8.6, 2.6 Hz, 1H), 7.05 (t, J = 5.4 Hz, 1H), 4.05-4.15 (m, 2H), 3.32-3.38 (m, 2H), 1.31 (s, 9H). MS: (ESI) m/z 498.2 (M + H)+. [001029] The synthesis of N10-(2-Aminoethyl)-N8-(3,4- dichlorophenyl)benzo[b][1,5]naphthyridine-8,10-diamine (138-9): A solution of tert-butyl (2-((8-((3,4-dichlorophenyl)amino)benzo[b][1,5]naphthyridin-10- yl)amino)ethyl)carbamate (170 mg, 0.34 mmol) in TFA (20% in dichloromethane, 5 mL) was stirred at room temperature for 1 hour. The reaction solution was concentrated. The crude was used for the next step directly. MS: (ESI) m/z 398.2 (M + H)+. [001030] The synthesis of (138-10): N10-(2-Aminoethyl)-N8-(3,4-dichlorophenyl)benzo[b][1,5]naphthyridine-8,10-diamine (176 mg, 0.44 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (138 mg, 0.44 mmol) and Et3N (90 mg, 0.89 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water (50 mL). The product was extracted with ethyl acetate (3 x 20 mL), dried over Na2SO4. The residue was purified by CC (ethyl acetate) to give 280 mg of title compound in 99% yield as a brown solid. MS: (ESI) m/z 640.2 (M + H)+. [001031] The synthesis of 1-(2-((8-((3,4-Dichlorophenyl)amino)benzo[b][1,5]naphthyridin-10- yl)amino)ethyl)guanidine (SRI-33442): A solution of 138-10 (60 mg, 0.094 mmol) in HCl (4M in 1,4-dioxane, 6 mL) was stirred at room temperature for 2 days. The reaction solution was concentrated to provide title compound (32 mg, 79%) as a red solid. [001032] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.89 (d, J = 2.8 Hz, 1H), 8.27 (dd, J = 8.8, 1.2 Hz, 1H), 8.17 (s, 1H), 7.95 (dd, J = 8.8, 4.0 Hz, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.23 (dd, J = 8.8, 2.4 Hz, 1H), 4.50-4.70 (m, 2H), 3.68 (t, J = 5.8 Hz, 2H). MS: (ESI) m/z 440.2 (M + H)+. [001033] Example 96: [001035] The synthesis of 2-(2-Bromoacridin-9-yl)acetonitrile (141-1): To a solution of 2-bromo- 9-(bromomethyl)acridine (1.2 g, 3.42 mmol) in ACN (15 mL) was added TMSCN (508.70 mg, 5.13 mmol) and TBAF (15 mL). The mixture was stirred at room temperature for 16 hours. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 0:1) to give 750 mg of title compound in 73.83% yield as a white solid. MS: (ESI) m/z 297.1 (M + H)+. [001036] The synthesis of 2-(2-(3,4-Dichlorophenylamino)acridin-9-yl)acetonitrile (141-2): To a solution of 2-(2-bromoacridin-9-yl)acetonitrile (400 mg, 1.35 mmol) in t-BuOH (10 mL) was added 3,4-dichloroaniline (218.09 mg, 1.35 mmol), Cs2CO3 (1.32 g, 4.04 mmol), t-Bubrettphos (65.43 mg, 0.14 mmol) and Pd2(dba)3 (123.62 mg, 0.14 mmol). The mixture was stirred at 90 oC for 3 hours. The reaction mixture was filtered to give filtrate. The filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:0 to 0:1) to give 300 mg of title compound in 58.92% yield as a yellow solid. MS: (ESI) m/z 378.1(M + H)+. [001037] The synthesis of 9-(2-Aminoethyl)-N-(3,4-dichlorophenyl)acridin-2-amine (142-3): To a solution of 2-(2-(3,4-dichlorophenylamino)acridin-9-yl)acetonitrile (200 mg, 0.52 mmol) in MeOH (5 mL) was added Raney Nickel (10 mg) and NH3.H2O (0.5 mL). The mixture was stirred at 25 oC for 16 hours under H2. The reaction mixture was filtered to give filtrate. The filtrate was concentrated to give 200 mg crude of title compound as a white solid. MS: (ESI) m/z 382.1 (M + H)+. [001038] The synthesis of (E)-tert-Butyl (tert-butoxycarbonylamino)(2-(2-(3,4- dichlorophenylamino)acridin-9-yl)ethylamino)methylenecarbamate (142-4): 9-(2-aminoethyl)-N-(3,4- dichlorophenyl)acridin-2-amine (200 mg, 0.52 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H- pyrazol-1-yl)methylene)carbamate (243.5 mg, 0.78 mmol) and Et3N (1 mL) in DMF (5 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water (50 mL). The product was extracted with ethyl acetate (3 x 50 mL), dried over Na2SO4. The residue was purified by CC (petroleum ether/ethyl acetate = 2/1) to give 160 mg of title compound in 61.21% yield as a yellow solid. MS: (ESI) m/z 624.3 (M + H)+. [001039] The synthesis of 1-(2-(2-(3,4-Dichlorophenylamino)acridin-9-yl)ethyl)guanidine (SRI- 33443): A solution of (E)-tert-butyl (tert-butoxycarbonylamino)(2-(2-(3,4- dichlorophenylamino)acridin-9-yl)ethylamino)methylenecarbamate (70 mg, 112.08 μmol) in TFA (15% in dichloromethane, 10 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by Prep-HPLC to provide the title compound (41.73 mg, 87.75%) as a white solid. [001040] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.54 (d, J = 9.2 Hz, 1H), 8.31-8.37 (m, 2H), 8.11-8.15 (m, 1H), 8.07 (dd, J = 2.0, 9.2 Hz, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.85-7.89 (m, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 2.4 Hz,1H), 7.39 (dd, J = 2.8, 8.8 Hz, 1H), 3.91-3.94 (m, 2H), 3.65-3.69 (m, 2H). MS: (ESI) m/z 424.2 (M + H)+. [001041] Example 97: [001042] Example Route for Example 97 (SRI-33454):
[001043] The synthesis of 1-(2-(4-(Trifluoromethyl)phenylamino)phenyl)ethanone (140-2): 1-(2-Aminophenyl)ethanone (2.70 g, 19.98 mmol), 1-bromo-4-(trifluoromethyl)benzene (4.49 g, 19.98 mmol), tris(dibenzylideneacetone)dipalladium(0) (914 mg, 0.99 mmol), tert-butylbrett-Phos (968 mg, 2.00 mmol) and cesium carbonate (13.02 g, 9.95 mmol) were dissolved in tert-butanol (80 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by CC (petroleum ether/ethyl acetate = 5/1) to give 3.58 g title compound in 64% yield as a yellow solid. MS: (ESI) m/z 280.2 (M + H)+. [001044] The synthesis of 2-(Trifluoromethyl)acridin-9(10H)-one (140-3): 1-(2-(4-(Trifluoromethyl)phenylamino)phenyl)ethanone (3.58 g, 12.82 mmol) and copper(I) iodide (488 mg, 2.56 mmol) were dissolved in DMSO/PhCl (1/1, 50 mL). The reaction solution was heated at 140 °C for 16 hours under Air. The mixture was concentrated to remove PhCl then cooled to room temperature and diluted with water (100 mL). The product was extracted with ethyl acetate (3x50 mL), dried over Na2SO4 and then concentrated. The crude was filtered, washed by ethyl acetate and concentrated to give 1.36 g title compound in 40% yield as a yellow solid. MS: (ESI) m/z 264.2 (M + H)+. [001045] The synthesis of 2-Bromo-7-(trifluoromethyl)acridin-9(10H)-one (140-4): To a solution of 2-(trifluoromethyl)acridin-9(10H)-one (1.36 g, 5.17 mmol) in DMF (20 mL) was added NBS (919 mg, 5.17 mmol) in portions and stirred at room temperature for 48 hours. The reaction mixture was diluted with water (40 mL), filtrated, washed by water and then concentrated to give 1.68 g of title compound in 95% yield as a yellow solid. MS: (ESI) m/z 341.8 (M + H)+. [001046] The synthesis of 2-Bromo-9-chloro-7-(trifluoromethyl)acridine (140-5): A solution of 2-bromo-7-(trifluoromethyl)acridin-9(10H)-one (700 mg, 2.05 mmol) in SOCl2 (25 mL) was stirred at 80 °C for 4 hours. The reaction solution was concentrated and then the mixture was diluted with water (50 mL), basified with 2N NaOH to pH=7. The product was extracted with ethyl acetate (3x50 mL), dried over Na2SO4 and then concentrated to give 480 mg of title compound in 65% yield as a yellow solid. MS: (ESI) m/z 359.8 (M + H)+. [001047] The synthesis of tert-Butyl 2-(2-bromo-7-(trifluoromethyl)acridin-9- ylamino)ethylcarbamate (140-6): A solution of 2-bromo-9-chloro-7-(trifluoromethyl)acridine (480 mg, 1.33 mmol) in tert-butyl 2- aminoethylcarbamate (10 mL) was stirred at 40 °C for 16 hours. Concentrated and purified by CC (petroleum ether/ethyl acetate = 5/1- 2/1) to give 500 mg title compound in 77% yield as a yellow solid. MS: (ESI) m/z 483.9 (M + H)+. [001048] The synthesis of tert-Butyl 2-(2-(3,4-dichlorophenylamino)-7-(trifluoromethyl)acridin-9- ylamino)ethylcarbamate (140-7): Tert-butyl 2-(2-bromo-7-(trifluoromethyl)acridin-9-ylamino)ethylcarbamate (500 mg, 1.03 mmol), 3,4-dichloroaniline (167 mg, 1.03 mmol), tris(dibenzylideneacetone)dipalladium(0) (94 mg, 0.103 mmol), tert-butylbrett-Phos (100 mg, 0.206 mmol) and cesium carbonate (673 mg, 2.06 mmol) were dissolved in tert-butanol (20 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 80 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by CC (petroleum ether/ethyl acetate =3/1- 1/1) to give 77 mg title compound in 65% yield as a red solid. MS: (ESI) m/z 565.2 (M + H)+. [001049] The synthesis of N9-(2-Aminoethyl)-N2-(3,4-dichlorophenyl)-7- (trifluoromethyl)acridine-2,9-diamine (140-8): A solution of tert-butyl 2-(2-(3,4-dichlorophenylamino)-7-(trifluoromethyl)acridin-9- ylamino)ethylcarbamate (377 mg, 0.67 mmol) in TFA (10% in dichloromethane, 50 mL) was stirred at room temperature for 16 hours, the reaction solution was concentrated and used for the next step directly. [001050] The synthesis of (Z)-tert-Butyl (tert-butoxycarbonylamino)(2-(2-(3,4- dichlorophenylamino)-7-(trifluoromethyl)acridin-9-ylamino)ethylamino)methylenecarbamate (140-9): N9-(2-Aminoethyl)-N2-(3,4-dichlorophenyl)-7-(trifluoromethyl)acridine-2,9-diamine (310 mg, 0.67 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (207 mg, 0.67 mmol) and Et3N (135 mg, 1.33 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water (10 mL). The product was extracted with ethyl acetate (3x10 mL), dried over Na2SO4. The residue was purified by CC (petroleum ether/ethyl acetate = 3/1) to give 300 mg title compound in 64% yield as a red solid. [001051] The synthesis of 1-(2-(2-(3,4-Dichlorophenylamino)-7-(trifluoromethyl)acridin-9- ylamino)ethyl)guanidine (SRI-33454): A solution of (Z)-tert-butyl (tert-butoxycarbonylamino)(2-(2-(3,4-dichlorophenylamino)-7- (trifluoromethyl)acridin-9-ylamino)ethylamino)methylenecarbamate (60 mg, 0.085 mmol) in HCl/dioxane (4 N, 6 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with CH3CN(6 mL) and filtrated, washed by CH3CN, ethyl acetate and then concentrated to give 32 mg of title compound in 74% yield as a red solid. [001052] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.85 (s, 1 H),8.13 (d, J = 8.8 Hz, 1H),7.97-8.03 (m, 2H), 7.81-7.89 (m, 2H), 7.47 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.14 (dd, J = 8.8, 2.0 Hz, 1H), 4.17-4.23 (m, 2H), 3.59-3.65 (m, 2H). MS: (ESI) m/z 507.0 (M + H)+. [001053] Example 98: [001055] The synthesis of tert-Butyl (2-((2-chloro-7-((4-chlorophenyl)amino)acridin-9- yl)amino)ethyl)carbamate (145-2): tert-butyl (2-((2-bromo-7-chloroacridin-9- yl)amino)ethyl)carbamate (460 mg, 1.02 mmol), 4-chloroaniline (131 mg, 1.03 mmol), tris(dibenzylideneacetone)dipalladium(0) (47 mg, 0.05 mmol), tert-butylbrett-Phos (50 mg, 0.10 mmol) and cesium carbonate (333 mg, 1.02 mmol) were dissolved in tert-butanol (25 mL). The reaction solution was degassed and purged with N2 for 5-10 minutes and then heated at 90 °C for 3 hours. The mixture was cooled to room temperature and ethyl acetate was added, filtered through diatomite. Concentrated and purified by CC (petroleum ether/ethyl acetate = 1/4) to give 172 mg title compound in 34% yield as a brown solid. MS: (ESI) m/z 497.2 (M + H)+. [001056] The synthesis of N9-(2-Aminoethyl)-7-chloro-N2-(4-chlorophenyl)acridine-2,9-diamine (145-3): A solution of tert-butyl (2-((2-chloro-7-((4-chlorophenyl)amino)acridin-9- yl)amino)ethyl)carbamate (172 mg, 0.35 mmol) in TFA (5% in dichloromethane, 5 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated. The crude was used for the next step directly. MS: (ESI) m/z 397.3 (M + H)+. [001057] The synthesis of (145-4): N9-(2-Aminoethyl)-7-chloro-N2-(4-chlorophenyl)acridine-2,9- diamine (138 mg, 0.35 mmol), tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1- yl)methylene)carbamate (108 mg, 0.35 mmol) and Et3N (71 mg, 0.70 mmol) in DMF (2 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water (10 mL). The product was extracted with ethyl acetate (3 x 10 mL), dried over Na2SO4. The residue was purified by CC (petroleum ether/ethyl acetate = 2/3) to give 210 mg of title compound in 95% yield as brown oil. MS: (ESI) m/z 639.3 (M + H)+. [001058] The synthesis of 1-(2-((2-Chloro-7-((4-chlorophenyl)amino)acridin-9- yl)amino)ethyl)guanidine (SRI-33455): A solution of 145-4 (80 mg, 0.125 mmol) in HCl (4M in 1,4- dioxane, 5 mL) was stirred at room temperature for 16 hours. The reaction solution was concentrated to provide title compound (57 mg, 89%) as a red solid. [001059] 1H NMR (400 MHz, DMSO-d6 + D2O) ^ 8.55 (s, 1H), 7.85-7.97 (m, 4H), 7.80 (d, J = 9.2 Hz, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.8, 2H), 4.18-4.25 (m, 2H), 3.65 (t, J = 5.2 Hz, 2H). MS: (ESI) m/z 439.3 (M + H)+. [001060] Synthesis of key Intermediates for SRI-31268 analogs series:
[001061] The synthesis of 4-Chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (I-1): To a stirred solution of 2-bromo 4-chloroaniline (10g, 48 mmol) in anhydrous DMSO (140 mL) were added Bis(pinacolato) diborane (18 g, 72 mmol), Pd(dppf)Cl2.CH2Cl2 (1.2 g, 1.4 mmol) and KOAc (12.2 g, 124 mmol) simultaneously and degassed and purged with Argon for 10-15 minutes. The resulting mixture was stirred and heated at 80 oC for 20-22 hours. The solution was cooled to room temp and water (150 mL) was added. Salts were dissolved and filtered the solid. The solid was suspended into DCM (200 mL) and insoluble salts were filtered. The organic layer was dried over Na2SO4 and filtered. The solvent was concentrated, and the residue was purified on silica column (100 g) and eluted with 1-20% EtOAc in hexane to give 9 g of the title compound with 73% yield. [001062] 1H NMR (399 MHz, Chloroform-d) ^ 7.54 (d, J = 2.6 Hz, 1H), 7.13 (dd, J = 8.6, 2.7 Hz, 1H), 6.54 (dd, J = 8.6, 0.4 Hz, 1H), 1.33 (s, 12H). [001063] The synthesis of N-(4-Chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4- methylbenzenesulfonamide (I-2): To a solution of the aniline (19.2 g, 75.8 mmol) in pyridine (200 mL) was added p-toluenesulfonyl chloride (15.2 g, 79.9 mmol,) at 0 °C portion-wise. After being stirred at 25 °C for 2-3 hours, pyridine was removed by rotary evaporator and the reaction mixture was poured into water. The product was extracted with CH2Cl2 (500 mL, 100 mL), dried over MgSO4, and concentrated in vacuo. The residue was dissolved in minimum volume of CH2Cl2 and stirred for 15 minutes using rotavapor and started to form solids. Hexanes was added to the above solution to form solid and let it sit for 2-3 hours. The solids were filtered and dried under high vacuum to give 26 g of title compound in 85% yield. [001064] 1H NMR (399 MHz, Chloroform-d) ^ 8.48 (s, 1H), 7.62 - 7.54 (m, 4H), 7.34 (dd, J = 8.7, 2.6 Hz, 1H), 7.20 - 7.14 (m, 2H), 2.34 (s, 3H), 1.29 (d, J = 1.0 Hz, 12H). [001065] The synthesis of N-(3'-Bromo-5-chloro-5'-hydroxy-[1,1'-biphenyl]-2-yl)-4- methylbenzenesulfonamide (I-3): To a solution of 3, 5-dibromophenol (64g, 255 mmol, 4 eq)in 1,4- dioxane and H2O (500 mL, 1,4-dioxane : H2O = 1:1) were added PdCl2(dppf)∙CH2Cl2 (3.6 g, 3.1 mmol, 5 mol%), Na2CO3 (2 eq), and 4-chloro N-Ts-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)aniline (26 g, 63 mmol, 1.0 eq) under Ar. After being stirred at 90 oC for 14 hours, the reaction mixture was cooled to room temperature. EtOAc (1L) was added and the organic layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified on a small silica plug to give 20.5 g of title compound in 71% yield. [001066] 1H NMR (399 MHz, Chloroform-d) ^ 7.68 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 8.3 Hz, 2H), 7.33 (dd, J = 8.8, 2.5 Hz, 1H), 7.26 -7.20 (m, 2H), 7.05 (d, J = 2.5 Hz, 1H), 7.01 (dd, J = 2.3, 1.7 Hz, 1H), 6.45 (s, 1H), 6.31 - 6.22 (m, 2H), 2.43 (s, 3H); MS: (ESI) m/z 452.17 (M+H)+. [001067] The synthesis of 3-Bromo-6-chloro-9-tosyl-9H-carbazol-1-ol (I-4): N-(3'-bromo-5- chloro-5'-hydroxy-[1,1'-biphenyl]-2-yl)-4-methylbenzenesulfonamide (6g, 13.2 mmol, 1 eq), Pd(OAc)2, (0.44g, 1.99 mmol, 15 mol%), bathocuproine (0.71g, 1.99 mmol, 15 mol%), and NaOAc (1.3g, 16.5 mmol, 1.25 eq) were dissolved in mesitylene (105 mL, 0.1 M). The resulting mixture was stirred at 100 °C under aerobic conditions (in a closed 500 mL Round Bottom Flask with a Septa, used a balloon with Air). After 20-24 hours, the reaction was completed, the reaction mixture was concentrated in vacuo. Water was added to the residue and salts were dissolved. Filtered the solids and washed with hexanes to give ~7 g of title compound. (*Purification is done on silica gel for small scale but for scale up, the product is stuck on the silica gel). Next reaction is carried out with this material without further purification. [001068] 1H NMR (399 MHz, Chloroform-d) ^ 9.33 (d, J = 0.4 Hz, 1H), 8.22 (dd, J = 8.9, 0.5 Hz, 1H), 7.66 (dd, J = 2.2, 0.6 Hz, 1H), 7.44 (ddd, J = 9.0, 2.2, 0.5 Hz, 1H), 7.41 (dd, J = 1.9, 0.6 Hz, 1H), 7.40 - 7.37 (m, 2H), 7.24 (dd, J = 1.9, 0.5 Hz, 1H), 7.11 - 7.01 (m, 2H), 2.28 (s, 3H). [001069] The synthesis of 3-Bromo-6-chloro-9-tosyl-9H-carbazol-1-yl pivalate (I-5): Pivaloyl chloride (1.4 mL, 11.6 mmol) was added to a solution of 3-bromo-6-chloro-9-tosyl-9H-carbazol-1-ol (3.5g, 7.7 mmol), triethylamine (2 mL, 15.5 mmol) and DMAP (94 mg, 0.77 mmol) in dichloromethane (50 mL) and the mixture was stirred at room temperature for overnight. The solution was washed with saturated aqueous ammonium chloride solution, the organic layer was dried (MgSO4) and the solvent was evaporated. The residue was purified on silica gel to provide title compound (3.8 g, 91%) as solid. [001070] 1H NMR (399 MHz, Chloroform-d) ^ 8.19 (dt, J = 8.9, 0.5 Hz, 1H), 7.71 (dd, J = 1.9, 0.5 Hz, 1H), 7.64 (dt, J = 2.2, 0.6 Hz, 1H), 7.42 (ddd, J = 8.9, 2.2, 0.5 Hz, 1H), 7.33 - 7.28 (m, 2H), 7.22 (dd, J = 1.8, 0.5 Hz, 1H), 7.00 - 6.94 (m, 2H), 2.23 (s, 3H), 1.47 (d, J = 0.6 Hz, 9H). [001071] The synthesis of 6-Chloro-3-(phenylamino)-9-tosyl-9H-carbazol-1-yl pivalate (I-6): Aniline (113 mg, 1.2 mmol), palladium acetate (31 mg, 0.14 mmol) XPhos (89 mg, 0.14 mmol) and caesium carbonate (381 g, 1.17 mmol) were dissolved in 1,4-dioxane (8 mL). The reaction solution was degassed and purged with Argon for 5-10 minutes and then heated at 105 oC. A solution of bromo compound (500 mg, 0.93 mmol) in 1,4-dioxane (9 mL) was added to above solution over a period of 1.5 hours using syringe pump. The mixture was heated at 105-107 oC under argon for 20 hours (total reaction time: 22 h). The mixture was cooled to room temperature and ethyl acetate was added, filtered through celite. Concentrated and purified on silica gel to give 350 mg of the title compound in 68% yield. [001072] 1H NMR (399 MHz, Chloroform-d) ^ 8.15 (d, J = 8.9 Hz, 1H), 7.52 (d, J = 2.2 Hz, 1H), 7.39 - 7.34 (m, 2H), 7.32 - 7.27 (m, 3H), 7.22 (d, J = 2.2 Hz, 1H), 7.09 (dt, J = 7.6, 1.1 Hz, 2H), 7.00 (td, J = 7.2, 1.0 Hz, 1H), 6.96 (d, J = 7.9 Hz, 2H), 6.74 (d, J = 2.2 Hz, 1H), 2.22 (s, 3H), 1.46 (d, J = 1.3 Hz, 12H); MS (ESI): 547.04 (M+H)+. [001073] The synthesis of 6-Chloro-3-(phenylamino)-9-tosyl-9H-carbazol-1-ol (I-7): Lithium aluminum hydride (0.29 mL, 2.2M in 2-Methyl THF) was slowly added to precooled (acetone with dry ice) a solution of 6-chloro-3-(phenylamino)-9-tosyl-9H-carbazol-1-yl pivalate (350 mg, 0.63 mmol). Note, added LAH to walls of the flask not directly to the solution. After being stirred for 15- 20 minutes, the reaction was quenched with ice pieces and a few drops of water. The product was extracted with ethyl acetate (2x25 mL), dried over MgSO4. The residue was purified on silica gel to give 190 mg of title compound in 64% yield. [001074] 1H NMR (399 MHz, Chloroform-d) ^ 9.16 (d, J = 0.9 Hz, 1H), 8.21 - 8.13 (m, 1H), 7.61 - 7.55 (m, 1H), 7.41 - 7.36 (m, 3H), 7.31 (ddd, J = 8.4, 7.4, 0.9 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 7.08 - 7.04 (m, 2H), 7.04 - 6.96 (m, 2H), 6.81 - 6.75 (m, 1H), 2.29 (s, 3H); MS: (ESI) m/z 463.18 (M+H)+. [001075] The synthesis of tert-Butyl (3-((6-chloro-3-(phenylamino)-9-tosyl-9H-carbazol-1- yl)oxy)propyl)carbamate (I-8): Di-tert-butyl azodicarboxylate (DBAD) was added to a solution of 6- chloro-3-(phenylamino)-9-tosyl-9H-carbazol-1-ol (50 mg, 0.1 mmol), tert-butyl (3- hydroxypropyl)carbamate (28 mg, 0.16 mmol) and triphenyl phosphine (68 mg, 0.28 mmol) in 2- methyl THF (3 mL) and the mixture was stirred at room temperature for overnight. The solution was evaporated. The residue was purified on silica gel to provide title compound (52 mg, 77%) as solid. [001076] 1H NMR (399 MHz, Chloroform-d) ^ 8.17 (dd, J = 8.9, 0.5 Hz, 1H), 7.64 (dd, J = 2.2, 0.5 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.37 (dd, J = 8.9, 2.2 Hz, 1H), 7.34 - 7.27 (m, 2H), 7.13 - 7.07 (m, 4H), 7.04 - 6.96 (m, 1H), 6.68 (d, J = 2.0 Hz, 1H), 4.10 - 4.01 (m, 2H), 3.29 (q, J = 6.1 Hz, 2H), 2.32 (s, 3H), 1.94 (q, J = 6.2 Hz, 2H), 1.41 (s, 9H). [001077] The synthesis of tert-Butyl (3-((6-chloro-3-(phenylamino)-9H-carbazol-1- yl)oxy)propyl)carbamate (I-9): Lithium aluminum hydride (LAH) (0.12 mL, 2.2M in 2-Methyl THF) was slowly added to precooled (ice bath) a solution of tert-butyl (3-((6-chloro-3-(phenylamino)-9H- carbazol-1-yl)oxy)propyl)carbamate (70 mg, 0.63 mmol). Note, added LAH to walls of the flask not directly to the solution. After being stirred for 15-20 minutes at 0 oC, the reaction was warmed to room temperature and stirred another 2-3 hours by which time all od starting material has been consumed. The reaction was cooled back to 0 oC and quenched with ice pieces and a few drops of water. The product was extracted with dichloro methane (2x25 mL), dried over MgSO4. The residue was purified on silica gel to give 45 mg of title compound in 82% yield. [001078] 1H NMR (399 MHz, Chloroform-d) ^ 7.93 - 7.82 (m, 1H), 7.46 - 7.28 (m, 3H), 7.24 (s, 2H), 7.01 (s, 2H), 6.88 (s, 1H), 6.80 (s, 1H), 4.77 (s, 1H), 4.13 (d, J = 7.1 Hz, 2H), 3.51 - 3.39 (m, 2H), 2.03 - 1.98 (m, 2H), 1.44 (s, 9H); MS: (ESI) m/z 466.09 (M+H)+ . [001079] Example 99: [001080] Example Route for Example 99 (SRI-31270): The synthesis of 1-(3-Aminopropoxy)-6- chloro-N-phenyl-9H-carbazol-3-amine (SRI-0031270): Trifluoracetic acid (90 uL, 0.9 mmol) was added to a solution of tert-butyl (3-((6-chloro-3-(phenylamino)-9H-carbazol-1- yl)oxy)propyl)carbamate (45 mg, 0.09 mmol in dichloromethane (2 mL) and the mixture was stirred at room temperature for overnight. Concentrated and the residue was purified on C18 column (6g) and eluted with 5-95% acetonitrile in water (0.1%fromic acid) to provide title compound (17 mg, 49%) as brown solid. [001081] 1H NMR (399 MHz, Methanol-d4) ^ 8.45 (s, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.47 - 7.36 (m, 2H), 7.29 (dd, J = 8.6, 2.1 Hz, 1H), 7.24 - 7.11 (m, 2H), 7.05 - 6.97 (m, 2H), 6.85 (d, J = 1.7 Hz, 1H), 6.74 (tt, J = 7.3, 1.1 Hz, 1H), 4.28 (t, J = 5.7 Hz, 2H), 3.27 (t, J = 7.1 Hz, 2H), 2.25 (p, J = 6.5 Hz, 2H); MS (ESI): 366.13 (M+H)+ . [001082] Example 100: [001083] Example Route for Example 100 (SRI-31268):
[001084] Title compound was prepared following similar protocol for compound SRI-31270 except the reagent is 3-hydroxy propyl N,N’ diboc guanidine. [001085] The synthesis of 1-(3-N,N’-Dibocguanidinepropoxy)-6-chloro-N-phenyl-9H-carbazol-3- amine: 1H NMR (399 MHz, Chloroform-d) ^ 11.47 (s, 1H), 8.18 (d, J = 8.9 Hz, 1H), 7.51 (d, J = 8.1 Hz, 2H), 7.42 - 7.34 (m, 1H), 7.29 (dd, J = 8.4, 7.3 Hz, 1H), 7.18 - 7.05 (m, 3H), 6.96 (t, J = 7.3 Hz, 1H), 4.06 (t, J = 7.2 Hz, 2H), 3.55 (s, 2H), 2.32 (s, 3H), 2.02 - 1.94 (m, 2H), 1.43 (m, 18H); MS (ESI): 762.51 (M+H)+ . [001086] 1-(3-((6-Chloro-3-(phenylamino)-9H-carbazol-1-yl)oxy)propyl)guanidine (SRI-31268): 1H NMR (399 MHz, Methanol-d4) ^ 8.63 - 8.44 (m, 2H), 7.89 (dd, J = 2.1, 0.5 Hz, 1H), 7.48 - 7.34 (m, 2H), 7.28 (dd, J = 8.6, 2.1 Hz, 1H), 7.22 - 7.13 (m, 2H), 7.06 - 6.96 (m, 2H), 6.83 (d, J = 1.7 Hz, 1H), 6.74 (tt, J = 7.4, 1.1 Hz, 1H), 4.23 (t, J = 5.9 Hz, 2H), 3.51 (t, J = 6.9 Hz, 2H), 2.17 (p, J = 6.2 Hz, 2H); MS (ESI): 407.97 (M+H)+ . [001087] Example 101: [001088] Example Route for Example 101 (SRI-31269):
[001089] Title compound was prepared following similar protocol for compound SRI-31270 except the reagent is tert-butyl 3-hydroxypyrrolidine-1-carboxylate. [001090] tert-Butyl 3-((3-bromo-6-chloro-9-tosyl-9H-carbazol-1-yl)oxy)pyrrolidine-1- carboxylate: 1H NMR (300 MHz, Chloroform-d) ^ 7.59 (d, J = 9.1 Hz, 1H), 7.49 - 7.40 (m, 3H), 7.14 (d, J = 8.1 Hz, 2H), 6.95 (s, 1H), 3.60 (dd, J = 12.5, 4.6 Hz, 3H), 2.33 (s, 3H), 1.74 (d, J = 6.1 Hz, 2H), 1.47 (m, 9H); MS: (ESI) m/z 618.96 (M+H)+. [001091] 6-Chloro-N-phenyl-1-(pyrrolidin-3-yloxy)-9H-carbazol-3-amine (SRI-31269): 1H NMR (399 MHz, Methanol-d4) ^ 8.51 (s, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.51 - 7.40 (m, 2H), 7.29 (dd, J = 8.7, 2.1 Hz, 1H), 7.17 (t, J = 7.7 Hz, 2H), 7.00 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 1.8 Hz, 1H), 6.75 (t, J = 7.3 Hz, 1H), 5.28 (d, J = 4.5 Hz, 1H), 3.74 - 3.45 (m, 4H), 2.55 - 2.25 (m, 2H); MS (ESI): 378.08 (M+H)+. [001092] Example 102: l [001093] Example Route for Example 102 (SRI-31279):
[001094] Title compound was prepared following similar protocol for compound SRI-31270 except the reagent is p-chloro aniline. [001095] 6-Chloro-3-((4-chlorophenyl)amino)-9-tosyl-9H-carbazol-1-yl pivalate: 1H NMR (399 MHz, Chloroform-d) ^ 8.18 - 8.12 (m, 1H), 7.53 - 7.46 (m, 1H), 7.39 - 7.33 (m, 1H), 7.30 (d, J = 6.6 Hz, 2H), 7.25 - 7.20 (m, 2H), 7.16 (dd, J = 2.2, 0.5 Hz, 1H), 7.01 - 6.94 (m, 3H), 6.71 (dd, J = 2.2, 0.5 Hz, 1H), 2.22 (s, 3H), 1.47 - 1.45 (m, 8H); MS: (ESI) m/z 580.85 (M+H)+ . [001096] 6-Chloro-3-((4-chlorophenyl)amino)-9-tosyl-9H-carbazol-1-ol: 1H NMR (399 MHz, Chloroform-d) ^ 9.18 (s, 1H), 8.17 (dd, J = 8.9, 0.5 Hz, 1H), 7.56 (dd, J = 2.2, 0.5 Hz, 1H), 7.42 - 7.36 (m, 3H), 7.26 - 7.20 (m, 2H), 7.08 - 7.00 (m, 4H), 6.93 - 6.86 (m, 1H), 6.73 (d, J = 2.2 Hz, 1H), 2.26 (s, 3H); MS: (ESI) m/z 537.96 (M+H)+. [001097] tert-Butyl (3-((6-chloro-3-((4-chlorophenyl)amino)-9-tosyl-9H-carbazol-1- yl)oxy)propyl)carbamate: 1H NMR (300 MHz, Chloroform-d) ^ 8.18 (d, J = 8.9 Hz, 1H), 7.65 (d, J = 2.2 Hz, 1H), 7.46 (d, J = 8.3 Hz, 2H), 7.38 (dd, J = 8.9, 2.2 Hz, 1H), 7.23 (s, 1H), 7.11 (d, J = 8.2 Hz, 2H), 7.08 - 6.98 (m, 3H), 4.07 (t, J = 5.9 Hz, 2H), 3.29 (d, J = 5.9 Hz, 2H), 2.33 (s, 3H), 1.93 (d, J = 6.2 Hz, 2H); MS: (ESI) m/z 654.09 (M+H)+. [001098] 1-(3-Aminopropoxy)-6-chloro-N-(4-chlorophenyl)-9H-carbazol-3-amine (SRI-31279): 1H NMR (399 MHz, Methanol-d4) ^ 8.48 (s, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.46 - 7.38 (m, 2H), 7.31 (dd, J = 8.6, 2.0 Hz, 1H), 7.16 - 7.11 (m, 2H), 6.98 - 6.93 (m, 2H), 6.83 (d, J = 1.7 Hz, 1H), 4.29 (t, J = 5.7 Hz, 2H), 3.28 (d, J = 7.2 Hz, 2H), 2.27 (h, J = 7.3, 6.5 Hz, 2H); MS (ESI): 399.93 (M+H)+ . [001099] Example 103: [001101] Title compound was prepared following similar protocol for compound SRI-31270 except the reagent is 2-(dimethylamino)ethan-1-ol. [001102] 6-Chloro-N-(4-chlorophenyl)-1-(2-(dimethylamino)ethoxy)-9-tosyl-9H-carbazol-3- amine: 1H NMR (300 MHz, Chloroform-d) ^ 8.44 (s, 1H), 8.15 (d, J = 8.9 Hz, 1H), 7.71 - 7.62 (m, 2H), 7.59 (d, J = 2.2 Hz, 1H), 7.54 (dd, J = 7.3, 1.6 Hz, 1H), 7.50 - 7.44 (m, 2H), 7.37 (dd, J = 8.9, 2.1 Hz, 1H), 7.31 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 6.1 Hz, 1H), 7.12 - 6.99 (m, 5H), 6.75 (s, 1H), 4.48 (s, 2H), 3.36 (s, 2H), 2.79 (s, 6H); MS: (ESI) m/z 568.05 (M+H)+. [001103] 6-Chloro-N-(4-chlorophenyl)-1-(2-(dimethylamino)ethoxy)-9H-carbazol-3-amine (SRI- 31281): The purification was done on the reverse phase C18 column.1H NMR (399 MHz, Methanol- d4) ^ 8.48 (s, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.32 (dd, J = 8.6, 2.1 Hz, 1H), 7.16 - 7.11 (m, 2H), 6.99 - 6.93 (m, 2H), 6.86 (d, J = 1.7 Hz, 1H), 4.45 (t, J = 4.9 Hz, 2H), 3.50 (t, J = 5.0 Hz, 2H), 2.90 (s, 6H); MS (ESI): 414.01 (M+H)+. [001104] Example 104: [001105] Example Route for Example 104 (SRI-31280): Title compound was prepared following similar protocol for compound SRI-31270 except the reagent is 2 tert-butyl (2- hydroxyethyl)carbamate. [001106] tert-Butyl (2-((6-chloro-3-((4-chlorophenyl)amino)-9-tosyl-9H-carbazol-1- yl)oxy)ethyl)carbamate: 1H NMR (300 MHz, Chloroform-d) ^ 8.23 (d, J = 9.0 Hz, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.47 (d, J = 8.3 Hz, 2H), 7.44 - 7.38 (m, 1H), 7.24 (d, J = 7.0 Hz, 2H), 7.12 (d, J = 8.1 Hz, 2H), 7.06 (s, 1H), 6.99 (d, J = 8.5 Hz, 2H), 6.55 (s, 1H), 4.01 (t, J = 4.8 Hz, 2H), 3.49 (q, J = 5.2 Hz, 2H), 2.33 (s, 3H), 1.49 (m, 9H); MS: (ESI) m/z 640.12 (M+H)+. [001107] tert-Butyl (2-((6-chloro-3-((4-chlorophenyl)amino)-9H-carbazol-1- yl)oxy)ethyl)carbamate: 1H NMR (300 MHz, Chloroform-d) ^ 7.90 (s, 1H), 7.41 - 7.32 (m, 4H), 7.24 - 7.14 (m, 3H), 6.90 (m, 2H), 4.16 (m, 2H), 3.62 (s, 3H), 1.46 (s, 9H); MS: (ESI) m/z 486.03 (M+H)+ . [001108] 1-(2-Aminoethoxy)-6-chloro-N-(4-chlorophenyl)-9H-carbazol-3-amine (SRI-31280): 1H NMR (300 MHz, Methanol-d4) ^ 8.48 (s, 1H), 7.95 (s, 1H), 7.40 (d, J = 35.0 Hz, 3H), 7.14 (d, J = 8.5 Hz, 2H), 6.96 (d, J = 8.5 Hz, 2H), 6.86 (s, 1H), 4.45 – 4.35 (m, 2H), 3.55 – 3.40 (m, 2H); MS (ESI): 386.02 (M+H)+. [001109] Example 105: [001111] The synthesis of 1-(3-N,N’-Dibocguanidinepropoxy)-6-chloro-N-p-chlorophenyl-9H- carbazol-3-amine: A mixture of 1-(3-aminopropoxy)-6-chloro-N-(4-chlorophenyl)-9H-carbazol-3- amine (24) (24 mg, 0.06 mmol, N,N-diboc protected S-methylisothiourea (60 mg, 0.24 mmol trimethyl amine (66 µL, 0.48 mmol) in THF: water (2mL: 17 µL) were stirred at 50-55 oC for 4 hr. Concentrated and purified on silica gel to give 25 mg of title compound in 65% yield. [001112] 1H NMR (300 MHz, Chloroform-d) ^ 7.91 (s, 1H), 7.51 - 7.29 (m, 3H), 7.18 (s, 2H), 6.86 (s, 2H), 4.22 (s, 2H), 3.80 (s, 2H), 2.17 (t, J = 5.7 Hz, 2H), 1.50 (d, J = 2.1 Hz, 16H); MS: (ESI) m/z 642.09 (M+H)+. [001113] 1-(3-((6-Chloro-3-((4-chlorophenyl)amino)-9H-carbazol-1-yl)oxy)propyl)guanidine (SRI-31306): 1H NMR (399 MHz, Methanol-d4) ^ 8.53 (s, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.48 - 7.37 (m, 2H), 7.30 (dd, J = 8.6, 2.1 Hz, 1H), 7.18 - 7.07 (m, 2H), 7.01 - 6.89 (m, 2H), 6.81 (d, J = 1.7 Hz, 1H), 4.23 (t, J = 5.8 Hz, 2H), 3.52 (t, J = 6.9 Hz, 2H), 2.18 (p, J = 6.3 Hz, 2H); MS (ESI): 442.01 (M+H)+. [001114] Example 106: l [001115] Example Route for Example 106 (SRI-31307): Title compound was prepared following similar protocol for compound SRI-31270 except the reagent is tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate. [001116] tert-Butyl 2-(((6-chloro-3-((4-chlorophenyl)amino)-9-tosyl-9H-carbazol-1- yl)oxy)methyl)pyrrolidine-1-carboxylate: 1H NMR (399 MHz, Chloroform-d) ^ 8.19 (d, J = 8.9 Hz, 1H), 7.66 (d, J = 2.2 Hz, 1H), 7.51 (d, J = 8.3 Hz, 2H), 7.38 (dd, J = 9.0, 2.3 Hz, 1H), 7.25 - 7.22 (m, 1H), 7.16 - 7.11 (m, 1H), 7.08 (s, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.21 (s, 2H), 4.22 (s, 3H), 3.77 (s, 1H), 3.37 (s, 2H), 2.34 (s, 2H), 1.98 - 1.76 (m, 3H), 1.47 (s, 9H); MS: (ESI) m/z 680.11 (M+H)+ . [001117] tert-Butyl 2-(((6-chloro-3-((4-chlorophenyl)amino)-9H-carbazol-1- yl)oxy)methyl)pyrrolidine-1-carboxylate (33): 16884-24.1H NMR (399 MHz, Chloroform-d) ^ 7.89 (s, 1H), 7.40 - 7.30 (m, 3H), 7.20 - 7.13 (m, 2H), 6.89 (s, 2H), 6.73 (s, 1H), 4.27 (d, J = 46.6 Hz, 3H), 3.43 (s, 3H), 2.15 - 1.86 (m, 6H), 1.27 (s, 9H); MS: (ESI) m/z 526.04 (M+H)+. [001118] 6-Chloro-N-(4-chlorophenyl)-1-(pyrrolidin-2-ylmethoxy)-9H-carbazol-3-amine (SRI- 31308): 1H NMR (300 MHz, Methanol-d4) ^ 8.51 (s, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.51 - 7.39 (m, 2H), 7.32 (dd, J = 8.7, 2.1 Hz, 1H), 7.19 - 7.07 (m, 2H), 7.01 - 6.91 (m, 2H), 6.86 (d, J = 1.7 Hz, 1H), 4.48 (dd, J = 10.4, 3.4 Hz, 1H), 4.27 (dd, J = 10.4, 7.5 Hz, 1H), 4.13 (dd, J = 7.8, 3.5 Hz, 1H), 3.51 - 3.39 (m, 2H), 2.41 - 1.95 (m, 4H); MS (ESI): 426.00 (M+H)+. [001119] Example 107: [001120] Example Route for Example 107 (SRI-31308): 6-Chloro-N-(4-chlorophenyl)-1- (pyrrolidin-3-ylmethoxy)-9H-carbazol-3-amine (SRI-31308): Title compound was prepared following similar protocol for compound SRI-31270.1H NMR (300 MHz, Chloroform-d) ^ 8.44 (s, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.41 - 7.29 (m, 2H), 7.10 - 6.97 (m, 2H), 6.94 - 6.81 (m, 2H), 6.74 (d, J = 1.8 Hz, 1H), 4.25 - 3.93 (m, 2H), 3.59 - 3.48 (m, 1H), 3.47 - 3.34 (m, 1H), 3.33 - 3.24 (m,2H), 2.95 – 2.86 (m, 1H), 2.27 – 2.16 (m, 1H), 1.98 – 1.92 (m, 1H); MS (ESI): 426.00 (M+H)+. [001121] Example 108: Title compound was prepared following similar protocol for compound SRI-31306. [001123] 1-(2-((6-Chloro-3-((4-chlorophenyl)amino)-9H-carbazol-1-yl)oxy)ethyl)N,N-diboc guanidine: 1H NMR (300 MHz, Chloroform-d) ^ 11.56 (s, 1H), 9.07 (s, 1H), 7.91 (s, 1H), 7.40 (s, 1H), 7.35 (s, 2H), 7.18 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 8.3 Hz, 2H), 6.75 (s, 1H), 4.25 (t, J = 5.2 Hz, 2H), 3.96 (d, J = 5.3 Hz, 2H), 1.53 (d, J = 7.1 Hz, 18H); MS: (ESI) m/z 628.07 (M+H)+. [001124] 1-(2-((6-Chloro-3-((4-chlorophenyl)amino)-9H-carbazol-1-yl)oxy)ethyl)guanidine (SRI- 31317). Title compound was prepared following similar protocol for compound 31.1H NMR (300 MHz, Methanol-d4) ^ 8.51 (s, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.47 - 7.37 (m, 2H), 7.30 (dd, J = 8.6, 2.1 Hz, 1H), 7.17 - 7.10 (m, 2H), 6.99 - 6.91 (m, 2H), 6.83 (d, J = 1.7 Hz, 1H), 4.30 (t, J = 4.9 Hz, 2H), 3.71 (t, J = 5.0 Hz, 2H); MS (ESI): 428.05 (M+H)+. [001125] Example 109: [001126] Example Route for Example 109 (SRI-31326): 6-Chloro-N-(4-chlorophenyl)-1-(2-((4,5- dihydro-1H-imidazol-2-yl)amino)ethoxy)-9H-carbazol-3-amine (SRI-31326): Title compound was prepared following similar protocol for compound SRI-31306 except reagent is 2-methyl thio-2- imidazoline hydrohiodide and diisopropylethylamine in MeOH. [001127] 1H NMR (300 MHz, Methanol-d4) ^ 8.42 (s, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.37 - 7.31 (m, 2H), 7.22 (dd, J = 8.7, 2.0 Hz, 1H), 7.07 - 7.00 (m, 2H), 6.90 - 6.82 (m, 2H), 6.73 (d, J = 1.7 Hz, 1H), 4.21 (t, J = 5.0 Hz, 2H), 3.63 (m, 6H); MS (ESI): 454.08 (M+H)+. [001128] Example 110: [001129] Example Route for Example 110 (SRI-31327): Title compound was prepared following similar protocol for compound SRI-31270 except reagent is tert-butyl 3-(hydroxymethyl)azetidine-1- carboxylate. [001130] tert-Butyl 3-(((6-chloro-3-((4-chlorophenyl)amino)-9-tosyl-9H-carbazol-1- yl)oxy)methyl)azetidine-1-carboxylate: 1H NMR (300 MHz, Chloroform-d) ^ 8.17 (d, J = 8.9 Hz, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.39 (dd, J = 8.9, 2.2 Hz, 1H), 7.28 - 7.23 (m, 2H), 7.17 - 7.11 (m, 2H), 7.08 (d, J = 2.0 Hz, 1H), 7.00 (d, J = 8.7 Hz, 2H), 6.64 (d, J = 2.0 Hz, 1H), 4.16 (d, J = 7.3 Hz, 2H), 4.08 - 3.97 (m, 2H), 3.69 (dd, J = 9.0, 5.1 Hz, 2H), 2.97 – 2.85 (m, 1H), 2.34 (s, 3H), 1.43 (s, 9H; MS: (ESI) m/z 665.97 (M+H)+. [001131] 1-(Azetidin-3-ylmethoxy)-6-chloro-N-(4-chlorophenyl)-9H-carbazol-3-amine (40): 16884-41 (SRI-31327): 1H NMR (300 MHz, Methanol-d4 ^ 8.58 (s, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.48 - 7.41 (m, 2H), 7.32 (dd, J = 8.6, 2.1 Hz, 1H), 7.17 - 7.10 (m, 2H), 6.99 - 6.92 (m, 2H), 6.85 (d, J = 1.7 Hz, 1H), 4.35 - 4.19 (m, 6H), 3.48 – 3.35 (m, 1H); MS (ESI): 412.06 (M+H)+. [001132] Example 111: [001133] Example Route for Example 111 (SRI-31328): Title compound was prepared following similar protocol for compound SRI-31270 except reagent is tert-butyl 4-(hydroxymethyl)piperidine-1- carboxylate. [001134] tert-Butyl 4-(((6-chloro-3-((4-chlorophenyl)amino)-9-tosyl-9H-carbazol-1- yl)oxy)methyl)piperidine-1-carboxylate: 1H NMR (300 MHz, Chloroform-d) ^ 8.15 (d, J = 8.9 Hz, 1H), 7.69 - 7.60 (m, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.41 - 7.35 (m, 1H), 7.27 - 7.20 (m, 2H), 7.17 - 7.11 (m, 2H), 7.09 - 7.04 (m, 1H), 7.00 (d, J = 8.6 Hz, 2H), 6.61 (d, J = 2.0 Hz, 1H), 4.15 – 4.06 (m, 2H), 3.80 (d, J = 6.6 Hz, 2H), 2.66 (d, J = 11.7 Hz, 2H), 2.35 (s, 3H), 1.93 – 1.82 (m, 1H), 1.74 (d, J = 12.7 Hz, 2H), 1.47 (d, J = 1.7 Hz, 9H), 1.12 (qd, J = 12.6, 4.4 Hz, 2H); MS: (ESI) m/z 694.0 (M+H)+. [001135] 6-Chloro-N-(4-chlorophenyl)-1-(piperidin-4-ylmethoxy)-9H-carbazol-3-amine (42): 16884-42 (SRI-31328).1H NMR (300 MHz, Methanol-d4) ^ 8.52 (s, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.47 - 7.36 (m, 2H), 7.30 (dd, J = 8.7, 2.0 Hz, 1H), 7.13 (d, J = 8.8 Hz, 2H), 7.02 - 6.89 (m, 2H), 6.79 (s, 1H), 4.05 (d, J = 5.3 Hz, 2H), 3.55 - 3.41 (m, 2H), 3.06 (s, 2H), 2.22 (d, J = 13.9 Hz, 3H), 1.63 (s, 2H); MS (ESI): 440.09 (M+H)+. [001136] Example 112: [001137] Example Route for Example 112 (SRI-31329): Title compound was prepared following similar protocol for compound SRI-31270 except reagent is tert-butyl 4-(2-hydroxyethyl)piperazine- 1-carboxylate. [001138] tert-Butyl 4-(2-((6-chloro-3-((4-chlorophenyl)amino)-9-tosyl-9H-carbazol-1- yl)oxy)ethyl)piperazine-1-carboxylate: 1H NMR (300 MHz, Chloroform-d) ^ 8.20 (dd, J = 8.9, 0.5 Hz, 1H), 7.72 - 7.61 (m, 1H), 7.60 - 7.54 (m, 1H), 7.52 - 7.44 (m, 1H), 7.40 (ddd, J = 9.0, 7.1, 1.9 Hz, 2H), 7.26 - 7.21 (m, 2H), 7.17 - 7.09 (m, 2H), 7.06 (d, J = 2.1 Hz, 1H), 7.03 - 6.93 (m, 2H), 6.66 (d, J = 2.0 Hz, 1H), 5.78 (s, 2H), 4.15 (t, J = 6.0 Hz, 2H), 3.43 (t, J = 5.0 Hz, 2H), 2.76 (t, J = 6.1 Hz, 2H), 2.49 (t, J = 5.1 Hz, 2H), 2.33 (s, 3H), 1.25 (s, 9H); MS: (ESI) m/z 709.07 (M+H)+. [001139] 6-Chloro-N-(4-chlorophenyl)-1-(2-(piperazin-1-yl)ethoxy)-9H-carbazol-3-amine (SRI- 31329): 1H NMR (300 MHz, Methanol-d4) ^ 7.92 (d, J = 2.0 Hz, 1H), 7.42 (d, J = 8.7 Hz, 2H), 7.30 (dd, J = 8.7, 2.1 Hz, 1H), 7.17 - 7.10 (m, 2H), 6.99 - 6.91 (m, 2H), 6.83 (d, J = 1.7 Hz, 1H), 4.33 (t, J = 5.2 Hz, 2H), 3.28 - 3.20 (m, 4H), 3.05 (t, J = 5.2 Hz, 2H), 2.94 (t, J = 5.3 Hz, 4H); MS (ESI): 455.09 (M+H)+. [001140] Embodiments in accordance with the present disclosure are directed to compounds which provide antimicrobial activity and/or inhibit LOX enzymes. In various embodiments, the compounds may provide antimicrobial activity against a panel of bacteria, such as those described above, and/or inhibit various LOX.

Claims

What is claimed is: 1. A compound of Formula I: wherein: ring A is a 5-7 membered heterocyclic ring or a 5-6 membered heteroaryl ring that is independently substituted with one to three R1 groups, and wherein at least one of the 5-7 members of the heterocyclic ring or at least one of the 5-6 members of the heteroaryl ring is N; ring B is a 5-6 membered heterocyclic ring, a 5-6 membered heteroaryl ring, a 6 membered aromatic ring, or a 6 membered cycloalkyl ring that is unsubstituted or independently substituted with up to four R2 groups, and optionally wherein at least one of the 5-6 members of the heterocyclic ring or at least one of the 5-6 members of the heteroaryl ring is N; ring C is a 6 membered aromatic ring that is unsubstituted or independently substituted with up to four R3 groups; each R1 independently comprising a H, a halo, C1-6 alkyl, NH(CH2)1-6Ra, (CH2)1-6Ra, (CH2)2- 6NH-Ra, NH(CH2)1-6RaRb, CH2NH(CH2)1-6Ra, or a 5-7 membered heterocyclic ring substituted with RaRb; each R2 independently comprising a H, a halo, C1-6 alkyl, NH(CH2)1-6Ra, NHRa, (CH2)1-6Ra, Ra, or C-(Ra)3; each R3 independently comprising a H, a halo, C1-6 alkyl, NHRa, NHRaRb, NH(CH2)1-6Ra, O(CH2)1-6Ra, ORa, O(CH2)1-6Ra-(Rb)2, O(CH2)1-6RaRb, (CH2)1-6Ra, (CH2)1-6RaRb, RaRb, or Ra; each Ra and Rb independently comprising a halo, an amine, an imine, a carboxyl, a carbonyl, a hydroxyl, a thioamide, a nitrile, -O-alkyl, C1-6 alkyl, C-(CH3)3, a 5-6 membered aromatic ring, a 5-6 membered cycloalkyl ring, or a 4-6 membered heterocyclic ring; and a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein each R1 group is independently selected from the group consisting of: , .
3. The compound of claim 1, wherein each R2 group is independently selected from the group consisting of: ,
4. The compound of claim 1, wherein each R3 group is independently selected from the group consisting of: ,
5. The compound of claim 1, wherein each Ra and Rb group is independently selected from the group consisting of: oxidized forms thereof.
6. The compound of claim 1, wherein the compound is selected from the group consisting of: ,
,
,
,
,
7. The compound of claim 1, wherein the compound is configured to provide antimicrobial activity in cells in vitro and in situ.
8. The compound of claim 7, wherein the compound is configured to: provide the antimicrobial activity against bacteria selected from the group consisting of: Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Enterococcus faecalis, Staphylococcus aureus, Serratia marcescens, Shigella dysenteriae, Enterobacter aerogenes, Salmonella paratyphi, and a combination thereof.
9. The compound of claim 1, wherein the compound is compound is configured to provide antimicrobial activity and inhibit a lipoxygenase (LOX) in cells in vitro and in situ.
10. The compound of claim 9, wherein the compound is configured to: provide the antimicrobial activity against bacteria selected from the group consisting of: Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Enterococcus faecalis, Staphylococcus aureus, Serratia marcescens, Shigella dysenteriae, Enterobacter aerogenes, Salmonella paratyphi, and a combination thereof; and/or inhibit the LOX selected from the group consisting of: 5-LOX, 15-LOX, and a combination thereof.
11. A compound of Formula II: Formula II wherein: ring A is a 5 membered heterocyclic ring or a 5 membered heteroaryl ring that is substituted with one R1 group; ring B is a 6 membered heterocyclic ring, a 6 membered heteroaryl ring, a 6 membered aromatic ring, or a 6 membered cycloalkyl ring that is unsubstituted or independently substituted with up to four R2 groups; ring C is a 6 membered aromatic ring that is unsubstituted or independently substituted with up to four R3 groups; each X independently comprising a C or N; R1 comprising a H, a halo, C1-6 alkyl, NH(CH2)1-6Ra, (CH2)1-6Ra, (CH2)1-6NH-Ra, NH(CH2)1- 6RaRb, CH2NH(CH2)1-6Ra, or a 5-7 membered heterocyclic ring substituted with RaRb; each R2 independently comprising a H, a halo, C1-6 alkyl, NH(CH2)1-6Ra, NHRa, or (CH2)1-6Ra, Ra,, or C-(Ra)3; each R3 independently comprising a H, a halo, C1-6 alkyl, NHRa, NHRaRb, NH(CH2)1-6Ra, O(CH2)1-6Ra,ORa, O(CH2)1-6Ra-(Rb)2, O(CH2)1-6RaRb, (CH2)1-6Ra, (CH2)1-6RaRb, RaRb, or Ra; each Ra and Rb independently comprising an amine, an imine, a carbonyl, a hydroxyl, a thioamide, a nitrile, -O-alkyl, C1-6 alkyl, a 5-6 membered aromatic ring, a 5-6 membered cycloalkyl ring, or a 4-6 membered heterocyclic ring; and a pharmaceutically acceptable salt thereof.
12. The method of claim 11, wherein the R1 group is selected from the group consisting of: ,
13. The compound of claim 11, wherein the R1 group is selected from the group consisting of: .
14. The compound of claim 11, wherein each R2 group is independently selected from the group consisting of: ,
15. The compound of claim 11, wherein each R3 group is independently selected from the group consisting of:
.
16. The compound of claim 11, wherein each Ra and Rb group is independently selected from the group consisting of: oxidized forms thereof.
17. The compound of claim 11, wherein the compound is selected from the group consisting of:
,
, , ,
,
18. The compound of claim 11, wherein the compound is configured to: provide an antimicrobial activity against bacteria selected from the group consisting of: Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Enterococcus faecalis, Staphylococcus aureus, Serratia marcescens, Shigella dysenteriae, Enterobacter aerogenes, Salmonella paratyphi, and a combination thereof; and/or inhibit a lipoxygenase (LOX) in cells in vitro and in situ, the LOX being selected from the group consisting of: 5-LOX, 15-LOX, and a combination thereof.
19. A compound of Formula III: Formula III wherein: ring A is a 6 membered heteroaryl ring that is substituted with one to three R1 group; ring B is a 6 membered heterocyclic ring, a 6 membered aromatic ring, or a 6 membered cycloalkyl ring that is unsubstituted or substituted with up to four R2 groups; ring C is a 6 membered aromatic ring that is unsubstituted or substituted with one to four R3 groups; each X independently comprising a C or N; each R1 independently comprising a H, a halo, C1-6 alkyl, NH(CH2)1-6Ra, (CH2)1-6Ra, (CH2)2- 6NH-Ra, NH(CH2)1-6RaRb, CH2NH(CH2)1-6Ra, or a 5-7 membered heterocyclic ring substituted with RaRb; each R2 independently comprising a H, a halo, C1-6 alkyl, NH(CH2)2-6Ra, NHRa, (CH2)1-6Ra, Ra, or C-(Ra)3; each R3 independently comprising a H, a halo, C1-6 alkyl, NHRa, NHRaRb, NH(CH2)1-6Ra, O(CH2)1-6Ra, ORa, O(CH2)2-6Ra-(Rb)2, O(CH2)2-6RaRb, (CH2)1-6Ra, (CH2)2-6RaRb, RaRb, or Ra; each Ra and Rb independently comprising a halo, an amine, an imine, a carboxyl, a carbonyl, a hydroxyl, a thioamide, a nitrile, -O-alkyl, C1-6 alkyl, C-(CH3)3, a 5-6 membered aromatic ring, a 5-6 membered cycloalkyl ring, or a 4-6 membered heterocyclic ring; and a pharmaceutically acceptable salt thereof.
20. The compound of claim 19, wherein each R1 group is independently selected from the group consisting of: ,
21. The compound of claim 19, wherein each R2 group is independently selected from the group consisting of: , .
22. The compound of claim 19, wherein each R2 group is independently selected from the group consisting of: .
23. The compound of claim 19, wherein each R3 group is independently selected from the ,
24. The compound of claim 19, wherein each R3 group is independently selected from the group consisting of: .
25. The compound of claim 19, wherein at least one R3 group comprises NH bound to a 6 membered aromatic ring that is substituted with one to three Cl.
26. The compound of claim 19, wherein each Ra and Rb group is independently selected from the group consisting of: oxidized forms thereof.
27. The compound of claim 19, wherein each Ra and Rb group is independently selected from the group consisting of: , and oxidized forms thereof.
28. The compound of claim 19, wherein the compound is selected from the group consisting of:
, 29. The compound of claim 19, wherein the compound is configured to: provide an antimicrobial activity against bacteria selected from the group consisting of: Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Enterococcus faecalis, Staphylococcus aureus, Serratia marcescens, Shigella dysenteriae, Enterobacter aerogenes, and Salmonella paratyphi and a combination thereof; and/or inhibit a lipoxygenase (LOX) in cells in vitro and in situ, the LOX being selected from the group consisting of: 5-LOX, 15-LOX, and a combination thereof.
EP23901388.1A 2022-12-06 2023-12-04 Antimicrobial compounds Pending EP4629980A1 (en)

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