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WO2015138895A1 - Hepatitis b core protein allosteric modulators - Google Patents

Hepatitis b core protein allosteric modulators Download PDF

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Publication number
WO2015138895A1
WO2015138895A1 PCT/US2015/020444 US2015020444W WO2015138895A1 WO 2015138895 A1 WO2015138895 A1 WO 2015138895A1 US 2015020444 W US2015020444 W US 2015020444W WO 2015138895 A1 WO2015138895 A1 WO 2015138895A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
compound
group
alkoxy
halogen
Prior art date
Application number
PCT/US2015/020444
Other languages
French (fr)
Inventor
William W. Turner
Lee Daniel Arnold
Hans Maag
Adam Zlotnick
Original Assignee
Indiana University Research And Technology Corporation
Assembly Biosciences, Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority to KR1020167028057A priority Critical patent/KR102363174B1/en
Priority to EA201691835A priority patent/EA201691835A1/en
Priority to CA2942533A priority patent/CA2942533C/en
Priority to RSP20191187 priority patent/RS59430B1/en
Priority to EP21191660.6A priority patent/EP3974426A1/en
Priority to SG11201607268UA priority patent/SG11201607268UA/en
Priority to AP2016009477A priority patent/AP2016009477A0/en
Priority to EP15761201.1A priority patent/EP3116316B1/en
Priority to EP19184535.3A priority patent/EP3607950A3/en
Priority to DK15761201.1T priority patent/DK3116316T3/en
Priority to US15/125,911 priority patent/US10183936B2/en
Priority to MX2016011800A priority patent/MX363600B/en
Priority to NZ723972A priority patent/NZ723972B2/en
Priority to BR112016020895-1A priority patent/BR112016020895B1/en
Application filed by Indiana University Research And Technology Corporation, Assembly Biosciences, Inc. filed Critical Indiana University Research And Technology Corporation
Priority to JP2016557019A priority patent/JP6602311B2/en
Priority to CN201580024580.0A priority patent/CN106413402B/en
Priority to PL15761201T priority patent/PL3116316T3/en
Priority to ES15761201T priority patent/ES2748029T3/en
Priority to AU2015229174A priority patent/AU2015229174B2/en
Publication of WO2015138895A1 publication Critical patent/WO2015138895A1/en
Priority to IL247575A priority patent/IL247575B/en
Priority to ZA2016/06209A priority patent/ZA201606209B/en
Priority to PH12016501762A priority patent/PH12016501762A1/en
Priority to US15/965,655 priority patent/US10947224B2/en
Priority to AU2019203754A priority patent/AU2019203754A1/en
Priority to HRP20191444 priority patent/HRP20191444T1/en
Priority to IL273132A priority patent/IL273132B/en
Priority to US17/154,721 priority patent/US20230019129A1/en
Priority to IL282391A priority patent/IL282391A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C07D223/20—Dibenz [b, e] azepines; Hydrogenated dibenz [b, e] azepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/38—[b, e]- or [b, f]-condensed with six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D281/14—[b, e]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D281/16—[b, f]-condensed
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • HBV Hepatitis B
  • liver cancer liver cancer
  • WHO World Health Organization
  • HBV can be spread by body fluids: from mother to child, by sex, and via blood products. Children born to HBV -positive mothers may also be infected, unless vaccinated at birth.
  • the virus particle is composed of a lipid enveloped studded with surface protein (HBsAg) that surrounds the viral core.
  • the core is composed of a protein shell, or capsid, built of 120 core protein (Cp) dimers, which in turn contains the relaxed circular DNA (rcDNA) viral genome as well as viral and host proteins.
  • Cp core protein
  • rcDNA relaxed circular DNA
  • cccDNA covalently closed circular DNA
  • the cccDNA is the template for viral RNAs and thus viral proteins.
  • Cp assembles around a complex of full-length viral RNA (the so-called pregenomic RNA or pgRNA and viral polymerase (P).
  • nucleos(t)ide therapy may lead to the emergence of antiviral drug resistance (Deres and Rubsamen-Waigmann, 1999; Tennant et al., 1998; Zhang et al., 2003) and - in rare patients- adverse events have been reported (Ayoub and Keeffe , 2011).
  • Nucleos(t)ide analogs suppress virus production, treating the symptom, but leave the infection intact. Interferon a has severe side effects and less tolerability among patients and is successful as a finite treatment strategy in only a small minority of patients. There is a clear on-going need for more effective treatments for HBV infections.
  • R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R L , Y, T, and L are defined herein.
  • methods of treating viral infections, such as hepatitis B comprising administering to patient a disclosed compound.
  • the present disclosure is directed in part to compounds having allosteric effector properties against Hepatitis B virus Cp, a protein found as a dimer, a multimer, and as the protein shell of the HBV core.
  • disclosed compounds may ultimately target multimerization of viral core proteins, which is central to HBV infection, where the core protein multimerizes into shell, or capsid, and/or disclosed compounds may for example, ultimately target interaction of viral core proteins with other macromolecules, such as host or viral nucleic acid, host proteins, or other viral proteins.
  • disclosed compounds may be considered in some embodiments CpAM— core protein allosteric modifiers. CpAM interaction with core protein can allosterically favor an assembly-active form of Cp dimer and lead to viral capsid assembly at an inappropriate time or place or lead to non-standard
  • CpAMs may additionally or alternatively affect steps of "upstream" of capsid assembly by altering the concentrations or nature of Cp available as dimer as compared to capsid or other multimeric forms.
  • Disclosed compounds or CpAMs may, in some embodiments, noticeably affect functions upstream of viral assembly such as modulation of cccDNA transcription, RNA stability and/or protein-protein interactions.
  • FIG. 1 illustrates synthetic scheme 1.
  • Figure 2 illustrates synthetic scheme 2.
  • alkyl refers to a saturated straight or branched hydrocarbon.
  • exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as Ci_ 6 alkyl, Ci_ 4 alkyl, and Ci_ 3 alkyl, respectively.
  • Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -butyl, 3 -methyl -2 -butyl, 2-methyl- 1-pentyl, 3 -methyl- 1-pentyl, 4- methyl- 1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.
  • alkenyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond.
  • alkenyl groups include, but are not limited to, a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein as C 2 - 6 alkenyl, and C 3 _ 4 alkenyl, respectively.
  • alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.
  • alkoxy refers to a straight or branched alkyl group attached to oxygen (alkyl-O-).
  • exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 2-6 carbon atoms, referred to herein as Ci_ 6 alkoxy, and C 2 _ 6 alkoxy, respectively.
  • alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, etc.
  • alkynyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond.
  • exemplary alkynyl groups include, but are not limited to, straight or branched groups of 2-6, or 3-6 carbon atoms, referred to herein as C 2 - 6 alkynyl, and C 3 _ 6 alkynyl, respectively.
  • Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc.
  • cycloalkyl or a “carbocyclic group” as used herein refers to a saturated or partially unsaturated hydrocarbon group of, for example, 3-6, or 4-6 carbons, referred to herein as C 3 _ 6 cycloalkyl or C4- 6 cycloalkyl, respectively.
  • exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl or cyclopropyl.
  • halo or halogen as used herein refer to F, CI, Br, or I.
  • heteroaryl or “heteroaromatic group” as used herein refers to a monocyclic aromatic 5-6 membered ring system containing one or more heteroatoms, for example one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, said heteroaryl ring may be linked to the adjacent radical though carbon or nitrogen. Examples of heteroaryl rings include but are not limited to furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine or pyrimidine etc.
  • heterocyclyl or “heterocyclic group” are art-recognized and refer to saturated or partially unsaturated 4-7 membered ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, heterocyclyl rings may be linked to the adjacent radical through carbon or nitrogen.
  • heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran or dihydrofuran etc
  • hydroxy and "hydroxyl” as used herein refers to the radical -OH.
  • Treatment includes the alleviation, prevention, reversal, amelioration or control of a pathology, disease, disorder, process, condition or event, including viral infection.
  • treatment is further to be understood as embracing the use of a drug to inhibit, block, reverse, restrict or control progression of viral infection.
  • pharmaceutical composition refers to compositions of matter comprising at least one pharmaceutical compound and optionally a pharmaceutically acceptable carrier.
  • the term "pharmaceutical compound” or “drug” refers to a free compound, its therapeutically suitable salts, solvates such as hydrates, specific crystal forms of the compound or its salts, or therapeutically suitable prodrugs of the compound.
  • compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate.
  • preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologies standards.
  • compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
  • the compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers.
  • stereoisomers when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),” “(-),” “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
  • the present invention encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated "( ⁇ )" in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
  • the compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond.
  • the symbol denotes a bond that may be a single, double or triple bond as described herein.
  • Substituents around a carbon-carbon double bond are designated as being in the "Z” or "E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the "E” and "Z” isomers.
  • Substituents around a carbon-carbon double bond alternatively can be referred to as "cis” or "trans,” where "cis” represents substituents on the same side of the double bond and "trans” represents substituents on opposite sides of the double bond.
  • Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring.
  • the arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the "Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both “Z” and "E” isomers.
  • Individual enantiomers and diasteriomers of compounds of the present invention can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art.
  • Stereoselective syntheses a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art.
  • Stereoselective syntheses encompass both enantio- and diastereoselective transformations, and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley- VCH: Weinheim, 2009.
  • the compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • the compound is amorphous.
  • the compound is a single polymorph.
  • the compound is a mixture of polymorphs.
  • the compound is in a crystalline form.
  • the invention also embraces isotopically labeled compounds of the invention which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 C1, respectively.
  • a compound of the invention may have one or more H atom replaced with deuterium.
  • isotopically-labeled disclosed compounds ⁇ e.g., those labeled with H and 14 C are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon- 14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the invention can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • terapéuticaally suitable salt refers to salts or zwitterions of
  • the salts may be prepared, for instance, during the final isolation and purification of the compounds or separately by reacting an amino group of the compounds with a suitable acid.
  • a compound may be dissolved in a suitable solvent, such as but not limited to methanol and water, and treated with at least one equivalent of an acid, for instance hydrochloric acid.
  • the resulting salt may precipitate out and be isolated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide the salt.
  • Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, form ate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para- toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric, and the like.
  • amino groups of a compound may also be quaternized with alkyl chlorides, bromides, and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl, and the like.
  • Basic addition salts may be prepared, for instance, during the final isolation and purification of pharmaceutical compounds by reaction of a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine.
  • a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine.
  • Quaternary amine salts may derived, for example, from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N- dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, ⁇ , ⁇ -dibenzylphenethylamine, 1-ephenamine, and N,N'- dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.
  • prodrug refers to those prodrugs or zwitterions which are suitable for use in contact with the tissues of subjects and are effective for their intended use.
  • prodrug refers to compounds that are transformed in vivo to a pharmaceutical compound, for example, by hydrolysis in blood.
  • prodrug refers to compounds that contain, but are not limited to, substituents known as “therapeutically suitable esters.”
  • therapeutically suitable ester refers to alkoxycarbonyl groups appended to the parent molecule on an available carbon atom.
  • a "therapeutically suitable ester” refers to alkoxycarbonyl groups appended to the parent molecule on one or more available aryl, cycloalkyl and/or heterocycle groups.
  • Compounds containing therapeutically suitable esters are an example, but are not intended to limit the scope of compounds considered to be prodrugs.
  • prodrug ester groups include pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as other such groups known in the art.
  • Other examples of prodrug ester groups are found in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
  • pharmaceutically effective amount and “effective amount”, as used herein, refer to an amount of a pharmaceutical formulation that will elicit the desired therapeutic effect or response when administered in accordance with the desired treatment regimen.
  • Disclosed compounds contemplated herein may in some embodiments be represented by Formula 1 :
  • T is selected from the group consisting of -C(O)-, -CH 2 -C(0)-, -N(C(0)-CH 3 )-, -NH-, - 0-, and -S(0) z -, where z is 0, 1 or 2;
  • Y is C(R U ) 2 , S(0) y , ⁇ and O wherein y is 0, 1, or 2;
  • ⁇ is selected from the group consisting of H, methyl, ethyl, propyl, phenyl and benzyl;
  • R L is selected from the group consisting of H, methyl, and -C(0)-Ci_ 3 alkyl;
  • L is a bond or Ci_ 4 straight chain alkylene optionally substituted by one or two
  • substituents each independently selected from the group consisting of methyl (optionally substituted by halogen or hydroxyl), ethenyl, hydroxyl, NR'R", phenyl, heterocycle, and halogen and wherein the Ci_ 4 straight chain alkylene may be interrupted by an -0-;
  • R is selected from the group consisting of H, phenyl or naphthyl (wherein the phenyl or naphthyl may be optionally substituted with one, two , three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 _ 6 alkynyl, Ci_ 6 alkoxy, NR'R", -C(O)- NR'R", - C(0)-Ci_ 6 alkyl, -C(0)-Ci_ 6 alkoxy, phenyl (optionally substituted by one, two or three
  • substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, Ci_ 6 alkoxy, NR'R", C(O)- NR'R", -C(0)-Ci_ 6 alkyl, -C(O)- Ci_ 6 alkoxy, -S(0) w -Ci_ 6 alkyl (where w is 1, 2 or 3), S(0) w -NR'R" (where w is 1, 2 or 3),-NR'- S(0) w , and -S(0) w -NR'R" (where w is 1, 2 or 3)), heteroaryl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, Ci_ 6 alkoxy, NR'R
  • 5-6 membered heteroaryl having one, two, or three heteroatoms each independently selected from O, N and S (wherein the 5-6 membered heteroaryl may be optionally substituted on a carbon with one, two , three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, Ci_ 6 alkoxy, phenyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, Ci_ 6 alkoxy, NR'R", C(O)- NR'R", -C(0)-Ci_ 6 alkyl, -C(0)-OH, -C(0)-Ci_ 6 alkoxy, -S(0) w -Ci_ 6 alkyl
  • R' is selected, independently for each occurrence, from H, methyl, ethyl, propyl, phenyl, and benzyl;
  • R' ' is selected, independently for each occurrence, from H, methyl, ethyl, propyl, butyl, carboxybenzyl, -C(0)-methyl and -C(0)-ethyl, or R' and R" taken together may form a 4-6 membered heterocycle; each of moieties R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are independently selected for each occurrence from the group consisting of hydrogen, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, halogen, hydroxyl, nitro, cyano, NR'R", -C(O)- NR'R", -S(0) w -Ci_ 6 alkyl (where w is 1, 2 or 3), -NR'- S(0) w, and -S(0) w -NR'R"(where w is 0, 1 or 2), Ci_ 6 alkoxy,-C
  • L may be selected from the group consisting of a bond, -CH 2 -, -CH 2 -CH 2 -, or CH 2 (CH 2 )-CH 2 -.
  • L is C 2 _ 3 alkylene, or in other embodiments, L is selected from the group consisting of -CH 2 -CH 2 -, - CH 2 (CH 2 )-CH 2 -, -CH 2 -CH 2 (OH)-, -CH 2 -CH 2 (CH 3 OH)-, and -CH 2 -CH 2 (OH)-CH 2 -.
  • L may be a bond, or for example, L may be C 2 _ 3 alkylene-0-.
  • L may be -0-CH 2 -CH 2 (OH)-, - CH 2 -CH 2 (CH 3 OH)-, or -CH 2 -CH 2 (OH)-CH 2 -. In other embodiments, L is -0-.
  • Y in certain embodiments, may be S(0) y (where y is 0, 1 or 2), or NR Y . In certain embodiments y is 0 or 2, for example, Y may be S.
  • R 2 is phenyl, for example, R 2 may be phenyl substituted by Ci_ 6 alkyl or Ci_ 6 alkoxy. In other embodiments, R is phenyl substituted by one or two substituents each selected from the group consisting of fluorine, chlorine, Ci_ 6 alkyl
  • R may be phenyl substituted by an 5-6
  • R may be a 5-6 membered heteroaryl, for example, R may be selected from the group consisting of:
  • R may be a 4-6 membered heterocycloalkyl, which may be optionally substituted as described above.
  • R may be selected from the group consisting of:
  • R is selected from the group consisting of H, halogen, phenyl, and Ci_ 6 alkyl
  • R is selected from the group consisting of H, halogen, phenyl, and Ci_ 6 alkyl (optionally substituted by one, two or three halogens);
  • R 42 is selected from the group consisting of H, halogen, phenyl, Ci_ 6 alkyl (optionally substituted by one, two or three halogens), Ci_ 6 alkoxy (optionally substituted by one, two or three halogens), NH 2 , -OCH3, NHCH3, and N(CH 3 ) 2 .
  • R 42 in some embodiments, may be independently selected for each occurrence from the group consisting of H, methyl, ethyl, propyl, -CF 3 , -CH 2 CH 3 , CI, F, phenyl, -NH 2 , -OCH 3 , NHCH 3 , and N(CH 3 ) 2 .
  • R 2 when R 2 is a heteroaryl, R 2 may be optionally substituted on a carbon by one or two substitutents each selected from the group consisting of fluorine, chlorine, phenyl, -NH 2; NH Ci_ 6 alkyl, and N(Ci_ 6 alkyl) 2; Ci_ 6 alkyl, and Ci_ 6 alkoxy.
  • R 11 is CH 2 or -CH 2 (CH3)- 2
  • R is a 4-6 membered heterocycloalkyl or C 4 _ 6 cycloalkyl
  • R is selected from the group of: tetrahydropyranyl, tetrahydrofuran, cyclopentane, cyclohexane, and cyclobutane.
  • R is selected from the group consisting of:
  • Y is S(0) y , wherein y is 0, 1, 2;
  • L is a bond or Ci_ 4 straight chain alkylene optionally substituted by one or two substituents each independently selected from the group consisting of methyl (optionally substituted by halogen or hydroxyl), hydroxyl and halogen;
  • R is selected from phenyl optionally substituted with one, two , three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, Ci_ 6 alkoxy, NR'R", -C(O)- NR'R", -C(0)-Ci_ 6 alkyl, -C(0)-Ci_ 6 alkoxy, phenyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, Ci_ ealkoxy, NR'R", C(O)- NR'R", -C(0)-Ci_ 6 alkyl, -C(0)-Ci_ 6 alkoxy, -S(0) w -Ci_ 6 alkyl
  • R' is selected, independently for each occurrence, from H, methyl, ethyl, and propyl,
  • R' ' is selected, independently for each occurrence, from H, methyl, ethyl, propyl, butyl, - C(0)-methyl and -C(0)-ethyl, or R' and R' ' taken together may form a 4-6 membered heterocycle; each of moieties R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are independently selected for each occurrence from the group consisting of hydrogen, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, halogen, hydroxyl, nitro, cyano, NR'R", -C(O)- NR'R", -S(0) w -Ci_ 6 alkyl (where w is 1 , 2 or 3), NR'- S(0) w , and S(0) w -NR'R" (where w is 0, 1 or 2), Ci_ 6 alkoxy,-C(0)-OH,
  • compounds of Formula 1, 1 ' and/or 1 " may have R 7 selected from H and F; and/or R 6 is selected from H and F; and/or R 5 is selected from H and F.
  • compounds of Formula 1, 1 ' and/or 1 " may have R 10 selected from the group consisting of H, methyl and F and/or R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and/or R 11 may be H.
  • R m and R m are each independently selected from the group consisting of H, halogen, Ci_ 6 alkyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), NR'R", and hydroxyl;
  • R is selected for each occurrence from the group consisting of H, halogen, hydroxyl, nitro, cyano, carboxy, Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 _ 6 alkynyl, Ci_ 6 alkoxy, NR'R", -C(0)-Ci_ 6 alkyl, - C(0)-Ci_ 6 alkoxy, phenyl, heteroaryl, C3_ 6 cycloalkyl, -S(0) w -Ci_ 6 alkyl (where w is 1, 2 or 3), - S(0) w -NR'R" (where w is 1, 2 or 3), and -NR'-S(0) w , (where w is 1, 2 or 3));
  • R' is selected, independently for each occurrence, from H, methyl, ethyl, and propyl;
  • R' ' is selected, independently for each occurrence, from H, methyl, ethyl, propyl, butyl, -C(0)-methyl and -C(0)-ethyl, or R' and R" taken together with the nitrogen to which they are attached may form a 4-6 membered heterocycle; each of moieties R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 is independently selected for each occurrence from the group consisting of hydrogen, Ci_ 6 alkyl, C 2 - 6 alkynyl, C 2 - 6 alkenyl, halogen, hydroxyl, nitro, cyano, and NR'R";
  • Ci_ 6 alkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, Ci_ 6 alkoxy, NR'R", -NR'-S(0) w, and S(0) w -NR'R”;
  • Ci_ 6 alkoxy may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_ 6 alkyl, NR'R", -NR'-S(0) w , and S(0) w -NR'R”;
  • C3_ 6 cycloalkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_ 6 alkyl, Ci_ 6 alky
  • a compound of Formula 2 may have R 7 is selected from H and F; and/or R 6 is selected from H and F; and/or R 5 is selected from H and F; and/or R 10 is selected from the group consisting of H, methyl and F; and/or each of R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 may be H.
  • R 3 is selected from the group consisting of phenyl and naphthyl.
  • R 3 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, carboxy, alkoxy, amino-cycloalkyl, phenyl, carbonyl-alkoxy, sulfonyl- alkyl, sulfonyl-amino, and sulfonyl-amino-alkyl.
  • R 4 is selected from the group consisting of pyridinyl, pyrimidinyl, thiazolyl, oxazolyl, piperidinyl, and piperazinyl.
  • R 4 may be optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, carboxy, alkoxy, amino-cycloalkyl, phenyl, carbonyl-alkoxy, sulfonyl-alkyl, sulfonyl-amino, and sulfonylamino- alkyl.
  • Y is C(R U ) 2 , S(0) Y , NR Y and O wherein y is 0, 1 , or 2;
  • R Y is selected from the group consisting of H, methyl, ethyl, propyl, phenyl and benzyl;
  • R M and R M are each independently selected from the group consisting of H, halogen, Ci_ 6 alkyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), C 2 _ 6 alkenyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), NR'R", and hydroxyl (e.g., R M and R M may each be H in certain embodiments);
  • R 62 is selected for each occurrence from the group consisting of H, halogen, hydroxyl, nitro, cyano, carboxy, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, Ci_ 6 alkoxy, NR'R" , -C(0)-Ci_ 6 alkyl, - C(0)-Ci_ 6 alkoxy, phenyl, heteroaryl, C3_ 6 cycloalkyl, -S(0) w -Ci_ 6 alkyl (where w is 1 , 2 or 3), - S(0) W -NR'R" (where w is 1 , 2 or 3), and -NR' -S(0) W , (where w is 1 , 2 or 3));
  • R' is selected, independently for each occurrence, from H, methyl, ethyl, and propyl; R' ' is selected, independently for each occurrence, from H, methyl, ethyl, propyl, butyl, - C(0)-methyl and -C(0)-ethyl, or R' and R" taken together with the nitrogen to which they are attached may form a 4-6 membered heterocycle; each of moieties R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 is independently selected for each occurrence from the group consisting of hydrogen, Ci_ 6 alkyl, C 2 - 6 alkynyl, C 2 - 6 alkenyl, halogen, hydroxyl, nitro, cyano, and NR'R"; wherein for each occurrence, Ci_ 6 alkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano
  • a compound of Formula 5 may have R 7 selected from H and F and/or R 6 is selected from H and F and/or R 5 may be selected from H and F; and/or R 10 may be selected from the group consisting of H, methyl and F; and/or R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 may be H.
  • Y of Formula 5 may be S.
  • Y is C(R U ) 2 , S(0) Y , NR Y and O wherein y is 0, 1, or 2;
  • R Y is selected from the group consisting of H, methyl, ethyl, propyl, phenyl and benzyl;
  • R m and R m are each independently selected from the group consisting of H, halogen, Ci
  • R m independently selected from halogen and hydroxyl), NR'R", and hydroxyl (e.g., R m and R may each be H in certain embodiments); R c is H or Ci_ 6 alkyl;
  • R is selected for each occurrence from the group consisting of H, halogen, hydroxyl, nitro, cyano, carboxy, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, Ci_ 6 alkoxy, NR'R", -C(0)-Ci_ 6 alkyl, - C(0)-Ci_ 6 alkoxy, phenyl, heteroaryl, C3_ 6 cycloalkyl, -S(0) w -Ci_ 6 alkyl (where w is 1, 2 or 3), - S(0) w -NR'R" (where w is 1, 2 or 3), and -NR'-S(0) w , (where w is 1, 2 or 3));
  • R' is selected, independently for each occurrence, from H, methyl, ethyl, and propyl;
  • R' ' is selected, independently for each occurrence, from H, methyl, ethyl, propyl, butyl, - C(0)-methyl and -C(0)-ethyl, or R' and R" taken together with the nitrogen to which they are attached may form a 4-6 membered heterocycle; each of moieties R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 is independently selected for each occurrence from the group consisting of hydrogen, Ci_ 6 alkyl, C 2 _ 6 alkynyl, C 2 _ 6 alkenyl, halogen, hydroxyl, nitro, cyano, and NR'R"; wherein for each occurrence, Ci_ 6 alkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, Ci_ 6
  • R c of a compound of formula 6 may be H or methyl, e.g., H; and/or R 7 may be selected from H and F; and/or R 6 may be selected from H and F; and/or R 5 may be selected from H and F; and/or R 10 may beselected from the group consisting of H, methyl and F; and/or R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 may be H.
  • the Y moiety of Formula 6 is S.
  • Y is C(R U ) 2 , S(0) y , NR Y and O wherein y is 0, 1, or 2; R Y is selected from the group consisting of H, methyl, ethyl, propyl, phenyl and benzyl;
  • R m and R m are each independently selected from the group consisting of H, halogen, Ci_ 6 alkyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), C 2 - 6 alkenyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), NR'R", and hydroxyl(e.g., R m and R m may each be H in certain embodiments);
  • R c is H or Ci_ 6 alkyl
  • R is selected from the group consisting of H, halogen, hydroxyl, nitro, cyano, carboxy, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, Ci_ 6 alkoxy, NR'R", -C(0)-Ci_ 6 alkyl, -C(0)-Ci_ 6 alkoxy, phenyl, heteroaryl, C 3 _ 6 cycloalkyl, -S(0) w -Ci_ 6 alkyl (where w is 1, 2 or 3), -S(0) w -NR'R" (where w is 1, 2 or 3), and -NR'-S(0) w , (where w is 1, 2 or 3));
  • R is selected from the group consisting of H, halogen, hydroxyl, nitro, cyano, carboxy, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, Ci_ 6 alkoxy, NR'R", -C(0)-Ci_ 6 alkyl, -C(0)-Ci_ 6 alkoxy, phenyl, heteroaryl, C 3 _ 6 cycloalkyl, -S(0) w -Ci_ 6 alkyl (where w is 1, 2 or 3), -S(0) w -NR'R" (where w is 1, 2 or 3), and -NR'-S(0) w , (where w is 1, 2 or 3));
  • R' is selected, independently for each occurrence, from H, methyl, ethyl, and propyl;
  • R' ' is selected, independently for each occurrence, from H, methyl, ethyl, propyl, butyl, - C(0)-methyl and -C(0)-ethyl, or R' and R" taken together with the nitrogen to which they are attached may form a 4-6 membered heterocycle; each of moieties R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 is independently selected for each occurrence from the group consisting of hydrogen, Ci_ 6 alkyl, C 2 _ 6 alkynyl, C 2 _ 6 alkenyl, halogen, hydroxyl, nitro, cyano, and NR'R"; wherein for each occurrence, Ci_ 6 alkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, Ci_ 6
  • R c is H or methyl.
  • compound of formula 7 may have R c as H; and/or R 7 may be selected from H and F; and/or R 6 may be selected from H and F; and/or R 5 may be selected from H and F; and/or R 10 may be selected from the group consisting of H, methyl and F; and/or each of R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 may be H.
  • the present disclosure also provides, in part, a compound selected from the group consisting a compound of Table 1, 2, 3, 4, 5, 6 and 7.
  • Also contemplated herein are compounds: N-((2-methylthiazol-5-yl)methyl)-l l-oxo-10,11- dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5-oxide, N-((2-aminothiazol-5-yl)methyl)- 1 l-oxo-10,1 l-dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5-oxide, N-((2-methylthiazol- 5-yl)methyl)-l l-oxo-10,1 l-dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide,
  • a method for the synthesis of disclosed compounds is provided.
  • the method follows Synthetic Scheme 1, as illustrated in FIG. 1.
  • a first mixture comprising reagents 1 and 2 is formed for synthetic step A to yield synthetic intermediate 3.
  • Synthetic step A may be conducted in an organic solvent, for instance a polar aprotic solvent such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dioxane, hexamethylphosphorotriamide, and tetrahydrofuran.
  • DMSO dimethyl sulfoxide
  • DMF dimethylformamide
  • dioxane dioxane
  • hexamethylphosphorotriamide hexamethylphosphorotriamide
  • tetrahydrofuran tetrahydrofuran
  • the reaction may be conducted in the presence of a base, for example a carbonate such as Li 2 C0 3 , Na 2 C0 3 , K 2 C0 3 , Rb 2 C0 3 , Cs 2 C0 3 , MgC0 3 , CaC0 3 , SrC0 3 , and BaC0 3 .
  • a base for example a carbonate such as Li 2 C0 3 , Na 2 C0 3 , K 2 C0 3 , Rb 2 C0 3 , Cs 2 C0 3 , MgC0 3 , CaC0 3 , SrC0 3 , and BaC0 3 .
  • moiety -YH is selected from the group consisting of -SH, -OH, and -
  • N(R 12 )H wherein R 12 is selected from the group consisting of hydrogen and alkyl.
  • R 12 is selected from the group consisting of hydrogen and alkyl.
  • moiety -Y- is selected from the group consisting of -S-, -
  • Moieties P and P are independently selected carboxyl protecting groups, such as methoxyl or ethoxyl groups.
  • at least one of P 3 and P 4 is an ammo protecting group, for example selected from the group consisting of carbobenzyloxy (Cbz), p- methoxybenzyl-carbonyl (Moz or MeOZ), tert-butyloxycarbonyl (BOC), 9- fluorenylmethyloxycarbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate group, p-Methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), sulfonamides (Nosyl and Nps).
  • moiety -N(P 3 )(P 4 ) may be a group that can be transformed in an amino group by appropriate chemical reactions.
  • moiety - N(P 3 )(P 4 ) may be an -N0 2 group that is transformed into an amino (-NH 2 ) moiety by reaction with a reductant.
  • Example activators include carbodiimides, such as ⁇ , ⁇ '- dicyclohexylcarbodiimide (DCC), ⁇ , ⁇ '-diisopropylcarbodiimide (DIC), and carbonyl diimidazole (CDI); and triazolols, such as 1-hydroxy-benzotriazole (HOBt) and l-hydroxy-7- aza-benzotriazole (HOAt).
  • Other activators include HBTU, HATU, HCTU, TBTU, and PyBOP.
  • step D intermediate 5 is reacted with a molecule of formula R NH 2 to create an amide bond and yield products of Formula 6.
  • the formation of the amide bond may be speeded up with an activator.
  • An exemplary Synthetic Scheme is illustrated in FIG. 2.
  • a method for treating a hepatitis B infection in a patient in need thereof comprising administering to a subject or patient an effective amount of a disclosed compound, and/or administering a first disclosed compound and optionally, and additional, different disclosed compound(s).
  • a method for treating a hepatitis B infection in a patient in need thereof comprising administering to a subject or patient a therapeutically effective amount of a pharmaceutical composition comprising a disclosed compound, or two or more disclosed compounds.
  • an indicated administration dose may be in the range between about 0.1 to about 1000 ⁇ g/kg body weight.
  • the administration dose of the compound may be less than 400 ⁇ g/kg body weight.
  • the administration dose may be less than 200 ⁇ g/kg body weight.
  • the administration dose may be in the range between about 0.1 to about 100 ⁇ g/kg body weight.
  • the dose may be conveniently administered once daily, or in divided doses up to, for example, four times a day or in sustained release form.
  • a compound may be administered by any conventional route, in particular: enterally, topically, orally, nasally, e.g. in the form of tablets or capsules, via suppositories, or parenterally, e.g. in the form of injectable solutions or suspensions, for intravenous, intra-muscular, subcutaneous, or intra-peritoneal injection.
  • Suitable formulations and pharmaceutical compositions will include those formulated in a conventional manner using one or more physiologically acceptable carriers or excipients, and any of those known and commercially available and currently employed in the clinical setting.
  • the compounds may be formulated for oral, buccal, topical, parenteral, rectal or transdermal administration or in a form suitable for administration by inhalation or insufflation (either orally or nasally).
  • compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, micro crystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g.
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g. lactose, micro crystalline cellulose or calcium hydrogen phosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g.
  • potato starch or sodium starch glycollate or wetting agents (e.g. sodium lauryl sulphate).
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g.
  • Preparations may also contain buffer salts, flavoring, coloring and sweetening agents as appropriate.
  • compositions for oral administration may also be suitably formulated to give controlled-release or sustained release of the active compound(s) over an extended period.
  • compositions may take the form of tablets or lozenges formulated in a conventional manner known to the skilled artisan.
  • a disclosed compound may also be formulated for parenteral administration by injection e.g. by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain additives such as suspending, stabilizing and/or dispersing agents.
  • the compound may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • Compounds may also be formulated for rectal administration as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other giyeerides.
  • a disclosed compound may be administered as part of a combination therapy in conjunction with one or more antivirals.
  • Example antivirals include nucleoside analogs, interferon a, and other assembly effectors, for instance h ' eteroaryldihydropyrimidrnes (EAPs) such as methyl 4-(2-cUoro ⁇ 4-iluorop.aen ⁇ d ⁇ ,4- d.mydropyriniidine-5-carboxylate (HAP-1).
  • a method of treating patient suffering from hepatitis B comprising administering to a subject a first amount of a disclosed compound and a second amount of an antiviral, or other anii HBV agent, for example a second amount of a second compound selected from the group consisting of: another HBV. caspid assembly promoter (such as certain compounds disclosed herein or -for example, GLS4,
  • viral entry inhibitors such, as Myrcludex B and related lipopeptide derivatives; HBsAg secretion inhibitors such as REP 9AC and related nucleic acid-based amphipathic polymers, HBF-0529 (PBHBV-001), PBHBV-2-15 as depicted below: :
  • HBc directed transbodies such as those described in Wang Y, et al, Transbody against hepatitis B virus core protein inhibits hepatitis B virus replication in vitro, Int. Immunopharmacol (2014), located at //dx.doi.
  • RNAi for example ALN-HBV, ARC-520, TKM-HBV, ddRNAi), antisense (ISIS-HBV), or nucleic acid based polymer: (REP 2139-Ca); immunostimulants such as Interferon alpha 2a (Roferon), Intron A (interferon alpha 2b), Pegasys (peginterferon alpha 2a), Pegylated IFN 2b, IFN lambda la and PEG IFN lambda la, Wellferon, Roferon, Infergen, lymphotoxin beta
  • OICR-9429 OICR-9429
  • PARP inhibitors APE inhibitors, DNMT inhibitors, LSD1 inhibitors, JMJD HDM inhibitors, and Bromodomain antagonists
  • kinase inhibitors such as TKB1 antagonists, PLK1 inhibitors, SRPK inhibitors, CDK2 inhibitors, ATM & ATR kinase inhibitors
  • STING Agonists Ribavirin; N-acetyl cysteine ; NOV-205 (BAM205); Nitazoxanide (Alinia)
  • Tizoxanide SB 9200 Small Molecule Nucleic Acid Hybrid (SMNH); DV-601 ; Arbidol; FXR agonists (such as GW 4064 and Fexaramin); antibodies, therapeutic proteins, gene therapy, and biologies directed against viral components or interacting host proteins.
  • the first and second amounts together comprise a
  • the first amount, the second amount, or both may be the same, more, or less than effective amounts of each compound administered as monotherapies.
  • Therapeutically effective amounts of a disclosed compound and antiviral may be coadministered to the subject, i.e., administered to the subject simultaneously or separately, in any given order and by the same or different routes of administration. In some instances, it may be advantageous to initiate administration of a disclosed compound first, for example one or more days or weeks prior to initiation of administration of the antiviral. Moreover, additional drugs may be given in conjunction with the above combination therapy.
  • a disclosed compound may be conjugated (e.g., covalently bound directly or through molecular linker to a free carbon, nitrogen (e.g. an amino group), or oxygen (e.g. an active ester) of a disclosed compound), with a detection moiety, e.g. a fluorophore moiety (such a moiety may for example re-emit a certain light frequency upon binding to a virus and/or upon photon excitation.
  • a detection moiety e.g. a fluorophore moiety (such a moiety may for example re-emit a certain light frequency upon binding to a virus and/or upon photon excitation.
  • Contemplated fluorophores include
  • AlexaFluor® 488 Invitrogen
  • BODIPY FL Invitrogen
  • fluorescein rhodamine
  • cyanine indocarbocyanine
  • anthraquinones fluorescent proteins
  • aminocoumarin aminocoumarin
  • Such disclosed compounds conjugated to a detection moiety may be used in e.g. a method for detecting HBV or biological pathways of HBV infection, e.g., in vitro or in vivo; and/or methods of assessing new compounds for biological activity.
  • reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 250 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 7% EtOAc/ hexanes to afford compound 37 (1.6 g, 61%) as an off-white solid. TLC: 10% EtOAc/ hexanes(i?
  • Example 7 Synthesis of 4-fluoro-ll-oxo-lO, ll-dihydrodibenzo ⁇ b, f ⁇ [1, 41 thiazepine-8- carboxylic acid (50) - a common intermediate
  • Example 8 Synthesis of 7-fluoro-ll-oxo-lO, 11-dihydrodibenzo ⁇ b, f ⁇ [1, 41 thiazepine-8- carboxylic acid (55) - a common intermediate
  • Example 10 2-methoxy-ll-oxo-10, 11-dihydrodibenzo ⁇ b, f ⁇ [1, 41 thiazepine-8-carboxylic acid (70) - a common intermediate
  • Example 11 7-methoxy-ll-oxo-lO, 11-dihydrodibenzo ⁇ b, f ⁇ [1, 41 thiazepine-8-carboxylic acid (76) - a common intermediate
  • Example 12 Synthesis of 6-methyl-ll-oxo-10, ll-dihydrodibenzo ⁇ b, f ⁇ [1, 41 thiazepine-8- carboxylic acid (82) - a common intermediate
  • Example 14 9-methyl-ll-oxo-10, ll-dihydrodibenzo ⁇ b, f ⁇ [1, 41 thiazepine-8-carboxylic acid (96) - a common intermediate and Synthesis of 7-methyl-ll-oxo-10, ll-dihydrodibenzo ⁇ b, f ⁇ [1, 41 thiazepine-8-carboxylic acid (88) a common intermediate - Alternate Approach
  • Example 16 ll-oxo-10, ll-dihydrodibenzo ⁇ b, f ⁇ [1, 41 thiazepine-7-carboxylic acid (140) - a common intermediate
  • reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 35 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5-7% EtOAc/ hexanes to afford compound P-37 (340 mg, 30%) as an off-white solid. TLC: 10% EtOAc/ hexanes (Rf.
  • reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 3-5% EtOAc/ hexanes to afford compound P-46 (290 mg, 29%) as yellow solid. TLC: 10% EtOAc/ hexanes (Rf.
  • reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with EtOAc (2 x 35 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 3% EtOAc/ hexanes to afford compound 3 (200 mg, 33%) as sticky solid. TLC: 10% EtOAc/ hexanes (Rf.
  • the reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo and diluted with water (20 mL) or the pH of the reaction mixture was adjusted to ⁇ 8 and extracted with CH 2 CI 2 (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified either through silica gel column chromatography or triturated to afford the desired product.
  • reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (5 mL) and extracted with CH 2 CI 2 (4 x 20 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to obtain crude. The crude was purified through silica gel column chromatography using 10% EtOAc/ hexanes to afford compound 281 (610 mg, 50%>) as an off white solid.
  • reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted water (100 mL) and extracted with 10% MeOH/ CH 2 C1 2 (2 x 50 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude compound was triturated with 50%> EtOAc/ hexanes (10 mL) and dried in vacuo to afford compound 364 (50 mg, 17%>) as an off-white solid. TLC: 70%> EtOAc/ hexanes (Rf.

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Abstract

ABSTRACT The present disclosure provides, in part, compounds having allosteric effector properties against Hepatitis B virus Cp. Also provided herein are methods of treating viral infections, such as hepatitis B, comprising administering to a patient in need thereof a disclosed compound.

Description

HEPATITIS B CORE PROTEIN ALLOSTERIC MODULATORS
STATEMENT OF GOVERNMENT SUPPORT
[0001] This invention was made with government support under AI067417 awarded by the National Institutes of Health. The government has certain rights in the invention.
RELATED APPLICATIONS
[0002] This application claims the benefit of and priority to United States Provisional Patent Applications serial nos. 61/952,467, filed March 13, 2014, and 62/010,025, filed June 10, 2014, the contents of each of which are hereby incorporated by reference.
BACKGROUND
[0003] Hepatitis B (HBV) causes viral Hepatitis that can further lead to chronic liver disease and increase the risk of liver cirrhosis and liver cancer (hepatocellular carcinoma). Worldwide, about 2 billion people have been infected with HBV, around 360 million people are chronically infected, and every year HBV infection causes more than one half million deaths (2009; WHO, 2009). HBV can be spread by body fluids: from mother to child, by sex, and via blood products. Children born to HBV -positive mothers may also be infected, unless vaccinated at birth.
[0004] The virus particle is composed of a lipid enveloped studded with surface protein (HBsAg) that surrounds the viral core. The core is composed of a protein shell, or capsid, built of 120 core protein (Cp) dimers, which in turn contains the relaxed circular DNA (rcDNA) viral genome as well as viral and host proteins. In an infected cell, the genome is found as a covalently closed circular DNA (cccDNA) in the host cell nucleus. The cccDNA is the template for viral RNAs and thus viral proteins. In the cytoplasm, Cp assembles around a complex of full-length viral RNA (the so-called pregenomic RNA or pgRNA and viral polymerase (P). After assembly, P reverse transcribes the pgRNA to rcDNA within the confines of the capsid to generate the DNA-filled viral core. For convenience, we divide the assembly process at the point of capsid assembly and pgRNA-packaging. Steps preceding this event are "upstream"; steps following RNA-packaging are "downstream". [0005] At present, chronic HBV is primarily treated with nucleos(t)ide analogs (e.g.
entecavir) that suppress the virus while the patient remains on treatment but do not eliminate the infection, even after many years of treatment. Once a patient starts taking nucleotide analogs most must continue taking them or risk the possibility of a life threatening immune response to viral rebound. Further, nucleos(t)ide therapy may lead to the emergence of antiviral drug resistance (Deres and Rubsamen-Waigmann, 1999; Tennant et al., 1998; Zhang et al., 2003) and - in rare patients- adverse events have been reported (Ayoub and Keeffe , 2011).
[0006] The only FDA approved alternative to nucleos(t)ide analogs is treatment with interferon a or pegylated interferon a. Unfortunately, the adverse event incidence and profile of interferon a can result in poor tolerability, and many patients are unable to complete therapy. Moreover, only a small percentage of patients are considered appropriate for interferon therapy, as only a small subset of patients are likely to have asustained clinical response to a course of interferon therapy. As a result, interferon based therapies are used in only a small percentage of all diagnosed patients who elect for treatment.
[0007] Thus, current HBV treatments can range from palliative to watchful waiting.
Nucleos(t)ide analogs suppress virus production, treating the symptom, but leave the infection intact. Interferon a has severe side effects and less tolerability among patients and is successful as a finite treatment strategy in only a small minority of patients. There is a clear on-going need for more effective treatments for HBV infections.
SUMMARY
[0008] Provided herein are compounds that can have properties such as those described below, where the compounds in some embodiments may be represented by:
Figure imgf000003_0001
Formula 1
Figure imgf000004_0001
wherein R2, R4, R5, R6, R7, R8, R9, R10, RL , Y, T, and L are defined herein. Also provided herein are methods of treating viral infections, such as hepatitis B, comprising administering to patient a disclosed compound.
[0009] For example, the present disclosure is directed in part to compounds having allosteric effector properties against Hepatitis B virus Cp, a protein found as a dimer, a multimer, and as the protein shell of the HBV core. Without being bound by theory, disclosed compounds may ultimately target multimerization of viral core proteins, which is central to HBV infection, where the core protein multimerizes into shell, or capsid, and/or disclosed compounds may for example, ultimately target interaction of viral core proteins with other macromolecules, such as host or viral nucleic acid, host proteins, or other viral proteins. For example, disclosed compounds may be considered in some embodiments CpAM— core protein allosteric modifiers. CpAM interaction with core protein can allosterically favor an assembly-active form of Cp dimer and lead to viral capsid assembly at an inappropriate time or place or lead to non-standard
intersubunit interactions, all resulting in defective capsids. CpAMs may additionally or alternatively affect steps of "upstream" of capsid assembly by altering the concentrations or nature of Cp available as dimer as compared to capsid or other multimeric forms. Disclosed compounds or CpAMs may, in some embodiments, noticeably affect functions upstream of viral assembly such as modulation of cccDNA transcription, RNA stability and/or protein-protein interactions.
BRIEF DESCRIPTION OF THE FIGURES [00010] Figure 1 illustrates synthetic scheme 1. [00011] Figure 2 illustrates synthetic scheme 2. DETAILED DESCRIPTION
[00012] The features and other details of the disclosure will now be more particularly described. Before further description of the present invention, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.
Definitions
[00013] As intended herein, the terms "a" and "an" include singular as well as plural references unless the context clearly dictates otherwise. For example, the term "an assembly effector" can include one or more such effectors.
[00014] The term "alkyl" as used herein refers to a saturated straight or branched hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as Ci_6alkyl, Ci_4alkyl, and Ci_ 3alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -butyl, 3 -methyl -2 -butyl, 2-methyl- 1-pentyl, 3 -methyl- 1-pentyl, 4- methyl- 1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.
[00015] The term "alkenyl" as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein as C2-6alkenyl, and C3_4alkenyl, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.
[00016] The term "alkoxy" as used herein refers to a straight or branched alkyl group attached to oxygen (alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 2-6 carbon atoms, referred to herein as Ci_6alkoxy, and C2_6alkoxy, respectively.
Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, etc. [00017] The term "alkynyl" as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight or branched groups of 2-6, or 3-6 carbon atoms, referred to herein as C2-6alkynyl, and C3_6alkynyl, respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc.
[00018] The terms "cycloalkyl" or a "carbocyclic group" as used herein refers to a saturated or partially unsaturated hydrocarbon group of, for example, 3-6, or 4-6 carbons, referred to herein as C3_6cycloalkyl or C4-6cycloalkyl, respectively. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl or cyclopropyl.
[00019] The terms "halo" or "halogen" as used herein refer to F, CI, Br, or I.
[00020] The terms "heteroaryl" or "heteroaromatic group" as used herein refers to a monocyclic aromatic 5-6 membered ring system containing one or more heteroatoms, for example one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, said heteroaryl ring may be linked to the adjacent radical though carbon or nitrogen. Examples of heteroaryl rings include but are not limited to furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine or pyrimidine etc.
[00021] The terms "heterocyclyl" or "heterocyclic group" are art-recognized and refer to saturated or partially unsaturated 4-7 membered ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, heterocyclyl rings may be linked to the adjacent radical through carbon or nitrogen. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran or dihydrofuran etc
[00022] The terms "hydroxy" and "hydroxyl" as used herein refers to the radical -OH.
[00023] "Treatment" as used herein includes the alleviation, prevention, reversal, amelioration or control of a pathology, disease, disorder, process, condition or event, including viral infection. In this context, the term "treatment" is further to be understood as embracing the use of a drug to inhibit, block, reverse, restrict or control progression of viral infection. [00024] As used herein, the term "pharmaceutical composition" refers to compositions of matter comprising at least one pharmaceutical compound and optionally a pharmaceutically acceptable carrier.
[00025] As used herein, the term "pharmaceutical compound" or "drug" refers to a free compound, its therapeutically suitable salts, solvates such as hydrates, specific crystal forms of the compound or its salts, or therapeutically suitable prodrugs of the compound.
[00026] Pharmaceutically or pharmacologically acceptable" include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologies standards.
[00027] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
[00028] The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term "stereoisomers" when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols "(+)," "(-)," "R" or "S," depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. The present invention encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated "(±)" in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
[00029] The compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond. The symbol denotes a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the "Z" or "E" configuration wherein the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the "E" and "Z" isomers. Substituents around a carbon-carbon double bond alternatively can be referred to as "cis" or "trans," where "cis" represents substituents on the same side of the double bond and "trans" represents substituents on opposite sides of the double bond.
[00030] Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the "Z" or "E" configuration wherein the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both "Z" and "E" isomers. Substituents around a carbocyclic or heterocyclic rings may also be referred to as "cis" or "trans", where the term "cis" represents substituents on the same side of the plane of the ring and the term "trans" represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated "cis/trans."
[00031] Individual enantiomers and diasteriomers of compounds of the present invention can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well known methods, such as chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art. Stereoselective syntheses encompass both enantio- and diastereoselective transformations, and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley- VCH: Weinheim, 2009.
[00032] The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form.
[00033] The invention also embraces isotopically labeled compounds of the invention which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31P, 32P, 35S, 18F, and 36C1, respectively. For example, a compound of the invention may have one or more H atom replaced with deuterium.
[00034] Certain isotopically-labeled disclosed compounds {e.g., those labeled with H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon- 14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the invention can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
[00035] The term "therapeutically suitable salt," refers to salts or zwitterions of
pharmaceutical compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders and effective for their intended use. The salts may be prepared, for instance, during the final isolation and purification of the compounds or separately by reacting an amino group of the compounds with a suitable acid. For example, a compound may be dissolved in a suitable solvent, such as but not limited to methanol and water, and treated with at least one equivalent of an acid, for instance hydrochloric acid. The resulting salt may precipitate out and be isolated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide the salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, form ate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para- toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric, and the like. The amino groups of a compound may also be quaternized with alkyl chlorides, bromides, and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl, and the like.
[00036] Basic addition salts may be prepared, for instance, during the final isolation and purification of pharmaceutical compounds by reaction of a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine. Quaternary amine salts may derived, for example, from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N- dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, Ν,Ν-dibenzylphenethylamine, 1-ephenamine, and N,N'- dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.
[00037] The term "therapeutically suitable prodrug," refers to those prodrugs or zwitterions which are suitable for use in contact with the tissues of subjects and are effective for their intended use. The term "prodrug" refers to compounds that are transformed in vivo to a pharmaceutical compound, for example, by hydrolysis in blood. The term "prodrug," refers to compounds that contain, but are not limited to, substituents known as "therapeutically suitable esters." The term "therapeutically suitable ester," refers to alkoxycarbonyl groups appended to the parent molecule on an available carbon atom. More specifically, a "therapeutically suitable ester," refers to alkoxycarbonyl groups appended to the parent molecule on one or more available aryl, cycloalkyl and/or heterocycle groups. Compounds containing therapeutically suitable esters are an example, but are not intended to limit the scope of compounds considered to be prodrugs. Examples of prodrug ester groups include pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as other such groups known in the art. Other examples of prodrug ester groups are found in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
[00038] The terms "pharmaceutically effective amount" and "effective amount", as used herein, refer to an amount of a pharmaceutical formulation that will elicit the desired therapeutic effect or response when administered in accordance with the desired treatment regimen.
US2011/0144086 describes the use of some diabenzothiazepine molecules (DBTs) as antimalarial "inhibitors of the plasmodial surface anion channel." However, no study of DBT molecules as anti-virals has yet been reported.
1. Disclosed compounds contemplated herein may in some embodiments be represented by Formula 1 :
Figure imgf000011_0001
Formula wherein:
T is selected from the group consisting of -C(O)-, -CH2-C(0)-, -N(C(0)-CH3)-, -NH-, - 0-, and -S(0)z-, where z is 0, 1 or 2;
Y is C(RU)2 , S(0)y, ΝΡνγ and O wherein y is 0, 1, or 2;
Ργ is selected from the group consisting of H, methyl, ethyl, propyl, phenyl and benzyl; RL is selected from the group consisting of H, methyl, and -C(0)-Ci_3alkyl;
L is a bond or Ci_4 straight chain alkylene optionally substituted by one or two
substituents each independently selected from the group consisting of methyl (optionally substituted by halogen or hydroxyl), ethenyl, hydroxyl, NR'R", phenyl, heterocycle, and halogen and wherein the Ci_4 straight chain alkylene may be interrupted by an -0-;
R is selected from the group consisting of H, phenyl or naphthyl (wherein the phenyl or naphthyl may be optionally substituted with one, two , three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, C2-6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", -C(O)- NR'R", - C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, phenyl (optionally substituted by one, two or three
substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", C(O)- NR'R", -C(0)-Ci_6alkyl, -C(O)- Ci_6alkoxy, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), S(0)w-NR'R" (where w is 1, 2 or 3),-NR'- S(0)w, and -S(0)w-NR'R" (where w is 1, 2 or 3)), heteroaryl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", C(O)- NR'R", -C(0)-Ci_6alkyl, -C(O)- Ci_6alkoxy, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), NR'-S(0)w, and -S(0)w-NR'R"(where w is 1, 2 or 3)), C3-6cycloalkyl, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), -S(0)w-NR'R" (where w is 1, 2 or 3), and -NR'-S(0)w, (where w is 1, 2 or 3)),
5-6 membered heteroaryl having one, two, or three heteroatoms each independently selected from O, N and S (wherein the 5-6 membered heteroaryl may be optionally substituted on a carbon with one, two , three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, phenyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", C(O)- NR'R", -C(0)-Ci_6alkyl, -C(0)-OH, -C(0)-Ci_6alkoxy, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), -NR'-S(0)w, and -S(0)w-NR'R"(where w is 1, 2 or 3)), heteroaryl, heterocycle, NR'R", - C(O)- NR'R", -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), -NR'- S(0)w, and -S(0)w-NR'R"(where w is 1, 2 or 3), and on a nitrogen by R'), Ci_6alkyl, Ci_6alkoxy, C2-6alkenyl, C3_iocycloalkyl (optionally substituted with one, two , three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, NR'R", -C(O)- NR'R", =CNR', Ci_6alkyl, Ci_6alkoxy, -C(0)-Ci_6alkyl, and -C(0)-Ci_ 6alkoxy, and wherein the C3_iocycloalkyl may optionally be a bridged cycloalkyl)), and a 4-6 membered heterocycloalkyl having one or two heteroatoms each independently selected from O, N and S (wherein the 4-6 membered heterocycloalkyl may be optionally substituted with one, two , three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, NR'R", -C(O)- NR'R", Ci_6alkyl, Ci_6alkoxy, -C(0)-Ci_6alkyl, and -C(0)-Ci_ 6alkoxy);
R' is selected, independently for each occurrence, from H, methyl, ethyl, propyl, phenyl, and benzyl;
R' ' is selected, independently for each occurrence, from H, methyl, ethyl, propyl, butyl, carboxybenzyl, -C(0)-methyl and -C(0)-ethyl, or R' and R" taken together may form a 4-6 membered heterocycle; each of moieties R4, R5, R6, R7, R8, R9, R10, and R11 are independently selected for each occurrence from the group consisting of hydrogen, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, halogen, hydroxyl, nitro, cyano, NR'R", -C(O)- NR'R", -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), -NR'- S(0)w, and -S(0)w-NR'R"(where w is 0, 1 or 2), Ci_6alkoxy,-C(0)-OH, -C(0)-Ci_6alkyl, and - C(0)-Ci_6alkoxy; wherein for each occurrence, Ci_6alkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, phenyl, NR'R", -C(O)- NR'R", S(0)w-methyl (where w is 1, 2 or 3), -NR'-S(0)w, and S(0)w-NR'R"(where w is 0, 1 or 2); Ci_6alkoxy may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, phenyl, NR'R", -C(O)- NR'R", S(0)w-Ci_6alkyl (where w is 1, 2 or 3), -NR'-S(0)w, and S(0)w-NR'R" (where w is 0, 1 or 2); and C3_6cycloalkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, Ci_ 6alkoxy, -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, and NR'R"; and pharmaceutically acceptable salts thereof.
[00039] For example, in certain embodiments, L may be selected from the group consisting of a bond, -CH2-, -CH2-CH2-, or CH2(CH2)-CH2-. For example, in certain embodiments, L is C2_ 3alkylene, or in other embodiments, L is selected from the group consisting of -CH2-CH2-, - CH2(CH2)-CH2-, -CH2-CH2(OH)-, -CH2-CH2(CH3OH)-, and -CH2-CH2(OH)-CH2-. L may be a bond, or for example, L may be C2_3alkylene-0-. For example, L may be -0-CH2-CH2(OH)-, - CH2-CH2(CH3OH)-, or -CH2-CH2(OH)-CH2-. In other embodiments, L is -0-.
[00040] Y, in certain embodiments, may be S(0)y (where y is 0, 1 or 2), or NRY. In certain embodiments y is 0 or 2, for example, Y may be S.
[00041] In certain other embodiments, R 2 is phenyl, for example, R 2 may be phenyl substituted by Ci_6alkyl or Ci_6alkoxy. In other embodiments, R is phenyl substituted by one or two substituents each selected from the group consisting of fluorine, chlorine, Ci_6alkyl
(optionally substituted by one, two or three fluorines), Ci_6alkoxy (optionally substituted by one, two or three fluorines), hydroxyl, NR'R", -S(0)2-NR'R", heteroaryl, and phenyl (optionally substituted by halogen or hydroxyl). For example, R may be phenyl substituted by an 5-6
Figure imgf000014_0001
2 2
[00042] In other embodiments, R may be a 5-6 membered heteroaryl, for example, R may be selected from the group consisting of:
Figure imgf000015_0001
2
[00043] In another embodiment, R may be a 4-6 membered heterocycloalkyl, which may be optionally substituted as described above. For example, R may be selected from the group consisting of:
Figure imgf000015_0002
wherein R is selected from the group consisting of H, halogen, phenyl, and Ci_6alkyl
52
(optionally substituted by one, two or three halogens); R is selected from the group consisting of H, halogen, phenyl, and Ci_6alkyl (optionally substituted by one, two or three halogens); and
R 42 is selected from the group consisting of H, halogen, phenyl, Ci_6alkyl (optionally substituted by one, two or three halogens), Ci_6alkoxy (optionally substituted by one, two or three halogens), NH2, -OCH3, NHCH3, and N(CH3)2.
[00044] R 42 , in some embodiments, may be independently selected for each occurrence from the group consisting of H, methyl, ethyl, propyl, -CF3, -CH2CH3, CI, F, phenyl, -NH2, -OCH3, NHCH3, and N(CH3)2.
[00045] In other embodiments, e.g. when R 2 is a heteroaryl, R 2 may be optionally substituted on a carbon by one or two substitutents each selected from the group consisting of fluorine, chlorine, phenyl, -NH2; NH Ci_6alkyl, and N(Ci_6alkyl)2; Ci_6alkyl, and Ci_6alkoxy. In certain embodiments, R11 is CH2 or -CH2(CH3)- 2
[00046] Also contemplated herein is a compound of formula 1 or 1 ' wherein R is a 4-6 membered heterocycloalkyl or C4_6cycloalkyl, for example, R is selected from the group of: tetrahydropyranyl, tetrahydrofuran, cyclopentane, cyclohexane, and cyclobutane. In an embodiment, R is selected from the group consisting of:
Figure imgf000016_0001
[00047] A compound represented by:
Figure imgf000016_0002
is also contemplated herein, wherein Y is S(0)y, wherein y is 0, 1, 2;
L is a bond or Ci_4 straight chain alkylene optionally substituted by one or two substituents each independently selected from the group consisting of methyl (optionally substituted by halogen or hydroxyl), hydroxyl and halogen;
R is selected from phenyl optionally substituted with one, two , three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_ 6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", -C(O)- NR'R", -C(0)-Ci_6alkyl, -C(0)-Ci_ 6alkoxy, phenyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_ ealkoxy, NR'R", C(O)- NR'R", -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), NR'-S(0)w, and -S(0)w-NR'R"(where w is 1, 2 or 3)), 5-6 membered heteroaryl having one, two, or three heteroatoms each independently selected from O, N and S (optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, Ci_6alkyl, C2-6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", C(O)- NR'R", -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, -S(0)w-Ci_6alkyl (where w is 1 , 2 or 3), -NR'-S(0)w, and -S(0)w-NR'R"(where w is 1 , 2 or 3)), C3_6cycloalkyl, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), S(0)w-NR'R" (where w is 1 , 2 or 3),-and -NR'-S(0)w, (where w is 1 , 2 or 3)), and a 5-6 membered heteroaryl having one, two, or three heteroatoms each independently selected from O, N and S (wherein the 5-6 membered heteroaryl may be optionally substituted on a carbon with one, two , three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, phenyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", C(O)- NR'R", -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, -S(0)w-Ci_6alkyl (where w is 1 , 2 or 3), S(0)w- NR'R" (where w is 1 , 2 or 3),-NR'-S(0)w, and -S(0)w-NR'R"(where w is 1 , 2 or 3)), heteroaryl, heterocycle, NR'R", -C(O)- NR'R", -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, -S(0)w-Ci_ 6alkyl (where w is 1 , 2 or 3),-NR'-S(0)w, and -S(0)w-NR'R"(where w is 1 , 2 or 3), and on a nitrogen by R');
R' is selected, independently for each occurrence, from H, methyl, ethyl, and propyl,
R' ' is selected, independently for each occurrence, from H, methyl, ethyl, propyl, butyl, - C(0)-methyl and -C(0)-ethyl, or R' and R' ' taken together may form a 4-6 membered heterocycle; each of moieties R4, R5, R6, R7, R8, R9, R10, and R11 are independently selected for each occurrence from the group consisting of hydrogen, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, halogen, hydroxyl, nitro, cyano, NR'R", -C(O)- NR'R", -S(0)w-Ci_6alkyl (where w is 1 , 2 or 3), NR'- S(0)w, and S(0)w-NR'R" (where w is 0, 1 or 2), Ci_6alkoxy,-C(0)-OH, -C(0)-Ci_6alkyl, and - C(0)-Ci_6alkoxy; wherein for each occurrence, Ci_6alkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, phenyl, NR'R", -C(O)- NR'R", S(0)w-methyl (where w is 1 , 2 or 3), -NR'-S(0)w, and S(0)w-NR'R"(where w is 0, 1 or 2); Ci_6alkoxy may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, phenyl, NR'R", -C(O)- NR'R", S(0)w-Ci_6alkyl (where w is 1, 2 or 3), -NR'-S(0)w, and S(0)w-NR'R" (where w is 0, 1 or 2); and C3_6cycloalkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, Ci_ 6alkoxy, -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, and NR'R" and pharmaceutically acceptable salts thereof.
[00048] In some embodiments, compounds of Formula 1, 1 ' and/or 1 " may have R7 selected from H and F; and/or R6 is selected from H and F; and/or R5 is selected from H and F. In some embodiments, compounds of Formula 1, 1 ' and/or 1 " may have R10 selected from the group consisting of H, methyl and F and/or R4, R5, R6, R7, R8, R9, R10, and/or R11 may be H.
[00049] In another embodiment a compound represented by Formula 2 is provided:
Figure imgf000018_0001
wherein
Rm and Rm are each independently selected from the group consisting of H, halogen, Ci_6alkyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), NR'R", and hydroxyl;
22
R is selected for each occurrence from the group consisting of H, halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, C2-6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", -C(0)-Ci_6alkyl, - C(0)-Ci_6alkoxy, phenyl, heteroaryl, C3_6cycloalkyl, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), - S(0)w-NR'R" (where w is 1, 2 or 3), and -NR'-S(0)w, (where w is 1, 2 or 3));
R' is selected, independently for each occurrence, from H, methyl, ethyl, and propyl;
R' ' is selected, independently for each occurrence, from H, methyl, ethyl, propyl, butyl, -C(0)-methyl and -C(0)-ethyl, or R' and R" taken together with the nitrogen to which they are attached may form a 4-6 membered heterocycle; each of moieties R4, R5, R6, R7, R8, R9, and R10 is independently selected for each occurrence from the group consisting of hydrogen, Ci_6alkyl, C2-6alkynyl, C2-6alkenyl, halogen, hydroxyl, nitro, cyano, and NR'R";
wherein for each occurrence, Ci_6alkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", -NR'-S(0)w, and S(0)w-NR'R"; Ci_ 6alkoxy may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, NR'R", -NR'-S(0)w, and S(0)w-NR'R"; C3_6cycloalkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_ 6alkyl, Ci_6alkoxy, -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, and NR'R"; phenyl may be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, Ci_6alkyl, C2_6alkenyl, C2-6alkynyl, Ci_6alkoxy, NR'R", C(O)- NR'R", -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), NR'-S(0)w, and -S(0)w-NR'R"(where w is 1 , 2 or 3), and heteroaryl may be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, Ci_6alkyl, C2-6alkenyl, C3-6cycloalkyl, C2-6alkynyl, Ci_6alkoxy, NR'R", C(O)- NR'R", -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), NR'-S(0)w, and - S(0)w-NR'R"(where w is 1, 2 or 3)), C3-6cycloalkyl; and
pharmaceutically acceptable salts thereof.
[00050] For example, a compound of Formula 2 may have R7 is selected from H and F; and/or R6 is selected from H and F; and/or R5 is selected from H and F; and/or R10 is selected from the group consisting of H, methyl and F; and/or each of R4, R5, R6, R7, R8, R9, R10, and R11 may be H.
[00051] For exam le, provided herein is a compound represented by
[00052]
Figure imgf000019_0001
, wherein the R moieties are described above.
For example, in an embodiment, provided herein is a compound represented by:
Figure imgf000020_0001
[00053] Also provided are compounds of Formula 3:
Figure imgf000020_0002
Formula 3 wherein the moiety R 3 is selected from the group consisting of phenyl and naphthyl. R 3 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, carboxy, alkoxy, amino-cycloalkyl, phenyl, carbonyl-alkoxy, sulfonyl- alkyl, sulfonyl-amino, and sulfonyl-amino-alkyl.
[00054] In addition, compounds of Formula 4 are provided:
Figure imgf000020_0003
Formula 4 wherein moiety R4 is selected from the group consisting of pyridinyl, pyrimidinyl, thiazolyl, oxazolyl, piperidinyl, and piperazinyl. R4 may be optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, carboxy, alkoxy, amino-cycloalkyl, phenyl, carbonyl-alkoxy, sulfonyl-alkyl, sulfonyl-amino, and sulfonylamino- alkyl.
[00055] In another embodiment, a compound represented by:
Figure imgf000021_0001
(Formula 5) is provided wherein
Y is C(RU)2 , S(0)Y, NRY and O wherein y is 0, 1 , or 2;
RY is selected from the group consisting of H, methyl, ethyl, propyl, phenyl and benzyl;
RM and RM are each independently selected from the group consisting of H, halogen, Ci_ 6alkyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), C2_6alkenyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), NR'R", and hydroxyl (e.g., RM and RM may each be H in certain embodiments);
R62 is selected for each occurrence from the group consisting of H, halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R" , -C(0)-Ci_6alkyl, - C(0)-Ci_6alkoxy, phenyl, heteroaryl, C3_6cycloalkyl, -S(0)w-Ci_6alkyl (where w is 1 , 2 or 3), - S(0)W-NR'R" (where w is 1 , 2 or 3), and -NR' -S(0)W, (where w is 1 , 2 or 3));
R' is selected, independently for each occurrence, from H, methyl, ethyl, and propyl; R' ' is selected, independently for each occurrence, from H, methyl, ethyl, propyl, butyl, - C(0)-methyl and -C(0)-ethyl, or R' and R" taken together with the nitrogen to which they are attached may form a 4-6 membered heterocycle; each of moieties R4, R5, R6, R7, R8, R9, and R10 is independently selected for each occurrence from the group consisting of hydrogen, Ci_6alkyl, C2-6alkynyl, C2-6alkenyl, halogen, hydroxyl, nitro, cyano, and NR'R"; wherein for each occurrence, Ci_6alkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", -NR'-S(0)w, and S(0)w-NR'R"; Ci_ 6alkoxy may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, NR'R", -NR'-S(0)w, and S(0)w-NR'R"; C3_6cycloalkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_ 6alkyl, Ci_6alkoxy, -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, and NR'R"; phenyl may be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, Ci_6alkyl, C2_6alkenyl, C2-6alkynyl, Ci_6alkoxy, NR'R", C(O)- NR'R", -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), NR'-S(0)w, and -S(0)w-NR'R"(where w is 1 , 2 or 3), and heteroaryl may be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, Ci_6alkoxy, NR'R", C(O)- NR'R", -C(0)-Ci_ 6alkyl, -C(0)-Ci_6alkoxy, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), NR'-S(0)w, and -S(0)w- NR'R"(where w is 1, 2 or 3)), and C3_6cycloalkyl; and pharmaceutically acceptable salts thereof.
In an embodiment, a compound of Formula 5 may have R7 selected from H and F and/or R6 is selected from H and F and/or R5 may be selected from H and F; and/or R10 may be selected from the group consisting of H, methyl and F; and/or R4, R5, R6, R7, R8, R9, R10, and R11 may be H.
[00056] In some embodiments,Y of Formula 5 may be S.
[00057] A compound represented by:
Figure imgf000023_0001
(Formula 6) is also provided wherein
Y is C(RU)2 , S(0)Y, NRY and O wherein y is 0, 1, or 2;
RY is selected from the group consisting of H, methyl, ethyl, propyl, phenyl and benzyl;
Rm and Rm are each independently selected from the group consisting of H, halogen, Ci
6alkyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), C2_6alkenyl (optionally substituted by one, two or three substituents each
m independently selected from halogen and hydroxyl), NR'R", and hydroxyl (e.g., Rm and R may each be H in certain embodiments); Rc is H or Ci_6alkyl;
72
R is selected for each occurrence from the group consisting of H, halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", -C(0)-Ci_6alkyl, - C(0)-Ci_6alkoxy, phenyl, heteroaryl, C3_6cycloalkyl, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), - S(0)w-NR'R" (where w is 1, 2 or 3), and -NR'-S(0)w, (where w is 1, 2 or 3));
R' is selected, independently for each occurrence, from H, methyl, ethyl, and propyl;
R' ' is selected, independently for each occurrence, from H, methyl, ethyl, propyl, butyl, - C(0)-methyl and -C(0)-ethyl, or R' and R" taken together with the nitrogen to which they are attached may form a 4-6 membered heterocycle; each of moieties R4, R5, R6, R7, R8, R9, and R10 is independently selected for each occurrence from the group consisting of hydrogen, Ci_6alkyl, C2_6alkynyl, C2_6alkenyl, halogen, hydroxyl, nitro, cyano, and NR'R"; wherein for each occurrence, Ci_6alkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", -NR'-S(0)w, and S(0)w-NR'R"; Ci_ 6alkoxy may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, NR'R", -NR'-S(0)w, and S(0)w-NR'R"; C3_6cycloalkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_ 6alkyl, Ci_6alkoxy, -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, and NR'R"; phenyl may be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", C(O)- NR'R", -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), NR'-S(0)w, and -S(0)w-NR'R"(where w is 1 , 2 or 3), and heteroaryl may be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", C(O)- NR'R", -C(0)-Ci_ 6alkyl, -C(0)-Ci_6alkoxy, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), NR'-S(0)w, -S(0)w- NR'R"(where w is 1, 2 or 3)), and C3_6cycloalkyl, and pharmaceutically acceptable salts thereof.
[00058] In some embodiments, Rc of a compound of formula 6 may be H or methyl, e.g., H; and/or R7 may be selected from H and F; and/or R6 may be selected from H and F; and/or R5 may be selected from H and F; and/or R10 may beselected from the group consisting of H, methyl and F; and/or R4, R5, R6, R7, R8, R9, R10, and R11 may be H.
[00059] In certain embodiments, the Y moiety of Formula 6 is S.
[00060] Provided herein, in certain embodiments, is a compound represented by:
Figure imgf000024_0001
Formula 7 wherein
Y is C(RU)2 , S(0)y, NRY and O wherein y is 0, 1, or 2; RY is selected from the group consisting of H, methyl, ethyl, propyl, phenyl and benzyl;
Rm and Rm are each independently selected from the group consisting of H, halogen, Ci_ 6alkyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), C2-6alkenyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), NR'R", and hydroxyl(e.g., Rm and Rm may each be H in certain embodiments);
Rc is H or Ci_6alkyl;
78
R is selected from the group consisting of H, halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, phenyl, heteroaryl, C3_6cycloalkyl, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), -S(0)w-NR'R" (where w is 1, 2 or 3), and -NR'-S(0)w, (where w is 1, 2 or 3));
79
R is selected from the group consisting of H, halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, phenyl, heteroaryl, C3_6cycloalkyl, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), -S(0)w-NR'R" (where w is 1, 2 or 3), and -NR'-S(0)w, (where w is 1, 2 or 3));
R' is selected, independently for each occurrence, from H, methyl, ethyl, and propyl;
R' ' is selected, independently for each occurrence, from H, methyl, ethyl, propyl, butyl, - C(0)-methyl and -C(0)-ethyl, or R' and R" taken together with the nitrogen to which they are attached may form a 4-6 membered heterocycle; each of moieties R4, R5, R6, R7, R8, R9, and R10 is independently selected for each occurrence from the group consisting of hydrogen, Ci_6alkyl, C2_6alkynyl, C2_6alkenyl, halogen, hydroxyl, nitro, cyano, and NR'R"; wherein for each occurrence, Ci_6alkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", -NR'-S(0)w, and S(0)w-NR'R"; Ci_ 6alkoxy may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, NR'R", -NR'-S(0)w, and S(0)w-NR'R"; C3_6cycloalkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_ 6alkyl, Ci_6alkoxy, -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, and NR'R"; phenyl may be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, Ci_6alkyl, C2-6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", C(O)- NR'R", -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), NR'-S(0)w, and -S(0)w-NR'R"(where w is 1, 2 or 3), and heteroaryl may be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3-6cycloalkyl, Ci_6alkoxy, NR'R", C(O)- NR'R", -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), NR'-S(0)w, and - S(0)w-NR'R"(where w is 1, 2 or 3), and pharmaceutically acceptable salts thereof.
Rc is H or methyl.
[00061] In certain embodiments, compound of formula 7 may have Rc as H; and/or R7 may be selected from H and F; and/or R6 may be selected from H and F; and/or R5 may be selected from H and F; and/or R10 may be selected from the group consisting of H, methyl and F; and/or each of R4, R5, R6, R7, R8, R9, R10, and R11 may be H.
[00062] For example, the present disclosure also provides, in part, a compound selected from the group consisting a compound of Table 1, 2, 3, 4, 5, 6 and 7. Also contemplated herein are compounds: N-((2-methylthiazol-5-yl)methyl)-l l-oxo-10,11- dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5-oxide, N-((2-aminothiazol-5-yl)methyl)- 1 l-oxo-10,1 l-dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5-oxide, N-((2-methylthiazol- 5-yl)methyl)-l l-oxo-10,1 l-dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide, N- ((2-aminothiazol-5-yl)methyl)- 11 -oxo- 10,11 -dihydrodibenzo[b,f] [ 1 ,4]thiazepine-8-carboxamide 5,5-dioxide, 1 l-oxo-N-(2-phenylbutyl)-10,l l-dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide, N-(2-(4,4-difluorocyclohexyl)ethyl)-l l-oxo-10,11- dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide 5,5-dioxide, 3'-(5,5-dioxido-l l-oxo-10,11- dihydrodibenzo[b,f] [ 1 ,4]thiazepine-8-carboxamido)-[ 1 , 1 '-biphenyl]-2-carboxylic acid, 9-methyl- N-((2-methylthiazol-5-yl)methyl)- 11 -oxo- 10,11 -dihydrodibenzo[b,f] [ 1 ,4]thiazepine-8- carboxamide, N-(2-(4'-fluoro-[l, -biphenyl]-4-yl)ethyl)-l l-oxo-10,11- dihydrodibenzo[b,f] [ 1 ,4]thiazepine-8-carboxamide 5 ,5-dioxide, N-((2-aminothiazol-5- yl)methyl)-9-methyl-l l-oxo-10,1 l-dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide, 11-oxo- N-(pyrimidin-5-ylmethyl)-10,l l-dihydro-5H-dibenzo[b,e][l,4]diazepine-8-carboxamide, 11- oxo-N-(2-(pyridin-2-yl)ethyl)-10,l l-dihydro-5H-dibenzo[b,e][l,4]diazepine-8-carboxamide, 11- oxo-N-(2-(pyridin-3-yl)ethyl)-10,l l-dihydro-5H-dibenzo[b,e][l,4]diazepine-8-carboxamide, 11- oxo-N-(pyridin-3-ylmethyl)-l 0, 11 -dihydro-5H-dibenzo[b,e] [ 1 ,4]diazepine-8-carboxamide, N-(2- ([1,1 '-biphenyl]-4-yl)ethyl)- 11 -oxo- 10,11 -dihydro-5H-dibenzo[b,e] [ 1 ,4]diazepine-8- carboxamide, 11 -oxo-N-(pyridin-4-yl)- 10,11 -dihydro-5H-dibenzo[b,e] [ 1 ,4]diazepine-8- carboxamide, N-(4-(N,N-dimethylsulfamoyl)phenethyl)-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][l,4]diazepine-8-carboxamide, N-([l,l'-biphenyl]-3-yl)-l l-oxo-10,1 l-dihydro-5H- dibenzo[b,e][ 1 ,4]diazepine-8-carboxamide, (Z)-N-((3-(methylimino)prop- 1 -en-2-yl)oxy)- 11- oxo-10,1 l-dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide, 1 l-oxo-N-(pyrimidin-5-yloxy)- 10,11 -dihydrodibenzo[b,f][ 1 ,4]thiazepine-8-carboxamide, 11 -oxo-N-(4-(pyrimidin-5-yl)benzyl)- 10,11 -dihydrodibenzo[b,f][ 1 ,4]thiazepine-8-carboxamide,N-(2-(4'-fluoro-[l , 1 '-biphenyl]-4- yl)ethyl)- 11 -oxo- 10,11 -dihydrodibenzo[b,f] [ 1 ,4]thiazepine-8-carboxamide,2-chloro-N-((2- methylthiazol-5-yl)methyl)- 11 -oxo- 10,11 -dihydrodibenzo[b,f] [1 ,4]thiazepine-8-carboxamide,2- chloro-11 -oxo-N-(pyridin-3-ylmethyl)- 10,11 -dihydrodibenzo[b,f] [ 1 ,4]thiazepine-8-carboxamide, 2-chloro- 11 -oxo-N-(pyrimidin-5-ylmethyl)-l 0, 11 -dihydrodibenzo[b,f] [ 1 ,4]thiazepine-8- carboxamide, 3-chloro-N-((2-methylthiazol-5-yl)methyl)-l l-oxo-10,11- dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide,3-chloro-l l-oxo-N-(pyridin-3-ylmethyl)- 10,1 l-dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide, 3-chloro-l l-oxo-N-(pyrimidin-5- ylmethyl)-10,l l-dihydrodibenzo[b,f][l,4]thiazepine-8-carboxamide, 1 l-methyl-N-((2- methylthiazol-5-yl)methyl)-6-oxo-6,l l-dihydro-5H-dibenzo[b,e]azepine-3-carboxamide, 11- methyl-6-oxo-N-(pyridin-3-ylmethyl)-6,l l-dihydro-5H-dibenzo[b,e]azepine-3-carboxamide, 11- methyl-6-oxo-N-(pyrimidin-5-ylmethyl)-6, 11 -dihydro-5H-dibenzo[b,e]azepine-3-carboxamide, 2-chloro- 11 -oxo-N-(thiazol-5-ylmethyl)- 10,11 -dihydrodibenzo[b,f] [ 1 ,4]thiazepine-8- carboxamide, 3-chloro-l l-oxo-N-(thiazol-5-ylmethyl)-10,l 1- dihydrodibenzo[b,f] [ 1 ,4]thiazepine-8-carboxamide, 11 -methyl-6-oxo-N-(thiazol-5-ylmethyl)- 6,1 l-dihydro-5H-dibenzo[b,e]azepine-3-carboxamide, and 1 l-oxo-N-(2-(thiazol-5-yl)propan-2- yl)- 10,11 -dihydrodibenzo[b,f] [ 1 ,4]thiazepine-8-carboxamide; or a pharmaceutically acceptable salt thereof.
[00063] In a second aspect, a method for the synthesis of disclosed compounds is provided. The method follows Synthetic Scheme 1, as illustrated in FIG. 1. A first mixture comprising reagents 1 and 2 is formed for synthetic step A to yield synthetic intermediate 3. Synthetic step A may be conducted in an organic solvent, for instance a polar aprotic solvent such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dioxane, hexamethylphosphorotriamide, and tetrahydrofuran. The reaction may be conducted in the presence of a base, for example a carbonate such as Li2C03, Na2C03, K2C03, Rb2C03, Cs2C03, MgC03, CaC03, SrC03, and BaC03.
[00064] In reagent 1, moiety -YH is selected from the group consisting of -SH, -OH, and -
N(R 12 )H, wherein R 12 is selected from the group consisting of hydrogen and alkyl. In intermediates 3, 4, 5, and in product 6, moiety -Y- is selected from the group consisting of -S-, -
12 1 2
0-, and -N(R )-. Moieties P and P are independently selected carboxyl protecting groups, such as methoxyl or ethoxyl groups. In some cases, at least one of P3 and P4 is an ammo protecting group, for example selected from the group consisting of carbobenzyloxy (Cbz), p- methoxybenzyl-carbonyl (Moz or MeOZ), tert-butyloxycarbonyl (BOC), 9- fluorenylmethyloxycarbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate group, p-Methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), sulfonamides (Nosyl and Nps). Alternatively, moiety -N(P3)(P4) may be a group that can be transformed in an amino group by appropriate chemical reactions. By way of example, moiety - N(P3)(P4) may be an -N02 group that is transformed into an amino (-NH2) moiety by reaction with a reductant.
1 2
[00065] In synthetic step B, protecting groups P and P are removed to yield carboxyl
1 2
moieties. In instances where P and P are alkoxy groups, this may be achieved by hydrolysis, for example in the presence of a base or acid. Group -N(P3)(P4) is transformed into an amino moiety, as exemplified above, to yield intermediate 4. In synthetic step C, the amino group of intermediate 4 is reacted with the carboxy group on the other phenyl moiety, forming the 1,4- thiazepan-5-one moiety of intermediate 5. The formation of this amide bond may be speeded up by the addition of activators. Example activators include carbodiimides, such as Ν,Ν'- dicyclohexylcarbodiimide (DCC), Ν,Ν'-diisopropylcarbodiimide (DIC), and carbonyl diimidazole (CDI); and triazolols, such as 1-hydroxy-benzotriazole (HOBt) and l-hydroxy-7- aza-benzotriazole (HOAt). Other activators include HBTU, HATU, HCTU, TBTU, and PyBOP.
[00066] In synthetic step D, intermediate 5 is reacted with a molecule of formula R NH2 to create an amide bond and yield products of Formula 6. As with synthetic step C, the formation of the amide bond may be speeded up with an activator. An exemplary Synthetic Scheme is illustrated in FIG. 2.
[00067] In a further aspect, a method for treating a hepatitis B infection in a patient in need thereof is provided, comprising administering to a subject or patient an effective amount of a disclosed compound, and/or administering a first disclosed compound and optionally, and additional, different disclosed compound(s). In another embodiment, a method for treating a hepatitis B infection in a patient in need thereof is provided, comprising administering to a subject or patient a therapeutically effective amount of a pharmaceutical composition comprising a disclosed compound, or two or more disclosed compounds.
[00068] For use in accordance with this aspect, the appropriate dosage is expected to vary depending on, for example, the particular compound employed, the mode of administration, and the nature and severity of the infection to be treated as well as the specific infection to be treated and is within the purview of the treating physician. Usually, an indicated administration dose may be in the range between about 0.1 to about 1000 μg/kg body weight. In some cases, the administration dose of the compound may be less than 400 μg/kg body weight. In other cases, the administration dose may be less than 200 μg/kg body weight. In yet other cases, the administration dose may be in the range between about 0.1 to about 100 μg/kg body weight. The dose may be conveniently administered once daily, or in divided doses up to, for example, four times a day or in sustained release form.
[00069] A compound may be administered by any conventional route, in particular: enterally, topically, orally, nasally, e.g. in the form of tablets or capsules, via suppositories, or parenterally, e.g. in the form of injectable solutions or suspensions, for intravenous, intra-muscular, subcutaneous, or intra-peritoneal injection. Suitable formulations and pharmaceutical compositions will include those formulated in a conventional manner using one or more physiologically acceptable carriers or excipients, and any of those known and commercially available and currently employed in the clinical setting. Thus, the compounds may be formulated for oral, buccal, topical, parenteral, rectal or transdermal administration or in a form suitable for administration by inhalation or insufflation (either orally or nasally).
[00070] For oral administration, pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, micro crystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g.
potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate).
Tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g.
methyl or propyl-p-hydroxybenzoates or sorbic acid). Preparations may also contain buffer salts, flavoring, coloring and sweetening agents as appropriate.
[00071] Preparations for oral administration may also be suitably formulated to give controlled-release or sustained release of the active compound(s) over an extended period. For buccal administration the compositions may take the form of tablets or lozenges formulated in a conventional manner known to the skilled artisan.
[00072] A disclosed compound may also be formulated for parenteral administration by injection e.g. by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain additives such as suspending, stabilizing and/or dispersing agents. Alternatively, the compound may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use. Compounds may also be formulated for rectal administration as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other giyeerides.
[001)73] in some cases, a disclosed compound may be administered as part of a combination therapy in conjunction with one or more antivirals. Example antivirals include nucleoside analogs, interferon a, and other assembly effectors, for instance h'eteroaryldihydropyrimidrnes (EAPs) such as methyl 4-(2-cUoro~4-iluorop.aen}d^ ,4- d.mydropyriniidine-5-carboxylate (HAP-1). For example, provided herein is a method of treating patient suffering from hepatitis B comprising administering to a subject a first amount of a disclosed compound and a second amount of an antiviral, or other anii HBV agent, for example a second amount of a second compound selected from the group consisting of: another HBV. caspid assembly promoter (such as certain compounds disclosed herein or -for example, GLS4,
BAY 41-4109, AT-130, DVR-23 (e.g., as depicted below),
Figure imgf000031_0001
mm-ws
VR 3-778 NVR1221 (by code); and N890 (as depicted below):
Figure imgf000031_0002
other CpAMs such as those disclosed in the following patent applications hereby incorporated by reference: WO2014037480, WO2014184328, WO2Q13006394, WO2014089296,
WO2014106019, WO2013102655, WO2014184350, WO2014184365, WO2014161888, WO2014131847, ¥02014033176, WO2Q1.4033167, and WO2014033170; Nucleoside analogs interfering with, viral polymerase, such as entecavir (Baraclude), Lamivudine, (Epivir-HB V), Telbivudine (Tyzeka, Sebivo), Adefovir dipivoxil (Hepsera), Tenofovir (Viread), Tenofovir alafenamide fomarate (TAP), prodrugs of tenofavir (e.g. AGX-1009), L-FMAlJ (Clevudine), LB80380 (Besifovir) and:
Figure imgf000032_0001
viral entry inhibitors such, as Myrcludex B and related lipopeptide derivatives; HBsAg secretion inhibitors such as REP 9AC and related nucleic acid-based amphipathic polymers, HBF-0529 (PBHBV-001), PBHBV-2-15 as depicted below: :
Figure imgf000032_0002
22: HBF-0529 23: FBHBV-2-15
01 as depicted below:
Figure imgf000032_0003
HBc directed transbodies such as those described in Wang Y, et al, Transbody against hepatitis B virus core protein inhibits hepatitis B virus replication in vitro, Int. Immunopharmacol (2014), located at //dx.doi. org/10.1016/j.intimp.2015.01.028; antiviral core protein mutant (such as Cpl83-V124W and related mutations as described in WO/2013/010069, WO2014/074906 each incorporated by reference ); inhibitors of HBx-interactions such as RNAi, antisense and nucleic acid based polymers targeting HBV RNA;, e.g., RNAi (for example ALN-HBV, ARC-520, TKM-HBV, ddRNAi), antisense (ISIS-HBV), or nucleic acid based polymer: (REP 2139-Ca); immunostimulants such as Interferon alpha 2a (Roferon), Intron A (interferon alpha 2b), Pegasys (peginterferon alpha 2a), Pegylated IFN 2b, IFN lambda la and PEG IFN lambda la, Wellferon, Roferon, Infergen, lymphotoxin beta agonists such as CBE11 and BS1); Non- Interferon Immune enhancers such as Thymosin alpha- 1 (Zadaxin) and Interleukin-7 (CYT107); TLR-7/9 agonists such as GS-9620, CYT003, Resiquimod; Cyclophilin Inhibitors such as NVP018; OCB-030; SCY-635; Alisporivir; NIM811 and related cyclosporine analogs; vaccines such as GS-4774, TG1050, Core antigen vaccine; SMAC mimetics such as birinapant and other IAP-antagonists; Epigenetic modulators such as KMT inhibitors (EZH1/2, G9a, SETD7, Suv39 inhibitors), PRMT inhibitors, HDAC inhibitors, SIRT agonists, HAT inhibitors, WD antagonists (e.g. OICR-9429), PARP inhibitors, APE inhibitors, DNMT inhibitors, LSD1 inhibitors, JMJD HDM inhibitors, and Bromodomain antagonists; kinase inhibitors such as TKB1 antagonists, PLK1 inhibitors, SRPK inhibitors, CDK2 inhibitors, ATM & ATR kinase inhibitors; STING Agonists; Ribavirin; N-acetyl cysteine ; NOV-205 (BAM205); Nitazoxanide (Alinia),
Tizoxanide; SB 9200 Small Molecule Nucleic Acid Hybrid (SMNH); DV-601 ; Arbidol; FXR agonists (such as GW 4064 and Fexaramin); antibodies, therapeutic proteins, gene therapy, and biologies directed against viral components or interacting host proteins.
[00074] In some embodiments, the first and second amounts together comprise a
pharmaceutically effective amount. The first amount, the second amount, or both may be the same, more, or less than effective amounts of each compound administered as monotherapies. Therapeutically effective amounts of a disclosed compound and antiviral may be coadministered to the subject, i.e., administered to the subject simultaneously or separately, in any given order and by the same or different routes of administration. In some instances, it may be advantageous to initiate administration of a disclosed compound first, for example one or more days or weeks prior to initiation of administration of the antiviral. Moreover, additional drugs may be given in conjunction with the above combination therapy.
[00075] In another embodiment, a disclosed compound may be conjugated (e.g., covalently bound directly or through molecular linker to a free carbon, nitrogen (e.g. an amino group), or oxygen (e.g. an active ester) of a disclosed compound), with a detection moiety, e.g. a fluorophore moiety (such a moiety may for example re-emit a certain light frequency upon binding to a virus and/or upon photon excitation. Contemplated fluorophores include
AlexaFluor® 488 (Invitrogen) and BODIPY FL (Invitrogen), as well as fluorescein, rhodamine, cyanine, indocarbocyanine, anthraquinones, fluorescent proteins, aminocoumarin,
methoxycoumarin, hydrooxycoumarin, Cy2, Cy3, and the like. Such disclosed compounds conjugated to a detection moiety may be used in e.g. a method for detecting HBV or biological pathways of HBV infection, e.g., in vitro or in vivo; and/or methods of assessing new compounds for biological activity.
EXAMPLES
[00076] The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials.
Example 1: Synthesis of ll-oxo-10, 11-dihydrodibenzo \b, f\ [1, 41 thiazepine-8-carboxylic acid (6) - a common intermediate
Figure imgf000035_0001
Synthesis of methyl 4-((2-(methoxycarbonyl) phenyl) thio)-3-nitrobenzoate (3):
Figure imgf000035_0002
[00077] To a stirred solution of methyl 4-fluoro-3-nitrobenzoate 2 (30 g, 150.67 mmol) in DMF (300 mL) under inert atmosphere were added cesium carbonate (58.76 g, 180.8 mmol) and methyl 2-mercaptobenzoate 1 (22.6 mL, 165.47 mmol) at RT; heated to 55-60 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (1500 mL) and the precipitated solid was filtered to obtain the crude. The crude was washed with water (500 mL), hexane (200 mL) and dried in vacuo to afford compound 3 (48.8 g, 93%) as yellow solid. TLC: 20% EtOAc/ hexanes (Rf: 0.4); 1H NMR (CDC13, 400 MHz): δ 8.85 (s, 1H), 7.99-7.92 (m, 2H), 7.66-7.56 (m, 3H), 6.93 (d, J= 8.6 Hz, 1H), 3.94 (s, 3H), 3.79 (s, 3H).
Synthesis of methyl 3-amino-4-((2-(methoxycarbonyl) phenyl) thio) benzoate (4):
Figure imgf000035_0003
[00078] To a stirred solution of compound 3 (48 g, 138.32 mmol) in MeOH (1000 mL) under inert atmosphere was added 10% Pd/C (20 g, wet) at RT under hydrogen atmosphere in an autoclave (100 psi pressure) and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, washed with 50% MeOH/ CH2CI2 (500 mL). The filtrate was removed in vacuo to obtain the crude which as triturated with diethyl ether (200 mL), washed with hexane (200 mL) and dried in vacuo to afford compound 4 (40 g, 91%) as yellow solid. TLC: 10% EtOAc/ hexanes (Rf. 0.3); 1H NMR (DMSO-< , 400 MHz): δ 7.95 (dd, J= 7.8, 1.4 Hz, 1H), 7.48-7.35 (m, 3H), 7.23 (td, J= 7.5, 1.1 Hz, 1H), 7.15 (dd, J= 8.0, 1.8 Hz, 1H), 6.66 (dd, J= 8.2, 0.8 Hz, 1H), 5.67 (br s, 2H), 3.88 (s, 3H), 3.84 (s, 3H).
Synthesis of 3-amino-4-((2-carboxyphenyl) thio) benzoic acid (5):
Figure imgf000036_0001
5
[00079] To a stirred solution of compound 4 (40 g, 126.18 mmol) in THF: H20 (5: 1, 400 mL) was added lithium hydroxide monohydrate (26 g, 619.0 mmol) at 0 °C; warmed to RT and stirred for 48 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was acidified with 2 N HC1 to ~2. The precipitated solid was filtered and dried in vacuo to afford compound 5 (34.6 g, 95%>) as an off-white solid.
TLC: 30% EtOAc/ hexanes (Rf. 0.1); 1H NMR (DMSO-</6, 500 MHz): δ 13.00 (br s, 2H), 7.93 (dd, J= 7.7, 1.0 Hz, 1H), 7.42 (s, 1H), 7.40-7.31 (m, 2H), 7.18 (t, J= 7.4 Hz, 1H), 7.13 (dd, J = 8.0, 1.6 Hz, 1H), 6.61 (d, J= 7.8 Hz, 1H), 5.55 (br s, 2H).
Synthesis of ll-oxo-10, 11-dihydrodibenzo [b,j\ [1, 4] thiazepine-8-carboxylic acid (6):
Figure imgf000036_0002
6 [00080] To a stirred solution of compound 5 (31 g, 107.26 mmol) in THF (600 mL) under inert atmosphere was added CDI (86.88 g, 536.29 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was acidified with 2 N HCl to pH~4. The obtained solid was filtered and further dried by using toluene (2 x 200 mL) to afford compound 6 (26 g, 90%) as white solid. TLC: 10% MeOH/ CH2C12 (Rf. 0.3); 1H NMR (DMSO-</6, 400 MHz): δ 13.22 (br s, 1H), 10.81 (s, 1H), 7.78 (s, 1H), 7.72-7.64 (m, 3H), 7.57-7.44 (m, 3H).
Example 2: Synthesis of 2-chloro-ll-oxo-10, 11-dihydrodibenzo \b, f\ [1, 41 thiazepine-8- carboxylic acid (14) - a common intermediate
Figure imgf000037_0001
Synthesis of 5-chloro-2-((4-methoxybenzyl) thio) benzonitrile (9):
Figure imgf000037_0002
9
[00081] To a stirred solution of 5-chloro-2-fluorobenzonitrile 7 (1 g, 6.41 mmol) in DMF (10 mL) under inert atmosphere was added cesium carbonate (2.30 g, 7.05 mmol) at RT; heated to 40 °C and to this was added (4-methoxyphenyl) methanethiol 8 (1.08 g, 7.05 mmol); heated to 60 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 3-5% EtOAc/ hexanes to afford compound 9 (1 g, 54%) as white solid. TLC: 10% EtOAc/ hexanes (Rf. 0.6); 1H-NMR (CDC13, 500 MHz): δ 7.57 (s, 1H), 7.39 (d, J= 8.0 Hz, 1H), 7.28-7.27 (m, 1H), 7.20 (d, J= 9.0 Hz, 2H), 6.81 (d, J= 9.0 Hz, 2H), 4.15 (s, 2H), 3.78 (s, 3H).
Synthesis of 5-chloro-2-mercaptobenzonitrile (10):
Figure imgf000038_0001
10
[00082] A stirred solution of compound 9 (1 g, 3.47 mmol) in trifluoro acetic acid (10 mL) under inert atmosphere was stirred at 70 °C for 5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude compound 10 (590 mg) which was carried to the next step without further purification. TLC: 30% EtOAc/ hexanes (Rf. 0.2); 1H-NMR (CDC13, 500 MHz): δ 7.57 (s, 1H), 7.41 (d, J= 9.0 Hz, 1H), 7.34 (d, J= 9.0 Hz, 1H), 4.08 (s, 1H).
Synthesis of methyl 4-((4-chloro-2-cyanophenyl) thio)-3-nitrobenzoate (11):
Figure imgf000038_0002
11
[00083] To a stirred solution of compound 10 (620 mg, 3.11 mmol) in DMF (10 mL) under inert atmosphere was added cesium carbonate (1.1 g, 3.42 mmol) at RT; heated to 40 °C and stirred for 10 min. To this was added methyl 4-fluoro-3-nitrobenzoate 2 (582 mg, 3.42 mmol) at 60 °C and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 25% EtOAc/ hexanes to afford compound 11 (600 mg, 55%) as pale yellow solid. TLC: 30% EtOAc/ hexanes (R/. 0.4); 1H-NMR (DMSO-< , 400 MHz): δ 8.66 (s, 1H), 8.33 (s, 1H), 8.05-8.03 (m, 1H), 7.98-7.92 (m, 2H), 7.02 (d, J= 8.4 Hz, 1H), 3.86 (s, 3H).
Synthesis of methyl 3-amino-4-((4-chloro-2-cyanophenyl) thio) benzoate (12):
Figure imgf000039_0001
12
[00084] To a stirred solution of compound 11 (450 mg, 1.29 mmol) in acetic acid (15 mL) under inert atmosphere was added iron powder (724 mg, 12.9 mmol) at RT; heated to 90 °C and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was basified with saturated NaHC03 solution (15 mL) and extracted with CH2CI2 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was triturated with 3%) EtOAc/ hexanes (2 x 5 mL) to afford compound 12 (290 mg, 70%) as pale yellow solid. TLC: 20% MeOH/ CH2C12 (R/. 0.7); 1H-NMR (DMSO-</6, 400 MHz): δ 8.05 (s, 1H), 7.63-7.60 (m, 1H), 7.48 (s, 1H), 7.43 (d, J= 8.0 Hz, 1H), 7.14 (d, J= 8.8 Hz, 1H), 6.75 (d, J= 8.8 Hz, 1H), 5.88 (s, 2H), 3.84 (s, 3H).
Synthesis of 2-((2-amino-4-carboxyphenyl) thio)-5-chlorobenzoic acid (13):
Figure imgf000039_0002
13
[00085] To a stirred solution of compound 12 (450 mg, 1.41 mmol) in MeOH (10 mL) was added potassium hydroxide (792 mg, 14.1 mmol) in water (3 mL) at 0 °C; heated to 90 °C and stirred for 9 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was acidified with 1 N HC1 to pH~4.0. The obtained solid was filtered, washed with ether (2 x 5 mL) and dried in vacuo to afford compound
(350 mg, 76%) as an off-white solid. TLC: 20% MeOH/ CH2C12 (Rf. 0.3); 1H-NMR (DMSO-</6, 400 MHz): δ 12.92 (br s, 2H), 7.89 (s, 1H), 7.44-7.38 (m, 3H), 7.14 (d, J= 8.8 1H), 6.60 (d, J= 8.8 Hz, 1H), 5.64 (br s, 2H).
[00086] Synthesis of 2-chloro-ll-oxo-lO, ll-dihydrodibenzo [b,j [1, 4] thiazepine-8 carboxylic acid (14):
Figure imgf000040_0001
14
[00087] To a stirred solution of compound 13 (30 mg, 0.09 mmol) in THF (2 mL) under inert atmosphere was added CDI (45 mg, 0.27 mmol) at RT and stirred for 7 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was acidified with 2 N HCl to pH~4.0. The obtained solid was filtered, washed with ether (2 x 3 mL) and dried in vacuo to afford compound 14 (15 mg, 53%) as an off- white solid. TLC: 15% MeOH/ CH2C12 (Rf. 0.5); 1H-NMR (DMSO-< , 400 MHz): δ 13.05 (br s, 1H), 10.98 (s, 1H), 7.80 (s, 1H), 7.72-7.70 (m, 3H), 7.64 (s, 2H).
Example 3: Synthesis of 3-chloro-ll-oxo-lO, ll-dihydrodibenzo \b, f\ [1, 41 thiazepine-8- carboxylic acid (21) - a common intermediate
Figure imgf000040_0002
Synthesis of 4-chloro-2-((4-methoxybenzyl) thio) benzonitrile (16):
Figure imgf000041_0001
16
[00088] To a stirred solution of 4-chloro-2-fluorobenzonitrile 15 (1 g, 6.41 mmol) in DMF (25 mL) under inert atmosphere was added cesium carbonate (2.30 g, 7.05 mmol) at RT; heated to 40 °C and to this was added (4-methoxyphenyl) methanethiol 8 (1.08 g, 7.05 mmol); heated to 60 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 4% EtOAc/ hexanes to afford compound 16 (900 mg, 48%) as white solid. TLC: 10% EtOAc/ hexanes (R/. 0.6); 1H-NMR (CDC13, 400 MHz): δ 7.51 (d, J= 8.4 Hz, 1H), 7.33 (s, 1H), 7.23- 7.20 (m, 3H), 6.84 (d, J= 8.4 Hz, 2H), 4.19 (s, 2H), 3.79 (s, 3H).
Synthesis of 4-chloro-2-mercaptobenzonitrile (17):
Figure imgf000041_0002
17
[00089] A stirred solution of compound 16 (900 mg, 3.11 mmol) in trifluoro acetic acid (10 mL) under inert atmosphere at RT was heated to 70 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude compound 17 (527 mg) as brown solid. The crude was carried to the next step without further purification. TLC: 5% MeOH/ CH2C12 (Rf. 0.1); 1H-NMR (CDC13, 400 MHz): δ 7.52 (d, J= 8.4 Hz, 1H), 7.41 (s, 1H), 7.22-7.19 (m, 1H), 4.13 (s, 1H).
Synthesis of methyl 4-((5-chloro-2-cyanophenyl) thio)-3-nitrobenzoate (18):
Figure imgf000041_0003
18 [00090] To a stirred solution of compound 17 (550 mg, 2.76 mmol) in DMF (15 mL) under inert atmosphere was added cesium carbonate (988 mg, 3.04 mmol) at RT; heated to 40 °C and stirred for 10 min. To this was added methyl 4-fluoro-3-nitrobenzoate 2 (515 mg, 3.04 mmol) at 60 °C and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL). The obtained solid was filtered, washed with 15% EtOAc/ hexanes (2 x 5 mL) and dried in vacuo to afford compound 18 (700 mg, 73%) as yellow solid. TLC: 20% EtOAc/ hexanes (Rf. 0.3); 1H-NMR (DMSO-< , 500 MHz): δ 8.69 (s, 1H), 8.18-8.15 (m, 2H), 8.10 (d, J= 8.5 Hz, 1H), 7.92 (d, J= 8.5 Hz, 1H), 7.10 (d, J= 9.0 Hz, 1H), 3.90 (s, 3H).
Synthesis of methyl 3-amino-4-((5-chloro-2-cyanophenyl) thio) benzoate (19):
Figure imgf000042_0001
19
[00091] To a stirred solution of compound 18 (700 mg, 2.01 mmol) in acetic acid (15 mL) under inert atmosphere was added iron powder (1.12 g, 20.11 mmol) at RT; heated to 90 °C and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was basified with 10%> NaHC03 solution (20 mL) and extracted with CH2CI2 (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 19 (500 mg, 78%) as yellow solid. TLC: 30% EtOAc/ hexanes (Rf. 0.8); 1H-NMR (DMSO-< , 500 MHz): δ 7.92 (d, J= 7.5 Hz, 1H), 7.51-7.43 (m, 3H), 7.17 (d, J= 8.0 Hz, 1H), 6.66 (s, 1H), 5.96 (s, 2H), 3.86 (s, 3H).
Synthesis of 2-((2-amino-4-carboxyphenyl) thio)-4-chlorobenzoic acid (20):
Figure imgf000042_0002
20
[00092] To a stirred solution of compound 19 (500 mg, 1.57 mmol) in MeOH (6 mL) was added potassium hydroxide (1.32 mg, 23.5 mmol) in water (6 mL) at 0 °C; heated to 90 °C and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (20 mL) and extracted with EtOAc (2 x 25 mL). The aqueous layer was acidified with 1 N HC1 to pH~6.0. The obtained solid was filtered, washed with ether (2 x 7 mL) and dried in vacuo to afford compound 20 (375 mg, 74%) as an off-white solid. TLC: 20% MeOH/ CH2C12 (Rf. 0.2); 1H-NMR (CDC13, 400 MHz): δ 8.05 (d, J= 8.4 Hz, 1H), 7.55-7.47 (m, 3H), 7.17-7.14 (m, 1H), 6.67 (s, 1H).
Synthesis of 3-chloro-ll-oxo-10, 11-dihydrodibenzo [b,j\ [1, 4] thiazepine-8-carboxylic acid
(21):
Figure imgf000043_0001
21
[00093] To a stirred solution of compound 20 (375 mg, 1.16 mmol) in THF (10 mL) under inert atmosphere was added CDI (564 mg, 3.48 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (15 mL) and acidified with 6 N HC1 to pH~l .0. The obtained solid was filtered, washed with ether (2 x 5 mL) and dried in vacuo to afford compound 21 (285 mg, 81%) as an off-white solid. TLC: 20% MeOH/ CH2C12 (Rf. 0.4); 1H-NMR (DMSO-< , 400 MHz): δ 14.56 (br s, 2H), 10.90 (s, 1H), 9.11 (s, 1H), 7.71-7.65 (m, 4H).
Example 4: Synthesis of l-fluoro-ll-oxo-10, 11-dihydrodibenzo \b, f\ [1, 41 thiazepine-8- carboxylic acid (28) - a common intermediate
Figure imgf000044_0001
Synthesis of methyl 2-fluoro-6-((4-methoxybenzyl) thio) benzoate (23):
Figure imgf000044_0002
23
[00094] To a stirred solution of methyl 2, 6-difluorobenzoate 22 (10 g, 58.13 mmol) in DMF (100 mL) under inert atmosphere were added (4-methoxyphenyl) methanethiol 8 (8.96 g, 58.13 mmol), cesium carbonate (20.8 g, 63.95 mmol) at 0 °C; warmed to 10 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (2 x 800 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10-15% EtOAc/ hexanes to afford compound 23 (7.5 g, 42%) as white solid. TLC: 10% EtOAc/ hexanes(i? 0.3); 1H NMR (DMSO-</6, 400 MHz) δ 7.53-7.44 (m, 1H), 7.35 (d, J= 8.0 Hz, 1H), 7.26 (d, J= 8.6 Hz, 2H), 7.15 (t, J= 9.0 Hz, 1H), 6.86 (d, J= 8.7 Hz, 2H), 4.22 (s, 2H), 3.72 (s, 3H), 3.33 (s, 3H). Synthesis of methyl 2-fluoro-6-mercaptobenzoate (24):
Figure imgf000045_0001
24
[00095] A stirred solution of compound 23 (7.5 g, 24.5 mmol) in trifluoro acetic acid (100 mL) at RT under inert atmosphere was heated to 60-65 °C and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed and dried in vacuo to obtain compound 24 (4.6 g) as brown syrup. The crude was carried forward for next step without further purification. TLC: 10% EtOAc/ hexanes (R/. 0.7).
Synthesis of methyl 2-fluoro-6-((4-(methoxycarbonyl)-2-nitrophenyl) thio) benzoate (25):
Figure imgf000045_0002
25
[00096] To a stirred solution of methyl 4-fluoro-3-nitrobenzoate 2 (4.5 g, 22.61 mmol) in DMF (100 mL) under inert atmosphere were added compound 24 (4.6 g, crude), cesium carbonate (11 g, 33.91 mmol) at RT; heated to 60-65 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (600 mL) and stirred for 1 h. The precipitated solid was filtered, titurated with 10% EtOAc/ hexanes(2 x 20 mL) and dried in vacuo to afford compound 25 (7 g, 85%) as yellow solid. TLC: 20% EtOAc/ hexanes (Rf: 0.3); 1H NMR (DMSO-</6, 400 MHz): δ 8.65 (s, 1H), 8.08 (dd, J = 8.6, 1.9 Hz, 1H), 7.79-7.72 (m, 1H), 7.67-7.61 (m, 2H), 7.01 (d, J= 8.6 Hz, 1H), 3.88 (s, 3H), 3.72 (s, 3H).
Synthesis of methyl 2-((2-amino-4-(methoxycarbonyl) phenyl) thio)-6-fluorobenzoate (26):
Figure imgf000045_0003
26 [00097] To a stirred solution of compound 25 (7.09 g, 19.17 mmol) in MeOH (200 mL) under inert atmosphere was added 10% Pd/ C (3.5 g) at RT and stirred under hydrogen at 80 psi for 16 h in an autoclave. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and washed with 40% MeOH/ CH2CI2 (3 x 500 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude compound was triturated with 20%> EtOAc/ hexanes (200 mL) and dried in vacuo to afford compound 26 (5 g, 78%) as an off-white solid. TLC: 20% EtOAc/ hexanes (R/. 0.4); 1H NMR (DMSO-< , 400 MHz): δ 7.45-7.36 (m, 3H), 7.19-7.11 (m, 2H), 6.68 (d, J= 7.7 Hz, 1H), 5.71 (s, 2H), 3.90 (s, 3H), 3.83 (s, 3H).
Synthesis of 2-((2-amino-4-carboxyphenyl) thio)-6-fluorobenzoic acid (27):
Figure imgf000046_0001
27
[00098] To a stirred solution of compound 26 (5 g, 14.92 mmol) in THF: H20 (5 : 1 , 90 mL) was added lithium hydroxide monohydrate (3.13 g, 74.62 mmol) at RT and stirred for 16 h and heated to 80 °C for 5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (200 mL) and acidified with 2 N HC1 to pH~4. The precipitated solid was filtered and dried in vacuo to afford compound 27 (4 g, 87%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf. 0.1); 1H NMR (DMSO-< , 400 MHz): δ 12.89 (br s, 1H), 7.42-7.36 (m, 2H), 7.35-7.31 (m, 1H), 7.14 -7.08 (m, 2H), 6.63 (d, J= 8.0 Hz, 1H), 5.75 (br s, 2H).
Synthesis of l-fluoro-ll-oxo-10, 11-dihydrodibenzo [b,j\ [1, 4] thiazepine-8-carboxylic acid (28):
Figure imgf000046_0002
28
[00099] To a stirred solution of compound 27 (4 g, 13.02 mmol) in THF (100 mL) under inert atmosphere was added CDI (10.56 g, 65.1 mmol) at RT and stirred for 26 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with ice cold water (80 mL) and acidified with 2 N HC1 to pH~4. The precipitated solid was filtered and dried in vacuo to afford compound 28 (3.3 g, 88%) as an off- white solid. TLC: 15% MeOH/ CH2C12 (Rf. 0.2); 1H NMR (DMSO-</6, 400 MHz): δ 13.33 (br s, 2H), 11.00 (s, 1H), 7.77 (s, 1H), 7.69-7.67 (m, 2H), 7.53-7.47 (m, 1H), 7.42-7.39 (m, 1H), 7.35-7.29 (m, 1H).
Example 5: Synthesis of 2-fluoro-ll-oxo-10, 11-dihydrodibenzo \b, f\ [1, 41 thiazepine-8- carboxylic acid (35) - a common intermediate
Figure imgf000047_0001
35
Synthesis of methyl-5-fluoro-2-((4-methoxybenzyl) thio) benzoate (30):
Figure imgf000047_0002
[000100] To a stirred solution of methyl 2, 5-difluorobenzoate 29 (1 g, 5.80 mmol) in DMF (20 mL) under argon atmosphere were added (4-methoxyphenyl) methanethiol 8 (985 mg, 6.39 mmol), cesium carbonate (2.07 g, 6.39 mmol) at RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with CH2CI2 (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5-7% EtOAc/ hexanes to afford compound 30 (700 mg, 40%) as white solid. TLC: 10% EtOAc/ hexanes (R/. 0.3); 1H-NMR (CDC13, 400 MHz): δ 7.64-7.61 (m, 1H), 7.32-7.29 (m, 3H), 7.17-7.09 (m, 1H), 6.86-6.82 (m, 2H), 4.09 (s, 2H), 3.90 (s, 3H), 3.79 (s, 3H).
Synthesis of methyl 5-fluoro-2-mercaptobenzoate (31):
Figure imgf000048_0001
31
[000101] A stirred solution of compound 30 (700 mg, 2.28 mmol) in trifluoro acetic acid (7 mL) at RT under argon atmosphere was heated to 60-65 °C and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed and dried in vacuo to obtain compound 31 (380 mg, 89%>) as brown syrup. TLC: 10%> EtOAc/ hexanes (R/. 0.7); 1H-NMR (DMSO-</6, 400 MHz): δ 7.70-7.58 (m, 2H), 7.42-7.35 (m, 1H), 5.42 (s, 1H), 3.86 (s, 3H).
Synthesis of methyl 5-fluoro-2-((4-(methoxycarbonyl)-2-nitrophenyl) thio) benzoate (32):
Figure imgf000048_0002
32
[000102] To a stirred solution of methyl 4-fluoro-3-nitrobenzoate 2 (350 mg, 1.75 mmol) in DMF (10 mL) under argon atmosphere were added compound 31 (360 mg, 1.93 mmol), cesium carbonate (1.14 g, 3.51 mmol) at RT; heated to 60-65 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with CH2CI2 (2 x 40 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 7-10% EtOAc/ hexanes to afford compound 32
(500 mg, 78%) as yellow solid. TLC: 10% EtOAc/ hexanes (Rf. 0.3); 1H-NMR (DMSO-< , 400 MHz): δ 8.64 (s, 1H), 8.04-8.02 (m, 1H), 7.83-7.79 (m, 2H), 7.64-7.59 (m, 1H), 7.01 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H), 3.71 (s, 3H).
Synthesis of methyl 2-((2-amino-4-(methoxycarbonyl) phenyl) thio)-5-fluorobenzoate (33):
Figure imgf000049_0001
33
[000103] To a stirred solution of compound 32 (500 mg, 1.36 mmol) in MeOH (10 mL) under argon atmosphere was added 10% Pd/ C (300 mg) at RT and stirred under hydrogen atmosphere (balloon pressure) for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and washed with 20% MeOH/ CH2CI2 (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 8-10% EtOAc/ hexanes to afford compound 33 (300 mg, 66%>) as pale yellow solid. TLC: 30% EtOAc/ hexanes^/ 0.5); 1H-NMR (DMSO-< , 400 MHz): δ 7.78 (d, J = 9.6 Hz, 1H), 7.45-7.41 (m, 2H), 7.35-7.30 (m, 1H), 7.14 (d, J= 9.6 Hz, 1H), 6.68-6.65 (m, 1H), 5.70 (s, 2H), 3.89 (s, 3H), 3.83 (s, 3H).
Synthesis of 2-((2-amino-4-carboxyphenyl) thio)-5-fluorobenzoic acid (34):
Figure imgf000049_0002
34
[000104] To a stirred solution of compound 33 (300 mg, 0.89 mmol) in THF: H20 (5: 1, 6 mL) under argon atmosphere was added lithium hydroxide monohydrate (188 mg, 4.47 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (15 mL) and acidified with 6 N HC1 to pH~4. The precipitated solid was filtered and dried in vacuo to afford compound 34
(180 mg, 66%) as white solid. TLC: 50% EtOAc/ hexanes(i? 0.2); 1H-NMR (DMSO-</6, 400 MHz): δ 12.99-12.96 (m, 2H), 7.69 (d, J= 6.8 Hz, 1H), 7.40 (t, J= 7.2 Hz, 2H), 7.29 (t, J= 7.2 Hz, 1H), 7.13 (d, J= 7.2 Hz, 1H), 6.64-6.61 (m, 1H), 5.64-5.61 (m, 2H).
Synthesis of 2-fluoro-ll-oxo-10, 11-dihydrodibenzo [b,j\ [1, 4] thiazepine-8-carboxylic acid (35):
Figure imgf000050_0001
35
[000105] To a stirred solution of compound 34 (180 mg, 0.58 mmol) in THF (10 mL) under argon atmosphere was added CDI (284 mg, 1.75 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with ice cold water (10 mL) and acidified with 6 N HC1 to pH~4. The precipitated solid was filtered and dried in vacuo to afford compound 35 (80 mg, 47%) as an off- white solid. TLC: 10% MeOH/ CH2C12 (Rf. 0.2); 1H-NMR (DMSO-</6, 400 MHz): δ 13.30 (br s, 1H), 10.93 (s, 1H), 7.70 (s, 1H), 7.67 (d, J= 7.6 Hz, 2H), 7.59 (t, J= 7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.40-7.35 (m, 1H).
Example 6: Synthesis of 3-fluoro-ll-oxo-lO, 11-dihydrodibenzo \b, f\ [1, 41 thiazepine-8- carboxylic acid (42) - a common intermediate
Figure imgf000051_0001
Synthesis of methyl 4-fluoro-2-((4-methoxybenzyl) thio) benzoate (37):
Figure imgf000051_0002
37
[000106] To a stirred solution of methyl 2-bromo-4-fluorobenzoate 36 (2 g, 8.58 mmol) in 1,4- dioxane (50 mL) under inert atmosphere were added (4-methoxyphenyl) methanethiol 8 (1.58 g, 10.25 mmol), cesium carbonate (4.18 g, 12.80 mmol) at RT and purged under argon atmosphere for 30 min. To this was added Pd(dppf)2Cl2 (306 mg, 0.42 mmol); heated to 120 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 250 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 7% EtOAc/ hexanes to afford compound 37 (1.6 g, 61%) as an off-white solid. TLC: 10% EtOAc/ hexanes(i? 0.4); 1H NMR (CDC13, 400 MHz): δ 8.01 (dd, J= 8.7, 6.2 Hz, 1H), 7.34 (d, J= 7.9 Hz, 2H), 7.04 (dd, J= 10.3, 2.4 Hz, 1H), 6.88-6.80 (m, 3H), 4.09 (s, 2H), 3.88 (s, 3H), 3.80 (s, 3H). Synthesis of methyl 4-fluoro-2-mercaptobenzoate (38):
Figure imgf000052_0001
38
[000107] A stirred solution of compound 37 (2.2 g, 7.18 mmol) in trifluoro acetic acid (30 mL) at RT under inert atmosphere was heated to 90 °C and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain compound 38 (1.33 g, crude) as brown syrup. The crude was carried forward for next step without further purification. TLC: 10% EtOAc/ hexanes (R/. 0.8).
Synthesis of methyl 4-fluoro-2-((4-(methoxycarbonyl)-2-nitrophenyl) thio) benzoate (39):
Figure imgf000052_0002
39
[000108] To a stirred solution of methyl 4-fluoro-3-nitrobenzoate 2 (1.29 g, 6.93 mmol) in DMF (50 mL) under inert atmosphere were added cesium carbonate (2.93 g, 9.01 mmol) and compound 38 (1.2 g, 6.03 mmol) at RT; heated to 55-60 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL), the precipitated solid was filtered to obtain the crude. The crude was washed with pentane (2 x 20 mL) and dried in vacuo to afford compound 39 (1.5 g, 68%) as yellow solid.
TLC: 10% EtOAc/ hexanes (R/. 0.3); 1H-NMR (DMSO-</6, 400 MHz): δ 8.63 (s, 1H), 8.13- 8.04 (m, 2H), 7.53-7.46 (m, 2H), 7.24 (d, J= 8.4 Hz, 1H), 3.89 (s, 3H), 3.72 (s, 3H).
Synthesis of 2-((4-carboxy-2-nitrophenyl) thio)-4-fluorobenzoic acid (40):
Figure imgf000052_0003
40
[000109] To a stirred solution of compound 39 (1.5 g, 4.10 mmol) in THF: H20 (4: 1, 20 mL) was added lithium hydroxide monohydrate (690 mg, 16.4 mmol) at RT, heated to 80 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was acidified with 2 N HC1 to ~6. The precipitated solid was filtered and dried in vacuo to afford compound 40 (1.2 g, 86%) as an off- white solid. TLC: 5% MeOH/ CH2C12 (Rf. 0.2); 1H-NMR (DMSO-< , 400 MHz): δ 13.46 (br s, 2H), 8.58 (s, 1H), 8.08-8.01 (m, 2H), 7.45-7.40 (m, 1H), 7.38-7.35 (m, 1H), 7.29 (d, J= 8.4 Hz, 1H).
Synthesis of 2-((2-amino-4-carboxyphenyl) thio)-4-fluorobenzoic acid (41):
Figure imgf000053_0001
[000110] To a stirred solution of compound 40 (1.2 g, 3.56 mmol) in MeOH (50 mL) under inert atmosphere was added 10%> Pd/ C (300 mg) at RT and stirred under hydrogen atmosphere (balloon pressure) for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, washed with MeOH (20 mL). The filtrate was removed in vacuo to obtain the crude which as triturated with 10% EtOAc/ n-pentane (50 mL) to afford compound 41 (1 g, 91%) as an off-white solid. TLC: 10% MeOH/ CH2C12 (Rf. 0.3); 1H-NMR (DMSO-< , 400 MHz): δ 12.96 (br s, 2H), 8.06-8.02 (m, 1H), 7.46 (s, 1H), 7.40 (d, J= 8.0 Hz, 1H), 7.16 (d, J= 8.0 Hz, 1H), 7.07-7.02 (m, 1H), 6.24 (d, J= 8.0 Hz, 1H), 5.67 (br s, 2H).
Synthesis of 3-fluoro-ll-oxo-10, 11-dihydrodibenzo [b,j\ [1, 4] thiazepine-8-carboxylic acid (42):
Figure imgf000053_0002
42
[000111] To a stirred solution of compound 41 (1 g, 3.25 mmol) in THF (30 mL) under inert atmosphere was added CDI (1.61 g, 9.77 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was acidified with 2 N
HC1 to pH~4. The obtained solid was filtered, washed with water (20 mL), ether (2 x 5 mL) and dried in vacuo to afford compound 42 (760 mg, 80%) as white solid. TLC: 10% MeOH/ CH2C12 (Rf. 0.3); 1H-NMR (DMSO-</6, 400 MHz): δ 13.24 (br s, 1H), 10.83 (s, 1H), 7.78-7.74 (m, 2H), 7.69-7.66 (m, 2H), 7.47-7.44 (m, 1H), 7.35-7.30 (m, 1H).
Example 7: Synthesis of 4-fluoro-ll-oxo-lO, ll-dihydrodibenzo \b, f\ [1, 41 thiazepine-8- carboxylic acid (50) - a common intermediate
Figure imgf000054_0001
Synthesis of methyl 2, 3-difluorobenzoate (44):
Figure imgf000054_0002
44
[000112] To a stirred solution of 2, 3-difluorobenzoic acid 43 (1 g, 6.28 mmol) in MeOH (10 mL) under inert atmosphere was added Cone. H2S04 (5 mL) at 0 °C and heated to reflux for 36 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (25 mL) and pH adjusted to ~8 with saturated sodium bicarbonate solution (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20%> EtOAc/ hexanes to afford compound 44 (800 mg, 74%) as an off-white solid. TLC: 40% EtOAc/ hexanes (Rf. 0.8); 1H NMR (DMSO-</6, 500 MHz) δ 7.80 - 7.65 (m, 2H), 7.41-7.23 (m, 1H), 3.88 (s, 3H).
Synthesis of methyl 3-fluoro-2-((4-methoxybenzyl) thio) benzoate (45):
Figure imgf000055_0001
45
[000113] To a stirred solution of compound 44 (800 mg, 4.65 mmol) in DMF (10 mL) under inert atmosphere were added (4-methoxyphenyl) methanethiol 8 (282 mg, 5.11 mmol), cesium carbonate (1.66 g, 5.11 mmol) at RT and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted water (25 mL) and extracted with ether (2 x 40 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 45 (750 mg, 53%) as an off- white solid. TLC: 20% EtOAc/ hexanes (Rf. 0.4); 1H NMR (DMSO-< , 500 MHz): δ 7.49-7.36 (m, 3H), 7.10 (d, J= 8.9 Hz, 2H), 6.79 (d, J= 8.9 Hz, 2H), 4.06 (s, 2H), 3.81 (s, 3H), 3.70 (s, 3H);
Synthesis of methyl 3-fluoro-2-mercaptobenzoate (46):
Figure imgf000055_0002
46
[000114] A stirred solution of compound 45 (750 mg, 2.45 mmol) in trifluoro acetic acid (7 mL) at RT under inert atmosphere was heated to 70 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain compound 46 (1.1 g, crude) as colorless liquid. The crude was carried forward for next step. TLC: 30% EtOAc/ hexanes (Rf. 0.8).
Synthesis of methyl 3-fluoro-2-((4-(methoxycarbonyl)-2-nitrophenyl) thio) benzoate (47):
Figure imgf000056_0001
47
[000115] To a stirred solution of compound 46 (5.96 g, 3.20 mmol) in DMF (100 mL) under inert atmosphere were added methyl 4-fluoro-3-nitrobenzoate 2 (5.8 g, 2.91 mmol), cesium carbonate (10.41 g, 3.20 mmol) at RT; heated to 80 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (25 mL). The obtained solid was filtered, washed with hexane (2 x 10 mL) and dried in vacuo to afford compound 47 (7.8 g, 73%) as an pale yellow solid. TLC: 30% EtOAc/ hexanes(i? 0.5); 1H NMR (DMSO-</6, 500 MHz): δ 8.67 (s, 1H), 8.05 (dd, J= 8.7, 1.7 Hz, 1H), 7.94-7.75 (m, 2H), 7.73-7.67 (m, 1H), 7.00 (d, J= 8.4 Hz, 1H), 3.88 (s, 3H), 3.77-3.64 (m, 3H).
Synthesis of methyl 2-((2-amino-4-(methoxycarbonyl) phenyl) thio)-3-fluorobenzoate (48):
Figure imgf000056_0002
48
[000116] To a stirred solution of compound 47 (670 mg, 1.83 mmol) in MeOH (10 mL) under inert atmosphere was added 10%> Pd/C (150 mg) at RT and stirred under hydrogen atmosphere (balloon pressure) for 12 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford compound 48 (500 mg, 81%) as an off-white solid. TLC: 30% EtOAc/ hexanes
(Rf. 0.4); 1H NMR (DMSO-< , 400 MHz): δ 7.58-7.50 (m, 2H), 7.48-7.41 (m, 1H), 7.33 (s, 1H), 7.04 (s, 2H), 5.59 (br s, 2H), 3.82 (s, 3H), 3.79 (s, 3H).
Synthesis of 2-((2-amino-4-carboxyphenyl) thio)-3-fluorobenzoic acid (49):
Figure imgf000056_0003
49
[000117] To a stirred solution of compound 48 (500 mg, 1.49 mmol) in THF: H20 (4: 1, 20 mL) was added lithium hydroxide monohydrate (376 mg, 8.95 mmol) at RT; heated to 80 °C and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (25 mL) and washed with diethyl ether (2 x 25 mL). The aqueous layer was acidified with 2 N HCl to pH~4 and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude which was washed with diethyl ether (2 x 5 mL) and dried in vacuo to afford compound 49 (300 mg, 65%) as an off-white solid. TLC: 10% MeOH/ CH2C12 (R/. 0.2); 1H NMR (DMSO-< , 500 MHz): δ 12.68 (br s, 2H), 7.54-7.45 (m, 2H), 7.39-7.32 (m, 1H), 7.28 (s, 1H), 7.09-7.06 (m, 1H), 7.02-6.96 (m, 1H), 5.56 (br s, 2H);
Synthesis of 4-fluoro-ll-oxo-10, 11-dihydrodibenzo [b,j\ [1, 4] thiazepine-8-carboxylic acid (50):
Figure imgf000057_0001
50
[000118] To a stirred solution of compound 49 (300 mg, 0.97 mmol) in THF (15 mL) under inert atmosphere was added CDI (474 mg, 2.92 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was acidified with 4 N HCl to ~2. The obtained solid was filtered, washed with diethyl ether (2 x 5 mL) and dried in vacuo to afford compound 50 (150 mg, 53%) as an off-white solid. TLC: 15% MeOH/ CH2C12 (Rf. 0.5); 1H NMR (DMSO-</6, 400 MHz): δ 13.38 (br s, 1H), 10.92 (s, 1H), 7.79 (s, 1H), 7.75-7.66 (m, 2H), 7.55-7.46 (m, 3H).
Example 8: Synthesis of 7-fluoro-ll-oxo-lO, 11-dihydrodibenzo \b, f\ [1, 41 thiazepine-8- carboxylic acid (55) - a common intermediate
Figure imgf000058_0001
Synthesis of methyl 2-fluoro-4-((2-(methoxycarbonyl) phenyl) thio)-5-nitrobenzoate (52):
Figure imgf000058_0002
52
[000119] To a stirred solution of methyl 2, 4-difluoro-5-nitrobenzoate 51 (9.0 g, 41.45 mmol) in DMF (100 mL) under inert atmosphere were added methyl 2-mercaptobenzoate 1 (6.97 g, 41.45 mmol), cesium carbonate (14.82 g, 45.60 mmol) at 0 °C; warmed to 10 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (800 mL) and extracted with EtOAc (2 x 500 mL). The combined organic extracts were dried under sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% EtOAc/ hexanes to afford compound 52 (11 g, 73%) as an off-white solid. TLC: 10% EtOAc/ hexanes (Rf 0.4); 1H NMR (DMSO-< , 400 MHz): δ 8.69 (d, J= 6.8 Hz, 1H), 8.04-7.92 (m, 1H), 7.81-7.69 (m, 3H), 6.60 (d, J= 11.5 Hz, 1H), 3.88 (s, 3H), 3.73 (s, 3H).
Synthesis of methyl 5-amino-2-fluoro-4-((2-(methoxycarbonyl) phenyl) thio) benzoate (53):
Figure imgf000058_0003
53 [000120] To a stirred solution of compound 52 (11 g, 30.13 mmol) in MeOH (400 mL) under inert atmosphere was added 10% Pd/ C (5 g) at RT and stirred under hydrogen atmosphere (balloon pressure) for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, washed with 30% MeOH/ CH2CI2 (3 x 60 mL). The filtrate was removed in vacuo to afford compound 53 (6.5 g, 64%>) as an off-white solid. TLC: 20% EtOAc/ hexanes (Rf. 0.4); 1H NMR (DMSO-</6, 400 MHz): δ 8.01-7.88 (m, 1H), 7.45-7.40 (m, 1H), 7.34-7.24 (m, 3H), 6.72 (dd, J= 8.2, 0.8 Hz, 1H), 5.51 (s, 2H), 3.88 (s, 3H), 3.85 (s, 3H).
Synthesis of 5-amino-4-((2-carboxyphenyl) thio)-2-fluorobenzoic acid (54):
Figure imgf000059_0001
54
[000121] To a stirred solution of compound 53 (6.5 g, 19.4 mmol) in THF: H20 (4: 1, 90 mL) was added lithium hydroxide monohydrate (4 g, 97.01 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was acidified with 2 N HC1 to ~4. The precipitated solid was filtered and dried in vacuo to afford compound 54 (4.5 g, 75.6%>) as an off-white solid. TLC: 30% EtOAc/ hexane (Rf. 0.2); 1H NMR (DMSO-< , 400 MHz): δ 13.19 (br s, 2H), 7.96 (dd, J = 7.7, 1.5 Hz, 1H), 7.39 (t, J = 7.3 Hz, 1H), 7.30 (d, J= 6.6 Hz, 1H), 7.27-7.20 (m, 2H), 6.68 (dd, J = 8.2, 0.7 Hz, 1H), 5.42 (br s, 2H).
Synthesis of 7-fluoro-ll-oxo-10, 11-dihydrodibenzo [b,j\ [1, 4] thiazepine-8-carboxylic acid (55):
Figure imgf000059_0002
55
[000122] To a stirred solution of compound 54 (4.5 g, 14.65 mmol) in THF (100 mL) under inert atmosphere was added CDI (11.88 g, 73.28 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with 2 N HC1 to pH~4; the precipitated solid was filtered, dried in vacuo to afford compound 55 (3.5 g, 83%) as an off-white solid. TLC: 15% MeOH/ CH2C12 (Rf 0.2); 1H NMR (DMSO-< , 400 MHz): δ 13.61 (br s, 1H), 10.75 (s, 1H), 7.74-7.65 (m, 2H), 7.59-7.45 (m, 4H).
Example 9: Synthesis of 7, 9-difluoro-ll-oxo-lO, ll-dihydrodibenzo \b, f\ [1, 41 thiazepine- 8-carboxylic acid (62) - a Common Intermediate
Figure imgf000060_0001
62
Synthesis of 2, 4, 6-trifluoro-3-nitrobenzoic acid (57):
Figure imgf000060_0002
57
[000123] To 2, 4, 6-trifluorobenzoic acid 56 (15 g, 85.22 mmol) at 0 °C, fuming nitric acid (20 mL) was added dropwise for 10 min; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (500 mL) and extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 57 (20 g) as pale yellow liquid. TLC: 5% MeOH/ CH2C12 + 0.05 mL CH3COOH (R 0.2); 1H NMR (DMSO-</6, 400 MHz): δ 14.12 (br s, 1H), 7.83 (td, J= 10.5, 2.1 Hz, 1H). Synthesis of methyl 2, 4, 6-trifluoro-3-nitrobenzoate (58):
Figure imgf000061_0001
58
[000124] To a stirred solution of compound 57 (20 g) in MeOH (200 mL) under argon atmosphere was added concentrated sulfuric acid (20 mL) dropwise for 20 min at 0 °C and heated to reflux for 48 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (500 mL) and extracted with EtOAc (4 x 200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5-8% EtOAc/ hexanes to afford compound 58 (14 g, 70% for 2 steps) as pale yellow syrup. TLC: 20% EtOAc/ hexane (Rf. 0.8); 1H NMR (DMSO-</6, 00 MHz): δ 7.88 (td, J= 10.6, 2.2 Hz, 1H), 3.93 (s, 3H).
Synthesis of methyl 2, 6-difluoro-4-((2-(methoxycarbonyl) phenyl) thio)-3-nitrobenzoate (59):
Figure imgf000061_0002
59
[000125] To a stirred solution of compounds 58 (14 g, 59.57 mmol) in DMF (300 mL) under inert atmosphere were added methyl 2-mercaptobenzoate 1 (11.1 g, 66.07 mmol), cesium carbonate (38.77 g, 119.14 mmol) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (200 mL) and extracted with EtOAc (3 x 300 mL). The combined organic extracts were washed with water (200 mL), brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography to afford compound 59 (14.5 g, 64%>) as yellow syrup. TLC: 10%> EtOAc/ hexanes (Rf. 0.2); 1H NMR (DMSO-</6, 500 MHz): δ 7.98 (dd, J= 7.7, 1.3 Hz, 1H), 7.66-7.61 (m, 1H), 7.59-7.55 (m, 1H), 7.46 (d, J= 7.8 Hz, 1H), 7.19 (d, J= 9.3 Hz, 1H), 3.93 (s, 3H), 3.81 (s, 3H).
Synthesis of methyl 3-amino-2, 6-difluoro-4-((2-(methoxycarbonyl) phenyl) thio) benzoate (60):
Figure imgf000062_0001
60
[000126] To a stirred solution of compound 59 (18 g, 46.99) in MeOH (400 mL) under inert atmosphere was added Pd/C (9 g, 50% wet) at RT and stirred under hydrogen atmosphere in an autoclave (5 kg/cm pressure) for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, washed with MeOH (500 mL). The filtrate was concentrated in vacuo to afford compound 60 (15.1 g, 91%>) as colorless semi solid. TLC: 20% EtOAc/ hexanes (Rf. 0.5); 1H NMR (DMSO-< , 500 MHz): δ 8.00-7.93 (m, 1H), 7.48-7.42 (m, 1H), 7.31-7.21 (m, 2H), 6.76-6.64 (m, 1H), 5.54-5.47 (m, 2H), 3.91 (s, 3H), 3.89 (s, 3H).
Synthesis of 3-amino-4-((2-carboxyphenyl) thio)-2, 6-difluorobenzoic acid (61):
Figure imgf000062_0002
61
[000127] To a stirred solution of compound 60 (15.1 g, 39.42 mmol) in THF: H20 (4: 1, 250 mL) was added lithium hydroxide monohydrate (8.3 g, 197.61 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo, diluted with water (100 mL) and washed with EtOAc (2 x 100 mL). The pH of the aqueous layer was acidified with 4 N HC1 to ~4. The precipitated solid was filtered, washed with water (100 mL), pentane (100 mL). The obtained solid was further dried using toluene (150 mL) to afford compound 61 (11 g, 79%) as an off-white solid. TLC: 20% EtOAc/ hexanes (Rf. 0.2); 1H NMR (DMSO-</6, 00 MHz): δ 13.24 (br s, 1H), 7.97 (dd, J= 7.7, 1.4 Hz, 1H), 7.46-7.39 (m, 1H), 7.28-7.19 (m, 2H), 6.66 (d, J= 8.2 Hz, 1H), 5.39 (br s, 2H).
Synthesis of 7, 9-difluoro-ll-oxo-10, 11-dihydrodibenzo [b,j\ [1, 4] thiazepine-8-carboxylic acid (62):
Figure imgf000063_0001
62
[000128] To a stirred solution of compound 61 (10 g, 30.76 mmol) in THF (200 mL) under argon atmosphere was added CDI (14.9 g, 81.97 mmol) at RT and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (300 mL) and the pH was adjusted to ~3 with 2 N HC1. The obtained solid was filtered, washed with water (100 mL), pentane (50 mL) and diethyl ether (150 mL) and dried in vacuo to obtain compound 62 (2.83 g, 30%) as brick red solid. TLC: 15% MeOH/ CH2C12 (R/. 0.3); 1H NMR (DMSO-< , 500 MHz): δ 14.19 (br s, 1H), 10.64 (s, 1H), 7.73-7.66 (m, 2H), 7.58- 7.48 (m, 3H).
Example 10: 2-methoxy-ll-oxo-10, 11-dihydrodibenzo \b, f\ [1, 41 thiazepine-8-carboxylic acid (70) - a common intermediate
SH
triflic
C02Me anhydride
OH pyridine
Figure imgf000064_0001
Cs2C03, Pd(dppf)2CI2
1 , 4-dioxane
63 64 65
Figure imgf000064_0002
66 67
Figure imgf000064_0003
68 69 70
Synthesis of methyl 5-methoxy-2-(((trifluoromethyl) sulfonyl) oxy) benzoate (64):
CO Me
OTf
64
[000129] To a stirred solution of methyl 2-hydroxy-5-methoxybenzoate 63 (2 g, 10.97 mmol) in pyridine (8 mL) under inert atmosphere was added triflic anhydride (3.56 g, 12.62 mmol) at 0 °C; warmed to RT and stirred for 2 h; heated to 40 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (40 mL) and extracted with ether (3 x 40 mL). The combined organic extracts were washed with 1 N HC1 (40 mL), water (40 mL), brine (40 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5-10% EtOAc/ hexanes to afford compound 64 (2.9 g, 85%) as colorless liquid. TLC: 10% EtOAc/ hexanes (Rf. 0.6); 1H-NMR (CDC13, 500 MHz): δ 7.50 (s, 1H), 7.09 (d, J= 7.5 Hz, 1H), 7.03 (d, J= 7.5 Hz, 1H), 3.94 (s, 3H), 3.84 (s, 3H).
Synthesis of methyl-5-methoxy-2-((4-methoxybenzyl) thio) benzoate (65): .0. .C02Me
'SPMB
65
[000130] To a stirred solution of compound 64 (500 mg, 1.59 mmol) in 1, 4-dioxane (10 mL) under inert atmosphere were added (4-methoxyphenyl) methanethiol 8 (270 mg, 1.75 mmol), cesium carbonate (1.035 g, 3.18 mmol) at RT and degassed for 20 min. To this was added Pd(dppf)2Cl2 (29.1 mg, 0.039 mmol); heated to 110 °C and stirred for 10 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10-15% EtOAc/ hexanes to afford compound 65 (280 mg, 55%) as pale yellow solid. TLC: 10% EtOAc/ hexanes(i? 0.4); 1H-NMR (CDC13, 500 MHz): δ 7.42 (s, 1H), 7.28-7.25 (m, 3H), 6.98 (d, J= 8.5 Hz, 1H), 6.84 (d, J= 8.5 Hz, 2H), 4.08 (s, 2H), 3.93 (s, 3H), 3.83 (s, 3H), 3.81 (s, 3H).
Synthesis of methyl 2-mercapto-5-methoxybenzoate (66):
Figure imgf000065_0001
66
[000131] A stirred solution of compound 65 (280 mg, 0.88 mmol) in trifluoro acetic acid (10 mL) at RT under inert atmosphere was heated to 70 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain compound 66 (170 mg, crude) as brown syrup. TLC: 10% MeOH/ CH2C12 (Rf. 0.8); 1H- NMR (DMSO-< , 400 MHz): δ 7.68 (d, J= 8.0 Hz, 1H), 7.48 (d, J= 7.2 Hz, 1H), 7.39 (s, 1H), 5.13 (s, 1H), 3.88 (s, 3H), 3.84 (s, 3H).
Synthesis of methyl 5-methoxy-2-((4-(methoxycarbonyl)-2-nitrophenyl) thio) benzoate (67):
Figure imgf000065_0002
67 [000132] To a stirred solution of compound 66 (150 mg, 0.75 mmol) in DMF (5 mL) under inert atmosphere were added methyl 4-fluoro-3-nitrobenzoate 2 (164 mg, 0.82 mmol), cesium carbonate (490 mg, 1.50 mmol) at RT; heated to 55-60 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with CH2CI2 (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 15-25% EtOAc/ hexanes to afford compound 67 (200 mg, 70%) as yellow solid. TLC: 10% EtOAc/ hexanes(R 0.3); 1H-NMR (DMSO-< , 400 MHz): δ 8.64 (s, 1H), 8.02 (d, J= 8.4 Hz, 1H), 7.69 (d, J= 8.8 Hz, 1H), 7.59-7.54 (m, 1H), 7.31 (d, J= 8.8 Hz, 1H), 6.94 (d, J= 8.8 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.68 (s, 3H).
Synthesis of methyl 2-((2-amino-4-(methoxycarbonyl) phenyl) thio)-5-methoxybenzoate
(68):
Figure imgf000066_0001
68
[000133] To a stirred solution of compound 67 (200 mg, 0.53 mmol) in MeOH (10 mL) under inert atmosphere was added 10%> Pd/ C (100 mg) at RT and stirred under hydrogen atmosphere (balloon pressure) for 26 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and washed with 50% CH2CI2/ MeOH (2 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 15-20%) EtOAc/ hexanes to afford compound 68 (120 mg, 65%>) as yellow solid. TLC: 30% EtOAc/ hexanes(R 0.6); 1H-NMR (DMSO-</6, 400 MHz): δ 7.42 (s, 2H), 7.36 (d, J= 8.0 Hz, 1H), 7.12 (d, J= 8.0 Hz, 1H), 7.05 (d, J= 8.4 Hz, 1H), 6.66 (d, J= 8.8 Hz, 1H), 5.61 (s, 2H), 3.87 (s, 3H), 3.83 (s, 3H), 3.75 (s, 3H).
Synthesis of 2-((2-amino-4-carboxyphenyl) thio)-5-methoxybenzoic acid (69):
Figure imgf000067_0001
69
[000134] To a stirred solution of compound 68 (120 mg, 0.34 mmol) in THF: H20 (4: 1 , 5 mL) was added lithium hydroxide monohydrate (72.5 mg, 1.72 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (10 mL) and acidified with 6 N HC1 to pH~4. The precipitated solid was filtered and dried in vacuo to afford compound 69 (80 mg, 73%) as an off- white solid. TLC: 40% EtOAc/ hexanes (Rf. 0.2); 1H-NMR (DMSO-</6, 400 MHz): δ 12.99 (br s, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 6.61 (d, J= 8.8 Hz, 1H), 5.54 (br s, 2H), 3.74 (s, 3H).
Synthesis of 2-methoxy-ll-oxo-10, 11-dihydrodibenzo [b,j\ [1, 4] thiazepine-8-carboxylic acid (70):
Figure imgf000067_0002
70
[000135] To a stirred solution of compound 69 (80 mg, 0.25 mmol) in THF (5 mL) under inert atmosphere was added CDI (122 mg, 0.75 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (10 mL) and acidified with 6 N HC1 to pH~4. The precipitated solid was filtered and dried in vacuo to afford compound 70 (40 mg, 53%) as an off-white solid.
TLC: 10% MeOH/ CH2C12 (Rf. 0.4); 1H-NMR (DMSO-< , 400 MHz): δ 13.15 (br s, 1H), 10.79 (s, 1H), 7.78 (s, 1H), 7.69-7.66 (m, 2H), 7.44-7.42 (m, 1H), 7.20-7.19 (m, 1H), 7.08-7.05 (m, 1H), 3.77 (s, 3H).
Example 11: 7-methoxy-ll-oxo-lO, 11-dihydrodibenzo \b, f\ [1, 41 thiazepine-8-carboxylic acid (76) - a common intermediate
Figure imgf000068_0001
74 75 76
Synthesis of methyl 4-fluoro-2-methoxy-5-nitrobenzoate (72):
Figure imgf000068_0002
[000136] To a stirred solution of methyl 4-fluoro-2-methoxybenzoate 71 (500 mg, 2.50 mmol) in sulfuric acid (1 mL) under inert atmosphere was added the mixture of nitric acid (0.125 mL), sulfuric acid (0.5 mL) at -5 °C and stirred for 10 min. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with CH2CI2 (2 x 30 mL). The combined organic extracts were washed with 10% NaHC03 solution (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was triturated with diethyl ether (2 x 5 mL) to afford compound 72 (200 mg, 33%) as an off-white solid. TLC: 20% EtOAc/ hexanes (R/. 0.4); 1H-NMR (CDC13, 400 MHz): δ 8.69 (d, J= 8.8 Hz, 1H), 6.83 (d, J= 12.8 Hz, 1H), 4.01 (s, 3H), 3.92 (s, 3H).
Synthesis of methyl 2-methoxy-4-((2-(methoxycarbonyl) phenyl) thio)-5-nitrobenzoate (73):
Figure imgf000068_0003
73
[000137] To a stirred solution of compound 72 (200 mg, 0.81 mmol) in DMF (4 mL) under inert atmosphere were added methyl 2-mercaptobenzoate 1 (151 mg, 0.89 mmol), cesium carbonate (318 mg, 0.97 mmol) at RT; heated to 80 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice water (20 mL) and extracted with EtOAc (2 x 35 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 15% EtOAc/ hexanes to afford compound 73 (200 mg, 61%) as yellow solid. TLC: 20% EtOAc/ hexanes (Rf. 0.4); 1H-NMR (CDC13, 400 MHz): δ 8.80 (s, 1H), 7.94-7.92 (m, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.61-7.59 (m, 2H), 6.30 (s, 1H), 3.90 (s, 3H), 3.82 (s, 3H), 3.52 (s, 3H).
Synthesis of methyl 5-amino-2-methoxy-4-((2-(methoxycarbonyl) phenyl) thio) benzoate
(74):
Figure imgf000069_0001
74
[000138] To a stirred solution of compound 73 (200 mg, 0.53 mmol) in MeOH (15 mL) under inert atmosphere was added 10%> Pd/C (100 mg) at RT and stirred under hydrogen atmosphere (balloon pressure) for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 15%) EtOAc/ hexanes to afford compound 74 (110 mg, 60%>) as yellow sticky solid. TLC: 20% EtOAc/ hexanes (Rf. 0.6); 1H-NMR (CDCI3, 400 MHz): δ 7.99 (d, J= 8.0 Hz, 1H), 7.54 (s, 1H), 7.34-7.31 (m, 1H), 7.20 (t, J= 8.0 Hz, 1H), 7.12 (s, 1H), 6.80 (d, J= 8.4 Hz, 1H), 3.96 (s, 3H), 3.88 (s, 3H), 3.80 (s, 3H).
Synthesis of 5-amino-4-((2-carboxyphenyl) thio)-2-methoxybenzoic acid (75):
Figure imgf000069_0002
75 [000139] To a stirred solution of compound 74 (110 mg, 0.31 mmol) in THF: H20 (5: 1, 3 mL) was added lithium hydroxide monohydrate (66 mg, 1.58 mmol) at RT; heated to 70 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (2 x 25 mL). The aqueous layer was acidified to pH~2 with 6 N HCl, the obtained solid was filtered, washed with n-hexane (2 x 5 mL) and dried in vacuo to afford compound 75 (70 mg, 70%) as an off- white solid. TLC: 10% MeOH/ CH2C12 (R/. 0.2); 1H-NMR (DMSO-< , 500 MHz): δ 12.78 (br s, 2H), 7.94 (d, J = 7.5 Hz, 1H), 7.36 (t, J= 7.5 Hz, 1H), 7.20 (t, J= 7.5 Hz, 1H), 7.13 (s, 1H), 7.05 (s, 1H), 6.67 (d, J= 8.5 Hz, 1H), 5.11 (br s, 2H), 3.68 (s, 3H).
Synthesis of 7-methoxy-ll-oxo-10, ll-dihydrodibenzo [b,j\ [1, 4] thiazepine-8-carboxylic acid (76):
Figure imgf000070_0001
76
[000140] To a stirred solution of compound 75 (70 mg, 0.21 mmol) in THF (2 mL) under inert atmosphere was added CDI (106 mg, 0.65 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo, diluted with ice water (15 mL), acidified with 6 N HCl, the obtained solid was filtered, washed with 20%) EtOAc/ hexanes and dried in vacuo to afford compound 76 (40 mg, 61%>) as an off- white solid. TLC: 5% MeOH/ CH2C12 (Rf. 0.3); 1H-NMR (DMSO-</6, 400 MHz): δ 12.88 (br s, 1H), 10.64 (s, 1H), 7.71-7.69 (m, 1H), 7.58-7.42 (m, 4H), 7.28 (s, 1H), 3.81 (s, 3H).
Example 12: Synthesis of 6-methyl-ll-oxo-10, ll-dihydrodibenzo \b, f\ [1, 41 thiazepine-8- carboxylic acid (82) - a common intermediate
Figure imgf000071_0001
Synthesis of methyl 4-bromo-3-methyl-5-nitrobenzoate (78):
Figure imgf000071_0002
78
[000141] To a stirred solution of methyl 4-bromo-3-methylbenzoate 77 (500 mg, 2.18 mmol) in sulfuric acid: trifluoro acetic acid (1 : 0.1, 6.6 mL) under inert atmosphere was added potassium nitrate (231 mg, 2.29 mmol) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 78 (540 mg, 95%) as yellow oil. TLC: 10% EtOAc/ hexanes (R/. 0.4); 1H-NMR (DMSO-< , 400 MHz): δ 8.25 (s, 1H), 8.17 (s, 1H), 3.89 (s, 3H), 2.53 (s, 3H).
Synthesis of methyl 4-((2-(methoxycarbonyl) phenyl) thio)-3-methyl-5-nitrobenzoate (79):
Figure imgf000071_0003
[000142] To a stirred solution of methyl 2-mercaptobenzoate 1 (575 mg, 2.18 mmol) in DMF (6 mL) under inert atmosphere were added cesium carbonate (1.42 g, 4.37 mmol), compound 78 (385 mg, 2.29 mmol) at RT; heated to 65 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 25 mL). The combined organic extracts were washed with water (15 mL), brine (15 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude. The crude was recrystallized using CH2CI2: n-pentane (1 : 4, 5 mL) to afford compound 79 (120 mg, 16%) as yellow solid. TLC: 20% EtOAc/ hexanes (R/. 0.4); 1H-NMR (DMSO-< , 400 MHz): δ 8.32 (s, 1H), 8.24 (s, 1H), 7.63-7.59 (m, 1H), 7.49-7.45 (m, 1H), 7.23 (t, J= 8.0 Hz, 1H), 6.61 (d, J= 8.0 Hz, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 2.35 (s, 3H).
Synthesis of methyl 3-amino-4-((2-(methoxycarbonyl) phenyl) thio)-5-methylbenzoate (80):
Figure imgf000072_0001
80
[000143] To a stirred solution of compound 79 (200 mg, 0.55 mmol) in MeOH (5 mL) under inert atmosphere was added Pd/C (70 mg) at RT and stirred under hydrogen atmosphere for 6 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude compound 80 (175 mg, 96%>) as yellow solid. TLC: 30%> EtOAc/ hexanes (R/. 0.7); 1H-NMR (DMSO-< , 400 MHz): δ 7.96 (d, J= 7.6 Hz, 1H), 7.38- 7.31 (m, 2H), 7.24-7.20 (m, 1H), 7.14 (s, 1H), 6.56 (d, J= 8.0 Hz, 1H), 5.67 (s, 2H), 3.89 (s, 3H), 3.83 (s, 3H), 2.25 (s, 3H).
Synthesis of 3-amino-4-((2-carboxyphenyl) thio)-5-methylbenzoic acid (81):
Figure imgf000072_0002
81
[000144] To a stirred solution of compound 80 (160 mg, 0.48 mmol) in THF: H20 (3: 1.5, 4.5 mL) was added lithium hydroxide (118 mg, 2.90 mmol) at RT and stirred for 24 h; heated to reflux and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (15 mL), filtered the precipitated solid and dried in vacuo to afford the crude compound 81 (140 mg, 96%) as an off- white solid. TLC: 30% EtOAc/ hexanes (Rf. 0.2); 1H-NMR (DMSO-< , 400 MHz): δ 13.00 (br s, 2H), 7.95 (d, J= 8.0 Hz, 1H), 7.35-7.29 (m, 2H), 7.19 (t, J= 7.6 Hz, 1H), 7.13 (s, 1H), 6.54 (d, J= 8.0 Hz, 1H), 5.30 (br s, 2H), 2.25 (s, 3H).
Synthesis of 6-methyl-ll-oxo-10, ll-dihydrodibenzo [b,j\ [1, 4] thiazepine-8-carboxylic acid (82):
Figure imgf000073_0001
82
[000145] To a stirred solution of compound 81 (140 mg, 0.46 mmol) in THF (5 mL) under inert atmosphere was added CDI (375 mg, 2.31 mmol) at RT and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo and neutralized with 1 N HCl, filtered the precipitated solid and dried in vacuo to afford the crude compound 82 (120 mg, 91%) as an off-white solid. TLC: 10% MeOH/ CH2C12 (Rf. 0.4); 1H- NMR (DMSO-< , 400 MHz): δ 13.05 (br s, 1H), 10.73 (s, 1H), 7.69-7.58 (m, 4H), 7.51-7.44 (m, 2H), 2.56 (s, 3H).
Example 13: Synthesis of 7-methyl-ll-oxo-lO, ll-dihydrodibenzo \b, f\ [1, 41 thiazepine-8- carboxylic acid (88) - a common intermediate
Figure imgf000074_0001
Synthesis of 4-fluoro-2-methyl-5-nitrobenzoic acid (84):
Figure imgf000074_0002
84
[000146] To a stirred solution of 4-fluoro-2-methylbenzoic acid 83 (500 mg, 3.24 mmol) in concentrated sulfuric acid (2.5 mL) under inert atmosphere was added potassium nitrate (655 mg, 6.49 mmol) at 0 °C; warmed to RT and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice water (20 mL), filtered the precipitated solid and dried in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH/ CH2CI2 to afford compound 84 (300 mg, 60%) as brown syrup. TLC: 10% MeOH/ CH2C12 (Rf. 0.3); 1H-NMR (DMSO-</6, 500 MHz): δ 13.56 (br s, 1H), 8.52 (d, J= 8.0 Hz, 1H), 7.61 (d, J= 12.5 Hz, 1H), 2.63 (s, 3H).
Synthesis of 4-((2-(methoxycarbonyl) phenyl) thio)-2-methyl-5-nitrobenzoic acid (85):
Figure imgf000074_0003
85
[000147] To a stirred solution of methyl 2-mercaptobenzoate 1 (514 mg, 3.08 mmol) in DMF (10 mL) under inert atmosphere were added cesium carbonate (1.81 g, 5.57 mmol), compound 84 (560 mg, 2.78 mmol) at RT; heated to 60 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water (20 mL) and pH was adjusted to ~2 with 1 N HC1, filtered the precipitated solid and dried in vacuo to afford compound 85 (500 mg, 52%) as an off-white solid.
TLC: 5% MeOH/ CH2C12 (Rf. 0.4); 1H-NMR (DMSO-</6, 400 MHz): δ 13.47 (br s, 1H), 8.59 (s, 1H), 7.94 (d, J= 7.2 Hz, 1H), 7.68-7.60 (m, 3H), 6.83 (s, 1H), 3.72 (s, 3H), 2.40 (s, 3H).
Synthesis of methyl 3-amino-4-((2-(methoxycarbonyl) phenyl) thio)-5-methylbenzoate (86):
Figure imgf000075_0001
86
[000148] To a stirred solution of compound 85 (500 mg, 1.45 mmol) in THF: H20 (2: 1, 15 mL) was added lithium hydroxide monohydrate (300 mg, 7.31 mmol) at RT and stirred for 8 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (15 mL), and pH was adjusted to ~2 with 1 N HC1, filtered the precipitated solid and dried in vacuo to afford crude compound 86 (500 mg) as an off-white solid. TLC: 5% MeOH/ CH2C12 (Rf. 0.1); 1H-NMR (DMSO-</6, 400 MHz): δ 13.51 (br s, 2H), 8.57 (s, 1H), 7.92 (d, J= 7.2 Hz, 1H), 7.64-7.58 (m, 2H), 7.53 (t, J= 8.0 Hz, 1H), 6.89 (s, 1H), 2.41 (s, 3H).
Synthesis of 5-amino-4-((2-carboxyphenyl) thio)-2-methylbenzoic acid (87):
Figure imgf000075_0002
87
[000149] To a stirred solution of compound 86 (500 mg) in MeOH (15 mL) under inert atmosphere was added Pd/ C (250 mg) at RT and stirred under hydrogen atmosphere for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to afford crude compound 87 (430 mg) as an off-white solid. TLC: MeOH/ CH2C12 (Rf. 0.1); LC-MS: 84.24%; 304.5 (M++l); (column; X-Select CSH C-18, (50 3.0 mm, 3.5 μηι); RT 3.75 min. 0.05% TFA (Aq): ACN; 0.8 mL/min).
Synthesis of 7-methyl-ll-oxo-10, ll-dihydrodibenzo [b,j\ [1, 4] thiazepine-8-carboxylic acid (88):
Figure imgf000076_0001
88
[000150] To a stirred solution of compound 87 (430 mg) in THF (20 mL) under inert atmosphere was added CDI (1.15 g, 7.09 mmol) at RT and stirred for 18 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo and neutralized with 1 N HCl, filtered the precipitated solid and dried in vacuo to afford the crude compound 88 (290 mg) as an off-white solid. TLC: 10% MeOH/ CH2C12 (Rf. 0.5); 1H-NMR (DMSO-< , 500 MHz): δ 13.15 (br s, 1H), 10.68 (s, 1H), 7.69-7.68 (m, 2H), 7.67-7.44 (m, 4H), 2.44 (s, 3H).
Example 14: 9-methyl-ll-oxo-10, ll-dihydrodibenzo \b, f\ [1, 41 thiazepine-8-carboxylic acid (96) - a common intermediate and Synthesis of 7-methyl-ll-oxo-10, ll-dihydrodibenzo \b, f\ [1, 41 thiazepine-8-carboxylic acid (88) a common intermediate - Alternate Approach
Figure imgf000077_0001
Synthesis of mixture of 4-fluoro-2-methyl-3-nitrobenzoic acid (89) and 4-fluoro-2-methyl-5- nitrobenzoic acid (84):
Figure imgf000077_0002
84 (major) 89 (minor) [000151] To a stirred solution of 4-fluoro-2-methylbenzoic acid 83 (10 g, 64.51 mmol) in acetic acid (50 mL) under inert atmosphere was added fuming nitric acid (50 mL) at RT and heated to 80 °C for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (100 mL). The precipitate was filtered and dried in vacuo to afford mixture of compounds 84 and 89 (5.3 g, 40%) as white solid. TLC: 70% EtOAc/ hexanes (R/. 0.4); 1H NMR (DMSO-</6, 00 MHz): δ 13.30 (br s, 2H), 8.52 (d, J= 8.0 Hz, 2H), 8.10 (dd, J= 8.9 5.9, Hz, 1H), 7.60 (d, J= 12.5 Hz, 2H), 7.56 (t, J= 9.3 Hz, 1H), 2.63 (s, 6H), 2.48 (s, 3H); (1H NMR showed mixture of compounds 84 and 89 in the ratio of 2: 1).
Synthesis of methyl 4-fluoro-2-methyl-3-nitrobenzoate (91) and methyl 4-fluoro-2-methyl- 5-nitrobenzoate (90):
Figure imgf000078_0001
90 91
[000152] To a stirred solution of compound 84 and 89 (10 g) in MeOH (100 mL) under argon atmosphere was cone, sulfuric acid (20 mL) at 0 °C and heated to reflux for 48 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford mixture of compounds 90 & 91 (6 g) as colorless thick syrup. TLC: 30% EtOAc/ hexane (Rf. 0.5); 1H NMR (DMSO-< , 500 MHz): δ 8.51 (d, J =7.8 Hz, 1H), 8.09 (dd, J= 8.8, 5.6 Hz, 0.5H), 7.63 (d, J= 12.4 Hz, 1H), 7.58 (t, J= 9.1 Hz, 0.5H), 3.87 (s, 4.5H), 2.62 (s, 3H), 2.45 (s, 1.5H); (1H NMR showed mixture of compounds 90: 91 in the ratio of 2: 1).
Synthesis of methyl 4-((2-(methoxycarbonyl) phenyl) thio)-2-methyl-3-nitrobenzoate (93) and methyl 4-((2-(methoxycarbonyl) phenyl) thio)-2-methyl-5-nitrobenzoate (92):
Figure imgf000078_0002
92 93 [000153] To a stirred solution of compounds 90 and 91 (11 g) in DMF (100 mL) under inert atmosphere were added methyl 2-mercaptobenzoate 1 (10.4 g, 61.97 mmol), cesium carbonate (18.5 g, 56.81 mmol) at 0 °C; heated to 80 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (200 mL), brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford a mixture of compounds 93 and 92 (12 g) as a yellow solid. TLC: 20% EtOAc/ hexanes (Rf. 0.2); LC-MS: 12.57% + 81.14%; 370.8 (M++l); (column; X-Select CSH C18, (50 3.0 mm, 3.5 μπι); RT 2.77 min. 0.05% Aq. TFA: ACN; 0.8 mL/min); RT 4.05, 4.14 min.
Synthesis of methyl 3-amino-4-((2-(methoxycarbonyl) phenyl) thio)-2-methylbenzoate (95) and Synthesis of methyl 5-amino-4-((2-(methoxycarbonyl) phenyl) thio)-2-methylbenzoate (94):
Figure imgf000079_0001
94 95
[000154] To a stirred solution of compound 93 and 92 (14 g, crude) in MeOH (500 mL) under inert atmosphere was added Pd/C (1.4 g, 50%> wet) at RT and stirred under hydrogen atmosphere in an autoclave (6 kg/ cm pressure) for 18 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, washed with MeOH (100 mL). The filtrate was concentrated in vacuo to obtain the crude. The crude was
recrystallized with EtOH (20 mL) and further purified through silica gel column chromatography column chromatography using 10%> EtOAc/ hexanes to afford compound 95 (3 g, 30%>) and 94 (8 g, 63%) as sticky off-white solids. TLC: 30% EtOAc/ hexanes (Rf. 0.4); 1H NMR (DMSO-< , 400 MHz) (95): δ 7.94 (d, J= 7.1 Hz, 1H), 7.40 (t, J= 7.3 Hz, 1H), 7.33-7.26 (m, 2H), 7.22 (dt, J= 7.6, 1.1 Hz, 1H), 6.67 (dd, J= 8.2, 0.8 Hz, 1H), 5.41 (s, 2H), 3.89 (s, 3H), 3.83 (s, 3H), 2.33 (s, 3H). 1H NMR (DMSO-i 6, 400 MHz) (94): δ 7.94 (dd, J= 7.8, 1.4 Hz, 1H), 7.42-7.38 (m, 1H), 7.32 (s, 1H), 7.26 (s, 1H), 7.22 (td, J =7.5, 1.0 Hz, 1H), 6.67 (dd, J = 8.1, 0.8 Hz, 1H), 5.41 (s, 2H), 3.88 (s, 2H), 3.82 (s, 3H), 2.33 (s, 3H). Synthesis of 3-amino-4-((2-carboxyphenyl) thio)-2-methylbenzoic acid (96):
Figure imgf000080_0001
96
[000155] To a stirred solution of compound 95 (2 g, 6.04 mmol) in THF: H20 (4: 1, 50 mL) was added lithium hydroxide monohydrate (2.5 g, 10.0 mmol) at 0 °C; warmed to RT and stirred for 48 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (10 mL) and washed with diethyl ether (2 x 50 mL). The pH of the aqueous layer was acidified with 4 N HC1 to ~1. The precipitated solid was filtered and dried in vacuo to afford compound 96 (1.2 g, 66%) as white solid. TLC: 20%> MeOH/ CH2C12 (Rf. 0.2); 1H NMR (DMSO-< , 400 MHz): δ 13.01 (br s, 2H), 7.94 (d, J= 7.4 Hz, 1H), 7.36 (t, J= 7.8 Hz, 1H), 7.28 (d, J= 8.0 Hz, 1H), 7.20 (dt, J= 7.4, 6.3 Hz, 1H), 6.95 (d, J= 8.0 Hz, 1H), 6.61 (d, J= 7.4 Hz, 1H), 5.25 (br s, 2H), 2.27 (s, 3H).
Synthesis of 9-methyl-ll-oxo-10, 11-dihydrodibenzo [b,j\ [1, 4] thiazepine-8-carboxylic acid (97):
Figure imgf000080_0002
97
[000156] To a stirred solution of compound 96 (2.6 g, 4.30 mmol) in THF (30 mL) under argon atmosphere was added CDI (3.5 g, 21.50 mmol) at RT; heated to 80 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (20 mL) and pH was adjusted with 4 N HC1 to ~2. The obtained solid was filtered, washed with diethyl ether and dried in vacuo to obtain compound 97(1.6 g, 67%) as an off white solid. TLC: 15% MeOH/ CH2C12 (Rf. 0.2); 1H NMR (DMSO-i 6, 400 MHz): δ 13.20 (br s, 1H), 10.23 (s, 1H), 7.74-7.60 (m, 1H), 7.56-7.51 (m, 2H), 7.50-7.42 (m, 3H), 2.47 (s, 3H).
Example 15: Synthesis of 3-carbamoyl-ll-oxo-lO, 11-dihydrodibenzo \b, f\ [1, 41
thiazepine-8-carboxylic acid (135) - a common intermediate
Figure imgf000081_0001
Synthesis of dimethyl 2-((4-methoxybenzyl) thio) terephthalate (126):
,C02Me
XX _PMB
126
[000157] To a stirred solution of dimethyl 2-bromoterephthalate 125 (1 g, 3.66 mmol) in 1, 4- dioxane (50 mL) under inert atmosphere were added (4-methoxyphenyl) methanethiol 8 (620 mg, 4.02 mmol), cesium carbonate (2.38 g, 7.32 mmol), Pd(dppf)2Cl2 (67 mg, 0.09 mmol) at RT and stirred under argon for 30 min; heated to 110 °C and stirred for 20 h in a sealed tube. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% EtOAc/ hexanes to afford compound 126 (680 mg, 54%) as an off-white solid. TLC: 10% EtOAc/ hexanes (Rf. 0.3); 1H-NMR (CDC13, 500 MHz): δ 8.06 (s, 1H), 7.99 (d, J= 8.5 Hz, 1H), 7.77 (d, J= 8.0 Hz, 1H), 7.34 (d, J= 8.5 Hz, 2H), 6.85 (d, J= 8.5 Hz, 2H), 4.18 (s, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.79 (s, 3H).
Synthesis of dimethyl 2-mercaptoterephthalate (127):
Figure imgf000082_0001
127
[000158] A stirred solution of compound 126 (1.47 g, 4.24 mmol) in trifluoro acetic acid (25 mL) under inert atmosphere at RT was heated to 80 °C and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude compound 127 (950 mg) as pale green semi-solid which was carried to the next step without any purification. TLC: 15% EtOAc/ hexanes (R/. 0.7).
Synthesis of dimethyl 2-((4-(terf-butoxycarbonyl)-2-nitrophenyl) thio) terephthalate (129):
Figure imgf000082_0002
129
[000159] To a stirred solution of tert-butyl 4-fluoro-3-nitrobenzoate 128 (400 mg, 1.65 mmol) in DMF (20 mL) under inert atmosphere were added compound 127 (525 mg, crude), cesium carbonate (1.07 g, 3.31 mmol) at RT; heated to 60 °C and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted water (25 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5-7% EtOAc/ hexanes to afford compound 129 (400 mg, 54%) as yellow solid. TLC: 10% EtOAc/ hexanes (R/. 0.4); 1H-NMR (CDC13, 400 MHz): δ 8.76 (s, 1H), 8.25 (s, 1H), 8.20-8.17 (m, 1H), 7.98 (d, J= 8.4 Hz, 1H), 7.92 (d, J= 8.4 Hz, 1H), 6.91 (d, J= 8.4 Hz, 1H), 3.93 (s, 3H), 3.82 (s, 3H), 1.58 (s, 9H).
Synthesis of dimethyl 2-((2-amino-4-(terf-butoxycarbonyl) phenyl) thio) terephthalate
(130):
Figure imgf000083_0001
130
[000160] To a stirred solution of compound 129 (1 g, 2.23 mmol) in MeOH (50 mL) under inert atmosphere was added 10% Pd/C (500 mg) at RT and stirred under hydrogen atmosphere (balloon pressure) for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to obtain the crude. The crude was triturated with 2% EtOAc/ n-pentane (2 x 5 mL) and dried in vacuo to afford compound 130 (800 mg, 86%) as an off-white solid. TLC: 15% EtOAc/ hexanes (R/. 0.4); 1H-NMR (DMSO-</6, 400 MHz): δ 8.05 (d, J= 8.0 Hz, 1H), 7.76-7.73 (m, 1H), 7.43-7.40 (m, 2H), 7.27 (s, 1H), 7.13-7.10 (m, 1H), 5.68 (br s, 2H), 3.91 (s, 3H), 3.75 (s, 3H), 1.55 (s, 9H).
Synthesis of 2-((2-amino-4-(terf-butoxycarbonyl) phenyl) thio) terephthalic acid (131):
Figure imgf000083_0002
131
[000161] To a stirred solution of compound 130 (250 mg, 0.59 mmol) in THF: H20 (4: 1, 10 mL) under inert atmosphere was added lithium hydroxide monohydrate (123 mg, 2.99 mmol) at RT and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (25 mL) and extracted with diethyl ether (2 x 25 mL). The aqueous layer was acidified with 2 N HCl to pH~6. The obtained solid was filtered and dried in vacuo to afford compound 131 (180 mg, 77%) as yellow solid. TLC: 10% MeOH/ CH2C12 (R/. 0.2); 1H-NMR (DMSO-</6, 400 MHz): δ 13.16 (br s, 2H), 8.02 (d, J= 8.0 Hz, 1H), 7.70 (d, J= 8.4 Hz, 1H), 7.44-7.40 (m, 2H), 7.16 (s, 1H), 7.13-7.09 (m, 1H), 5.64 (br s, 2H), 1.55 (s, 9H).
Synthesis of 8-(terf-butoxycarbonyl)-ll-oxo-10, 11-dihydrodibenzo [b,j\ [1, 4] thiazepine-3- carboxylic acid (132):
Figure imgf000084_0001
132
[000162] To a stirred solution of compound 131 (180 mg, 0.46 mmol) in THF (9 mL) under inert atmosphere was added CDI (225 mg, 1.39 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (15 mL) and acidified with HC1. The obtained solid was filtered and dried in vacuo to afford compound 132 (150 mg, 87%) as an off-white solid. TLC: 7% MeOH/ CH2C12 (Rf. 0.2); 1H-NMR (DMSO-</6, 400 MHz): δ 13.32 (br s, 1H), 10.93 (s, 1H), 8.02 (d, J= 8.4 Hz, 1H), 7.97-7.94 (m, 1H), 7.81-7.77 (m, 2H), 7.71-7.62 (m, 1H), 7.43-7.42 (m, 1H), 1.55-1.51 (m, 9H).
Synthesis of terf-butyl 3-carbamoyl-ll-oxo-lO, 11-dihydrodibenzo [b,j\ [1, 4] thiazepine-8- carboxylate (134):
Figure imgf000084_0002
134
[000163] To a stirred solution of compound 132 (150 mg, 0.40 mmol) in DMF (9 mL) under inert atmosphere were added HATU (307 mg, 0.80 mmol), ammonium chloride 133 (43 mg, 0.80 mmol), diisopropyl ethyl amine (0.3 mL, 1.60 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL). The obtained solid was filtered, triturated with 10% EtOAc/ hexanes (2 x 5 mL) and dried in vacuo to afford compound 134 (95 mg, 63%>) as white solid. TLC: 7% MeOH/ CH2C12 (R/. 0.6); 1H-NMR (DMSO-</6, 400 MHz): δ 10.89 (s, 1H), 8.15 (s, 1H), 8.00 (s, 1H), 7.89 (d, J= 8.0 Hz, 1H), 7.77-7.76 (m, 2H), 7.74-7.69 (m, 1H), 7.64 (d, J= 8.0 Hz, 1H), 7.58 (br s, 1H), 1.52 (s, 9H).
Synthesis of 3-carbamoyl-ll-oxo-lO, 11-dihydrodibenzo [b,j\ [1, 4] thiazepine-8-carboxylic acid (135):
Figure imgf000085_0001
135
[000164] To a stirred solution of compound 134 (95 mg, 0.25 mmol) in EDC (10 mL) under inert atmosphere was added trifluoroacetic acid (293 mg, 2.56 mmol) at RT; heated to 80 °C and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered. The obtained solid was triturated with 5% CH2CI2 (2 x 5 mL) and dried in vacuo to afford compound 135 (70 mg, 87%) as white solid. TLC: 10% MeOH/ CH2C12 (Rf. 0.2); 1H-NMR (DMSO-< , 500 MHz): δ 10.93 (s, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.81-7.76 (m, 2H), 7.72-7.68 (m, 2H), 7.59 (s, 1H).
Example 16: ll-oxo-10, ll-dihydrodibenzo \b, f\ [1, 41 thiazepine-7-carboxylic acid (140) - a common intermediate
Figure imgf000085_0002
139 140
Synthesis of methyl 3-((2-(methoxycarbonyl) phenyl) thio)-4-nitrobenzoate (137):
Figure imgf000085_0003
137
[000165] To a stirred solution of methyl 3-fluoro-4-nitrobenzoate 136 (100 mg, 0.50 mmol) in DMF (3 mL) under argon atmosphere was added cesium carbonate (180 mg, 0.55 mmol) at RT and heated to 40 °C. To this was added methyl 2-mercaptobenzoate 1 (93 mg, 0.55 mmol) in DMF (1 mL) drop wise for 3 min and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was diluted with water (30 mL) and extracted with CH2CI2 (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 137 (120 mg, 69%) as yellow crystalline solid. TLC: 20% EtOAc/ hexanes (Rf. 0.3); 1H-NMR (DMSO-< , 400 MHz): δ 8.30 (d, J= 8.4 Hz, 1H), 7.99-7.93 (m, 2H), 7.65-7.60 (m, 3H), 7.49 (d, J= 7.6 Hz, 1H), 3.80 (s, 3H), 3.74 (s, 3H).
Synthesis of 3-((2-carboxyphenyl) thio)-4-nitrobenzoic acid (138):
Figure imgf000086_0001
138
[000166] To a stirred solution of compound 137 (100 mg, 0.26 mmol) in THF (7 mL) under argon atmosphere was added lithium hydroxide monohydrate (28 mg, 0.66 mmol) in water (3 mL) at RT; heated to reflux and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo, diluted with water (20 mL) and pH was adjusted to ~2 with 1 N HCl. The obtained solid was filtered and dried in vacuo to afford compound 138 (72 mg, 85%) as yellow solid. TLC: 10% MeOH/ CH2C12 (Rf. 0.2); 1H-NMR (DMSO-</6, 400 MHz): δ 13.49 (br s, 2H), 8.25 (d, J= 8.4 Hz, 1H), 7.96-7.91 (m, 2H), 7.66 (s, 1H), 7.60-7.54 (m, 2H), 7.40 (d, J= 7.6 Hz, 1H).
Synthesis of 4-amino-3-((2-carboxyphenyl) thio) benzoic acid (139):
Figure imgf000086_0002
139
[000167] To a stirred solution of compound 138 (70 mg, 0.20 mmol) in MeOH (5 mL) under argon atmosphere was added 10%> Pd/C (10 mg) and stirred under hydrogen atmosphere (balloon pressure) for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, washed with MeOH (2 x 5 mL) and the filtrate was concentrated in vacuo to afford compound 139 (53 mg, 90%) as an off-white solid. TLC: 20% MeOH/ CH2C12 (R/. 0.3); 1H-NMR (DMSO-< , 400 MHz): δ 12.91 (br s, 2H), 7.94 (d, J= 6.4 Hz, 1H), 7.86 (s, 1H), 7.76 (d, J= 8.4 Hz, 1H), 7.37 (t, J= 8.0 Hz, 1H), 7.19 (t, J= 7.6 Hz, 1H), 6.83 (d, J= 8.8 Hz, 1H), 6.63 (d, J= 8.0 Hz, 1H), 6.14 (br s, 2H).
Synthesis of ll-oxo-10, 11-dihydrodibenzo [b,j\ [1, 4] thiazepine-7-carboxylic acid (140):
Figure imgf000087_0001
140
[000168] To a stirred solution of compound 139 (50 mg, 0.17 mmol) in dry THF (3 mL) under argon atmosphere was added CDI (84 mg, 0.51 mmol) at 0 °C; warmed to RT and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with 1 N HC1 (3 mL), water (10 mL). The obtained solid was filtered, washed with ether (2 x 5 mL) and dried in vacuo to afford compound 140 (28 mg, 61 >) as white solid.
TLC: 20% MeOH/ CH2C12 (Rf. 0.5); 1H-NMR (DMSO-< , 400 MHz): δ 13.10 (br s, 1H), 10.97 (s, 1H), 8.05 (s, 1H), 7.89 (d, J= 8.4 Hz, 1H), 7.69 (d, J= 7.6 Hz, 1H), 7.57 (d, J= 7.6 Hz, 1H), 7.53-7.44 (m, 2H), 7.31 (d, J= 8.4 Hz, 1H).
Example 17: Synthesis of 8-aminodibenzo \b, f\ [1, 41 thiazepin-11 (10H)-one (145) - a common intermediate
Figure imgf000088_0001
145
Synthesis of methyl 2-((4-amino-2-nitrophenyl) thio) benzoate (142):
Figure imgf000088_0002
142
[000169] To a stirred solution of 4-fluoro-3-nitroaniline 141 (500 mg, 3.20 mmol) in DMF (6 mL) under inert atmosphere was added cesium carbonate (1.14 g, 3.50 mmol) at RT and heated to 40 °C. To this was added methyl 2-mercaptobenzoate 1 (592 mg, 3.50 mmol) in DMF (1 mL) drop wise for 3 min and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (35 mL) and extracted with CH2CI2 (2 x 35 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 15% EtOAc/ hexanes to afford compound 142 (600 mg, 62%) as brown syrup. TLC: 30%> EtOAc/ hexanes (R/. 0.5); 1H-NMR (DMSO-</6, 400 MHz): δ 7.91 (d, J= 8.0 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.30-7.20 (m, 2H), 7.10 (s, 1H), 6.87-6.84 (m, 1H), 6.79 (d, J= 8.0 Hz, 1H), 6.24 (s, 2H), 3.84 (s, 3H). Synthesis of 2-((4-amino-2-nitrophenyl) thio) benzoic acid (143):
Figure imgf000089_0001
143
[000170] To a stirred solution of compound 142 (600 mg, 1.98 mmol) in THF: H20 (10: 3, 13 mL) under inert atmosphere was added lithium hydroxide monohydrate (406 mg, 9.90 mmol) at RT; heated to 60 °C and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The aqueous layer was acidified with HCl to pH~2. The obtained solid was filtered and dried in vacuo to afford compound 143 (350 mg, 61%) as orange solid. TLC: 10% MeOH/ CH2C12 (R/. 0.3); 1H-NMR (DMSO-</6, 500 MHz): δ 13.18 (s, 1H), 7.89 (d, J= 7.5 Hz, 1H), 7.38 (t, J= 7.0 Hz, 1H), 7.28 (d, J= 9.0 Hz, 1H), 7.19 (t, J= 8.0 Hz, 1H), 7.07 (s, 1H), 6.84 (d, J= 8.5 Hz, 1H), 6.71 (d, J= 8.5 Hz, 1H), 6.23 (s, 2H).
Synthesis of 2-((2, 4-diaminophenyl) thio) benzoic acid (144):
Figure imgf000089_0002
144
[000171] To a stirred solution of compound 143 (350 mg, 1.20 mmol) in MeOH (10 mL) under inert atmosphere was added 10%> Pd/C (100 mg) at RT and stirred under hydrogen atmosphere (balloon pressure) for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated in vacuo to obtain the crude. The crude was washed with n-pentane (2 x 10 mL) and dried in vacuo to afford compound 144 (250 mg, 80%) as white solid. TLC: 10% MeOH/ CH2C12 (R/. 0.3); 1H-NMR (DMSO-< , 400 MHz): δ 12.60 (br s, 1H), 7.87 (d, J= 7.6 Hz, 1H), 7.32 (t, J= 8.4 Hz, 1H), 7.12 (t, J= 6.8 Hz, 1H), 6.90 (d, J= 8.0 Hz, 1H), 6.72 (d, J= 8.0 Hz, 1H), 6.02 (s, 1H), 5.93 (d, J= 8.4 Hz, 1H), 5.02-4.98 (m, 4H).
Synthesis of 8-aminodibenzo [b,j\ [1, 4] thiazepin-11 (10H)-one (145):
Figure imgf000090_0001
145
[000172] To a stirred solution of compound 144 (150 mg, 0.57 mmol) in DMF (4 mL) under inert atmosphere were added HOBt (233 mg, 1.73 mmol), EDCI.HC1 (330 mg, 5.19 mmol), diisopropyl ethyl amine (0.5 mL, 2.87 mmol) at 0 °C; warmed to RT and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (30 mL). The obtained solid was filtered, washed with hexanes (2 x 10 mL) and dried in vacuo to afford compound 145 (80 mg, 57%) as an off-white solid. TLC: 5% MeOH/ CH2C12 (Rf. 0.5); 1H-NMR (DMSO-</6, 400 MHz): δ 10.40 (s, 1H), 7.63 (d, J= 6.8 Hz, 1H), 7.45-7.37 (m, 3H), 7.12 (d, J= 8.4 Hz, 1H), 6.39 (s, 1H), 6.31 (d, J= 8.4 Hz, 1H), 5.46 (s, 2H).
Example 18: Synthesis of ll-oxo-10, 11-dihydrodibenzo \b, f\ [1, 41 thiazepine-8-carboxylic acid 5-oxide (156) - a common intermediate
Figure imgf000090_0002
Synthesis of ll-oxo-10, 11-dihydrodibenzo [ϋ,β [1, 4] thiazepine-8-carboxylic acid 5-oxide (156):
Figure imgf000090_0003
156
[000173] To a stirred solution of 6 (2.5 g, 9.21 mmol) in CH2C12 (50 mL) under inert atmosphere was added m-chloro perbenzoic acid (1.59 g, 9.21 mmol) at RT and stirred for 48 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was the volatiles were removed in vacuo to obtain the crude. The crude was triturated with 10% MeOH/ CH2CI2 (2 x 5 mL), isopropanol (10 mL) to afford compound 156 (2.3 g, 87%) as white solid. TLC: 10% MeOH/ CH2C12 + 0.05 mL CH3COOH (R/. 0.4); 1H NMR (DMSO-< , 500 MHz): δ 13.36 (br s, 1H), 11.08 (s, 1H), 7.96 (d, J= 7.8 Hz, 1H), 7.92-7.87 (m, 1H), 7.85-7.66 (m, 3H), 7.63 (t, J= 7.8 Hz, 1H), 7.53 (t, J= 7.8 Hz, 1H);
Example 19: Synthesis of ll-oxo-10, ll-dihydrodibenzo \b, f\ [1, 41 thiazepine-8-carboxylic acid 5, 5-dioxide (159) - a common intermediate
Figure imgf000091_0001
159
Synthesis of methyl ll-oxo-10, ll-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxylate (157):
Figure imgf000091_0002
157
[000174] To a stirred solution of 6 (500 mg, 1.84 mmol) in MeOH: CH2C12 (1 : 1 , 20 mL) under argon atmosphere was added CH2N2 (prepared in situ using N-nitrosomethyl urea (0.95 g, 9.2 mmol) + KOH (0.51 g, 9.22 mmol) at 0 °C; warmed to RT and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 157 (450 mg, 86%) as white solid. TLC: 30% EtOAc/ hexanes (R/. 0.5); 1H-NMR (DMSO-< , 500 MHz): δ 10.82 (s, 1H), 7.82 (s, 1H), 7.75-7.69 (m, 3H), 7.58-7.63 (m, 3H), 3.82 (s, 3H). Synthesis of methyl ll-oxo-10, 11-dihydrodibenzo [b, [1, 4] thiazepine-8-carboxylate 5, 5- dioxide (158):
Figure imgf000092_0001
158
[000175] To a stirred solution of 157 (5 g, 17.54 mmol) in acetic acid (25 mL) was added 30% aqueous hydrogen peroxide (100 mL) at 0 °C; warmed to 50 °C and stirred for 72 h. The reaction was monitored by TLC; after completion of the reaction, the obtained solid was filtered, washed with water (100 mL), 10% EtOAc/ hexanes (100 mL) and dried in vacuo to afford compound 158 (3.5 g, 64%) as white solid. TLC: 5% MeOH/ CH2C12 (R/. 0.3); 1H NMR (DMSO-</6, 500 MHz): δ 11.58 (s, 1H), 8.09 (d, J= 8.4 Hz, 1H), 8.01-7.95 (m, 3H), 7.93-7.83 (m, 3H), 3.88 (s, 3H).
Synthesis of ll-oxo-10, 11-dihydrodibenzo [b,j\ [1, 4] thiazepine-8-carboxylic acid 5, 5- dioxide (159):
Figure imgf000092_0002
159
[000176] To a stirred solution of compound 158 (3.5 g, 11.04 mmol) in a mixture of THF: MeOH: H20 (2: 2: 1, 25 mL) was added lithium hydroxide monohydrate (1.3 g, 33.12 mmol) portion wise for 10 min at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (20 mL) and acidified with 1 N HC1 to pH~2. The obtained solid was filtered, washed with isopropyl alcohol (15 mL) and dried in vacuo to obtain compound 159 (2.8 g, 84%) as white solid. TLC: 5% MeOH/ CH2C12 (R/. 0.1); 1H NMR (DMSO-</6, 400 MHz): δ 13.65 (br s, 1H), 11.55 (s, 1H), 8.07 (d, J= 8.3 Hz, 1H), 8.03-7.82 (m, 6H).
Example 20: Synthesis of 5-methyl-ll-oxo-lO, ll-dihvdro-5H-dibenzo \b, e] [1, 41 diazepine-8-carboxylic acid (164) - a common intermediate
Figure imgf000093_0001
Synthesis of methyl 4-((2-(methoxycarbonyl) phenyl) amino)-3-nitrobenzoate (161):
Figure imgf000093_0002
[000177] To a stirred solution of methyl 2-aminobenzoate 160 (5 g, 33.07 mmol) in NMP (13 mL) under inert atmosphere were added diisopropylethylamine (18 mL, 103.46 mmol), methyl 4-fluoro-3-nitrobenzoate 2 (9.87 g, 49.61 mmol) at RT; heated to 120 °C in a sealed tube and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with diethyl ether (50 mL) and stirred for 1 h. The obtained solid was filtered, washed with diethyl ether (10 mL) and dried in vacuo to afford compound 161 (3.2 g, 29%) as yellow solid. TLC: 20% EtOAc/ hexanes (Rf. 0.4); 1H NMR (DMSO-< , 400 MHz): δ 11.13 (s, 1H), 8.67 (s, 1H), 8.11-7.94 (m, 2H), 7.70-7.62 (m, 2H), 7.58 (d, J= 9.0 Hz, 1H), 7.32-7.27 (m, 1H), 3.87 (s, 6H).
Synthesis of methyl 4-((2-(methoxycarbonyl) phenyl) (methyl) amino)-3-nitrobenzoate (162):
Figure imgf000093_0003
162
[000178] To a stirred solution of compound 161 (3 g, 9.09 mmol) in DMF (30 mL) under inert atmosphere were added cesium carbonate (5.9 g, 18.15 mmol), methyl iodide (0.84 mL, 13.59 mmol) at RT and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (60 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 162 (2.73 g, 88%) as yellow solid. TLC: 30% EtOAc/ hexanes (Rf. 0.4); 1H NMR (DMSO-</6, 00 MHz): δ 8.07 (s, 1H), 8.06 (d, J= 7.8 Hz, 1H), 7.71 (dd, J= 7.8, 1.5 Hz, 1H), 7.62 (t, J= 7.3 Hz, 1H), 7.40-7.26 (m, 3H), 3.84 (s, 3H), 3.53 (s, 3H), 3.38 (s, 3H).
Synthesis of methyl 5-methyl-ll-oxo-10, ll-dihydro-5H-dibenzo [b, e] [1, 4] diazepine-8- carboxylate (163):
Figure imgf000094_0001
163
[000179] To a stirred solution of compound 162 (2.73 g, 7.93 mmol) in acetic acid (36 mL) under inert atmosphere was added iron powder (7 g, 127.2 mmol) at RT; heated to 80 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with CH2CI2 (50 mL), stirred for 2 h and filtered through celite and the filtrate was concentrated in vacuo to obtain the crude. The crude was dissolved in CH2CI2 (200 mL), washed with saturated aqueous NaHC03 solution (100 mL), brine (100 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to afford compound
163 (2 g, 91%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf. 0.4); 1H NMR (DMSO-</6, 500 MHz): δ 10.33 (s, 1H), 7.68 (dd, J= 8.5, 1.9 Hz, 1H), 7.65-7.61 (m, 2H), 7.50 (t, J= 7.8 Hz, 1H), 7.28 (d, J= 8.4 Hz, 1H), 7.21 (d, J= 8.1 Hz, 1H), 7.10 (t, J= 7.4 Hz, 1H), 3.80 (s, 3H), 3.33 (s, 3H).
Synthesis of 5-methyl-ll-oxo-10, ll-dihydro-5H-dibenzo [b, e] [1, 4] diazepine-8-carboxylic acid (164):
Figure imgf000095_0001
[000180] To a stirred solution of compound 163 (2 g, 7.09 mmol) in THF: H20 (1 : 1 , 80 mL) was added lithium hydroxide monohydrate (900 mg, 21.42 mmol) at RT and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was adjusted to ~2 with 2 N HC1. The precipitated solid was filtered and dried in vacuo to afford compound 164 (1.7 g, 89%) as an off-white solid. TLC: 40% EtOAc/ hexanes (Rf: 0.2); 1H NMR (DMSO-</6, 400 MHz): δ 12.82 (br s, 1H), 10.33 (s, 1H), 7.70-7.60 (m, 3H), 7.51 (t, J= 7.8 Hz, 1H), 7.27 (d, J= 8.5 Hz, 1H), 7.21 (d, J= 7.8 Hz, 1H), 7.11 (t, J= 7.2 Hz, 1H), 3.32 (s, 3H).
Example 21: Synthesis of 5-ethyl-ll-oxo-10, ll-dihvdro-5H-dibenzo \b, e] [1, 41 diazepine- 8-carboxylic acid (167) - a common intermediate
Figure imgf000095_0002
167
Synthesis of methyl 4-(ethyl (2-(methoxycarbonyl) phenyl) amino)-3-nitrobenzoate (165):
Figure imgf000095_0003
165
[000181] To a stirred solution of compound 161 (2.9 g, 8.78 mmol) in DMF (40 mL) under inert atmosphere were added cesium carbonate (6 g, 18.46 mmol), ethyl iodide (1.06 mL, 12.82 mmol) at RT and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (60 mL), extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude which was titurated with n-pentane (20 mL) to afford compound 165 (2.8 g, 89%) as pale yellow solid. TLC: 30% EtOAc/ hexanes (Rf. 0.5); 1H NMR (DMSO- , 500 MHz): δ 8.05 (dd, J= 9.0, 2.0 Hz, 1H), 8.02 (s, 1H), 7.62-7.57 (m, 2H), 7.45 (d, J= 9.0 Hz, 1H), 7.33 (d, J= 8.1 Hz, 1H), 7.28 (t, J= 7.5 Hz, 1H), 3.94 (q, J= 7.1 Hz, 2H), 3.82 (s, 3H), 3.44 (s, 3H), 1.20 (t, J= 7.1 Hz, 3H).
Synthesis of methyl 5-ethyl-ll-oxo-10, ll-dihydro-5H-dibenzo [b, e] [1, 4] diazepine-8- carboxylate (166):
Figure imgf000096_0001
166
[000182] To a stirred solution of compound 165 (2.8 g, 7.82 mmol) in acetic acid (40 mL) under inert atmosphere was added iron powder (6.8 g, 125.1 mmol) at RT; heated to 80 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with CH2CI2 (50 mL), stirred for 2 h and filtered through celite. The filtrate was concentrated in vacuo to obtain the crude. The crude was diluted with CH2CI2 (200 mL), washed with saturated aqueous sodium bicarbonate solution (100 mL) and brine (100 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 166 (2.2 g, 96%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf. 0.3); 1H NMR (DMSO- , 500 MHz): δ 10.35 (br s, 1H), 7.70 (dd, J = 8.5, 1.9 Hz, 1H), 7.67 (s, 1H), 7.62 (d, J= 7.5 Hz, 1H), 7.51 (t, J= 8.1 Hz, 1H), 7.29 (d, J= 8.4 Hz, 1H), 7.22 (d, J= 8.1 Hz, 1H), 7.12 (t, J= 7.4 Hz, 1H), 3.31 (s, 5H), 1.11 (t, J= 6.9 Hz, 3H).
Synthesis of 5-ethyl-ll-oxo-10, ll-dihydro-5H-dibenzo [b, e] [1, 4] diazepine-8-carboxylic acid (167):
Figure imgf000097_0001
167
[000183] To a stirred solution of compound 166 (2.1 g, 7.09 mmol) in THF: H20 (1 : 1 , 60 mL) was added lithium hydroxide monohydrate (890 mg, 21.26 mmol) at RT and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was acidified to ~2 with 2 N HC1. The precipitated solid was filtered, washed with water (50 mL) and dried in vacuo to afford compound 167 (1.6 g, 80%) as an off-white solid. TLC: 30% EtOAc/ hexanes (R/. 0.2); 1H NMR (DMSO-</6, 00 MHz): δ 12.82 (br s, 1H), 10.33 (s, 1H), 7.69-7.59 (m, 3H), 7.53-7.48 (m, 1H), 7.24 (dd, J= 19.7, 8.2 Hz, 2H), 7.12 (t, J= 7.5 Hz, 1H), 3.79 (br s, 2H), 1.12 (t, J= 7.0 Hz, 3H).
Example 22: Synthesis of 5-benzyl-ll-oxo-10, ll-dihvdro-5H-dibenzo \b, e] [1, 41 diazepine- 8-carboxylic acid (170) - a common intermediate
Figure imgf000097_0002
170
Synthesis of methyl 4-(benzyl (2-(methoxycarbonyl) phenyl) amino)-3-nitrobenzoate (168):
Figure imgf000097_0003
168
[000184] To a stirred solution of compound 161 (2.5 g, 7.57 mmol) in DMF (40 mL) under inert atmosphere were added cesium carbonate (4.92 g, 15.15 mmol), benzyl bromide (1.34 mL, 11.36 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (60 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% EtOAc/ hexanes to afford compound 168 (3 g, 91%) as colorless thick syrup. TLC: 20% EtOAc/ hexanes (Rf. 0.4); 1H NMR (DMSO-</6, 500 MHz): δ 8.04 (s, 1H), 7.97 (dd, J= 8.8, 1.9 Hz, 1H), 7.61-7.57 (m, 1H), 7.56- 7.50 (m, 3H), 7.40 (t, J= 8.2 Hz, 2H), 7.34 (t, J= 7.7 Hz, 2H), 7.28-7.23 (m, 2H), 5.20 (s, 2H), 3.81 (s, 3H), 3.39 (s, 3H).
Synthesis of methyl 5-benzyl-ll-oxo-10, ll-dihydro-5H-dibenzo [b, e] [1, 4] diazepine-8- carboxylate (169):
Figure imgf000098_0001
169
[000185] To a stirred solution of compound 168 (950 mg, 2.26 mmol) in acetic acid (10 mL) under inert atmosphere was added iron powder (2 g, 36.36 mmol) at RT; heated to 80 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with CH2CI2 (50 mL), filtered through celite and the filtrate was
concentrated in vacuo to obtain the crude. The crude was dissolved in CH2CI2 (200 mL), washed with saturated aqueous sodium bicarbonate solution (100 mL) and brine (100 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to afford compound
169 (800 mg, 98%) as an off-white solid. TLC: 20% EtOAc/ hexanes (Rf. 0.4); 1H NMR (DMSO- , 500 MHz): δ 10.42 (s, 1H), 7.66 (s, 1H), 7.62 (d, J= 8.1 Hz, 2H), 7.48- 7.34 (m, 4H), 7.33-7.21 (m, 3H), 7.15 (t, J= 7.2 Hz, 1H), 7.09 (t, J= 7.4 Hz, 1H), 5.04 (br s, 2H), 3.79 (s, 3H).
Synthesis of 5-benzyl-ll-oxo-10, ll-dihydro-5H-dibenzo [b, e] [1, 4] diazepine-8-carboxylic acid (170):
Figure imgf000099_0001
170
[000186] To a stirred solution of compound 169 (2 g, 5.58 mmol) in THF: H20 (1 : 1, 80 mL) was added lithium hydroxide monohydrate (703 mg, 16.73 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The pH of the residue was acidified with 6 N HC1 to pH ~2 and stirred for 1 h. The precipitated solid was filtered and dried in vacuo to afford compound 170 (1.5 g, 78%) as an off- white solid. TLC: 50% EtOAc/ hexanes (R/. 0.2); 1H NMR (DMSO-</6, 500 MHz): δ 12.87 (br s, 1H), 10.39 (s, 1H), 7.65-7.55 (m, 3H), 7.47- 7.21 (m, 7H), 7.16-7.04 (m, 2H), 5.02 (br s, 2H).
Example 23: Synthesis of 3-methoxy-ll-oxo-lO, ll-dihydrodibenzo \b, f\ [1, 41 thiazepine-8- carboxylic acid (P-42)
Figure imgf000099_0002
P-41 P-42
[000187] Synthesis of methyl 4-methoxy-2-(((trifluoromethyl) sulfonyl) oxy) benzoate (P- 36): To a stirred solution of methyl 2-hydroxy-4-methoxybenzoate P-35 (1 g, 5.49 mmol) in pyridine (5 mL) under argon atmosphere was added triflic anhydride (1 mL, 6.31 mmol) drop wise at 0 °C; warmed to RT and stirred for 2 h; heated to 40 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (25 mL) and extracted with diethyl ether (2 x 30 mL). The combined organic extracts were washed with 1 N HC1 (15 mL), water (15 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% EtOAc/ hexanes to afford compound P-36 (1.58 g, 92%) as colorless syrup. TLC: 10% EtOAc/ hexanes (Rf. 0.6); 1H-NMR (CDC13, 500 MHz): δ 8.06 (d, J= 9.0 Hz, 1H), 6.95 (d, J= 8.5 Hz, 1H), 6.78 (s, 1H), 3.93 (s, 3H), 3.88 (s, 3H).
[000188] Synthesis of methyl-4-methoxy-2-((4-methoxybenzyl) thio) benzoate (P-37): To a stirred solution of compound P-36 (1 g, 3.18 mmol) in 1, 4-dioxane (15 mL) under argon atmosphere were added (4-methoxyphenyl) methanethiol (539 mg, 3.50 mmol), cesium carbonate (2 g, 6.36 mmol) at RT and degassed under argon for 20 min. To this was added Pd(dppf)2Cl2 (233 mg, 0.31 mmol); heated to 80 °C and stirred for 8 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 35 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5-7% EtOAc/ hexanes to afford compound P-37 (340 mg, 30%) as an off-white solid. TLC: 10% EtOAc/ hexanes (Rf. 0.4); 1H-NMR (CDC13, 500 MHz): δ 7.96 (d, J= 8.5 Hz, 1H), 7.38-7.37 (m, 1H), 7.35 (d, J= 9.0 Hz, 1H), 6.85 (d, J = 8.0 Hz, 2H), 6.82 (s, 1H), 6.64 (d, J= 8.5 Hz, 1H), 4.10 (s, 2H), 3.86 (s, 3H), 3.79 (s, 6H).
[000189] Synthesis of methyl 2-mercapto-4-methoxybenzoate (P-38): A stirred solution of compound P-37 (330 mg, 1.03 mmol) in trifluoro acetic acid (5 mL) under argon atmosphere was heated to reflux and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude compound P-38 (340 mg) as brown syrup which was carried to the next step without any further purification. TLC: 10% EtOAc/ hexanes {Rf. 0.7).
[000190] Synthesis of methyl 4-methoxy-2-((4-(methoxycarbonyl)-2-nitrophenyl) thio) benzoate (P-39): To a stirred solution of compound P-38 (200 mg, 1.01 mmol) in DMF (5 mL) under argon atmosphere were added methyl 4-fluoro-3-nitrobenzoate (201 mg, 1.01 mmol), cesium carbonate (656 mg, 2.02 mmol) at RT; heated to 40 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (20 mL) and extracted with EtOAc (2 x 25 mL). The combined organic extracts were washed with water (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 15% EtOAc/ hexanes to afford compound P-39 (280 mg, 74%) as yellow solid. TLC: 20% EtOAc/ hexanes (Rf. 0.4); 1H-NMR (CDC13, 400 MHz): δ 8.84 (d, J= 7.2 Hz, 1H), 8.03 (d, J= 8.8 Hz, 1H), 7.96-7.92 (m, 1H), 7.78 (s, 1H), 7.17-7.12 (m, 1H), 7.08-6.93 (m, 1H), 3.96-3.93 (m, 3H), 3.85 (s, 3H), 3.80-3.74 (m, 3H).
[000191] Synthesis of methyl 2-((2-amino-4-(methoxycarbonyl) phenyl) thio)-4- methoxybenzoate (P-40): To a stirred solution of compound P-39 (270 mg, 0.71 mmol) in MeOH (10 mL) under argon atmosphere was added 10% Pd/C (80 mg) at RT and stirred under hydrogen atmosphere (balloon pressure) for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, washed with CH2CI2 (2 x 25 mL) and the filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 15% EtOAc/ hexanes to afford compound P-40 (180 mg, 79%) as colorless syrup. TLC: 20% EtOAc/ hexanes (Rf. 0.5); 1H- NMR (CDC13, 400 MHz): δ 8.03 (d, J= 8.8 Hz, 1H), 7.54-7.40 (m, 1H), 7.08 (d, J= 8.8 Hz, 1H), 6.79-6.72 (m, 1H), 6.66-6.63 (m, 1H), 6.21-6.14 (m, 1H), 3.95-3.88 (m, 5H), 3.85 (s, 3H), 3.65 (s, 3H).
[000192] Synthesis of 2-((2-amino-4-carboxyphenyl) thio)-4-methoxybenzoic acid (P-41):
To a stirred solution of compound P-40 (160 mg, 0.46 mmol) in THF: H20 (2: 1, 6 mL) under argon atmosphere was added lithium hydroxide monohydrate (96 mg, 2.30 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo, diluted with water (20 mL), acidified with 1 N HC1 to pH~6. The obtained precipitate was filtered and dried in vacuo to afford compound P-41 (85 mg, crude) as an off-white solid. TLC: 50% EtOAc/ hexanes (Rf. 0.2); 1H-NMR (DMSO-</6, 400 MHz): δ 12.84 (br s, 2H), 7.95 (d, J= 8.8 Hz, 1H), 7.44 (s, 1H), 7.40 (d, J= 8.0 Hz, 1H), 6.13 (s, 1H), 5.58 (br s, 2H), 3.80-3.69 (m, 2H), 3.60 (s, 3H).
[000193] Synthesis of 3-methoxy-ll-oxo-10, 11-dihydrodibenzo [b,j\ [1, 4] thiazepine-8- carboxylic acid (P-42): To a stirred solution of compound 41 (80 mg, 0.25 mmol) in THF (8 mL) under argon atmosphere was added CDI (203 mg, 1.25 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo, diluted with water (20 mL), acidified with dilute HC1. The obtained precipitate was filtered and dried in vacuo to afford compound P-42 (50 mg, crude) as an off-white solid. TLC: 5% MeOH/ CH2C12 (Rf. 0.3); 1H-NMR (DMSO-</6, 400 MHz): δ 13.18 (br s, 1H), 10.64 (s, 1H), 7.77 (s, 1H), 7.66 (s, 2H), 7.16-7.07 (m, 1H), 7.01 (d, J= 8.8 Hz, 1H), 6.82-6.79 (m, 1H), 3.80 (s, 3H).
Example 24: Synthesis of 2-methyl-ll-oxo-lO, ll-dihydrodibenzo \b, f\ [1, 41 thiazepine-8- carboxylic acid (P-51)
Figure imgf000102_0001
[000194] Synthesis of methyl 2-hydroxy-5-methylbenzoate (P-44): To a stirred solution of 2- hydroxy-5-methylbenzoic acid P-43 (2 g, 13.15 mmol) in MeOH (65 mL) under argon atmosphere was added sulphuric acid (0.65 mL) at RT; heated to reflux and stirred for 20 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with ice water (50 mL) and extracted with ether (3 x 40 mL). The combined organic extracts were washed with 10% aqueous NaHC03 solution (until the pH becomes neutral), dried over sodium sulfate, filtered and concentrated in vacuo to obtain compound P-44 (2 g, 92%) as colorless liquid. TLC: 10% EtOAc/ hexanes (Rf. 0.7); 1H-NMR (CDC13, 500 MHz): δ 10.57 (s, 1H), 7.65 (s, 1H), 7.29 (d, J= 7.5 Hz, 1H), 6.90 (d, J= 8.0 Hz, 1H), 3.96 (s, 3H), 2.30 (s, 3H).
[000195] Synthesis of methyl 5-methyl-2-(((trifluoromethyl) sulfonyl) oxy) benzoate (P- 45): To a stirred solution of compound P-44 (2 g, 12.04 mmol) in pyridine (8 mL) under argon atmosphere was added trifluoro methane sulfonic anhydride (2.3 mL, 13.85 mmol) at 0 °C;
warmed to RT and stirred for 2 h; heated to 40 °C and stirred for 8 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (50 mL) and extracted with ether (3 x 50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), 1 N HC1 (40 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 3-5% EtOAc/ hexanes to afford compound P-45 (2.6 g, 72%) as colorless liquid. TLC: 7% EtOAc/ hexanes (Rf. 0.6); 1H-NMR (CDC13, 500 MHz): δ 7.88 (s, 1H), 7.40 (d, J= 8.5 Hz, 1H), 7.17 (d, J= 8.0 Hz, 1H), 3.96 (s, 3H), 2.42 (s, 3H).
[000196] Synthesis of methyl 2-((4-methoxybenzyl) thio)-5-methylbenzoate (P-46): To a stirred solution of compound P-45 (1 g, 3.35 mmol) in 1, 4-dioxane (15 mL) under argon atmosphere were added (4-methoxyphenyl) methanethiol (568 mg, 3.69 mmol), cesium carbonate (2.18 g, 6.71 mmol) at RT and degassed for 20 min. To this was added Pd(dppf)2Cl2 (61.4 mg, 0.083 mmol); heated to 110 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 3-5% EtOAc/ hexanes to afford compound P-46 (290 mg, 29%) as yellow solid. TLC: 10% EtOAc/ hexanes (Rf. 0.5); 1H-NMR (CDC13, 400 MHz): δ 7.75 (s, 1H), 7.30 (d, J= 8.8 Hz, 2H), 7.22-7.21 (m, 2H), 6.83 (d, J= 8.8 Hz, 2H), 4.09 (s, 2H), 3.89 (s, 3H), 3.79 (s, 3H), 2.32 (s, 3H).
[000197] Synthesis of methyl 2-mercapto-5-methylbenzoate (P-47): A stirred solution of compound P-46 (200 mg, 0.66 mmol) in trifluoro acetic acid (10 mL) at RT under argon atmosphere was heated to 70-75 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to afford compound P-47 (100 mg, crude) as yellow syrup. TLC: 10% EtOAc/ hexanes (Rf. 0.7); 1H-NMR (DMSO-</6, 500 MHz): δ 7.74 (s, 1H), 7.44 (d, J= 8.0 Hz, 1H), 7.26 (d, J= 7.5 Hz, 1H), 5.20 (s, 1H), 3.82 (s, 3H), 2.28 (s, 3H).
[000198] Synthesis of methyl 2-((4-(methoxycarbonyl)-2-nitrophenyl) thio)-5- methylbenzoate (P-48): To a stirred solution of compound P-47 (100 mg, 0.50 mmol) in DMF (5 mL) under argon atmosphere were added methyl 4-fluoro-3-nitrobenzoate (100 mg, 0.55 mmol), cesium carbonate (326 mg, 1.00 mmol) at RT; heated to 60 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (30 mL) and extracted with CH2CI2 (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% EtOAc/ hexanes to afford compound P-48 (100 mg, 55%) as yellow solid. TLC: 10% EtOAc/ hexanes (R/. 0.3); 1H-NMR (DMSO-< , 400 MHz): δ 8.63 (s, 1H), 8.03 (d, J= 8.8 Hz, 1H), 7.78 (s, 1H), 7.61 (d, J= 7.6 Hz, 1H), 7.55-7.53 (m, 1H), 6.99 (d, J= 8.4 Hz, 1H), 3.87 (s, 3H), 3.68 (s, 3H), 2.43 (s, 3H).
[000199] Synthesis of methyl 2-((2-amino-4-(methoxycarbonyl) phenyl) thio)-5- methylbenzoate (P-49): To a stirred solution of compound P-48 (400 mg, 1.10 mmol) in MeOH (20 mL) under argon atmosphere was added 10%> Pd/ C (200 mg) at RT and stirred under hydrogen atmosphere (balloon pressure) for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and washed with 50% MeOH/ CH2CI2 (2 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 7-10% EtOAc/ hexanes to afford compound P-49 (220 mg, 60%) as pale yellow solid. TLC: 20% EtOAc/ hexanes (R/. 0.5); 1H-NMR (DMSO-< , 500 MHz): δ 7.77 (s, 1H), 7.44 (s, 1H), 7.40 (d, J= 7.5 Hz, 1H), 7.21 (d, J= 8.0 Hz, 1H), 7.16-7.14 (m, 1H), 6.57 (d, J= 8.5 Hz, 1H), 5.63 (br s, 2H), 3.87 (s, 3H), 3.84 (s, 3H), 2.27 (s, 3H).
[000200] Synthesis of 2-((2-amino-4-carboxyphenyl) thio)-5-methylbenzoic acid (P-50): To a stirred solution of compound P-49 (220 mg, 0.66 mmol) in THF: ¾0 (5: 1, 6 mL) under argon atmosphere was added lithium hydroxide monohydrate (139 mg, 3.32 mmol) at RT and stirred for 20 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (15 mL) and acidified with 6 N HC1 to pH~4. The precipitated solid was filtered and dried in vacuo to afford compound P-50 (110 mg, 55%) as an off-white solid. TLC: 20% EtOAc/ hexanes (Rf. 0.2); 1H-NMR (DMSO-< , 500 MHz): δ 12.96 (br s, 2H), 7.76 (s, 1H), 7.42 (s, 1H), 7.37 (d, J= 8.0 Hz, 1H), 7.18 (d, J= 8.0 Hz, 1H), 7.15-7.13 (m, 1H), 6.54 (d, J= 8.0 Hz, 1H), 5.54 (br s, 2H), 2.26 (s, 3H).
[000201] Synthesis of 2-methyl-ll-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8- carboxylic acid (P-51): To a stirred solution of compound P-50 (110 mg, 0.36 mmol) in THF (10 mL) under argon atmosphere was added CDI (176 mg, 1.08 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with ice cold water (20 mL) and acidified with 6 N HC1 to pH~4. The precipitated solid was filtered and dried in vacuo to afford compound P-51 (60 mg, 58%) as white solid. TLC: 10% MeOH/ CH2C12 (Rf. 0.6); 1H-NMR (DMSO-< , 400 MHz): δ 13.21 (br s, 1H), 10.76 (s, 1H), 7.76 (s, 1H), 7.65 (s, 2H), 7.50 (s, 1H), 7.41 (d, J= 8.0 Hz, 1H), 7.30 (d, J= 8.0 Hz, 1H), 2.29 (s, 3H).
Example 25: Synthesis of 3-methyl-ll-oxo-lO, 11-dihydrodibenzo \b, f] [1, 41 thiazepine-8- carboxylic acid (P-8)
Figure imgf000106_0001
[000202] Synthesis of methyl 4-methyl-2-(((trifluoromethyl) sulfonyl) oxy) benzoate (P-2):
To a stirred solution of methyl 2-hydroxy-4-methylbenzoate P-l (950 mg, 5.70 mmol) in pyridine (9.5 mL) under argon atmosphere was added triflic anhydride (1.05 mL, 6.20 mmol) drop wise at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was acidified with 6 N HC1 and extracted with diethyl ether (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 2% EtOAc/ hexanes to afford compound P-2 (1.2 g, 71%) as colorless liquid. TLC: 10% EtOAc/ hexanes (R/. 0.7); 1H-NMR (CDC13, 400 MHz): δ 7.98 (d, J= 8.0 Hz, 1H), 7.28 (d, J= 8.0 Hz, 1H), 7.09 (s, 1H), 3.94 (s, 3H), 2.45 (s, 3H). [000203] Synthesis of methyl 2-((4-methoxybenzyl) thio)-4-methylbenzoate (P-3): To a stirred solution of compound 2 (600 mg, 2.01 mmol) in 1, 4-dioxane (12 mL) under argon atmosphere were added (4-methoxyphenyl) methanethiol (341 mg, 2.21 mmol), cesium carbonate (1.3 g, 4.02 mmol) at RT and degassed under argon for 20 min. To this was added Pd(dppf)2Cl2 (36.8 mg, 0.05 mmol); heated to 100 °C and stirred for 48 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with EtOAc (2 x 35 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 3% EtOAc/ hexanes to afford compound 3 (200 mg, 33%) as sticky solid. TLC: 10% EtOAc/ hexanes (Rf. 0.4); 1H-NMR (CDC13, 500 MHz): δ 7.85 (d, J= 8.5 Hz, 1H), 7.32 (d, J= 8.0 Hz, 2H), 7.14 (s, 1H), 6.94 (d, J= 8.5 Hz, 1H), 6.84 (d, J= 8.0 Hz, 2H), 4.10 (s, 2H), 3.86 (s, 3H), 3.78 (s, 3H), 2.34 (s, 3H).
[000204] Synthesis of methyl 2-mercapto-4-methylbenzoate (P-4): A stirred solution of compound P-3 (200 mg, 0.65 mmol) in trifluoro acetic acid (4 mL) under argon atmosphere at RT was heated to 80 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude compound P- 4 (115 mg) which was carried to the next step without any further purification. TLC: 10% EtOAc/ hexanes {Rf. 0.8).
[000205] Synthesis of methyl 2-((4-(methoxycarbonyl)-2-nitrophenyl) thio)-4- methylbenzoate (P-5): To a stirred solution of methyl 4-fluoro-3-nitrobenzoate (120 mg, 0.60 mmol) in DMF (4 mL) under argon atmosphere were added compound P-4 (115 mg, crude), cesium carbonate (392 mg, 1.20 mmol) at RT; heated to 60 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 35 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% EtOAc/ hexanes to afford compound P-5 (120 mg, 55%) as yellow solid. TLC: 15% EtOAc/ hexanes (Rf. 0.7); 1H-NMR (CDC13, 400 MHz): δ 8.85 (s, 1H), 7.95-7.89 (m, 2H), 7.46 (s, 1H), 7.38 (d, J= 8.8 Hz, 1H), 6.93 (d, J= 8.4 Hz, 1H), 3.93 (s, 3H), 3.76 (s, 3H), 2.42 (s, 3H). [000206] Synthesis of methyl 2-((2-amino-4-(methoxycarbonyl) phenyl) thio)-4- methylbenzoate (P-6): To a stirred solution of compound P-5 (120 mg, 0.33 mmol) in MeOH (10 mL) under argon atmosphere was added 10% Pd/C (60 mg) at RT and stirred under hydrogen atmosphere (balloon pressure) for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, washed with n-pentane (2 x 5 mL) and dried in vacuo to afford compound P-6 (90 mg, 82%) as yellow sticky solid. TLC: 15% EtOAc/ hexanes (R/. 0.5); 1H-NMR (DMSO-< , 400 MHz): δ 7.86 (d, J= 8.0 Hz, 1H), 7.45 (s, 1H), 7.40 (d, J= 8.0 Hz, 1H), 7.15 (d, J= 8.0 Hz, 1H), 7.05 (d, J= 8.0 Hz, 1H), 6.44 (s, 1H), 5.65 (br s, 2H), 3.85-3.84 (m, 6H), 2.13 (s, 3H).
[000207] Synthesis of 2-((2-amino-4-carboxyphenyl) thio)-4-methylbenzoic acid (P-7): To a stirred solution of compound P-6 (90 mg, 0.27 mmol) in THF: H20 (2: 1, 3 mL) under argon atmosphere was added lithium hydroxide monohydrate (56 mg, 1.35 mmol) at RT and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (2 x 20 mL). The aqueous layer was acidified with 2 N HC1, the obtained solid was filtered, washed with n-hexane (2 x 5 mL) and dried in vacuo to afford compound P-7 (60 mg, 73%) as an off-white solid. TLC: 10% MeOH/ CH2C12 (Rf. 0.2); 1H-NMR (DMSO-</6, 500 MHz): δ 12.95 (br s, 2H), 7.85 (d, J= 8.0 Hz, 1H), 7.44 (s, 1H), 7.38 (d, J= 8.0 Hz, 1H), 7.15 (d, J= 7.5 Hz, 1H), 7.02 (d, J= 8.0 Hz, 1H), 6.42 (s, 1H), 5.57 (br s, 2H), 2.13 (s, 3H).
[000208] Synthesis of 3-methyl-ll-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8- carboxylic acid (P-8): To a stirred solution of compound P-7 (60 mg, 0.19 mmol) in THF (4 mL) under argon atmosphere was added CDI (96 mg, 0.59 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo, diluted with water (20 mL), acidified with dil. HC1 to pH~ 3. The obtained precipitate was filtered and dried in vacuo to afford compound P-8 (45 mg, 80%) as an off-white solid. TLC: 10% MeOH/ CH2C12 (R/. 0.3); 1H-NMR (DMSO-</6, 400 MHz): δ 13.12 (br s, 1H), 10.72 (s, 1H), 7.76 (d, J= 8.0 Hz, 2H), 7.59 (d, J= 8.0 Hz, 2H), 7.37 (s, 1H), 7.26 (s, 1H), 2.30 (s, 3H). Example 26: Preparation of Compounds
[000209] Acids similar to compound 6 (compounds 14, 21, 28, 35, 42, 50, 55, 62, 70, 76, 82, 88, 97, 135, 140, 145, 150, 155, 156, 159, 164, 167, 170, P-8, P-42, P-51) were synthesized as mentioned above and converted to final products either using commercially available amines or by using prepared amines employing Procedures A, B, C, D, E, F, G, H and the results are captured in Table 1.
Figure imgf000109_0001
Procedure A:
[000210] To a stirred solution of 6 (50 mg, 0.18 mmol) in DMF (3 mL) under argon
atmosphere were added EDCI.HC1 (50 mg, 0.22 mmol), HOBt (35 mg, 0.22 mmol), 2-(5-methyl- 1, 3, 4-thiadiazol-2-yl) ethan-l-amine hydrochloride 187 (50 mg, 0.22 mmol) and diisopropyl ethyl amine (0.1 mL, 0.55 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and stirred for 1 h. The crude was extracted with EtOAc or the precipitated material was either directly dried in vacuo or triturated or purified through silica gel column chromatography to afford the desired compound.
Procedure B:
[000211] To a stirred solution of 6 (40 mg, 0.14 mmol) in DMF (4 mL) under argon
atmosphere were added pyridin-3 -amine 182 (15 mg, 0.16 mmol), HATU (84 mg, 0.22 mmol), diisopropyl ethyl amine (0.05 mL, 0.29 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (15 mL), the obtained precipitate was filtered, or extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered, concentrated in vacuo to obtain the crude. The crude was extracted with EtOAc or the precipitated material was directly dried in vacuo, triturated or purified through silica gel column chromatography to afford the desired compound. Procedure C:
[000212] To a stirred solution of compound 35 (50 mg, 0.17 mmol) in CH2CI2 (5 mL) were added oxalyl chloride (0.03 mL, 0.34 mmol) or (0.06 mL, 0.69 mmol), DMF (0.01 mL) under argon atmosphere at 0 °C; warmed to 10 °C and stirred for 2-3 h. After completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was carried to the next step without further purification.
[000213] To a stirred solution of crude acid chloride (70 mg, crude) in CH2CI2 (5 mL) under argon atmosphere were added 2-chloro-4-fluoroaniline 184 (25 mg, 0.17 mmol) and pyridine (0.07 mL, 0.86 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with CH2CI2 (2 x 30 mL). The combined organic extracts were washed with 1 N HC1 (20 mL), 10% NaHC03 solution (30 mL), brine (15 mL) dried over sodium sulfate, filtered and concentrated in vacuo to obtain crude. The precipitated material was either directly dried in vacuo or triturated or purified through silica gel column chromatography /preparative HPLC or by acid-base treatment to afford the desired compound.
Procedure D:
[000214] To a stirred solution of 6 (40 mg, 0.14 mmol) in DMF (3 mL) under argon atmosphere was added CDI (71.7 mg, 0.17 mmol) at 0 °C; warmed to RT and stirred for 2 h. To this were added (4-(trifluoromethoxy) phenyl) methanamine 172 (33.8 mg, 0.17 mmol), and diisopropyl ethyl amine (0.05 mL, 0.29 mmol) and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mass was diluted with water (15 mL) and stirred for 1 h. The precipitate was filtered or extracted with EtOAc or CH2CI2 and the obtained solid was dried in vacuo or purified by column chromatography or triturated to afford the desired product.
Procedure E:
[000215] A stirred solution of 6 (40 mg, 0.14 mmol) in thionyl chloride (1 mL) under argon atmosphere was heated to 90 °C and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain acid chloride (50 mg, crude) which was carried to the next step without further purification. To a stirred solution of 2- amino pyridine 181 (15 mg, 0.16 mmol) in CH2CI2 (5 mL) under argon atmosphere were added pyridine (0.035 mL), acid chloride (50 mg, crude) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude which was purified through silica gel column
chromatography using 2% MeOH/ CH2CI2 to afford the desired product.
Procedure F:
[000216] To a stirred solution of compound 35 (50 mg, 0.17 mmol) in CH2CI2 (5 mL) under argon atmosphere were added ethyl 2-amino-2-(pyridin-2-yl) acetate hydrochloride 249 (26 mg, 0.17 mmol), propylphosphonic anhydride (-50% solution in EtOAc, 0.22 mL, 0.34 mmol), NMM (0.037 mL, 0.34 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo and diluted with water (20 mL) or the pH of the reaction mixture was adjusted to ~8 and extracted with CH2CI2 (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified either through silica gel column chromatography or triturated to afford the desired product.
Procedure G:
[000217] To a stirred solution of compound 159 (100 mg, 0.33 mmol) in CH3CN (2 mL) under argon atmosphere was added thiazol-2-amine 231 (36 mg, 0.36 mmol), propylphosphonic anhydride (-50% solution in EtOAc, 0.8 mL, 1. 32 mmol) and NMM (0.14 mL, 1.32 mmol) at RT in a microwave vial and heated at 100 °C and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo and diluted with water (20 mL) and the precipitated solid was filtered. The obtained solid was either directly dried in vacuo or titurated or purified by column chromatography to afford the desired product.
Procedure H:
[000218] To a stirred solution of compound 159 (100 mg, 0.33 mmol) in CH2C12 (12 mL) under argon atmosphere were added EDCI.HC1 (188.8 mg, 0.98 mmol), 6-fluorobenzo [d] thiazol-2-amine 241 (61 mg, 0.36 mmol) and DMAP (120.7 mg, 0.98 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the precipitated solid was filtered washed with water and titurated to afford the desired product.
I l l
Figure imgf000113_0001
112
Figure imgf000114_0001
Figure imgf000115_0001
Preparation of amines for compound synthesis Synthesis of 2-cyclohexylethanamine hydrochloride (261):
Figure imgf000115_0002
[000219] To a stirred solution of 2-(cyclohex-l-en-l-yl) ethanamine 260 (500 mg, 4.00 mmol) in MeOH (10 mL) under argon atmosphere was added 10% Pd/C (50 mg) at RT and stirred under hydrogen atmosphere (balloon pressure) for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, washed with MeOH (2 x 5 mL) and the filtrate was concentrated in vacuo. The residue was triturated with CH2C12: EtOAc (1 : 1, 2 mL), diethyl ether in 1 N HC1 (4 mL) to afford compound 261 (250 mg, 38%) as white solid. TLC: 20% EtOAc/ hexanes (R/. 0.3); 1H-NMR (DMSO-</6, 500 MHz): δ 7.79 (br s, 2H), 2.77 (t, J= 7.5 Hz, 2H), 1.66-1.59 (m, 5H), 1.45-1.41 (m, 2H), 1.32-1.28 (m, 1H), 1.23-1.11 (m, 3H), 0.91-0.84 (m, 2H).
Synthesis of 2-(4-fluorophenoxy) ethan-l-amine hydrochloride (265)
Figure imgf000116_0001
[000220] Synthesis of 2-(4-fluorophenoxy) acetonitrile (264): To a stirred solution of 4- fluorophenol 262 (1.74 mL, 18.96 mmol) in acetone (50 mL) under argon atmosphere were added potassium carbonate (6.5 g, 47.40 mmol), chloro acetonitrile 263 (1 mL, 15.80 mmol) at RT; heated to reflux and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was extracted with diethyl ether (3 x 40 mL). The combined organic extracts were washed with NaOH solution (30 mL), water (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 264 (2.4 g, 90%) as brown syrup. TLC: 10% EtOAc/ hexanes (Rf. 0.3); 1H-NMR (CDC13, 400 MHz): δ 7.06-7.01 (m, 2H), 6.98-6.89 (m, 2H), 4.73 (s,
2H).
[000221] Synthesis of 2-(4-fluorophenoxy) ethan-l-amine hydrochloride (265): To a stirred solution of compound 264 (200 mg, 1.32 mmol) in MeOH (10 mL) under argon atmosphere were added HCI (0.3 mL), Pd/C (90 mg) and stirred under hydrogen atmosphere (balloon pressure) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with saturated sodium potassium tartrate solution (20 mL) and extracted with diethyl ether (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 265 (130 mg, 65%) as an off-white solid. TLC: 10% EtOAc/ hexanes (Rf. 0.2); 1H-NMR (DMSO-< , 400 MHz): δ 8.31-8.28 (m, 2H), 7.17-7.12 (m, 2H), 7.02-6.98 (m, 2H), 4.16 (t, J= 5.2 Hz, 2H), 3.17 (t, J= 5.2
Hz, 2H).
Synthesis of 2-(4-fluorocyclohexyl) ethan-l-amine hydrochloride (269)
Figure imgf000117_0001
266 267 268 269
[000222] Synthesis of 2-(4-hydroxycyclohexyl) acetonitrile (267): To a stirred solution of 2- (4-oxocyclohexyl) acetonitrile 266 (200 mg, 1.45 mmol) in EtOH (10 mL) under argon atmosphere was added sodium borohydride (82.7 mg, 2.18 mmol) at 0 °C; warmed to 10-15 °C and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice cold water (2 mL) and the volatiles were removed in vacuo. The residue was diluted with water (20 mL) and extracted with CH2CI2 (2 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 267 (180 mg, 89%) as colorless syrup. TLC: 50% EtOAc/ hexanes (Rf. 0.4); 1H-NMR (CDCI3, 400 MHz): δ 3.62-3.55 (m, 1H), 2.30-2.24 (m, 2H), 2.06-2.01 (m, 2H), 1.92- 1.88 (m, 2H), 1.80-1.78 (m, 1H), 1.70-1.63 (m, 2H), 1.59-1.56 (m, 1H), 1.40-1.16 (m, 2H).
[000223] Synthesis of 2-(4-fluorocyclohexyl) acetonitrile (268): To a stirred solution of compound 267 (180 mg, 1.29 mmol) in CH2CI2 (5 mL) under argon atmosphere was added DAST (313 mg, 1.94 mmol) at -20 °C; warmed to RT and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice cold water (20 mL) and extracted with CH2CI2 (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5-7% EtOAc/ hexanes to afford compound 268 (35 mg, 19%) as colorless syrup. TLC: 20% EtOAc/ hexanes (Rf. 0.4); 1H-NMR (CDCI3, 500 MHz): δ 4.88-4.79 (m, 1H), 2.27 (d, J= 7.0 Hz, 2H), 2.10-2.08 (m, 2H), 1.77-1.70 (m, 3H), 1.57-1.33 (m, 4H).
[000224] Synthesis of 2-(4-fluorocyclohexyl) ethan-l-amine hydrochloride (269): To a stirred solution of compound 268 (35 mg, 0.24 mmol) in ether (5 mL) under argon atmosphere was added lithium aluminium hydride (18.8 mg, 0.49 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated sodium potassium tartrate solution (10 mL) at 0-5 °C and extracted with ether (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was dissolved in ether (3 mL), slowly added 2 N HC1 in ether (10 mL) and stirred for 1 h. The precipitated solid was filtered and dried in vacuo to afford compound 269 (12 mg, 33%) as pale yellow solid. TLC: 30%> EtOAc/ hexanes (R/. 0.2); 1H-NMR (DMSO-</6, 400 MHz): δ 7.81 (br s, 2H), 4.87 (br s, 1H), 4.75 (br s, 1H), 2.82-2.77 (m, 2H), 1.89-1.84 (m, 2H), 1.59-1.40 (m, 6H), 1.20 (t, J= 10.0 Hz, 2H).
Synthesis of 3-methoxy-3-methylbutan-l-amine (273)
Figure imgf000118_0001
[000225] Synthesis of 3-methoxy-3-methylbutyl 4-methylbenzenesulfonate (271): To a stirred solution of 3-methoxy-3-methylbutan-l-ol 270 (1 g, 8.46 mmol) in pyridine (15 mL) under argon atmosphere was added tosyl chloride (1.6 g, 8.46 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was quenched with saturated NaHC03 solution (20 mL) and extracted with EtOAc (2 x 10 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to afford compound 271 (1.8 g, 78%>) as colorless syrup. TLC: 30% EtOAc/ hexanes (R/. 0.7); 1H-NMR (CDC13, 400 MHz): δ 7.79 (d, J = 8.4 Hz, 2H), 7.34 (d, J= 7.6 Hz, 2H), 4.13 (t, J= 7.2 Hz, 2H), 3.10 (s, 3H), 2.45 (s, 3H), 1.87 (t, J= 7.6 Hz, 2H), 1.12 (s, 6H).
[000226] Synthesis of l-azido-3-methoxy-3-methylbutane (272): To a stirred solution of compound 271 (1 g, 3.67 mmol) in DMF (10 mL) under argon atmosphere was added sodium azide (478 mg, 7.34 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to afford compound 272 (525 mg, 76%) as white solid. TLC: 30% EtOAc/ hexanes (R/. 0.7); 1H-NMR (CDC13, 400 MHz): δ 3.34 (t, J = 7.6 Hz, 2H), 3.18 (s, 3H), 1.78 (t, J=8.0 Hz, 2H), 1.18 (s, 6H).
[000227] Synthesis of 3-methoxy-3-methylbutan-l -amine (273): To a stirred solution of compound 272 (400 mg, 2.79 mmol) in EtOH (5 mL) under argon atmosphere was added 10%> Pd/C (250 mg) at RT and stirred under hydrogen atmosphere (balloon pressure) for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 80% EtOAc/ hexanes to afford compound 273 (320 mg, 33%>) as colorless syrup. TLC: 70%> EtOAc/ hexanes (R/. 0.3); 1H- NMR (CDC13, 400 MHz): δ 3.18 (s, 3H), 2.80 (t, J= 8.0 Hz, 0.5 H), 2.70 (t, J= 7.6 Hz, 1H), 2.49 (t, J= 8.0 Hz, 0.5H), 1.71 (t, J= 7.6 Hz, 2H), 1.56 (s, 6H).
Synthesis of 3-phenyl-3-(pyrrolidin-l-yl) propan-l-amine (277)
Figure imgf000119_0001
274 276
[000228] Synthesis of 3-phenyl-3-(pyrrolidin-l-yl) propanenitrile (276): To a stirred solution of cinnamonitrile 274 (500 mg, 3.87 mmol) in H20 (15 mL) were added pyrrolidine 275 (412 mg, 5.80 mmol), eerie ammonium nitrate (2.1 g, 3.87 mmol) at RT, heated to 60 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 25%> EtOAc/ hexanes to afford compound 276 (300 mg, 39%>) as colorless syrup. TLC: 30%> EtOAc/ hexanes (Rf. 0.5); 1H-NMR (CDC13, 400 MHz): δ 7.39-7.31 (m, 5H), 3.50-3.35 (m, 1H), 2.80-2.70 (m, 2H), 2.60-2.45 (m, 4H), 1.89-1.72 (m, 4H).
[000229] Synthesis of 3-phenyl-3-(pyrrolidin-l-yl) propan-l-amine (277): To a stirred solution of compound 276 (150 mg, 0.75 mmol) in THF (10 mL) under argon atmosphere were added lithium aluminium hydride (57 mg, 1.50 mmol), H2SO4 (0.04 mL, 0.75 mmol) at 0 °C; warmed to RT and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated sodium sulphate and the reaction mixture was filtered through celite, washed with EtOAc (2 x 5 mL).The volatiles were removed in vacuo to afford compound 277(100 mg, 65%) as an off-white solid. TLC: 10% MeOH/ EtOAc (Rf. 0.3); 1H-NMR (CDC13, 400 MHz): δ 7.31-7.30 (m, 5H), 3.26-3.22 (m, 1H), 2.59- 2.40 (m, 4H), 2.39-2.37 (m, 2H), 2.14-2.10 (m, 1H), 2.10 -2.04 (m, 1H), 1.98-1.72 (m, 6H).
Synthesis of 2-(5-methyl-l, 3, 4-oxadiazol-2-yl) ethan-l-amine hydrochloride (283)
Figure imgf000120_0001
278 279 281 l2, TPP,
Et3N, CH2CI2
Figure imgf000120_0002
HCl
282 283
[000230] Synthesis of 3-((terf-butoxycarbonyl) amino) propanoic acid (279): To a stirred solution of 3-aminopropanoic acid 278 (5 g, 51.02 mmol) in THF (50 mL) were added 1 M aqueous sodium hydroxide solution (25 mL) and Boc-anhydride (11.3 mL, 51.02 mmol) at 0 °C; warmed to RT and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The aqueous layer was washed with diethyl ether (2 x 50 mL) and the pH was adjusted to ~6 with 4 M HCl and extracted with diethyl ether (4 x 50 mL). The combined organic extracts were washed with brine (100 mL), dried over sodium sulphate, filtered and concentrated in vacuo to obtain compound 279 (8 g, 79%) as an off-white solid. TLC: 50% EtOAc/ hexanes (Rf. 0.3); 1H-NMR (DMSO-</6, 500 MHz): δ 12.18 (br s, 1H), 6.81 (t, J= 4.8 Hz, 1H), 3.11 (q, J= 6.9 Hz, 2H), 2.34 (t, J= 7.1 Hz, 2H), 1.36 (s, 9H). [000231] Synthesis of tert-buty\ (3-(2-acetylhydrazinyl)-3-oxopropyl) carbamate (281) To a stirred solution of compound 279 (1 g, 5.29 mmol) in CH2CI2 (15 ML) under argon atmosphere were added EDCI.HC1 (1.3 g, 6.87 mmol), HOBt (714 mg, 5.29 mmol), triethyl amine (0.99 ML, 6.87 mmol), acetic acid hydrazide 280 (430 mg, 5.82 mmol) at 0 °C; warmed to RT and stirred for 1.5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (5 mL) and extracted with CH2CI2 (4 x 20 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to obtain crude. The crude was purified through silica gel column chromatography using 10% EtOAc/ hexanes to afford compound 281 (610 mg, 50%>) as an off white solid. TLC: 10%> EtOAc/ hexanes (Rf 0.3); 1H-NMR (DMSO-</6, 400 MHz): δ 9.70 (s, 2H), 6.73 (t, J= 4.7 Hz, 1H), 3.13 (q, J= 6.6 Hz, 2H), 2.27 (t, J= 7.4 Hz, 2H), 1.83 (s, 3H), 1.37 (s, 9H).
[000232] Synthesis of terf-butyl (2-(5-methyl-l, 3, 4-oxadiazol-2-yl) ethyl) carbamate
(282) : To a stirred solution of triphenyl phosphine (428 mg, 1.63 mmol) in CH2CI2 (5 mL) under argon atmosphere were added iodine (414 mg, 1.63 mmol) and stirred for 15 min. To this were added triethyl amine (0.47 mL, 3.26 mmol), compound 281 (200 mg, 0.81 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 4% EtOAc/ hexanes to afford crude compound 282 (360 mg) as an off-white solid. TLC: 10% EtOAc/ hexanes (Rf. 0.7); 1H NMR shows mixture of compound and TPPO as major impurity. 1H-NMR (DMSO-</6, 400 MHz): δ 7.68-7.49 (m, 48H-TPPO as impurity), 6.97 (t, J= 5.0 Hz, 1H), 3.27 (q, J= 6.5 Hz, 2H), 2.89 (t, J= 6.7 Hz, 2H), 2.43 (s, 3H), 1.35 (s, 9H).
[000233] Synthesis of 2-(5-methyl-l, 3, 4-oxadiazol-2-yl) ethan-l-amine hydrochloride
(283) : To a stirred solution of compound 282 (350 mg) in CH2CI2 (5 mL) under argon
atmosphere was added 4 N HC1 in 1, 4-dioxane (4 mL) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was titurated with CH2CI2 (2 mL), diethyl ether (5 mL) and n-pentane (5 mL) and dried in vacuo to afford crude compound 283 (60 mg) as brown solid. TLC: 10% EtOAc/ hexanes (Rf 0.1). Synthesis of (2-ethylthiazol-5-yl) methanamine hydrochloride (292)
LiAIH4
Dry THF
Figure imgf000122_0001
284 286 28
8
N MsCI, Et3N i N NaN3, DMF ,ρΝ TPP, THF: H20
DMAP, CH2CI2 4N HCI in
1 , 4-dioxane
289 290 29
1
Figure imgf000122_0002
292
[000234] Synthesis of ethyl 2-chloro-3-oxopropanoate (286): To a stirred solution of ethyl 2- chloroacetate 284 (5 g, 40.98 mmol) and 285 (3.03 g, 40.98 mmol) in diisopropyl ether (100 mL) under argon atmosphere was added potassium tert-butoxide (5.49 g, 45.08 mmol) portion wise for 10 min at 0 °C; warmed to RT and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the pH of the reaction mixture was adjusted to ~ 6 using 5 N HCI. The obtained solid was filtered, washed with diethyl ether (200 mL) and dried in vacuo to afford compound 286 (6 g) as pale brown syrup. TLC: 30% EtOAc/ hexanes (R/. 0.2); LC-MS:
21.49% + 75.58%; 149.0 (M+-l); (column; X-Select C-18, (50 x 3.0 mm, 3.5 μπ ; RT 0.56 min, 0.77 min. 5 Mm Aq.NH4OAc: ACN 0.8 mL/min).
[000235] Synthesis of ethyl 2-ethylthiazole-5-carboxylate (288): To a stirred solution of compound 286 (1 g) in ethanol (25 mL) under argon atmosphere were added propanethioamide 287 (594 mg, 6.67 mmol), dry magnesium sulfate (4 g) at RT and heated to reflux for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo, diluted with EtOAc (2 x 100 mL). The combined organic extracts were washed with saturated sodium bicarbonate solution (2 x 100 mL), brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through flash column chromatography using 6%> EtOAc/ hexanes to afford compound 288 (330 mg, 27%) as brown syrup. TLC: 10% EtOAc/ hexanes (Rf. 0.4); 1H-NMR (DMSO-</6, 400 MHz): δ 8.29 (s, lH), 4.30 (q, J= 7.1 Hz, 2H), 3.04 (q, J= 7.5 Hz, 2H), 1.31 (t, J= 7.3 Hz, 3H), 1.29 (t, J = 7.3 Hz, 3H).
[000236] Synthesis of (2-ethylthiazol-5-yl) methanol (289) (SAP-MA1426-31): To a stirred suspension of lithium aluminium hydride (205 mg, 5.40 mmol) in dry THF (15 mL) under inert atmosphere was added compound 288 (500 mg, 2.70 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was cooled to 0 °C, quenched with 20% aqueous sodium hydroxide solution (3 mL), filtered through celite and washed with EtOAc (3 x 100 mL). The filtrate was dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 289 (310 mg, 80%>) as pale yellow solid. TLC: 50% EtOAc/ hexanes (Rf. 0.4). 1H-NMR (CDC13, 400 MHz): δ 7.51 (s, 1H), 4.82 (s, 2H), 3.01 (q, J = 7.5 Hz, 2H), 1.38 (t, J= 7.6 Hz, 3H).
[000237] Synthesis of 5-(chloromethyl)-2-ethylthiazole (290) (SAP-MA1426-34): To a stirred solution of compound 289 (300 mg, 2.09 mmol) in CH2CI2 (15 ML) under inert atmosphere were added triethyl amine (0.6 mL, 4.20 mmol), DMAP (25.6 mg, 0.21 mmol) and mesyl chloride (0.19 mL, 2.51 mmol) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with CH2CI2 (3 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 290 (500 mg, crude) as pale yellow syrup. TLC: 30% EtOAc/ hexanes (Rf. 0.8); LC-MS: 30.71%; 162.0 (M++l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 μιη); RT 2.14 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).
[000238] Synthesis of 5-(azidomethyl)-2-ethylthiazole (291) (SAP-MA1426-35): To a stirred solution of compound 290 (500 mg, 2.26 mmol) in DMF (20 mL) under inert atmosphere was added sodium azide (294 mg, 4.52 mmol) at RT and heated to 80 °C for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through flash column chromatography using 15% EtOAc/ hexanes to afford compound 291 (250 mg, 71%) as pale yellow syrup. TLC: 20% EtOAc/ hexanes (Rf. 0.4); 1H- NMR (CDC13, 400 MHz): δ 7.56 (s, 1H), 4.49 (s, 2H), 3.03 (q, J= 7.6 Hz, 2H), 1.40 (t, J= 7.6 Hz, 3H);
[000239] Synthesis of (2-ethylthiazol-5-yl) methanamine hydrochloride (292): To a stirred solution of compound 291 (250 mg, 1.48 mmol) in THF: H20 (5: 1, 12 mL) was added triphenyl phosphine (780 mg, 2.97 mmol) at RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The obtained solid was further dried using toluene (2 x 5 mL) to obtain the crude amine.
[000240] The above compound was dissolved in CH2C12 (5 mL) added 4 N HC1 in 1 , 4- dioxane (4 mL) under inert atmosphere at 0 °C and stirred for 30 min. The volatiles were removed in vacuo to obtain the crude, which was titurated with EtOAc (2 mL), diethyl ether (2 mL) and pentane (5 mL) to afford compound 292 (180 mg, 68%>) as an off-white solid. TLC: 5% MeOH/ CH2C12 (R/. 0.2); 1H NMR (DMSO-</6, 500 MHz): δ 8.48 (br s, 3H), 7.74 (s, 1H), 4.25 (q, J= 5.5 Hz, 2H), 2.98 (q, J= 7.5 Hz, 2H), 1.28 (t, J= 7.5 Hz, 3H);
Synthesis of (2-isopropylthiazol-5-yl) methanamine hydrochloride (298)
Figure imgf000124_0001
[000241] Synthesis of ethyl 2-isopropylthiazole-5-carboxylate (294): To a stirred solution of compound 286 (3.05 g) in ethanol (60 mL) under argon atmosphere were added 2- methylpropanethioamide 293 (1.5 g, 14.56 mmol), dry magnesium sulfate (5 g) at RT and heated to reflux for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with saturated sodium bicarbonate solution (100 mL), extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through flash column chromatography using 2% EtOAc/ hexanes to afford compound 294 (550 mg, 17%) as brown syrup. TLC: 10% EtOAc/ hexanes (R/. 0.5); 1H NMR (500 MHz, DMSO-< ) 5 8.31 (s, 1H), 4.30 (q, J= 7.0 Hz, 2H), 3.36-3.29 (m, 1H), 1.34 (d, J= 6.9 Hz, 6H), 1.29 (t, J = 7.1 Hz, 3H).
[000242] Synthesis of (2-isopropylthiazol-5-yl) methanol (295): To a stirred solution of compound 294 (550 mg, 2.76 mmol) in dry THF (10 mL) under inert atmosphere was added lithium aluminium hydride (210 mg, 5.52 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was cooled to 0 °C, quenched with 15% aqueous sodium hydroxide solution (3 mL), filtered through celite and washed with EtOAc (100 mL). The filtrate was dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 295 (360 mg, 83%) as pale yellow syrup. TLC: 50% EtOAc/ hexanes (R/. 0.3). 1H NMR (400MHz, DMSO-</6) δ 7.47 (s, 1H), 5.43 (t, J= 5.7 Hz, 1H), 4.61 (dd, J= 5.6, 0.6 Hz, 2H), 3.26-3.19 (m, 1H), 1.30 (d, J = 6.9 Hz, 6H).
[000243] Synthesis of 5-(chloromethyl)-2-isopropylthiazole (296): To a stirred solution of compound 295 (350 mg, 2.23 mmol) in CH2CI2 (20 mL) under inert atmosphere were added triethyl amine (0.64 mL, 4.45 mmol), DMAP (27.2 mg, 0.22 mmol) and mesyl chloride (0.2 mL, 2.67 mmol) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with CH2CI2 (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 296 (500 mg, crude) as pale yellow syrup. TLC: 40% EtOAc/ hexanes (Rf: 0.8); LC-MS: 70.54%; 175.8 (M++l); (column; Ascentis Express CI 8, (50 x 3.0 mm, 2.7 μιη); RT 2.34 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).
[000244] Synthesis of 5-(azidomethyl)-2-isopropylthiazole (297): To a stirred solution of compound 296 (500 mg, 2.26 mmol) in DMF (20 mL) under inert atmosphere was added sodium azide (445 mg, 6.85 mmol) at RT and heated to 80 °C for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through column chromatography using 8% EtOAc/ hexanes to afford compound 297 (255 mg, 63%) as colorless liquid. TLC: 10% EtOAc/ hexanes (Rf. 0.4); 1H NMR (500 MHz, DMSO-< ): δ = 7.67 (s, 1H), 4.69 (s, 2H), 3.29-3.24 (m, 1H), 1.32 (d, J= 6.9 Hz, 8H).
[000245] Synthesis of (2-isopropylthiazol-5-yl) methanamine hydrochloride (298): To a stirred solution of compound 297 (250 mg, 1.37 mmol) in THF: H20 (5: 1, 12 mL) was added triphenyl phosphine (720 mg, 2.74 mmol) at RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The obtained solid was further dried using toluene (2 x 5 mL) to obtain the crude amine.
[000246] The above crude compound was dissolved in CH2C12 (5 mL) added 4 N HC1 in 1, 4- dioxane (10 mL) under inert atmosphere at 0 °C and stirred for 30 min. The volatiles were removed in vacuo to obtain the crude, which was titurated with EtOAc (2 mL), diethyl ether (2 mL) and pentane (5 mL) to afford compound 298 (170 mg, 65%>) as low melting hygroscopic solid. TLC: 5% MeOH/ CH2C12 (Rf. 0.2); 1H NMR (500 MHz, DMSO-</6): δ 8.29 (br s, 2H), 7.72 (s, 1H), 4.25 (d, J= 5.8 Hz, 2H), 3.29-3.24 (m, 1H), 1.30 (d, J= 6.9 Hz, 6H)
Synthesis of (2-methoxythiazol-5-yl) methanamine (300)
Figure imgf000126_0001
299 300
[000247] Synthesis of (2-methoxythiazol-5-yl) methanamine (300): Sodium metal (46.6 mg, 2.02 mmol) was added slowly to MeOH (5 mL) under argon atmosphere and stirred for 15 min in a sealed tube. To this was added (2-chlorothiazol-5-yl) methanamine 299 (100 mg, 0.67 mmol) and the reaction mixture was heated to 80 °C for 3 h. The reaction was monitored by TLC; after completion the reaction, the reaction mixture was extracted with 20% MeOH/ CH2C12 (3 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude compound 300 (32 mg, 33%). The crude was carried forward for next step without purification. TLC: 5% MeOH/ CH2C12 (Rf. 0.2); LC-MS: 90.34%; 145.0 (M++l); (column; X-Select CSH C18, (50 3.0 mm, 3.5 μιη); RT 0.88 min. 2.5 mM Aq.NH4OOCH + 5% ACN: ACN + 5% 2.5 mM Aq. NH4OOCH; 1.2 mL/min).
Synthesis of 5-(aminomethyl) thiazol-2-amine dihydrochloride (303)
(Boc)20 4 N HCI in 1 , 4-Dioxane
NCA Jl >~ NHBoc Jl ^~NH2 HCI
NH2
NiCI2,NaBH4, CH2CI2
NHBoc N rH2 H sCI
MeOH
301 302 303
[000248] Synthesis of tert-buty\ ((2-((tert-butoxycarbonyl) amino) thiazol-5-yl) methyl) carbamate (302): To a stirred solution of 2-aminothiazole-5-carbonitrile 301 (300 mg, 2.40 mmol) in MeOH (50 mL) were added Boc-anhydride (1.5 mL, 7.20 mmol), nickel(II) chloride (571 mg, 2.40 mmol) at 0 °C. To this was added sodium borohydride (638 mg, 16.80 mmol) portion wise for 10 min at 0 °C; warmed to RT and stirred for 18 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with EtOAc (100 mL) and water (75 mL), filtered through celite. The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to obtain compound 302 (300 mg) as colorless syrup. TLC: 10% MeOH/ CH2C12 (Rf. 0.5); 1H NMR (DMSO-</6, 500 MHz): δ 11.24 (br s, 1H), 7.38 (br s, 1H), 7.11 (s, 1H), 4.17 (d, J= 5.5 Hz, 2H), 1.39 (s, 9H), 1.37 (s, 9H).
[000249] Synthesis of 5-(aminomethyl) thiazol-2-amine dihydrochloride (303): To a stirred solution of compound 302 (300 mg) in CH2C12 (10 mL) was added 4 N HCI in 1, 4-dioxane (5 mL) under argon atmosphere at 0-5 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed under reduced pressure. The obtained solid was washed with CH2C12 (5 mL), EtOAc (5 mL) and dried in vacuo to afford compound 303 (120 mg, HCI salt) as yellow solid. TLC: 10% MeOH/ CH2C12 (R/. 0.2); 1H NMR (DMSO-</6, 500 MHz): δ 9.31 (br s, 1H), 8.53 (br s, 2H), 8.14 (br s, 1H), 7.37 (br s, 1H), 7.27 (br s, 1H), 7.17 (br s, 1H), 4.07 (d, J= 5.5 Hz, 2H).
Synthesis of 4-(aminomethyl)- V-methylthiazol-2-amine hydrochloride (308) (Boc)20, Et3N MeNH2 306 N_ / NHBoc g/ CH2CI2
Figure imgf000128_0001
DIPEA H
304 305 307
4 N HCI in 1 ,4-Dioxane
Figure imgf000128_0002
308
[000250] Synthesis of tert-butyl ((2-chlorothiazol-4-yl) methyl) carbamate (305): To a stirred solution of (2-chlorothiazol-4-yl) methanamine 304 (200 mg, 1.35 mmol) in CH2CI2 (10 mL) were added triethylamine (0.6 mL, 4.14 mmol) and Boc-anhydride (0.6 mL, 2.7 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The aqueous layer was washed with CH2CI2 (50 mL), washed with water (50 mL). The organic extract was dried over sodium sulphate, filtered and concentrated in vacuo to obtain compound 305 (200 mg, 60%) as pale yellow sticky solid. TLC: 5% MeOH/ CH2C12 (Rf. 0.4); 1H NMR (DMSO-</6, 400 MHz): δ 7.56 (br s, 1H), 7.49 (s, 1H), 4.24 (d, J= 5.9 Hz, 3H), 1.39 (s, 9H).
[000251] Synthesis of terf-butyl ((2-(methylamino) thiazol-4-yl) methyl) carbamate (307):
A mixture of compound 305 (100 mg, 0.41 mmol) and methyl amine 306 (5 mL, 33% solution in EtOH) in a sealed tube under argon atmosphere was added diisopropyl ethylamine (0.2 mL, 1.21 mmol) under argon atmosphere at RT and heated to 120 °C for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was purified through silica gel column chromatography using 70% EtOAc/ hexanes to afford compound 307 (90 mg, 92%) as colorless sticky solid. TLC: 50% EtOAc/ hexanes (Rf. 0.2); 1H NMR (DMSO-i 6, 400 MHz): δ 7.26 (d, J= 5.6 Hz, 2H), 6.77 (s, 1H), 4.05 (d, J= 5.7 Hz, 2H), 2.76 (d, J= 4.8 Hz, 3H), 1.38 (s, 9H).
[000252] Synthesis of 4-(aminomethyl)- V-methylthiazol-2-amine hydrochloride (308) To a stirred solution of compound 307 (90 mg, 0.37 mmol) in CH2CI2 (3 mL) under argon atmosphere was added 4 N HCI in 1, 4-dioxane (3 mL) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was titurated with diethyl ether (5 mL) and dried in vacuo to afford compound 308 (70 mg, HCI salt) as brown solid. TLC: 30% EtOAc/ hexanes (Rf. 0.1); 1H NMR (DMSO- < , 400 MHz): δ 9.73-9.27 (m, 1H), 8.39 (br s, 3H), 7.35 (s, 1H), 4.08 (q, J = 5.3 Hz, 2H), 2.95 (s, 3H).
Synthesis of 4-(aminomethyl)-7V, 7V-dimethylthiazol-2-amine hydrochloride (310)
4 N HCI in 1 ,4-Dioxane
CH2CI2
Figure imgf000129_0001
30S 310
Figure imgf000129_0002
[000253] Synthesis of tert-buty\ ((2-(dimethylamino) thiazol-4-yl) methyl) carbamate
(310) : To a stirred solution of compound 305 (100 mg, 0.41 mmol) in CH3CN (3 mL) under argon atmosphere were added dimethyl amine hydrochloride 310 (648 mg, 8.06 mmol) and diisopropyl ethylamine (0.2 mL, 1.21 mmol) in a sealed tube at RT and heated to 120 °C for 54 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with EtOAc (2 x 50 mL) washed with water (20 mL). The organic extract was dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 310 (80 mg, 77%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf. 0.2); 1H NMR (DMSO-i 6, 400 MHz): δ 7.29 (t, J = 4.8 Hz, 1H), 6.89 (s, 1H), 4.08 (d, J = 5.9 Hz, 2H), 2.97 (s, 6H), 1.38 (s, 9H).
[000254] Synthesis of 4-(aminomethyl)-7V, N-dimethylthiazol-2-amine hydrochloride
(311) : To a stirred solution of compound 310 (100 mg, 0.38 mmol) in CH2CI2 (3 mL) under argon atmosphere was added 4 N HCI in 1 , 4-dioxane (3 mL) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was titurated with diethyl ether (5 mL) and dried in vacuo to afford compound 311 (75 mg, HC1 salt) as an off-white solid. TLC: 50% EtOAc/ hexanes (Rf. 0.1); 1H NMR (DMSO-< , 400 MHz): δ 8.44 (br s, 3H), 7.38 (s, 1H), 4.10 (q, J= 5.6 Hz, 2H), 3.14 (s, 6H).
Synthesis of (4-ethylthiazol-5-yl) methanamine hydrochloride (319)
Figure imgf000130_0001
316 317 318
Et
NH7 HCI
319
[000255] Synthesis of ethyl 2-chloro-3-oxopentanoate (313): To a stirred solution of ethyl 3- oxopentanoate 312 (1 g, 6.94 mmol) in CH2CI2 (20 mL) under argon atmosphere was added sulfuryl chloride (0.56 ML, 6.94 mmol) at 0 °C; warmed to RT and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to afford compound crude 313 (1 g) as colorless liquid. TLC: 10%> EtOAc/ hexanes (Rf. 0.5); 1H NMR (DMSO-i 6, 400 MHz): δ 5.66-5.55 (m, 1H), 5.66-5.55 (m, 1H), 4.22 (q, J= 7.1 Hz, 3H), 2.73-2.67 (m, 2H), 1.22 (t, J= 7.1 Hz, 3H), 0.99 (t, J= 7.2 Hz, 3H).
[000256] Synthesis of ethyl 4-ethylthiazole-5-carboxylate (315): To a stirred solution of compound 313 (1 g, crude) in EtOH (10 mL) under inert atmosphere was added thioformamide 314 (3.3 g, 55.55 mmol) at RT; heated at 80 °C and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through column chromatography using 40%> EtOAc/ hexanes to afford compound 315 (300 mg, 30%) as yellow solid. TLC: 20% EtOAc/ hexanes (Rf. 0.4); LC- MS: 51.18%; 185.9 (M++l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 μπι); RT 2.24 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).
[000257] Synthesis of (4-ethylthiazol-5-yl) methanol (316): To a stirred solution of compound 315 (300 mg, 1.62 mmol) in THF (10 mL) under inert atmosphere was added lithium aluminium hydride (123 mg, 3.24 mmol) at 0 °C; warmed to RT and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated 10% NaOH solution (1 mL), filtered through celite. The filtrate was concentrated in vacuo to obtain the crude. The crude was purified through column chromatography using 30%> EtOAc/ hexanes to afford compound 316 (200 mg, 86%) as yellow solid. TLC: 30% EtOAc/ hexanes (Rf. 0.4); 1H NMR (DMSO-< , 400 MHz): δ 8.86 (s, 1H), 5.45 (t, J= 5.5 Hz, 1H), 4.62 (d, J= 5.5 Hz, 2H), 2.67 (q, J= 7.5 Hz, 2H), 1.17 (t, J = 7.5 Hz, 3H).
[000258] Synthesis of 5-(chloromethyl)-4-ethylthiazole (317): To a stirred solution of compound 316 (200 mg, 1.39 mmol) in CH2CI2 (10 mL) under inert atmosphere were added triethyl amine (0.4 mL, 4.17 mmol), mesyl chloride (0.3 mL, 2.79 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated NaHC03 solution (5 mL). The organic extract was dried over sodium sulphate, filtered and concentrated in vacuo to obtain compound 317 (200 mg, crude) as yellow solid. TLC: 30% EtOAc/ hexanes (Rf: 0.7); 1H NMR (DMSO-< , 400 MHz): δ 9.01 (s, 1H), 5.08 (s, 2H), 2.76 (q, J= 7.5 Hz, 2H), 1.20 (t, J= 7.5 Hz, 3H).
[000259] Synthesis of 5-(azidomethyl)-4-ethylthiazole (318): To a stirred solution of compound 317 (400 mg, 2.48 mmol) in DMF (10 mL) under argon atmosphere was added sodium azide (322 mg, 4.96 mmol) at RT; warmed to 80 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold water (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to afford crude compound 318 (350 mg) as yellow liquid. The crude was carried forward for next step without further purification. TLC: 20% EtOAc/ hexanes (Rf. 0.5).
[000260] Synthesis of (4-ethylthiazol-5-yl) methanamine hydrochloride (319): To a stirred solution of compound 318 (350 mg) in THF: H20 (4: 1, 20 mL) was added triphenyl phosphine (1.3 g, 5.20 mmol) at RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude.
[000261] The crude was diluted with CH2C12 (2 mL) cooled to 0 °C; added 4 N HC1 1 , 4- dioxane (5 mL) under argon atmosphere and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude which was titurated with diethyl ether (2 x 5 mL) dried in vacuo to afford compound 319 (136 mg) as an off-white solid. TLC: 40% EtOAc/ hexanes (R/. 0.2); LC-MS: 89.95%; 142.9 (M++l);
(column; Ascentis Express CI 8, (50 x 3.0 mm, 2.7 μπι); RT 1.29 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).
Synthesis of (4-isopropylthiazol-5-yl) methanamine hydrochloride (327)
Figure imgf000132_0001
326 327
[000262] Synthesis of ethyl 2-chloro-4-methyl-3-oxopentanoate (321): To a stirred solution of ethyl 4-methyl-3-oxopentanoate 320 (5 g, 31.64 mmol) in Toluene (50 mL) under argon atmosphere was added sulfuryl chloride (4.26 g, 31.64 mmol) at 0 °C; warmed to RT and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to afford compound crude 321 (6 g) as brown syrup. TLC: 10%> EtOAc/ hexanes (R/. 0.8). [000263] Synthesis of ethyl 4-isopropylthiazole-5-carboxylate (323): To a stirred solution of compound 321 (2.1 g) in ethanol (30 mL) under argon atmosphere was added thioformamide 322 (0.667 g, 10.93 mmol) at RT and heated to reflux for 30 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with EtOAc (200 mL), washed with saturated sodium bicarbonate solution (100 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 323 (230 mg, 11%) as brown syrup. TLC: 10% EtOAc/ hexanes (Rf. 0.5); LC-MS: 93.64%; 199.9 (M++l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 μπι); RT 2.49 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).
[000264] Synthesis of (4-isopropylthiazol-5-yl) methanol (324): To a stirred solution of compound 323 (230 mg, 1.15 mmol) in THF (10 mL) under inert atmosphere was added lithium aluminium hydride (87 mg, 2.28 mmol) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was cooled to 0 °C, quenched with ice-cold water (10 mL), 15% aqueous sodium hydroxide solution (5 mL), filtered through celite and washed with EtOAc (100 mL). The filtrate was dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 324 (112 mg) as an off-white solid. TLC: 20% EtOAc/ hexanes (Rf. 0.2). 1H NMR (DMSO-</6, 400 MHz): δ 8.85 (s, 1H), 5.45 (t, J = 5.5 Hz, 1H), 4.64 (d, J= 5.5 Hz, 2H), 3.14-3.07 (m, 1H), 1.19 (d, J= 6.8 Hz, 6H).
[000265] Synthesis of 5-(chloromethyl)-4-isopropylthiazole (325): To a stirred solution of compound 324 (112 mg) in CH2CI2 (10 mL) under inert atmosphere were added triethyl amine (0.21 mL, 2.13 mmol), mesyl chloride (0.08 mL, 0.97 mmol) at 0 °C; warmed to RT and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with CH2CI2 (50 mL) washed with NaHC03 solution (50 mL), brine (50 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 325 (126 mg) as brown thick syrup. TLC: 30%> EtOAc/ hexanes {Rf. 0.8); LC- MS: 87.83%; 175.8 (M++l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 μιη); RT 2.30 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).
[000266] Synthesis of 5-(azidomethyl)-4-isopropylthiazole (326): To a stirred solution of compound 325 (126 mg, 0.53 mmol) in DMF (10 mL) under inert atmosphere was added sodium azide (70 mg, 1.07 mmol) at RT and heated to 80 °C for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with EtOAc (75 mL) washed with water (50 mL). The organic extract were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 326 (82 mg, 63%) as thick syrup. TLC: 30%> EtOAc/ hexanes (Rf. 0.7); 1H NMR (DMSO-</6, 500 MHz): δ 9.01 (s, 1H), 4.74 (s, 2H), 3.30- 3.21 (m, 1H), 1.21 (d, J= 6.8 Hz, 6H);
[000267] Synthesis of (4-isopropylthiazol-5-yl) methanamine hydrochloride (327): To a stirred solution of compound 326 (80 mg, 0.43 mmol) in THF: H20 (4: 1, 10 mL) was added triphenyl phosphine (230 mg, 0.87 mmol) at RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The obtained solid was further dried using toluene (2 x 5 mL) to obtain the crude.
[000268] The crude compound was dissolved in CH2C12 (3 mL) added 4 N HC1 in 1 , 4-dioxane (2 mL) under inert atmosphere at 0 °C and stirred for 1 h. The volatiles were removed in vacuo to obtain the crude, which was washed with diethyl ether (2 mL) to afford compound 327 (42 mg, 50%) as an off-white solid. TLC: 10% MeOH/ CH2C12 (Rf. 0.2); 1H NMR (DMSO-di, 400 MHz): δ 9.02 (s, 1H), 8.26 (br s, 2H), 4.24 (q, J= 5.6 Hz, 2H), 3.24-3.17 (m, 1H), 1.19 (d, J= 6.8 Hz, 6H).
Synthesis of (4-chlorothiazol-5-yl) methanamine hydrochloride (337)
Figure imgf000135_0001
328 329 330 LAH
Figure imgf000135_0002
CI CI CI
MsCI, Et3N / NaN, / TPP, THF: H,0
II / \ PH.r U \ DMF 1 S 4N HCI
H CH2C'2 Ms N3 in 1 , 4-Dioxane
334 335 336
CI
S NH2.HCI
337
[000269] Synthesis of thiazolidine-2, 4-dione (329): To a stirred solution of 2-chloroacetic acid 328 (5 g, 52.9 mmol) in H20 (10 mL) was added thiourea 314 (3.80 g, 52.9 mmol) at 0 °C stirred for 30 min added concentrated HCI (6 mL) dropwise for 15 min; heated at 1 10 °C and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was cooled to 0 °C and stirred for 30 min. The precipitated solid was filtered and dried in vacuo to afford compound 329 (3.2 g, 47%) as white solid. TLC: 30%> EtOAc/ hexanes (R/. 0.2); 1H NMR (400 MHz, DMSO-< ): δ 12.01 (br s. 1H), 4.15 (s, 2H).
[000270] Synthesis of 2, 4-dichlorothiazole-5-carbaldehyde (330): A mixture of compound
329 (2.7 g, 23.07 mmol) in DMF (1.23 mL, 15.98 mmol) at 0 °C under argon atmosphere was added phosphorous oxychloride (8.15 mL, 87.17 mmol) dropwise for 15 min at 0 °C; warmed to
RT and stirred for 1 h; heated to 120 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was poured into ice cold water slowly and extracted with CH2C12 (3 x 100 mL). The combined organic extracts were washed with saturated
NaHCC"3 solution (100 mL), water (100 mL), dried over sodium sulfate, filtered and
concentrated in vacuo to obtain the crude. The crude was purified through column
chromatography using 5% EtOAc/ hexanes to afford compound 330 (1.4 g, 33%) as brown color oil. TLC: 30% EtOAc/ hexanes {Rf. 0.8); 1H NMR (500 MHz, DMSO-</6): δ 9.87 (s, 1H).
[000271] Synthesis of 2,4-dichloro-5-(l, 3-dioxolan-2-yl) thiazole (331): To a stirred solution of compound 330 (1.4 g, 7.73 mmol) in Toluene (20 mL) under argon atmosphere was added ethane-1, 2-diol (1.43 g, 23.20 mmol), /?-toluenesulfonic acid (133 mg, 0.77mmol) at 0 °C;
heated at 110 °C and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with 10% aqueous NaHC03 solution (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through column chromatography using 10%> EtOAc/ hexanes to afford compound 331 (1.7 g, 98%>) as yellow oil. TLC: 10% EtOAc/ hexanes {Rf. 0.2); 1H NMR (400 MHz, CDC13): δ 6.04 (s, 1H), 4.14-4.07 (m, 2H), 4.06-4.00 (m, 2H).
[000272] Synthesis of 4-chloro-5-(l, 3-dioxolan-2-yl) thiazole (332): To a stirred solution of compound 331 (1.7 g, 7.55 mmol) in THF (20 ML) under argon atmosphere was added n-butyl lithium (3.9 mL, 9.82 mmol, 2.5 M solution in THF) dropwise for 10 min at -78 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice cold water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through column chromatography using 5%> EtOAc/ hexanes to afford compound 332 (1.1 g, 76%>) as yellow oil. TLC: 10%> EtOAc/ hexanes {Rf. 0.2); 1H NMR (CDC13, 500 MHz): δ 8.74 (s, 1H), 6.16 (s, 1H), 4.19-4.15 (m, 2H), 4.08-4.04 (m, 2H).
[000273] Synthesis of 4-chlorothiazole-5-carbaldehyde (333): To a stirred solution of compound 332 (1.1 g, 5.75 mmol) in THF (10 mL) was added 5 N aqueous HC1 in 1, 4-dioxane (6 mL) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was poured into brine (20 mL) extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with saturated sodium bicarbonate (100 mL) dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 333 (800 mg, 95%) as yellow oil. TLC: 10% EtOAc/ hexanes {Rf. 0.3); 1H NMR (CDC13, 500 MHz): δ 10.11 (s, 1H), 9.00 (s, 1H). [000274] Synthesis of (4-chlorothiazol-5-yl) methanol (334): To a stirred solution of compound 333 (750 mg, 5.10 mmol) in dry THF (20 mL) under inert atmosphere was added lithium aluminium hydride (193 mg, 5.10 mmol) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was cooled to 0 °C, quenched with 30% aqueous sodium hydroxide solution (3 mL) extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 334 (520 mg, 68%) as yellow oil. TLC: 10%> EtOAc/ hexanes (R/. 0.3); 1H NMR (CDC13, 500 MHz): δ 8.69 (m, 1H), 4.88 (s, 2H).
[000275] Synthesis of (4-chlorothiazol-5-yl) methyl methanesulfonate (335): To a stirred solution of compound 334 (520 mg, 3.48 mmol) in CH2CI2 (15 mL) under inert atmosphere were added triethyl amine (1.23 mL, 8.71 mmol) and mesyl chloride (0.34 mL, 4.18 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with CH2CI2 (2 x 50 mL). The combined organic extracts were washed with saturated NaHC03 (50 mL) dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 335 (600 mg, crude) as brown liquid. TLC: 10% EtOAc/ hexanes (R/. 0.81H NMR (CDC13, 500 MHz): δ 8.74 (s, 1H), 4.79 (s, 2H), 1.44 (s, 3H).
[000276] Synthesis of 5-(azidomethyl)-4-chlorothiazole (336): To a stirred solution of compound 335 (600 mg, 2.64 mmol) in DMF (10 mL) under inert atmosphere was added sodium azide (343 mg, 5.28 mmol) at RT and heated to 100 °C for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (100 mL) and extracted with diethyl ether (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 336 (250 mg, 54%>) as yellow oil. TLC: 8% EtOAc/ hexanes (Rf. 0.5); 1H NMR (CDC13, 400 MHz) δ 8.74 (s, 1H), 4.58 (s, 2H).
[000277] Synthesis of (4-chlorothiazol-5-yl) methanamine hydrochloride (337): To a stirred solution of compound 336 (250 mg, 1.43 mmol) in THF: H2O (3: 1, 13 ML) was added triphenyl phosphine (752 mg, 2.87 mmol) at RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo and the residue was acidified with 4 N HC1 in 1, 4-dioxane (2 mL) at 0 °C. The volatiles were removed in vacuo and the obtained solid was washed with EtOAc (2 mL), diethyl ether (2 mL) to afford compound 337 (110 mg) as yellow solid. TLC: 5% MeOH/ CH2C12 (Rf. 0.2); 1H NMR (DMSO-< , 400 MHz): δ 9.19 (s, 1H), 8.52 (br s, 3H), 4.24 (q, J= 5.6 Hz, 2H);
Synthesis of oxetan-3-ylmethanamine (341)
Figure imgf000138_0001
[000278] Synthesis of 3-(nitromethyl) oxetan-3-ol (339): To a stirred solution of oxetan-3- one 338 (500 mg, 0.69 mmol) in nitromethane (1.25 mL) under argon atmosphere was added triethyl amine (0.25 mL) at RT and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain crude. The crude was purified through silica gel column chromatography using 25% EtOAc/ hexanes to afford compound 339 (750 mg, 81%) as an off white solid. TLC: 30% EtOAc/ hexanes (Rf. 0.3); 1H NMR (DMSO-< , 400 MHz): δ 6.47 (s, 1H), 4.93 (s, 2H), 4.64 (d, J= 7.5 Hz, 2H), 4.49 (d, J = 7.3 Hz, 2H).
[000279] Synthesis of 3-(nitromethylene) oxetane (340): To a stirred solution of compound 339 (750 mg, 5.63 mmol) in CH2C12 (10 mL) under inert atmosphere were added triethyl amine (3.17 mL, 22.55 mmol), mesyl chloride (1.20 mL, 15.50 mmol), at 0 °C; cooled -78 °C and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain crude. The crude was purified through silica gel column chromatography using 25%> EtOAc/ hexanes to afford compound 340 (380 mg, 58%>) as an off white solid. TLC: 10% EtOAc/ hexanes (Rf. 0.51H NMR (CDC13, 400 MHz): δ 6.94-6.92 (m, 1H), 5.68-5.64 (m, 2H), 5.41-5.36 (m, 2H).
[000280] Synthesis of oxetan-3-ylmethanamine (341): To a stirred solution of compound 340 (500 mg, 4.34 mmol) in MeOH (10 mL) under inert atmosphere was added Pd(OH)2 (100 mg) at RT; heated at 45 °C stirred under hydrogen atmosphere (balloon pressure) for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and washed with MeOH (20 mL). The filtrate was evaporated in vacuo to obtain the crude which was triturated with diethyl ether (2 x 10 mL) to afford crude compound 341 (100 mg) as pale brown solid. TLC: 10% MeOH / CH2C12 (Rf. 0.2); Mass (m/z) (Agilent 6310 Ion Trap): 88.5 (M++l).
[000281] Synthesis of 2, 2, 2-trifluoro-l-((2-(oxazol-5-yl) ethylH4-azanyl) ethan-l-one (347)
Figure imgf000139_0001
-NHBoc TFA
CH2CI2
346 347
[000282] Synthesis of oxazol-5-ylmethanol (343): To a stirred solution of ethyl oxazole-5- carboxylate 342 (2 g, 14.18 mmol) in EtOH (20 mL) under argon atmosphere was added sodium borohydride (1.07 g, 28.36 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (25 mL) and extracted with 5% MeOH/ CH2C12 (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH/ CH2C12 to afford compound 343 (810 mg, 58%) as colorless syrup. TLC: 5% MeOH/ CH2C12 (Rf. 0.3); 1H-NMR (DMSO-</6, 500 MHz): δ 8.28 (s, 1H), 7.04 (s, 1H), 5.36 (t, J= 6.0 Hz, 1H), 4.47 (d, J= 6.0 Hz, 2H).
[000283] Synthesis of 5-(chloromethyl) oxazole (344): To a stirred solution of compound 343 (800 mg, 8.08 mmol) in CH2C12: n-hexane (1 : 1, 10 mL) under argon atmosphere was added thionyl chloride (1.2 mL, 16.16 mmol) at 0 °C; heated to reflux and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was neutralized with saturated NaHC03 solution (20 mL) and extracted with ether (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude compound 344 (700 mg) as colorless syrup. TLC: 40% EtOAc/ hexanes (Rf. 0.5); 1H- NMR (CDC13, 400 MHz): δ 7.89 (s, 1H), 7.10 (s, 1H), 4.62 (s, 2H).
[000284] Synthesis of 2-(oxazol-5-yl) acetonitrile (345): To a stirred solution of compound 344 (700 mg, 5.95 mmol) in DMF (8 mL) under argon atmosphere was added sodium cyanide (1.02 g, 20.85 mmol) at RT; heated to 70 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with ether (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude compound 345 (650 mg) as colorless syrup. TLC: 40% EtOAc/ hexanes (Rf. 0.3); 1H-NMR (CDC13, 400 MHz): δ 7.89 (s, 1H), 7.10 (s, 1H), 3.84 (s, 2H).
[000285] Synthesis of tert-buty\ (2-(oxazol-5-yl) ethyl) carbamate (346): To a stirred solution of compound 345 (50 mg, 0.46 mmol) in MeOH (3 mL) under argon atmosphere were added Boc-anhydride (0.21 mL, 0.92 mmol), nickel chloride hexahydrate (11 mg, 0.04 mmol), sodium borohydride (122 mg, 3.24 mmol) portion wise for 5 min at 0 °C; warmed to RT and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with MeOH (10 mL), filtered through celite and the filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 30%) EtOAc/ hexanes to afford compound 346 (68 mg, 71%>) as colorless syrup. TLC: 50% EtOAc/ hexanes (Rf. 0.5); 1H-NMR (CDCI3, 400 MHz): δ 7.82 (s, 1H), 6.85 (s, 1H), 4.64 (br s, 1H), 3.42-3.40 (m, 2H), 2.89 (t, J= 6.4 Hz, 2H), 1.43 (s, 9H).
[000286] Synthesis of 2, 2, 2-trifluoro-l-((2-(oxazol-5-yl) ethylH4-azanyl) ethan-l-one (347): To a stirred solution of compound 346 (65 mg, 0.30 mmol) in CH2CI2 (3 mL) under argon atmosphere was added trifluoro acetic acid (0.14 mL, 1.83 mmol) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude compound 347 (50 mg) as colorless syrup. TLC: 60% EtOAc/ hexanes (Rf. 0.2); 1H-NMR (DMSO-</6, 500 MHz): δ 8.30 (s, 1H), 7.85- 7.79 (m, 2H), 7.02 (s, 1H), 3.10-3.05 (m, 2H), 2.98 (t, J= 7.5 Hz, 2H).
Synthesis of 2, 2, 2-trifluoro-l-((2-(thiazol-5-yl) ethylH4-azanyl) ethan-l-one (352) OH CH3SO2CI CI NaCN CN
DIPEA, CH2CI; EtOH: H20
348 349 350
Figure imgf000141_0001
351 352
[000287] Synthesis of 5-(chloromethyl) thiazole (349): To a stirred solution of thiazol-5- ylmethanol 348 (1 g, 8.69 mmol) in CH2CI2 (50 mL) under argon atmosphere were added mesyl chloride (1.09 g, 9.56 mmol) drop wise for 15 min, diisopropyl ethyl amine (1.23 g, 9.56 mmol) at 0-5 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was washed with saturated NaHC03 solution (20 mL) and purified through silica gel column chromatography using 50% EtOAc/ hexanes to afford compound 349 (650 mg, 57%) as yellow liquid. TLC: 5% MeOH/ CH2C12 (Rf. 0.7); 1H-NMR (CDCI3, 500 MHz): δ 8.84 (s, 1H), 7.86 (s, 1H), 4.84 (s, 2H).
[000288] Synthesis of 2-(thiazol-5-yl) acetonitrile (350): To a stirred solution of compound 349 (650 mg, 4.92 mmol) in EtOH: H20 (4: 1, 10 mL) under argon atmosphere was added sodium cyanide (361 mg, 7.38 mmol) at RT; heated to 80 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (20 mL) and extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 70%> EtOAc/ hexanes to afford compound 350 (250 mg, 41%) as colorless semi-solid. TLC: 70% EtOAc/ hexanes (R/. 0.4); 1H-NMR (CDC13, 500 MHz): δ 8.81 (s, 1H), 7.85 (s, 1H), 3.84 (s, 2H).
[000289] Synthesis of tert-butyl (2-(thiazol-5-yl) ethyl) carbamate (351): To a stirred solution of compound 350 (50 mg, 0.40 mmol) in MeOH (3 mL) under argon atmosphere were added Boc-anhydride (175 mg, 0.80 mmol), nickel chloride hexahydrate (9.75 mg, 0.04 mmol), sodium borohydride (107 mg, 2.82 mmol) portion wise for 5 min at 0-5 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered, washed with EtOAc (2 x 10 mL) and the filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 50% EtOAc/ hexanes to afford compound 351 (20 mg, 22%) as brown solid. TLC: 70% EtOAc/ hexanes (R/. 0.6); 1H-NMR (DMSO-</6, 400 MHz): δ 8.92 (s, 1H), 7.65 (s, 1H), 6.98-6.96 (m, 1H), 3.15 (q, 2H), 2.95 (t, J= 6.8 Hz, 2H), 1.39 (s, 9H).
[000290] Synthesis of 2-(thiazol-5-yl) ethan-l-amine (352): To a stirred solution of compound 351 (20 mg, 0.08 mmol) in CH2CI2 (3 mL) under argon atmosphere was added trifluoro acetic acid (60 mg, 0.53 mmol) at 0-5 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude compound 352 (10 mg) as colorless liquid. The crude was carried to the next step without any further purification. TLC: 70% EtOAc/ hexanes (R/. 0.2); 1H-NMR (DMSO-</6, 400 MHz): δ 9.01 (s, 1H), 7.95-7.89 (m, 2H), 7.76 (s, 1H), 3.16-3.10 (m, 4H).
Synthesis of 2-(4-(pyrimidin-5-yl) phenyl) ethan-l-amine (359)
Figure imgf000142_0001
358 359
[000291] Synthesis of 5-(4-bromophenyl) pyrimidine (355): To a stirred solution of 5- bromopyrimidine 353 (1 g, 6.32 mmol) in DMF: H20 (4: 1, 25 mL) were added sodium carbonate (1 g, 9.43 mmol) and (4-bromophenyl) boronic acid 354 (1.26 g, 6.32 mmol), purged under argon atmosphere for 30 min. To this was added Pd(PPh3)4 (731 mg, 0.63 mmol) at RT; heated to 80 °C and stirred for 2.5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mass was filtered through celite; the filtrate was diluted with water (100 mL) and extracted with EtOAc (3 x 15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 15% EtOAc/ hexanes to afford compound 355 (1 g, 67%) as white solid. TLC: 30% EtOAc/ hexanes (Rf. 0.3); 1H-NMR (DMSO-< , 500 MHz): δ 9.20 (s, 1H), 9.15 (s, 2H), 7.93 (d, J= 8.5 Hz, 2H), 7.74 (d, J= 9.0 Hz, 2H).
[000292] Synthesis of (£)-3-(4-(pyrimidin-5-yl) phenyl) acrylamide (357): To a stirred solution of 5-(4-bromophenyl) pyrimidine 355 (1 g, 4.27 mmol) in DMF (10 mL) under inert atmosphere was added acrylamide 356 (364 mg, 5.12 mmol) at RT and purged under argon for 10 min. To this were added o-tolyl phosphine (142 mg, 0.47 mmol), Pd(OAc)2 (4.78 mg, 0.021 mmol), and diisopropyl ethyl amine (0.9 mL, 7.32 mmol) at RT; heated to 130 °C and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite washed with 50% MeOH/ CH2C12 (2 x 10 mL), the filtrate was concentrated under reduced pressure to afford the crude. The crude was washed with 50%> MeOH/ CH2C12 (2 x 15 mL), dried in vacuo to afford compound 357 (600 mg, 62%>) as white solid. TLC: 40% EtOAc/ hexanes (Rf. 0.2); 1H NMR (400MHz, DMSO-d6) δ 9.23-9.16 (m, 3H), 7.88 (d, J= 8.3 Hz, 2H), 7.72 (d, J= 8.3 Hz, 2H), 7.56 (br s, 1H), 7.48 (d, J= 15.9 Hz, 1H), 7.14 (br s, 1H), 6.70 (d, J= 15.9 Hz, 1H).
[000293] Synthesis of 3-(4-(pyrimidin-5-yl) phenyl) propanamide (358): To a stirred solution of compound 357(150 mg, 0.64 mmol) in EtOH (4 mL) under inert atmosphere were added 10% Pd/ C (50 mg) and triethylamine (0.092 mL, 0.64 mmol) at RT and stirred under H2 (balloon pressure) for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite. The filtrate was concentrated in vacuo to obtain the crude which was purified by silicagel column chromatography using 3%> MeOH/ CH2Cl2 to afford compound 358 (65 mg, 43%) as white solid. TLC: 30% EtOAc/ hexanes (Rf. 0.2); 1H- NMR (DMSO-</6, 400 MHz): δ 9.16 (s, 1H), 9.12 (s, 2H), 7.72 (d, J= 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.29 ( br s, 1H), 6.76 (br s, 1H), 2.87 (t, J= 8.0 Hz, 2H), 2.39 (t, J= 8.0 Hz, 2H).
[000294] Synthesis of 2-(4-(pyrimidin-5-yl) phenyl) ethan-l-amine (359): To a stirred solution of compound 358 (65 mg, 0.28 mmol) in THF: H20 (1 : 1, 3 mL) were added NaOH (128 mg, 0.91 mmol), phenyl- 3-iodanediyl diacetate (92 mg, 0.28 mmol) at 0 °C and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the pH of the reaction mixture was adjusted to ~ 2 using 3 N HCI and extracted with CH2CI2 (2 x 50 mL). The pH of the aqueous layer was basified to ~ 8 with 3 N NaOH, extracted with THF (2 x 100 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to afford crude compound 359 (40 mg) as white solid. TLC: 10% MeOH/ CH2C12 (Rf 0.3); 1H- NMR (DMSO-</6, 400 MHz): δ 9.16 (s, 1H), 9.11 (s, 2H), 7.72 (d, J= 8.4 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 2.81-2.66 (m, 2H), 1.78-1.69 (m, 2H).
Synthesis of 2-(2-phenylpyrimidin-5-yl) ethan-l-amine hydrochloride (366)
Figure imgf000144_0001
[000295] Synthesis of 5-bromo-2-iodopyrimidine (361): To a stirred solution of 5-bromo-2- chloropyrimidine 360 (1 g, 5.16 mmol) in CH2C12 (10 mL) was added hydrogen iodide (5 mL, 57%) aqueous solution) at -10 °C; warmed to 0 °C and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with solid K2C03 (2 g), diluted with water (100 mL) and extracted with CH2C12 (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain crude compound 361 (1.4 g, 94%) as yellow solid. TLC: 10% EtOAc/ hexanes (Rf 0.7); 1H-NMR (DMSO-< , 400 MHz): δ 8.55 (s, 2H).
[000296] Synthesis of 5-bromo-2-phenylpyrimidine (363): To a stirred solution of compound 361 (1.4 g) in DMF: H20 (4: 1, 20 mL) were added sodium carbonate (783 mg, 7.39 mmol) and phenylboronic acid 362 (451 mg, 3.69 mmol), purged under argon for 30 min. To this was added Pd(PPh3)4 (570 mg, 0.49 mmol) at RT; heated to 80 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mass was filtered through celite; the filtrate was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered, concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 2% EtOAc/ hexanes to afford compound 363 (400 mg, 35%) as white solid. TLC: 10% EtOAc/ hexanes (Rf. 0.9); 1H-NMR (DMSO-</6, 400 MHz): δ 8.83 (s, 2H), 8.41-8.39 (m, 2H), 7.50-7.48 (m, 3H).
[000297] Synthesis of (£)-3-(2-phenylpyrimidin-5-yl) acrylamide (364): To a stirred solution of compound 363 (300 mg, 1.28 mmol) in DMF (20 mL) under inert atmosphere was added acrylamide 356 (109 mg, 1.53 mmol) at RT and purged under argon for 10 min. To this were added o-tolyl phosphine (42 mg, 0.07 mmol), palladium acetate (15.7 mg, 0.07 mmol), and diisopropyl ethyl amine (0.28 mL, 1.53 mmol) at RT; heated to 140 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted water (100 mL) and extracted with 10% MeOH/ CH2C12 (2 x 50 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude compound was triturated with 50%> EtOAc/ hexanes (10 mL) and dried in vacuo to afford compound 364 (50 mg, 17%>) as an off-white solid. TLC: 70%> EtOAc/ hexanes (Rf. 0.2); 1H-NMR (DMSO-</6, 400 MHz): δ 9.10 (s, 2H), 8.43-8.41 (m, 2H), 7.64 (br s, 1H), 7.55-7.54 (m, 3H), 7.47 (d, J= 16.0 Hz, 1H), 7.22 (br s, 1H), 6.85 (d, J= 16.0 Ηζ,ΙΗ).
[000298] Synthesis of 3-(2-phenylpyrimidin-5-yl) propanamide (365): To a stirred solution of compound 364 (50 mg, 0.22 mmol) in EtOH (2 mL) under inert atmosphere were added triethyl amine (0.032 mL, 0.22 mmol), 10% Pd/ C (17 mg, dry) at RT and stirred under hydrogen atmosphere (balloon pressure) for 4 h. The reaction was monitored by LC-MS; after completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to obtain the crude which was triturated with 10% EtOAc/ n-pentane (2 x 5 mL) and dried in vacuo to afford compound 365 (30 mg, 60%>) as an off-white solid. TLC: 5%> MeOH/ CH2C12 (Rf. 0.5); 1H-NMR (DMSO-</6, 400 MHz): δ 8.76 (s, 2H), 8.37-8.35 (m, 2H), 7.52-7.50 (m, 3H), 7.31 (br s, 1H), 6.80 (br s, 1H), 2.85 (t, J= 7.2 Hz, 2H), 2.46 (t, J= 7.2 Hz, 2H).
[000299] Synthesis of tert-buty\ (2-(2-phenylpyrimidin-5-yl) ethyl) carbamate (366): To a stirred solution of compound 365 (15 mg, 0.06 mmol) in THF (2 mL) were added sodium hydroxide (8 mg, 0.2 mmol) in water (0.5 mL), phenyl-λ -iodanediyl diacetate (21 mg, 0.06 mmol) at 0 °C and stirred for 30 min. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (25 mL) and extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 366 (10 mg, 51%) as sticky solid. TLC: 50% EtOAc/ hexanes (Rf. 0.9); 1H-NMR (CDC13, 400 MHz): δ 8.65 (s, 2H), 8.42-8.40 (m, 2H), 7.49-7.47 (m, 3H), 4.62 (br s, 1H), 3.43-3.38 (m, 2H), 2.84 (t, J= 7.2 Hz, 2H), 1.43 (s, 9H).
[000300] Synthesis of 2-(2-phenylpyrimidin-5-yl) ethan-l-amine hydrochloride (367): To a stirred solution of compound 366 (80 mg, 0.35 mmol) in CH2CI2 (3 ML) was added 4N HC1 in 1, 4-Dioxane (0.7 mL) under argon atmosphere at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude and was washed with 20%> CH2CI2/ n-pentane (2 x 5 mL) and dried in vacuo to afford compound 367 (50 mg, HC1 salt) as white solid. TLC: 10% MeOH/ CH2C12 (Rf. 0.1); 1H-NMR (DMSO-< , 400 MHz): δ 8.84 (s, 2H), 8.40-8.37 (m, 2H), 8.07 (br s, 2H), 7.54- 7.52 (m, 3H), 3.19-3.14 (m, 2H), 2.97 (t, J= 7.2 Hz, 2H).
Synthesis of (4-(pyrimidin-5-yl) phenyl) methanamine (372)
OH
NaBH4 MsCI, Et3N
MeOH i N CH2CI2
368 369
Figure imgf000147_0001
370 371
Figure imgf000147_0002
372
[000301] Synthesis of (4-(pyrimidin-5-yl) phenyl) methanol (369): To a stirred solution of 4- (pyrimidin-5-yl) benzaldehyde 368 (500 mg, 2.71 mmol) in MeOH (20 mL) under argon atmosphere and sodium borohydride (155 mg, 39.99 mmol) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, volatiles were removed in vacuo. The residue was diluted with brine solution (100 mL), extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH/ CH2CI2 to afford compound 369 (260 mg, 51%) as white solid. TLC: 20% EtOAc/ hexanes (Rf. 0.4); 1H-NMR (CDCI3, 500 MHz): δ 9.20 (s, 1H), 8.93 (s, 2H), 7.58 (d, J= 8.5 Hz, 2H), 7.53 (d, J= 8.0 Hz, 2H), 4.79 (s, 2H).
[000302] Synthesis of 4-(pyrimidin-5-yl) benzyl methanesulfonate (370): To a stirred solution of compound 369 (260 mg, 1.39 mmol) in CH2CI2 (10 mL) under argon atmosphere were added triethyl amine (0.3 mL, 2.09 mmol), methane sulfonyl chloride (0.16 mL, 2.09 mmol) at 0 °C; warmed to RT and stirred for 14 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL), washed with 10%) NaHC03 solution (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain crude compound 370 (300 mg) as thick syrup. The crude was carried to the next step without further purification. TLC: 5% MeOH/ CH2C12 (Rf. 0.4). [000303] Synthesis of 5-(4-(azidomethyl) phenyl) pyrimidine (371): To a stirred solution of compound 370 (300 mg, crude) in DMF (6 mL) under argon atmosphere was added sodium azide (74 mg, 1.13 mmol) at RT; heated to 60 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice water (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 371 (45 mg) as colorless thick syrup. TLC: 30% EtOAc/ hexanes (Rf. 0.6); 1H-NMR (CDC13, 400 MHz): δ 9.22 (s, 1H), 8.96 (s, 2H), 7.61 (d, J= 8.4 Hz, 2H), 7.48 (d, J= 8.0 Hz, 2H), 4.43 (s, 2H).
[000304] Synthesis of (4-(pyrimidin-5-yl) phenyl) methanamine (372): To a stirred solution of compound 371 (40 mg, 0.18 mmol) in THF: H20 (9: 1, 2 mL) was added triphenyl phosphine (74 mg, 0.28 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10%> MeOH/ CH2C12 to afford compound 372 (23 mg, 66%) as an off-white solid. TLC: 10% MeOH/ CH2C12 (Rf. 0.2); 1H- NMR (DMSO-< , 400 MHz): δ 9.21 (s, 1H), 9.17 (s, 2H), 8.27 (br s, 2H), 7.87 (d, J= 8.0 Hz, 2H), 7.64 (d, J= 8.4 Hz, 2H), 4.07 (s, 2H).
Synthesis of (2-phenylpyrimidin-5-yl) methanamine (377)
Figure imgf000148_0001
376 377
[000305] Synthesis of (2-phenylpyrimidin-5-yl) methanol (374): To a stirred solution of 2- phenylpyrimidine-5-carbaldehyde 373 (200 mg, 1.08 mmol) in MeOH (20 mL) under argon atmosphere was added sodium borohydride (74 mg, 2.17 mmol) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (50 mL), extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH/ CH2C12 to afford compound 374 (135 mg, 65%) as colorless solid. TLC: 40% EtOAc/ MeOH (Rf. 0.3); 1H-NMR (DMSO-< , 500 MHz): δ 8.83 (s, 2H), 8.40-8.38 (m, 2H), 7.53-7.51 (m, 3H), 5.45 (t, J= 5.5 Hz, 1H), 4.58 (d, J= 5.5 Hz, 2H).
[000306] Synthesis of (2-phenylpyrimidin-5-yl) methyl methanesulfonate (375): To a stirred solution of compound 374 (130 mg, 0.69 mmol) in CH2C12 (5 mL) under argon atmosphere were added triethyl amine (0.4 mL, 2.09 mmol) and methane sulfonyl chloride (0.07 mL, 0.84 mmol) at 0 °C; warmed to RT and stirred for 30 min. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted CH2C12 (50 mL), washed with water (2 x 20 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain crude compound 375 (150 mg) as yellow oil. The crude was carried to the next step without further purification. TLC: 50% EtOAc/ hexanes (Rf. 0.5); 1H- NMR (DMSO-< , 500 MHz): 9.00 (t, J= 10.0 Hz, 2H), 8.42-8.41 (m, 2H), 7.56-7.55 (m, 3H), 5.40 (s, 2H), 3.32 (s, 3H).
[000307] Synthesis of 5-(azidomethyl)-2-phenylpyrimidine (376): To a stirred solution of compound 375 (150 mg) in DMF (6 mL) under argon atmosphere was added sodium azide (56 mg, 0.76 mmol) at RT; heated to 60 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice water (20 mL) and extracted with diethyl ether (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain crude. The crude was purified through silica gel column chromatography using 20%> EtOAc/ hexanes to afford compound 376 (60 mg, 49%>) as colorless syrup. TLC: 40% EtOAc/ hexanes (Rf. 0.9); 1H NMR (DMSO-^, 400 MHz): δ 8.94 (s, 2H), 8.41 (dd, J= 6.8, 3.0 Hz, 2H), 7.56-7.53 (m, 3H), 4.63 (s, 2H).
[000308] Synthesis of (2-phenylpyrimidin-5-yl) methanamine (377): To a stirred solution of compound 376 (90 mg, 0.42 mmol) in THF: H20 (9: 1, 4 mL) was added triphenyl phosphine (167 mg, 0.63 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% MeOH/ CH2CI2 to afford compound 377 (30 mg, 38%) as yellow solid. TLC: 10% MeOH/ CH2C12 (Rf. 0.2); 1H NMR (DMSO 500 MHz): δ 8.96 (s, 2H), 8.40 (d, J= 3.9 Hz, 2H), 7.59-7.45 (m, 3H), 6.84 (br s, 2H), 4.01 (s, 2H).
Synthesis of thiazol-5-amine hydrochloride (380)
Figure imgf000150_0001
378 379 380
[000309] Synthesis of terf-butyl thiazol-5-ylcarbamate (379): To a stirred solution of thiazole-5-carboxylic acid 378 (400 mg, 3.1 mmol) in t-butanol (6 mL) were added
diphenylphosphonic azide (1.34 mL, 6.18 mmol) and triethyl amine (0.89 mL, 6.18 mmol) at RT and heated to 100 °C for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 30% EtOAc/ hexanes to afford compound 379 (300 mg, 48%) as white solid. TLC: 50% EtOAc/ hexanes (Rf. 0.8); 1H-NMR (DMSO-</6, 400 MHz): δ 10.60 (br s, 1H), 8.51 (s, 1H), 8.40 (s, 1H), 1.49 (s, 9H).
[000310] Synthesis of thiazol-5-amine hydrochloride (380): To a stirred solution of compound 379 (300 mg, 1.5 mmol) in MeOH (5 mL) was added 4 N HCI in 1, 4-Dioxane (5 mL) under argon atmosphere at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was washed with n-pentane (2 x 5 mL) and dried in vacuo to afford compound 380 (150 mg, HCI salt) as pale yellow solid. TLC: 50% EtOAc/ hexanes (Rf: 0.1); 1H-NMR (DMSO-</6, 500 MHz): δ 9.10 (s, 1H), 7.22 (s, 1H).
Synthesis of 3-(pyrimidin-5-yl) aniline (383)
Figure imgf000151_0001
353 381 382
Figure imgf000151_0002
383
[000311] Synthesis of 5-(3-nitrophenyl) pyrimidine (382): To a stirred solution of 5- bromopyrimidine 353 (2 g, 12.58 mmol) and (3-nitrophenyl) boronic acid 381 (2.3 g, 13.84 mmol) in 1, 2-dimethoxy ethane: H20 (4: 1, 20 mL) under inert atmosphere were added sodium carbonate (2.66 g, 25.17 mmol) at RT and purged under argon atmosphere for 20 min. To this was added Pd(PPh3)4 (726 mg, 0.62 mmol) and heated to 110 °C for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The obtained solid was filtered, dried in vacuo to obtain the crude which was purified through silicagel column chromatography in 50% EtOAc/ hexanes to afford compound 382 (2.5 g, 68%) as an off-white solid. TLC: 60% EtOAc/ hexanes (Rf: 0.3); 1H NMR (DMSO-</6, 400 MHz): δ 9.27 (s, 3H), 8.66-8.63 (m, 1H), 8.37-8.25 (m, 2H), 7.84 (t, J= 8.0 Hz, 1H).
[000312] Synthesis of 3-(pyrimidin-5-yl) aniline (383): To a stirred solution of compound
382 (1.7 g, 8.45 mmol) in EtOH (30 mL) under inert atmosphere was added 10% Pd/C (500 mg) under argon atmosphere and stirred under H2 atmosphere (balloon pressure) for 5 h. After completion of the reaction, the reaction mixture was filtered through celite, washed with 5% MeOH/ CH2C12 (50 mL). The filtrate was concentrated in vacuo to obtain the crude which was triturated with mixture of ether: pentane (1 : 1, 10 ML) and dried in vacuo to afford compound
383 (1.2 g, 86%) as an off-white solid. TLC: 70% % EtOAc/ hexanes (R/. 0.2); 1H NMR (DMSO-< , 400 MHz): δ 9.15 (s, 1H), 9.00 (s, 2H), 7.17 (t, J= 7.8 Hz, 1H), 6.91 - 6.86 (m, 2H), 6.69-6.64 (m, 1H), 5.27 (s, 3H). Synthesis of 3-(pyrimidin-4-yl) aniline (386)
Figure imgf000152_0001
[000313] Synthesis of 2, 4-dichloro-6-(3-nitrophenyl) pyrimidine (385): To a stirred solution of 2, 4, 6-trichloropyrimidine 384 (500 mg, 2.76 mmol) and (3-nitrophenyl) boronic acid 382 (594 mg, 2.76 mmol) in 1, 2-dimethoxy ethane (10 mL) under inert atmosphere were added sodium carbonate (878 mg, 8.28 mmol) at RT and purged under argon atmosphere for 20 min. To this was added Pd(PPh3)4 (159 mg, 0.13 mmol) and heated to 80 °C for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% EtOAc/ hexanes to afford crude compound 385 (200 mg) as yellow solid which was carried forward for next step. TLC: 10%> EtOAc/ hexanes (R/. 0.7).
[000314] Synthesis of 3-(pyrimidin-4-yl) aniline (386): To a stirred solution of compound 385 (200 mg, crude) in EtOAc (50 mL) under inert atmosphere were added sodium acetate (304 mg, 3.71 mmol), 10%> Pd/C (100 mg, wet) under argon atmosphere and stirred under ¾ atmosphere (balloon pressure) for 6 h. After completion of the reaction, the reaction mixture was filtered through celite, washed with 50% MeOH/ CH2CI2 (50 mL). The filtrate was concentrated in vacuo to obtain the crude which was purified through silicagel column chromatography in 90% EtOAc/ hexanes to afford compound 386 (100 mg, 78%) as an off-white solid. TLC: 70% % EtOAc/ hexanes (R/. 0.4); 1H NMR (400 MHz, DMSO-< ): δ 9.19 (s, 1H), 8.80 (d, J= 5.4 Hz, 1H), 7.91 (dd, J= 5.4, 1.4 Hz, 1H), 7.45-7.43 (m, 1H), 7.30 (d, J= 7.7 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 6.74 (d, J= 7.5 Hz, 1H), 5.31 (s, 2H). Synthesis of 3-(thiazol-5-yl) aniline (389)
Figure imgf000153_0001
387 388 389
[000315] To a stirred solution of 5-bromothiazole 387 (350 mg, 2.13 mmol) in 2-methyl THF (5 mL) under inert atmosphere were added 3-aminophenylboronic acid pinacol ester 388 (600 mg, 2.35 mmol), sodium carbonate (565 mg, 5.33 mmol), at RT and stirred under argon atmosphere for 20 min. To this was added Pd(dppf)2Cl2 (78 mg, 0.106 mmol) and heated to 110 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 80% EtOAc/ hexanes to afford compound 389 (200 mg, 52%) as yellow syrup. TLC: 70% EtOAc/ hexanes (Rf. 0.4); LC-MS: 84.49%; 176.8 (M++l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 μπι); RT 1.40 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).
Synthesis of 3'-amino-[l, l'-biphenyl]-4-ol (392)
Figure imgf000153_0002
[000316] To a stirred solution of 3-bromoaniline 390 (400 mg, 2.32 mmol) and (4- hydroxyphenyl) boronic acid 391 (353 mg, 2.55 mmol) in MeOH (4 mL) under inert atmosphere were added sodium carbonate (493 mg, 4.65 mmol) at RT and purged under argon atmosphere for 20 min. To this was added Pd(OAc)2 (156 mg, 0.23 mmol) and heated to 80 °C for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, washed with MeOH (20 mL). The filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography in 20% EtOAc/ hexanes to afford compound 392 (160 mg) as brick red solid. TLC: 30%> EtOAc/ hexanes (Rf. 0.4); LC-MS: 67.89%; 185.9 (M++l); (column; Ascentis Express C18, (50 3.0 mm, 2.7 μπι); RT 2.10 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min).
Synthesis of 5-phenyloxazol-2-amine (396)
Figure imgf000154_0001
393 394 396
[000317] Synthesis of 2-bromo-2-phenylacetaldehyde (394): To a stirred solution of 2- phenylacetaldehyde 393 (500 mg, 4.16 mmol) in 1, 4-Dioxane (2 mL) under inert atmosphere was added bromine (0.27 mL, 4.99 mmol) at 0 °C and stirred for 20 min; warmed to RT and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to afford crude compound 394 (800 mg) as green syrup. The crude was carried forward for next step without further purification. TLC: 10% EtOAc/ hexanes (Rf 0.7);
[000318] Synthesis of 5-phenyloxazol-2-amine (396): To a stirred solution of compound 394 (800 mg, crude) in EtOH (10 mL) under inert atmosphere was added urea 395 (482 mg, 8.04 mmol) at RT; heated at 80 °C and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo and the residue was diluted with water (60 mL). The pH was neutralized with 10% aqueous NaHCOs solution (10 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through flash column chromatography using 2-3%> MeOH/ CH2CI2 to afford compound 396 (200 mg, 32%) as an off-white solid. TLC: 5% MeOH/ CH2C12 (Rf. 0.5); 1H NMR (400 MHz, DMSO- d6): δ 7.45 (d, J= 7.2 Hz, 2H), 7.36 (t, J= 7.8 Hz, 2H), 7.21-7.16 (m, 2H), 6.81 (s, 2H);
Synthesis of 5-phenylthiazol-2-amine (397)
Figure imgf000155_0001
[000319] Synthesis of 5-phenylthiazol-2-amine (397): To a stirred solution of 2-bromo-2- phenylacetaldehyde 394 (860 mg, crude) in EtOH (20 mL) under inert atmosphere was added thiourea (658 mg, 8.64 mmol) at RT; heated at 80 °C and stirred for 8 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The pH of the residue was neutralized with 10% aqueous NaHC03 solution (10 mL) and extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through flash column chromatography using 2-3% MeOH/ CH2CI2 to afford compound 397 (500 mg, 66%) as an off-white solid. TLC: 5% MeOH/ CH2C12 (Rf. 0.6); 1H NMR (400 MHz, DMSO-< ): δ 7.43-7.38 (m, 3H), 7.32 (t, J= 7.8 Hz, 2H), 7.17 (tt, J= 7.5, 0.9 Hz, 1H), 7.12 (s, 2H).
Synthesis of l-methoxy-3-(pyrimidin-5-yl) propan-2-amine hydrochloride (401)
O
■> NHBoc
Figure imgf000155_0002
398 399
4N HCI in 1 ,4-Dioxane
NH2.HCI
■ NHBoc CH2CI2
400
401
[000320] Synthesis of terf-butyl (l-hydroxy-3-(pyrimidin-5-yl) propan-2-yl) carbamate (399): To a stirred solution of methyl 2-((tert-butoxycarbonyl) amino)-3-(pyrimidin-5-yl) propanoate 398 (200 mg, 0.71 mmol) in MeOH (5 mL) under inert atmosphere was added sodium borohydride (105 mg, 2.84 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with 10% MeOH/ CH2CI2 (5 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 8% MeOH/ CH2C12 to afford compound 399 (110 mg, 61%) as an off-white solid. TLC: 10% MeOH/ CH2CI2 (Rf. 0.4); 1H NMR (DMSO-< , 400 MHz): δ 8.99 (s, 1H), 8.61 (s, 2H), 6.70 (d, J= 9.0 Hz, 1H), 4.82 (t, J= 5.4 Hz, 1H), 3.61 (br s, 2H), 3.45-3.34 (m, 2H), 2.93-2.82 (m, 1H), 1.26 (s, 9H)
[000321] Synthesis of terf-butyl (l-methoxy-3-(pyrimidin-5-yl) propan-2-yl) carbamate (400): To a stirred solution of compound 399 (100 mg, 0.39 mmol) in THF (10 mL) were added triethyl benzyl ammonium chloride (9 mg, 0.03 mmol), 50%> aqueous sodium hydroxide solution (3.5 mL) and methyl iodide (0.02 mL, 0.39 mmol) at 0 °C; warmed to RT and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 3% MeOH/ CH2CI2 to afford compound 400 (70 mg, 67%) as colorless syrup. TLC: 5% MeOH/ CH2C12 (Rf. 0.5); 1H NMR (DMSO-< , 400 MHz): δ 9.00 (s, 1H), 8.62 (s, 2H), 6.84 (d, J= 8.8 Hz, 1H), 3.78 (brs, 2H), 3.29-3.23 (m, 5H), 2.85 (dd, J= 13.8, 4.1 Hz, 1H), 1.28-1.21 (m, 9H).
[000322] Synthesis of l-methoxy-3-(pyrimidin-5-yl) propan-2-amine hydrochloride (401):
To a stirred solution of compound 400 (60 mg, 0.22 mmol) in CH2CI2 (3 mL) was added 4 N HC1 in 1, 4-Dioxane (1 mL) under argon atmosphere at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was washed with n-pentane (2 x 5 mL) and dried in vacuo to afford compound 401 (40 mg, HC1 salt) as brown solid. TLC: 5% MeOH/ CH2C12 (Rf. 0.1); 1H NMR (DMSO-< , 400 MHz): δ 9.11 (s, 1H), 8.75 (s, 2H), 8.24 (br s, 2H), 3.68-3.59 (m, 1H), 3.53-3.48 (m, 1H), 3.39 (dd, J= 10.5, 5.7 Hz, 1H), 3.30 (s, 3H), 2.95 (t, J= 7.3 Hz, 2H).
Synthesis of 4-(2-aminoethyl)- V, V-dimethylbenzenesulfonamide hydrochloride (406)
Figure imgf000157_0001
[000323] Synthesis of 4-(2-bromoethyl) benzenesulfonyl chloride (403): To a stirred solution of (2-bromoethyl) benzene 402 (5 g, 27.02 mmol) in CH2CI2 (15 mL) under argon atmosphere was added chlorosulfonic acid (5.4 mL, 81.08 mmol) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion the reaction, the reaction mixture was poured into ice-cold water (100 mL) extracted with CH2CI2 (2 x 150 mL). The combined organic extracts were washed with brine (100 mL), separated dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 403 (5 g) as colorless thick syrup. TLC: 10% EtOAc/ hexanes (Rf. 0.6); 1H-NMR (DMSO-^, 400 MHz): δ 8.00 (d, J = 8.4 Hz, 2H), 7.47 (d, J= 8.8 Hz, 2H), 3.62 (t, J= 7.2 Hz, 2H), 3.30 (t, J= 7.2 Hz, 2H).
[000324] Synthesis of 4-(2-bromoethyl)- V, V-dimethylbenzenesulfonamide (404): To a stirred solution of compound 403 (5 g, crude) in THF (100 mL) under argon atmosphere were added pyridine (14.37 mL, 176.05 mmol), dimethylamine hydrochloride 309 (7.1 g, 88.02 mmol) at 0 °C; warmed to RT and stirred for 1 h. The reaction was monitored by TLC; after completion the reaction, the volatiles were removed in vacuo. The residue was diluted with CH2CI2 (500 mL) and washed with 1 N HC1 (15 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to obtain crude. The crude was titurated with pentane (30 mL) and dried in vacuo to afford compound 404 (3.5 g, 68%) as an off-white solid. TLC: 20%> EtOAc/ hexane (Rf. 0.5); 1H NMR (CDC13, 400 MHz): δ 7.74 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H), 3.60 (t, J= 7.2 Hz, 2H), 3.25 (t, J= 7.3 Hz, 2H), 2.72 (s, 6H).
[000325] Synthesis of 4-(2-azidoethyl)- V, V-dimethylbenzenesulfonamide (405): To a stirred solution of compound 404 (500 mg, 1.71 mmol) in DMF (10 mL) under inert atmosphere was added sodium azide (335 mg, 5.15 mmol) at RT and heated to 80 °C for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (20 mL) and extracted with CH2CI2 (2 x 200 mL). The combined organic extracts were dried under sodium sulfate, filtered and concentrated in vacuo to afford compound 405 (350 mg, 80%) as thick syrup. TLC: 20% EtOAc/ hexane (Rf. 0.6); 1H-NMR (DMSO-^, 400 MHz): δ 7.73 (d, J= 8.4 Hz, 2H), 7.40 (d, J= 6.8 Hz, 2H), 3.56 (t, J= 6.8 Hz, 2H), 2.97 (t, J = 6.8 Hz, 2H), 2.71 (s, 6H).
[000326] Synthesis of 4-(2-aminoethyl)- V, V-dimethylbenzenesulfonamide hydrochloride (406): To a stirred solution of compound 405 (350 mg, 1.37 mmol) in a mixture of THF: H20 (4: 1, 10 mL) was added triphenyl phosphine (1.08 g, 4.13 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 3-5%o MeOH/ CH2Cl2 to afford free amine (200 mg) as thick syrup.
[000327] To a stirred solution of the free amine (200 mg) in CH2C12 (2 mL) under argon atmosphere was added 4 N HC1 in 1, 4-dioxane (0.5 mL) at 0 °C and stirred for 10 min. The volatiles were removed in vacuo to obtain the crude which was washed with diethyl ether (2 x 5 mL) and dried in vacuo to afford compound 406 (125 mg, 35%>) as white solid. TLC: 10%> MeOH/ CH2C12 (R/. 0.2); 1H-NMR (DMSO-^, 400 MHz): δ 8.04 (br s, 2H), 7.70 (d, J= 8.4 Hz, 2H), 7.54 (d, J= 8.4 Hz, 2H), 3.15-3.05 (m, 2H), 3.01-2.98 (m, 2H), 2.60 (s, 6H).
Synthesis of 4-(3-aminopropyl)- V, V-dimethylbenzenesulfonamide hydrochloride (410)
H.HCI
CISO3H
CHCI3 CI02S^ pyridine, THF
402 407 408
Figure imgf000159_0001
409 410
[000328] Synthesis of 4-(3-bromopropyl) benzenesulfonyl chloride (407): To a stirred solution of (2-bromoethyl) benzene 402 (5 g, 27.02 mmol) in CHCI3 (15 mL) under argon atmosphere was added chlorosulfonic acid (5.4 mL, 81.08 mmol) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion the reaction, the reaction mixture was poured into ice-cold water (100 mL) extracted with CH2CI2 (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 407 (5 g) as colorless thick syrup. TLC: 10% EtOAc/ hexanes (Rf. 0.4); 1H NMR (CDCI3, 400 MHz): δ 7.97 (d, J= 8.8 Hz, 2H), 7.45 (d, J= 8.8 Hz, 2H), 3.40 (t, J = 6.4 Hz, 2H), 2.93 (t, J= 7.2 Hz, 2H), 2.24-2.17 (m, 2H).
[000329] Synthesis of 4-(3-chloropropyl)- V, 7V-dimethylbenzenesulfonamide (408): To a stirred solution of compound 407 (5 g, crude) in THF (100 mL) under argon atmosphere were added pyridine (14.42 mL, 176.6 mmol), dimethylamine hydrochloride 309 (7.2 g, 88.33 mmol) at 0 °C; warmed to RT and stirred for 1 h. The reaction was monitored by TLC; after completion the reaction, the volatiles were removed the in vacuo. The residue was diluted with water (100 mL) and extracted with CH2CI2 (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 408 (3 g) as white sticky solid. TLC: 20% EtOAc/ hexanes (Rf. 0.5); 1H NMR (CDC13, 400 MHz): δ 7.71 (d, J= 8.4 Hz, 2H), 7.37 (d, J= 8.0 Hz, 2H), 3.53 (t, J= 6.4 Hz, 1H), 3.40 (t, J= 6.4 Hz, 1H), 2.87 (t, J= 7.2 Hz, 2H), 2.71 (s, 6H), 2.23-2.08 (m, 2H).
[000330] Synthesis of 4-(3-azidopropyl)-7V, N-dimethylbenzenesulfonamide (409): To a stirred solution of compound 408 (3 g, 9.83 mmol) in DMF (50 mL) under inert atmosphere was added sodium azide (1.91 g, 29.50 mmol) at RT and heated to 70-80 °C for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice- cold water (20 mL) and extracted with EtOAc (2 x 150 mL). The combined organic extracts were dried under sodium sulfate, filtered and concentrated in vacuo to afford compound 409 (2 g, 76%) as colorless thick syrup. TLC: 20% EtOAc/ hexane (Rf. 0.6); 1H NMR (CDC13, 500 MHz): δ 7.71 (d, J= 8.1 Hz, 2H), 7.36 (d, J= 8.1 Hz, 2H), 3.32 (t, J= 6.7 Hz, 2H), 2.82-2.77 (m, 2H), 2.71 (s, 6H), 1.98-1.91 (m, 2H).
[000331] Synthesis of 4-(3-aminopropyl)- V, V-dimethylbenzenesulfonamide
hydrochloride (410): To a stirred solution of compound 409 (2.35 g, 8.76 mmol) in a mixture of THF: H20 (4: 1 , 100 mL) was added triphenyl phosphine (6.89 g, 26.30 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 15% MeOH/ CH2Cl2 to afford free amine (2 g) as thick syrup.
[000332] To a stirred solution of the above compound (2 g) in CH2C12 (20 mL) under argon atmosphere was added 4 N HC1 in 1 , 4-dioxane (10 mL) at 0 °C and stirred for 10 min. The solvent was decanted and the obtained solid was dried in vacuo to afford compound 410 (1.5 g,
70%) as white solid. TLC: 10% MeOH/ CH2C12 (Rf. 0.2); 1H-NMR (DMSO-</6, 400 MHz): δ 8.08 (br s, 3H), 7.68 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 2.81-2.75 (m, 4H), 2.59 (s, 6H), 1.94-1.86 (m, 2H).
[000333] Synthesis of 3'-methoxy-[l, l'-biphenyl]-3-amine (412)
Figure imgf000160_0001
390 411 412
[000334] To a stirred solution of 3-bromoaniline 390 (1 g, 5.81 mmol) and (3-methoxyphenyl) boronic acid 411 (883 mg, 5.81 mmol) in Toluene: MeOH (1 : 1 , 20 mL) under inert atmosphere were added sodium carbonate (2.15 g, 20.34 mmol in 10 mL of H20) at RT and purged under argon atmosphere for 20 min. To this was added Pd(PPh3)4 (335 mg, 0.28 mmol) and heated to 100 °C for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, washed with 50% MeOH/ CH2CI2 (150 mL). The filtrate was evaporated in vacuo to obtain the crude which was purified through silica gel column chromatography in 70% EtOAc/ hexanes to afford compound 412 (500 mg, 54%) as yellow thick syrup. TLC: 70% EtOAc/ hexanes (Rf. 0.5); 1H NMR (400 MHz, CDC13): δ 7.35-7.30 (m, 1H), 7.25-7.19 (m, 1H), 7.17-7.13 (m, 1H), 7.10-7.08 (m, 1H), 7.00-6.96 (m, 1H), 6.92-6.85 (m, 2H), 6.68-6.65 (m, 1H), 3.85 (s, 3H), 3.72 (br s, 2H);
Synthesis of 3'-amino-[l, l'-biphenyl]-3-ol (413)
Figure imgf000161_0001
[000335] A mixture of compound 412 (400 mg, 2.01 mmol) in hydrogen iodide (5 mL, 57%> aqueous solution) was refluxed for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice-cold water and the pH was neutralized with 10% sodium bicarbonate solution (5 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The obtained solid was filtered, dried in vacuo to obtain the crude which was purified through silicagel column chromatography in 80% EtOAc/ hexanes to afford compound 413 (200 mg, 54%) as an off-white solid. TLC: 50% EtOAc/ hexanes (Rf. 0.4); 1H NMR (400 MHz, DMSO-< ): δ 9.41 (s, 1H), 7.20 (t, J = 7.8 Hz, 1H), 7.06 (t, J = 7.8 Hz, 1H), 6.99-6.88 (m, 2H), 6.78-6.76 (m, 1H), 6.73-6.68 (m, 2H), 6.55-6.52 (m, 1H), 5.12 (s, 2H).
Synthesis of 2-(tetrahydrofuran-2-yl) ethan-l-amine hydrochloride (415) i) LAH, ether, RT, 16 h CIH Η,Ν^
J ii) 4 N HCI in 1 , 4-Dioxane \ 7
414 415
[000336] To a stirred solution of 2-(tetrahydrofuran-2-yl) acetonitrile 414 (2 g, 17.99 mmol) in ether (20 mL) under argon atmosphere was added lithium aluminium hydride (1.36 g, 35.83 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated sodium potassium tartrate solution (30 mL) at 0-5 °C and extracted with ether (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude.
[000337] The crude was dissolved in CH2C12 (5 mL) cooled to 0 °C and added 4 N HC1 in 1 , 4- dioxane (10 mL) under argon atmosphere and stirred at the same temperature for 30 min. The volatiles were removed in vacuo. The obtained solid was titurated with CH2C12 (2 x 5 mL) and in vacuo to afford compound 415 (500 mg, HC1 salt) as sticky solid. TLC: 10% MeOH/ CH2C12 (Rf. 0.2).
Synthesis of 2-(4-(2H-l, 2, 3-triazol-2-yl) phenyl) ethan-l-amine hydrochloride (421)
Figure imgf000162_0001
418 420 421
[000338] Synthesis of 4-(2H-l, 2, 3-triazol-2-yl) benzaldehyde & 4-(lH-l, 2, 3-triazol-l-yl) benzaldehyde (418 & 419): To a stirred solution of 4-fluorobenzaldehyde 417 (2 g, 16 mmol) in DMF (50 mL) under argon atmosphere were added lH-1, 2, 3-triazole 417 (1.32 g, 19.2 mmol), potassium carbonate (3.3 g, 24 mmol) at RT; heated to 100 °C and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (35 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 418 (800 mg, 29%>) and using 40%> EtOAc/ hexanes to afford compound 419 (1 g, 36%>) as yellow solids. [000339] Compound 418 analytical data: TLC: 20% EtOAc/ hexanes (R/. 0.8); 1H-NMR (DMSO-</6, 400 MHz): δ 10.05 (s, 1H), 8.27 (s, 2H), 8.25 (d, J= 8.8 Hz, 2H), 8.11 (d, J= 8.8 Hz, 2H).
[000340] Compound 419 analytical data: TLC: 20% EtOAc/ hexanes (R/. 0.3); 1H-NMR (DMSO-</6, 400 MHz): δ 10.07 (s, 1H), 8.98 (s, 1H), 8.19 (d, J= 8.8 Hz, 2H), 8.13 (d, J= 8.8 Hz, 2H), 8.04 (s, 1H).
[000341] Synthesis of (£)-2-(4-(2-nitrovinyl) phenyl)-2H-l, 2, 3-triazole (420): To a stirred solution of compound 418 (400 mg, 2.31 mmol) in AcOH (10 mL) under argon atmosphere were added nitromethane (1.41 mL, 23.12 mmol), ammonium acetate (267 mg, 3.46 mmol) at RT; heated to 100 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo and diluted with water (20 mL). The obtained solid was filtered, washed with n-hexane and dried in vacuo to afford compound 420 (400 mg, 80%) as yellow solid. TLC: 20% EtOAc/ hexanes (R/. 0.3); 1H-NMR (DMSO-</6, 400 MHz): δ 8.29-8.18 (m, 4H), 8.13-8.05 (m, 4H).
[000342] Synthesis of 2-(4-(2H-l, 2, 3-triazol-2-yl) phenyl) ethan-l-amine hydrochloride (421): To a stirred solution of compound 420 (200 mg, 0.92 mmol) in MeOH (10 mL) under argon atmosphere were added 10%> Pd/C (100 mg), HCl (0.2 mL) at RT and stirred under hydrogen atmosphere (balloon pressure) for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to obtain the crude. The crude was triturated with 2 M HCl in Et20 (2 x 5 mL) and dried in vacuo to afford compound 421 (100 mg, 48%>) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf: 0.2); 1H-NMR (DMSO-</6, 400 MHz): δ 8.16 (s, 2H), 8.12 (br s, 2H), 7.98 (d, J= 8.4 Hz, 2H), 7.46 (d, J= 8.4 Hz, 2H), 3.10-3.05 (m, 2H), 2.96 (t, J= 8.4 Hz, 2H).
Synthesis of benzyl (4-(4-(2-aminoethyl) phenoxy) butyl) carbamate hydrochloride (427) (Boc)20, 1 M aq.NaOH 425, TPP, DIAD
-OH -OH
H2N — 1 , 4-Dioxane BocHN^ W— // ' THF
422 423 4 N HCl in 1 , 4-Dioxane
Figure imgf000164_0001
426
427
[000343] Synthesis of tert-buty\ (4-hydroxyphenethyl) carbamate (423): To a stirred solution of 4-(2-aminoethyl) phenol 422 (1 g, 7.29 mmol) in 1, 4-dioxane: H20 (1 : 1, 30 mL) were added 2 M aqueous sodium hydroxide solution (2 mL) and Boc-anhydride (1.9 mL, 8.25 mmol) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the pH of the reaction mixture cooled to 0 °C, acidified with 1 M HCl to ~3 and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to afford compound 423 (1.5 g, 87%) as an off-white solid. TLC: 50% EtOAc/ hexanes (Rf. 0.8); 1H NMR (DMSO-</6, 500 MHz): δ 9.15 (s, 1H), 6.95 (d, J= 8.4 Hz, 2H), 6.83 (t, J= 5.4 Hz, 1H), 6.64 (d, J= 8.1 Hz, 2H), 3.09-3.00 (m, 2H), 2.56-2.51 (m, 2H), 1.35 (s, 9H).
[000344] Synthesis of benzyl (4-hydroxybutyl) carbamate (425): To a stirred solution of 4- aminobutan-l-ol 424 (1.0 g, 11.23 mmol) in CH2C12 (15 mL) under argon atmosphere were added triethyl amine (1.78 mL, 12.35 mmol) and benzyl chloroformate (1.76 mL, 12.35 mmol, 50% solution in toluene) at 0 °C; warmed to RT and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with saturated ammonium chloride (50 mL) at 0 °C. The organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford compound 425 (2.1 g, 84%>) as colorless liquid. TLC: 50% EtOAc/ hexanes (Rf. 0.5); 1H NMR (DMSO-< , 500 MHz): δ 7.40- 7.22 (m, 6H), 4.98 (s, 2H), 4.37 (t, J= 5.1 Hz, 1H), 3.36 (q, J= 5.8 Hz, 2H), 2.97 (q, J= 6.3 Hz, 2H), 1.51-1.28 (m, 4H).
[000345] Synthesis of tert-buty\ (4-(4-(((benzyloxy) carbonyl) amino) butoxy) phenethyl) carbamate (426): To a stirred solution of compound 423 (1.5 g, 6.32 mmol) and compound 425 (1.4 g, 6.32 mmol) in THF (50 mL) under argon atmosphere at 0 °C were added triphenyl phosphine (1.65 g, 6.32 mmol), diisopropyl azodicarboxylate (1.4 mL, 6.96 mmol) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was dissolved in 10% EtOAc/ hexanes (5 mL) and the precipitated solid was filtered, washed with hexane (20 mL), dried in vacuo to afford compound 426 (1.9 g, 68%) as an off-white solid. TLC: 5% MeOH/ CH2C12 (Rf. 0.7); 1H NMR (DMSO-</6, 500 MHz): δ 8.89 (s, 1H), 7.68-7.51 (m, 5H), 7.40-7.24 (m, 2H), 7.07 (d, J= 8.4 Hz, 1H), 6.88-6.78 (m, 2H), 5.00 (s, 2H), 4.80-4.73 (m, 2H), 3.91 (t, J = 6.4 Hz, 2H), 3.11-3.02 (m, 2H), 2.60 (t, J= 7.5 Hz, 2H), 1.72-1.64 (m, 2H), 1.56- 1.52 (m, 2H), 1.18 (d, J = 6.1 Hz, 9H).
[000346] Synthesis of benzyl (4-(4-(2-aminoethyl) phenoxy) butyl) carbamate
hydrochloride (427): To a stirred solution of compound 426 (500 mg, 1.13 mmol) in CH2C12 (5 mL) was added 4 N HC1 in 1, 4-dioxane (3 mL) under argon atmosphere at 0-5 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed under reduced pressure. The obtained solid was washed with diethyl ether (10 mL), n-pentane (10 mL) and dried in vacuo to afford compound 427 (200 mg, 47%>) as white solid. TLC: 5% MeOH/ CH2C12 (Rf. 0.4); 1H NMR (DMSO-< , 500 MHz): δ 7.88 (br s, 3H), 7.39-7.28 (m, 5H), 7.15 (d, J= 8.7 Hz, 2H), 6.88 (d, J= 8.7 Hz, 2H), 5.00 (s, 2H), 3.93 (t, J = 6.4 Hz, 2H), 3.04 (q, J= 6.7 Hz, 2H), 2.97 (d, J= 6.4 Hz, 2H), 2.81-2.76 (m, 2H), 1.73-1.65 (m, 2H), 1.57-1.51 (m, 2H).
Synthesis of 4-phenyloxazol-2-amine (429)
Figure imgf000165_0001
428 429 [000347] Synthesis of 4-phenyloxazoI-2-amine (429): To a stirred solution of 2-bromo- l- pben !ethan- I -orte 428 (100 mg, 0.50 mmol) in CHjC (5 ml) under inert atmosphere was added urea 395 (301 nig, 5.02 mmol) at RT; heated at 80 °C and stirred for 16 h, The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through flash column chromatography using 30% EtOAc/ hexanes to afford compound 429 (50 mg, 63%) as an off-white solid. TLC: 50% EtOAc/ hexanes (R/, 0,6); 1H NMR (400 MHz, DMSO- ): δ 7.86 (s, III), 7.63 (d, J= 7.0 Hz, 2H), 7.35 (t, J 7.6 Hz, 2H), 7,26-7.22 (m, 1H), 6.70 (s, 2H).
Table 1 : Synthesis of compounds from compounds 6, 14, 21, 28, 35, 42, 50, 55, 62, 70, 76, 82, 88, 97, 03, 112, 118, 124, 135, 140, 145, 150, 155, 156, 159, 64, 167, 170, P-42 and various amines
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
(in, 4H), 7.32
(d, .7=8.0 Hz, 2H), 7.24 (d, J = 8.0 ί/.2H), 3.43 (t, 7-6,5 Hz, 2H), 2.82 (t, ,7-7.0 Hz, 2H);
(DMSO- 400 MHz): δ 10.76 (s, 1H), 9.04 (t, .7=6.0 Hz, IH), 7,71-7.61 (m, 4H), 7.55-7.43
389.2 (m,3H),7,18(t,
1183 A, 6 43
(M+i) : .7-7,2 III, IH),
7,08-7.03 (m, 3H),4.40(d, - 6.0 Hz, 2H), 2,72 (i, j - 6,0 Hz, 2H), 2,26 (s, 3H);
(DMSO- 400 MHz): δ 10.77 (s, IH), 8.58- 8.57 (m; IH), 7.69-7.63 (m,
389.2 3H), 7.55-7.45
] 184 A, 6 43
(M l)+; OMR), 7.09- 7,07 (m,4H), ■ 3.44-3.39 (m, 2K),2.75 (t, = 7.6 Hz, 2H), 2.24 (s, 3H);
{DMSG- 400 MHz): δ 10.76 (s. Hi), 8.58- 8.57 (m, IH), 7.67-7.61 (m, 3H), 7.53-7.41
403.2 (m, 4H), 7.10-
11S5 A, 6 42
(M+l)+; 7.08 (mf 4H), - t- 3.42-3.37 (m,
2H),2.74(t,J = 7.2 Hz, 21 i) 2.55-2,51 (m,
2H), 1.12 (t, j = 7.6 Hz, 3H);
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
(DMSO- 400
MHz): δ 11.05- 11.04(mJH), 1 8.54-8.53 (m, 1H), 7.81-7.73 (m, 3H), 7.68-
459.2 7.60 (m, 4H),
1205 A, 156 50
(MVl); 3.26-3.25 (m,
3H), 1.70-1.62 (m, 6H), 1.39- 1.37 (m,2H), 1.23-1.14 (m, 2H), 0.88-0.85 (i , 2H);
(DMSQ- 00 : MHz): δ 10.75 (s, 1H), 8.49 (t, J - 5.6 Hz.1H), 7,69-7.63 (m, 3H), 7.56-7,45 (m,4HV3.77-
369.3 3,70 (m, 2HK
1209 A, 6 56
(M'h+1); 3.59-3.54 (m,
Figure imgf000185_0001
1,90 {.¾ 1H, 1.83-1.76 (m, 2H), 1.69-1.63 (m,2H), 1.43- 1.34 (m, !H);
(DMSO-4500 MHz): 810.78 (s, lH),9.14(t, /-6.0 Hz, 1H), 8,49 (s, 1H),
362.4
1210 A, 6 56 7,74-7.65 (m,
(M++l);
5H), 7,55-7.44 (m, 3H), 7,28- 7.23 (m, 2H), 4.53 (d, J =5.5 Hz, 2H);
{DMSO-4500 MHz): δ 10.76 (s, 1H), 9.12 (t, J- -- 6.0 Hz, HI).
362.1 8.52 (s, 1H),
1211 A, 6 66 g.45-8.44 (m>
(M"+l);
lH), 7,70 (d, J - 10,0 Hz, 1H), 7.67-7,60 (m, 4H), 7.55-7.44 (m, 3H), 7.33 (t,
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
Figure imgf000238_0001
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000241_0001
Figure imgf000242_0001
Figure imgf000243_0001
Figure imgf000244_0001
Figure imgf000245_0001
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0001
Figure imgf000249_0001
Figure imgf000250_0001
Figure imgf000251_0001
Figure imgf000252_0001
Figure imgf000253_0001
Figure imgf000254_0001
Figure imgf000255_0001
Figure imgf000256_0001
Figure imgf000257_0001
Figure imgf000258_0001
Figure imgf000259_0001
Figure imgf000260_0001
Figure imgf000261_0001
Figure imgf000262_0001
Figure imgf000263_0001
Figure imgf000264_0001
Figure imgf000265_0001
Figure imgf000266_0001
Figure imgf000267_0001
Figure imgf000268_0001
Figure imgf000269_0001
Figure imgf000270_0001
Figure imgf000271_0001
Figure imgf000272_0001
Figure imgf000273_0001
Figure imgf000274_0001
Figure imgf000275_0001
Figure imgf000276_0001
Figure imgf000277_0001
Figure imgf000278_0001
Figure imgf000279_0001
Figure imgf000280_0001
Figure imgf000281_0001
Figure imgf000282_0001
Figure imgf000283_0001
Figure imgf000284_0001
Example 27: Synthesis of Compounds 1268 and 1269
Figure imgf000285_0001
[000348] Synthesis of methyl 2-cyano-2-phenylacetate (432): To a stirred solution of sodium hydride (60%, 2.5 g, 63.82 mmol) in anhydrous toluene (50 mL) under argon atmosphere was added 2-phenyl acetonitrile 430 (5 g, 42.55 mmol) at 0 °C and stirred for 30 min. To this dimethyl carbonate 431 (5.74 g, 63.82 mmol) in anhydrous toluene (30 mL) was added drop wise for 10 min and stirred at 0 °C for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with saturated ammonium chloride (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude compound was purified through silica gel column chromatography using 20%> EtOAc/ hexanes to afford compound 432 (4.8 g, 64%>) as colorless syrup. TLC: 30%> EtOAc/ hexanes (Rf. 0.7); 1H-NMR (CDC13, 400 MHz): δ 7.47-7.39 (m, 5H), 4.74 (s, 1H), 3.81 (s, 3H).
[000349] Synthesis of methyl 3-amino-2-phenylpropanoate (433): To a stirred solution of compound 432 (1 g, 5.71 mmol) in MeOH (50 mL) under argon atmosphere were added Boc- anhydride (2.49 g, 11.42 mmol), nickel dichloride hexahydrate (135 mg, 0.57 mmol) and sodium borohydride (1.5 g, 39.99 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with MeOH (30 mL), filtered through celite and the filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 30% EtOAc/ Hexanes to afford racemic compound 433 (550 mg, 36%>) as an off white solid. TLC: 20%> EtOAc/ hexanes (Rf. 0.4); 1H-NMR (DMSO-^, 500 MHz): δ 7.34 (t, J= 7.0 Hz, 2H), 7.30-7.25 (m, 3H), 6.93 (t, J= 6.0 Hz, 1H), 3.85 (t, J= 7.5 Hz, 1H), 3.60 (s, 3H), 3.28-3.23 (m,lH), 1.34 (s, 9H). The racemic compound 433 was purified through chiral preparative HPLC to afford compound 434 Fr-I (120 mg) and compound 435 Fr-II (90 mg) as off-white solids.
Compound 434 Fr-I analytical data:
[000350] Chiral HPLC: 99.27%, Rt= 9.58 min (Chiralcel AD-H, 250 x 4.6 mm, 5 μιη);
mobile phase (A) 0.1% DEA in n-Hexane (B) EtOH (A: B: 98: 2); Flow Rate: 1.0 mL/min).
Compound 435 Fr-II analytical data:
[000351] Chiral HPLC: 99.29%, Rt=10.87 min (Chiralcel AD-H, 250 x 4.6 mm, 5 μιη);
mobile phase (A) 0.1% DEA in n-Hexane (B) EtOH (A: B: 98: 2); Flow Rate: 1.0 mL/min).
[000352] Synthesis of methyl (R)-2-phenyl-3-((2, 2, 2-trifluoroacetylH4-azanyl) propanoate (436): To a stirred solution of compound 434 (Fr-I) (50 mg, 0.17 mmol) in CH2CI2 (2 mL) under inert atmosphere was added trifluoroacetic acid (0.026 mL, 0.35 mmol) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude compound 436 (20 mg, TFA salt) as off-white solid. TLC: 70% EtOAc/ hexanes (Rf. 0.2); 1H-NMR (DMSO-d6, 400 MHz): δ 8.10 (br s, 2H), 7.41-7.28 (m, 5H), 4.03 (t, J= 6.0 Hz, 1H), 3.63 (s, 3H), 3.48 (t, J= 9.2 Hz, 1H), 3.12-3.08 (m, 1H). [000353] Synthesis of methyl (R)-3-(ll-oxo-10, 11-dihydrodibenzo [ϋ,β [1, 4] thiazepine- 8-carboxamido)-2-phenylpropanoate (437): To a stirred solution of compound 6 (70 mg, 0.25 mmol) in DMF (5 mL) under argon atmosphere were added EDCI.HC1 (73.9 mg, 0.38 mmol), HOBt (30 mg, 0.38 mmol), compound 436 (70 mg, 0.38 mmol), diisopropyl ethyl amine (0.09 mL, 0.51 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 10 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 90% EtOAc/ Hexanes to afford compound 437 (70 mg, 63%) as colorless syrup. TLC: 5% MeOH/ CH2C12 (Rf. 0.5); 1H-NMR (DMSO-^, 400 MHz): δ 10.75 (s, 1H), 8.65 (t, J= 5.6 Hz, 1H), 7.68 (d, J= 7.2 Hz, 2H), 7.67-7.60 (m, 4H), 7.54-7.49 (m, 2H), 7.49-7.44 (m, 3H), 7.35-7.25 (m, 1H), 4.02 (t, J= 7.2 Hz, 1H), 3.80-3.73 (m, 1H), 3.55 (t, J= 6.4 Hz, 1H), 3.47 (s, 3H).
[000354] Synthesis of (R)-3-(ll-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8- carboxamido)-2-phenylpropanoic acid (1268): To a stirred solution of compound 437 (40 mg, 0.092 mmol) in THF: H20 (4: 1, 2.5 mL) was added LiOH.H20 (7.7 mg, 0.18 mmol) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, diluted with water (5 mL), pH was adjusted to ~ 6 using 1 N HC1 and extracted with EtOAc (2 x 10 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to afford 1268 (25 mg, 65%>) as white solid. TLC: 10%> MeOH/ CH2C12 (Rf. 0.5); 1H-NMR (DMSO-^, 400 MHz): δ 12.49 (br s, 1H), 10.76 (s, 1H), 8.62 (t, J = 5.6 Hz, 1H), 7.68 (d, J= 7.2 Hz, 1H), 7.66-7.61 (m, 2H), 7.54-7.42 (m, 4H), 7.34-7.23 (m, 5H), 3.92 (t, J= 7.6 Hz, 1H), 3.77-3.72 (m, 1H), 3.57-3.50 (m, 1H); LC-MS: 90.53%; 419.4 (M++l); (column; X-bridge C-18, (50 x 3.0 mm, 3.5 μιη); RT 3.76 min. 0.05% TFA (Aq) : ACN; 0.8 mL/min); UPLC (purity): 93.78%; (column : Acquity BEH C-18 (50 x 2.1 mm, 1.7 μ); RT 2.04 min. ACN : 0.025% TFA (Aq); 0.5 mL/min).
[000355] Synthesis of methyl (5)-2-phenyl-3-((2, 2, 2-trifluoroacetylH4-azanyl) propanoate (438): To a stirred solution of compound 435 (Fr-II) (90 mg, 0.32 mmol) in CH2C12 (3 mL) under inert atmosphere was added trifluoroacetic acid (0.073 mL, 0.64 mmol) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude compound 438 (90 mg, TFA salt) as an off-white solid. TLC: 70% EtOAc/ Hexanes (R/. 0.2); 1H-NMR (DMSO-</6, 400 MHz): δ 8.10 (br s, 2H), 7.41-7.28 (m, 5H), 4.03 (t, J= 6.0 Hz, 1H), 3.63 (s, 3H), 3.48 (t, J= 9.2 Hz, 1H), 3.12-3.08 (m, 1H).
[000356] Synthesis of methyl (5)-3-(ll-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8- carboxamido)-2-phenylpropanoate (439): To a stirred solution of compound 6 (70 mg, 0.25 mmol) in DMF (5 mL) under argon atmosphere were added EDCI.HC1 (73.9 mg, 0.38 mmol), HOBt (52 mg, 0.38 mmol), compound 438 (70 mg, 0.38 mmol), diisopropyl ethyl amine (0.09 mL, 0.51 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 10 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 80% EtOAc/ hexanes to afford compound 439 (70mg, 63%) as an off-white solid. TLC: 5% MeOH/ CH2C12 (Rf. 0.5); 1H-NMR (DMSO-</6, 400 MHz): δ 10.77 (s, 1H), 8.65 (t, J= 5.6 Hz, 1H), 7.69 (d, J= 7.2 Hz, 1H), 7.65-7.61 (m, 2H), 7.55-7.45 (m, 4H), 7.37-7.34 (m, 2H), 7.31-7.27 (m, 3H), 4.02 (t, J= 7.2 Hz, 1H), 3.80-3.74 (m, 1H), 3.59 (s, 3H), 3.56-3.53 (m,lH).
[000357] Synthesis of (5)-3-(ll-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8- carboxamido)-2-phenylpropanoic acid (1269): To a stirred solution of compound 439 (40 mg, 0.09 mmol) in THF : H20 (4: 1, 2.5 mL) was added lithium hydroxide monohydrate (7.7 mg, 0.18 mmol) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, diluted with water (5 mL), the pH was adjusted to ~ 6 using 1 N HC1 and extracted with EtOAc (2 x 10 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to afford 1269 (25 mg, 65%>) as white solid. TLC: 10% MeOH/ CH2C12 (R/. 0.3); 1H-NMR (DMSO-^, 400 MHz): δ 12.51 (br s, 1H), 10.76 (s, 1H), 8.62 (t, J= 5.6 Hz, 1H), 7.68 (d, J=7.2 Hz, 1H), 7.66-7.61 (m, 2H), 7.54-7.43 (m, 4H), 7.34-7.23 (m, 5H), 3.92 (t, J= 7.6 Hz, 1H), 3.77-3.72 (m, 1H), 3.57-3.50 (m, 1H); LC-MS: 96.04%; 417.8 (M-l)+; (column; X-select C-18, (50 3.0 mm, 3.5 μπι); RT 2.38 min. 5.0 mM NH4OAc : ACN; 0.8 mL/min); UPLC (purity): 96.12%; (column : Acquity BEH C-18 (50 x 2.1 mm, 1.7 μ); RT 2.03 min. ACN : 0.025% TFA (Aq); 0.5 mL/min). Example 28: Synthesis of Compound 1239
Figure imgf000289_0001
[000358] Synthesis of tert-butyl (2-cyanophenyl) carbamate (441): To a stirred solution of 2- aminobenzonitrile 440 (1 g, 8.47 mmol) in CH2CI2 (15 mL) under argon atmosphere were added Boc-anhydride (1.84 g, 4.76 mmol) and triethyl amine (0.83 mL, 5.96 mmol), DMAP (0.1 mg, catalytic amount) at 0 °C; warmed to RT and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 30% EtOAc/ hexanes to afford compound 441 (500 mg, 28%) as white solid. TLC: 30% EtOAc/ hexanes (Rf. 0.8); 1H- NMR (DMSO-dtf, 400 MHz): δ 9.25 (br s, 1H), 7.85 (d, J= 7.6 Hz, 1H), 7.73 (t, J= 7.6 Hz, 1H), 7.53 (d, J= 8.0 Hz, 1H), 7.45 (t, J= 7.6 Hz, 1H), 1.35 (br s, 9H).
[000359] Synthesis of terf-butyl (2-cyanophenyl) (methyl) carbamate (442): To a stirred solution of compound 441 (500 mg, 2.29 mmol) in DMF (10 mL) under argon atmosphere were added sodium hydride (60%>, 55 mg, 2.29 mmol), methyl iodide (325 mg, 2.29 mmol) at 0 °C; warmed to RT and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice cold water (10 mL), extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 40% EtOAc/ hexanes to afford compound 442 (480 mg, 88%) as white solid. TLC: 30% EtOAc/ hexanes (Rf. 0.5); 1H-NMR (DMSO-^, 400 MHz): δ 7.85 (d, J= 7.6 Hz, 1H), 7.73 (t, J= 7.6 Hz, 1H), 7.53 (d, J= 7.6 Hz, 1H), 7.45 (t, J= 7.6 Hz, 1H), 3.18 (s, 3H), 1.35 (br s, 9H).
[000360] Synthesis of tert-butyl (2-(aminomethyl) phenyl) (methyl) carbamate (443): To a stirred solution of compound 442 (50 mg, 0.21 mmol) in MeOH (3 mL) under argon atmosphere was added Raney Nickel (20 mg), methanolic ammonia (1.5 mL) at RT and stirred under hydrogen atmosphere (balloon pressure) for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, washed with MeOH (2 x 5 mL) and the filtrate was concentrated in vacuo to obtain the crude. The crude was washed with diethyl ether (2 x 10 mL) and dried in vacuo to afford compound 443 (40 mg, 80%>) as white solid. TLC: 50% EtOAc/ hexanes (R/. 0.2); 1H-NMR (DMSO-^, 400 MHz): δ 7.52 (d, J = 7.2 Hz, 1H), 7.28-7.20 (m, 2H), 7.12 (t, J= 5.6 Hz, 1H), 3.60-3.57 (m, 2H), 3.14 (br s, 3H), 1.25 (s, 9H).
[000361] Synthesis of tert-butyl methyl (2-((ll-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamido) methyl) phenyl) carbamate (444): To a stirred solution of compound 6 (40 mg, 0.14 mmol) in DMF (3 mL) under argon atmosphere were added EDCI.HC1 (42 mg, 0.22 mmol), HOBt (30 mg, 0.22 mmol), compound 443 (37.6 mg, 0.16 mmol), diisopropyl ethyl amine (0.05 mL, 0.29 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (20 mL). The precipitate was filtered and the obtained solid was dried in vacuo to afford compound 444 (40 mg, 55%) as white solid. TLC: 5% MeOH/ CH2C12 (Rf. 0.5); LC-MS: 93.49%; 390.3 (M++l) (Des-Boc).
[000362] Synthesis of 7V-(2-(methylamino) benzyl)-ll-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide (1239): A stirred solution of compound 444 (40 mg, 0.08 mmol) in 4 N HC1 in 1 , 4-dioxane (2 mL) under argon atmosphere at 0-5 °C was stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with saturated NaHC03 solution (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with water (15 mL), dried over sodium sulphate, filtered and concentrated in vacuo to afford 1239 (10 mg, 32%) as white solid. TLC: 5% MeOH/ CH2CI2 (Rf. 0.4); 1H-NMR (DMSO-< , 400 ΜΗζ):δ 10.74 (s, 1H), 8.96 (t, J= 6.0 Hz, 1H), 7.72-7.60 (m, 4H), 7.55-7.43 (m, 3H), 7.08 (t, J= 7.6 Hz, 1H ), 7.02 (d, J= 7.2 Hz, 1H), 6.53 (t, J= 7.2 Hz, 2H), 5.38-5.37 (m, 1H), 4.29 (d, J= 7.2 Hz, 2H), 2.72 (d, J= 4.8 Hz, 3H); LC-MS: 93.74%; 390.3 (M++l); (column; X-select CSH C-18, (50 x 3.0 mm, 3.5 μιη); RT 3.44 min. 0.05% TFA (Aq) : ACN; 0.8 mL/min); UPLC (purity): 94.35%; (column : Acquity UPLC BEH C-18 (2.1 x 50 mm, 1.7 μ); RT 1.87 min. ACN : 0.025% TFA (Aq); 0.5 mL/min).
Example 29: Synthesis of Compound 1244
Figure imgf000291_0001
[000363] Synthesis of tert-butyl 4-(cyanomethylene) piperidine-l-carboxylate (447): To a stirred solution of diethyl (cyanomethyl) phosphonate 445 (978 mg, 5.52 mmol) in anhydrous THF (10 mL) under argon atmosphere was added LiHMDS (1 mL, 5.52 mmol, 1M in THF) was added drop wise for 10 min at -78 °C. To this was added tert-butyl 4-oxopiperidine-l- carboxylate 446 (1 g, 5.01 mmol) in THF (2 mL) dropwise for 10 min and stirred for 3 h at the same temperature. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 15% EtOAc/ hexanes to afford compound 447 (900 mg, 82%) as white solid. TLC: 30% EtOAc/ hexanes (Rf. 0.5); 1H NMR (CDC13, 400 MHz) δ 5.19 (s, 1H), 3.54-3.49 (m, 4H), 2.56 (t, J= 5.8 Hz, 2H), 2.33 (t, J= 5.6 Hz, 2H), 1.48 (s, 9H);
[000364] Synthesis of tert-buty\ 4-(2-aminoethyl) piperidine-l-carboxylate (448): To a stirred solution of 447 (100 mg, 0.45 mmol) in AcOH (5 mL) under argon atmosphere was added 10% Pd/C (50 mg) at RT and stirred under hydrogen atmosphere (balloon pressure) for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mass was filtered through celite and washed with EtOAc (3 x 15 mL) and the volatiles were removed in vacuo to afford compound 448 (70 mg, mixture of isomers) as pale brown syrup. TLC: 6% MeOH/ CH2C12 (Rf. 0.2); 1H-NMR (DMSO-</6, 400 MHz): δ 3.89 (d, J= 12.4 Hz, 2H), 2.70-2.68 (m, 2H), 1.68-1.65 (m, 2H), 1.59 (d, J= 12.0 Hz, 1H), 1.38 (s, 9H), 1.33-1.28 (m, 4H), 0.99-0.89 (m, 2H).
[000365] Synthesis of tert-butyl 4-(2-(ll-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine- 8-carboxamido) ethyl) piperidine-l-carboxylate (449): To a stirred solution of compound 6 (40 mg, 0.14 mmol) in DMF (3 mL) under argon atmosphere were added EDCI.HC1 (42 mg, 0.22 mmol), HOBt (30 mg, 0.22 mmol), compound 448 (40 mg, 0.17 mmol), diisopropyl ethyl amine (0.05 mL, 0.29 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was triturated with EtOAc: H20 (1 : 5, 12 mL), filtered and the precipitate was dried in vacuo to afford compound 449 (36 mg, 51%) as white solid. TLC: 7%> MeOH/ CH2C12 (R/. 0.7); 1H-NMR (DMSO-< , 400 MHz): δ 10.76 (s, 1H), 8.47 (br s, 1H), 7.69-7.63 (m, 3H), 7.57-7.53 (m, 2H), 7.47 (t, J= 8.8 Hz, 2H), 3.89 (d, J= 10.8 Hz, 2H), 3.26- 3.25 (m, 2H), 2.67 (s, 3H), 1.64 (d, J= 10.8 Hz, 2H), 1.42-1.41 (m, 2H), 1.37 (s, 9H), 0.97-0.95 (m, 2H).
[000366] Synthesis of ll-oxo- V-(2-(piperidin-4-yl) ethyl)-10, 11-dihydrodibenzo [b,j\ [1, 4] thiazepine-8-carboxamide (1244): To a stirred solution of compound 449 (36 mg, 0.07 mmol) in CH2C12 (3 mL) under argon atmosphere was added trifluoro acetic acid (0.03 mL, 0.37 mmol) at 0 °C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was neutralized with 10% NaHC03 solution (15 mL) and extracted with EtOAc (3 x 15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford 1244 (15 mg, 53%) as an off-white solid. TLC: 7% MeOH/ CH2C12 (Rf. 0.2); 1H-NMR (DMSO-< , 400 MHz): δ 10.77 (br s, 1H), 8.48 (t, J = 5.6 Hz, 1H), 7.69-7.64 (m, 3H), 7.57-7.43 (m, 4H), 3.26-3.25 (m, 3H), 3.16-3.12 (m, 2H), 2.68 (t, J= 10.0 Hz, 2H), 1.77-1.74 (m, 2H), 1.44 (t, J = 6.8 Hz, 3H); 1.23-1.13 (m, 2H); LC-MS: 90.01%; 382.4 (M++l); (column; X-select CSH C-18, (50 3.0 mm, 3.5 μπ ; RT 2.97 min. 0.05% TFA (Aq) : ACN; 0.8 mL/min); UPLC (purity): 92.90%; (column : Acquity UPLC BEH C-18 (2.1 x 50 mm, 1.7 μ); RT 1.60 min. ACN : 0.025% TFA (Aq); 0.5 mL/min).
Example 30: Synthesis of Compounds 1651 and 1652
Figure imgf000293_0001
453 454 (Racemic)
Figure imgf000293_0002
[000367] Synthesis of V-methoxy- V-methylthiazole-5-carboxamide (451): To a stirred solution of thiazole-5-carboxylic acid 378 (1.5 g, 1 1.61 mmol) in CH2C12 (30 mL) under argon atmosphere were added EDCI.HCI (2.45 g, 12.78 mmol), HOBt (785 mg, 135.13 mmol), Ν,Ο- dimethyl hydroxylamine hydrochloride 450 (1.36 g, 97.6 mmol) and diisopropyl ethyl amine (10 mL, 58.09 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with CH2CI2 (3 x 50 mL). The combined organic extracts were washed with 1 N HC1 (20 mL), saturated NaHC03 solution (30 mL), brine (50 mL) and dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through combi flash chromatography using 30-40% EtOAc/ hexanes to afford compound 451 (1.2 g, 60%) as colorless syrup. TLC: 5% MeOH/ CH2C12 (Rf. 0.6); 1H NMR (DMSO-< , 400 MHz): 9.32 (s, 1H), 8.52 (s, 1H), 3.77 (s, 3H), 3.30 (s, 3H).
[000368] Synthesis of l-(thiazol-S-yl) ethan-l-one (452): To a stirred solution of compound 451 (1.2 g, 6.97 mmol) in THF (20 mL) under argon atmosphere was added methyl magnesium bromide (3.2 mL, 10.46 mmol, 3 M solution in Et20) dropwise for 10 min at -10 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through combi flash chromatography using 25-30%) EtOAc/ hexanes to afford compound 452 (800 mg, 90%>) as white solid. TLC: 50% EtOAc/ hexanes (Rf. 0.6); 1H NMR (DMSO-</6, 400 MHz): δ 9.40 (s, 1H), 8.71 (s, 1H), 2.60 (s, 3H).
[000369] Synthesis of l-(thiazol-S-yl) ethan-l-one oxime (453): To a stirred solution of compound 452 (800 mg, 6.29 mmol) in MeOH (20 mL) under inert atmosphere was added hydroxyl amine hydrochloride (875 mg, 12.59 mmol) and pyridine (2 mL) dropwise for 5 min at 0 °C warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo diluted with water (50 mL) and stirred for 30 min. The precipitated solid was filtered dried in vacuo to afford compound 453 (800 mg, 90%>) as white solid. TLC: 40% EtOAc/ hexanes (Rf. 0.4, 0.6); 1H NMR (DMSO-</6, 400 MHz)
(Mixture of E/Z isomers): δ 11.86 (s, 1H), 11.41 (s, 0.6 H), 9.19 (s, 1H), 9.01 (s, 0.56 H), 8.35 (s, 1H), 8.15 (s, 0.65 H), 2.31 (s, 3H), 2.21 (s, 2H).
[000370] Synthesis of l-(thiazol-S-yl) ethan-l-amine (454): To a stirred solution of compound 453 (800 mg, 5.63 mmol) in MeOH: acetic acid (1 : 1, 20 mL) under inert atmosphere were zinc powder (2.2 g, 33.80 mmol) at RT; heated at 50 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite washed with MeOH (3 x 10 mL). The filtrate were removed in vacuo, the residue was diluted with water (20 mL), basified with aqueous ammonia (15 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude compound 454 (racemic) (700 mg, 92%) as brown syrup. TLC: 5% MeOH/ CH2C12 (Rf. 0.4, 0.6); 1H NMR (DMSO-< , 400 MHz): δ 8.90 (s, 1H), 7.71 (s, 1H), 4.33-4.28 (m, 1H), 3.38 (t, J= 6.4 Hz, 1H), 1.87 (s, 3H).
[000371] Synthesis of ll-oxo-7V-(l-(thiazol-5-yl) ethyl)-10, 11-dihydrodibenzo [b,j [1, 4] thiazepine-8-carboxamide (455 Racemic): Using Procedure A the title compound was prepared with DBT-Acid (150 mg, 0.55 mmol) and compound 454 racemic (109 mg, 0.66) to afford compound 455 (Racemic) (100 mg, 48%); TLC: 5% MeOH/ CH2C12 (Rf. 0.5); 1H NMR
(DMSO-</6, 400 MHz): δ 10.87 (br s, 1H), 9.14 (d, J= 8.0 Hz, 1H), 8.95 (s, 1H), 7.79 (d, J= 3.6 Hz, 2H), 7.70-7.58 (m, 3H), 7.56-7.42 (m, 3H), 5.48-5.41 (m, 1H), 1.60 (s, 3H); LC-MS:
98.31%; 381.9 (M++l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 μιη); RT 2.03 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 97.68%; (column; Eclipse XDB C-18 (150 x 4.6 mm, 5.0 μιη); RT 7.58 min. ACN : 0.05% TFA (Aq); 1.0 mL/min) (IP14012554); Chiral HPLC: 35.10%, Rt= 9.01 min (Chiralpak-IA, 250 x 4.6 mm, 5 μιη); mobile phase (A) 0.1% DEA in n-Hexane (B) CH2C12: MeOH (50: 50) (A: B:: 63: 35); Flow Rate: 1.0 mL/min).
[000372] The racemic compound 455 (100 mg) was separated by preparative HPLC using a CHIRALPAK-IC column (250 x 20 mm x 5 μιη) (10 mg loading; mobile phase (A) 0.1% DEA in n-Hexane (B) CH2C12: MeOH: DMF (65: 35: 05) (A: B:: 75: 25) to afford 1651 (10 mg) and 1652 (15 mg) as an off-white solids.
Analytical Data of 1651:
[000373] TLC: 5% MeOH/ CH2C12 (Rf. 0.5); 1H NMR (DMSO-</6, 400 MHz): δ 10.75 (s, 1H), 9.02 (d, J= 7.8 Hz, 1H), 8.95 (s, 1H), 7.79 (s, 1H), 7.72-7.64 (m, 3H), 7.62-7.58 (m, 1H), 7.56- 7.41 (m, 3H), 5.45 (t, J= 7.0 Hz, 1H), 1.57 (d, J= 6.8 Hz, 3H); LC-MS: 96.06%; 381.8 (M++l); (column; Ascentis Express CI 8, (50 3.0 mm, 2.7 μιη); RT 2.03 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 95.02%; (column; Zorbax SB C-18 (150 x 4.6 mm, 3.5 μιη); RT 7.79 min. ACN : 0.05% TFA (Aq); 1.0 mL/min)
(IP15010530); Chiral HPLC: 96.24%, Rt= 14.33 min (Chiralpak-IA, 250 x 4.6 mm, 5 μιη); mobile phase (A) 0.1% DEA in n-Hexane (B) CH2C12: MeOH: DMF (65: 35: 05) (A: B:: 75: 25); Flow Rate: 1.0 mL/min). Note: Alternatively the racemic compound 454 was resolved and one fraction had led to 1651.
Analytical Data of 1652:
[000374] TLC: 5% MeOH/ CH2C12 (R/. 0.5); 1H NMR (DMSO-< , 400 MHz): δ 10.75 (s, 1H), 9.03 (d, J= 8.3 Hz, 1H), 8.95 (s, 1H), 7.79 (s, 1H), 7.71-7.63 (m, 3H), 7.62-7.58 (m, 1H), 7.56- 7.42 (m, 3H), 5.48-5.47(m, 1H), 1.57 (d, J= 6.9 Hz, 3H); LC-MS: 96.65%; 381.9 (M++l);
(column; Ascentis Express CI 8, (50 3.0 mm, 2.7 μιη); RT 2.68 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 98.53%; (column; Zorbax SB C-18 (150 x 4.6 mm, 3.5 μιη); RT 7.76 min. ACN : 0.05% TFA (Aq); 1.0 mL/min)
(IP15010229). Chiral HPLC: 99.87%, Rt= 16.90 min (Chiralpak-IA, 250 x 4.6 mm, 5 μιη); mobile phase (A) 0.1% DEA in n-Hexane (B) CH2C12: MeOH: DMF (65: 35: 05) (A: B:: 75: 25); Flow Rate: 1.0 mL/min).
Example 31: Synthesis of Compounds 1653 and 1633
Figure imgf000296_0001
1633 1653
[000375] Synthesis of tert-butyl 2-((ll-oxo-10, 11-dihydrodibenzo [ϋ,β [1, 4] thiazepine-8- carboxamido) methyl) pyrrolidine-l-carboxylate (457): Using Procedure A the title compound was prepared with compound 6 (300 mg, 1.10 mmol), tert-butyl 2-(aminomethyl) pyrrolidine- 1-carboxylate 456 (0.24 mL, 1.21 mmol) and was obtained in 50% yield as an off- white solid; TLC: 10% MeOH/ CH2C12 (Rf. 0.7); 1H NMR (DMSO-</6, 400 MHz): δ 10.76 (br s, 1H), 8.53 (t, J = 5.5 Hz, 1H), 7.71-7.63 (m, 3H), 7.56-7.43 (m, 4H), 3.95-3.79 (m, 1H), 3.52-3.35 (m, 1H), 3.26-3.19 (m, 3H), 1.86-1.71 (m, 4H), 1.38 (s, 9H).
[000376] Synthesis of ll-oxo- V-(pyrrolidin-2-ylmethyl)-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide hydrochloride (1633): To a stirred solution of compound 457 (250 mg, 0.55 mmol) in CH2C12 (5 mL) under argon atmosphere was added 4 N HC1 in 1 , 4-dioxane (1 mL) at 0 °C; warmed to RT and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to afford compound 1633 (150 mg, 77%; HC1 salt) as an off-white solid. TLC: 10% MeOH/ CH2C12 (Rf. 0.1); 1H NMR
(DMSO-< , 400 MHz): δ 10.82 (br s, 1H), 8.88 (br s, 3H), 7.74-7.62 (m, 4H), 7.56-7.43 (m, 3H),
3.67- 3.57 (m, 1H), 3.56-3.46 (m, 2H), 3.24-3.07 (m, 2H), 2.07-1.95 (m, 1H), 1.95-1.78 (m, 2H),
1.68- 1.59 (m, 1H); LC-MS: 96.49%; 354.0 (M++l) (-HC1); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 μιη); RT 1.64 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 96.28%; (column; Zorbax SB C-18 (150 x 4.6 mm, 3.5 μιη); RT 6.64 min. ACN : 0.05% TFA (Aq); 1.0 mL/min).
[000377] Synthesis of V-((l-acetylpyrrolidin-2-yl) methyl)-ll-oxo-10, 11-dihydrodibenzo [b,j\ [1, 4] thiazepine-8-carboxamide (1653): To a stirred solution of compound 1633 (100 mg, 0.25 mmol) in CH2C12 (5 mL) under argon atmosphere were added triethylamine (0.12 mL, 0.77 mmol), acetyl chloride (0.02 mL, 0.30 mmol) at 0 °C; warmed to RT, stirred for 12 h. The reaction was monitored by TLC; after completion the reaction, the reaction the volatiles were removed in vacuo; the residue was basified with saturated NaHC03 solution and extracted with CH2C12 (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH/ CH2C12 to afford 1653 (20 mg, 20%>) as an off- white solid. TLC: 10% MeOH/ CH2Cl2 (Rf. 0.6); 1H NMR (DMSO-^, 400 MHz): δ 10.84-10.73 (m, 1H), 8.87-8.55 (m, 1H), 7.72-7.63 (m, 3H), 7.60-7.43 (m, 4H), 4.17-3.94 (m, 1H), 3.53-3.33 (m, 3H), 3.32-3.30 (m, 0.5H), 3.20-3.09 (m, 0.5H), 2.08-1.92 (m, 3H), 1.88-1.70 (m, 4H); LC-MS:
99.36%; 396.4 (M++l); (column; X-Select C-18, (50 x 3.0 mm, 3.5 μπι); RT 3.34 min, 0.77 min. 5 mM Aq.NH4OAc: ACN 0.8 mL/min). HPLC (purity): 98.67%; (column; Eclipse XDB C-18 (150 x 4.6 mm, 5.0 μπι); RT 7.28 min. ACN: 5 mM Aq. NH4OAc; 1.0 mL/min). Example 32: Synthesis of Compounds 1615 and 1608
Figure imgf000298_0001
[000378] Synthesis of tert-butyl 3-((ll-oxo-10, 11-dihydrodibenzo [ϋ,β [1, 4] thiazepine-8- carboxamido) methyl) pyrrolidine-l-carboxylate (459): Using Procedure A the title compound was prepared with 6 (300 mg, 1.10 mmol), tert-butyl 3-(aminomethyl) pyrrolidine-l- carboxylate 458 (0.24 mL, 1.21 mmol) and was obtained in 60% yield as an off-white solid; TLC: 10% MeOH/ CH2C12 (Rf. 0.5); 1H NMR (DMSO-< , 400 MHz): δ 10.76 (s, 1H), 8.61 (t, J = 5.0 Hz, 1H), 7.72-7.63 (m, 3H), 7.60-7.42 (m, 4H), 3.34-3.18 (m, 1H), 3.28-3.13 (m, 4H), 2.99-2.92 (m, 1H), 2.42-2.34 (m, 1H), 1.94-1.82 (m, 1H), 1.64-1.50 (m, 1H), 1.37 (s, 9H).
[000379] Synthesis of ll-oxo- V-(pyrrolidin-3-ylmethyl)-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide hydrochloride (1608): To a stirred solution of compound 459 (300 mg, 0.66 mmol) in CH2C12 (5 mL) under argon atmosphere was added 4 N HCI in 1, 4-dioxane (1 mL) at 0 °C; warmed to RT and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to afford compound 1608 (200 mg, 78%; HCI salt) as an off-white solid. TLC: 10% MeOH/ CH2C12 (Rf. 0.1); 1H-NMR (DMSO-< , 400 MHz): δ 10.78 (s, 1H), 8.88 (br s, 2H), 8.70 (t, J= 5.7 Hz, 1H), 7.71-7.65 (m, 3H), 7.59 (dd, J= 8.2, 2.0 Hz, 1H), 7.56-7.43 (m, 3H), 3.27-3.15 (m, 5H), 3.15-3.04 (m, 1H), 2.94-2.80 (m, 1H), 2.04-1.92 (m, 1H), 1.69-1.56 (m, 1H); LC-MS: 98.04%; 353.9 (M++l) (- HCI); (column; Ascentis Express CI 8, (50 x 3.0 mm, 2.7 μιη); RT 1.64 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); UPLC (purity): 97.21%; (column; Acquity UPLC BEH C-18 (50 x 2.1 mm, 1.7 μ); RT 1.55 min. ACN : 0.025% TFA (Aq); 0.5 mL/min) (IP14120205).
[000380] Synthesis of V-((l-acetylpyrrolidin-3-yl) methyl)-ll-oxo-10, 11-dihydrodibenzo [b,j\ [1, 4] thiazepine-8-carboxamide (1615): To a stirred solution of compound 1608 (100 mg, 0.28 mmol) in CH2CI2 (5 mL) under argon atmosphere were added triethylamine (0.12 mL, 0.84 mmol), acetyl chloride (0.02 mL, 0.33 mmol) at 0 °C; warmed to RT, stirred for 12 h. The reaction was monitored by TLC; after completion the reaction, the reaction the volatiles were removed in vacuo; the residue was basified with saturated NaHC03 solution and extracted with CH2CI2 (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH/ CH2CI2 to afford 1615 (30 mg, 26%) as an off- white solid. TLC: 10% MeOH/ CH2C12 (Rf. 0.6); 1H NMR (DMSO-< , 400 MHz): δ 10.71 (m, 1H), 8.69 - 8.58 (m, 1H), 7.72-7.63 (m, 3H), 7.61-7.41 (m, 4H), 3.55-3.34 (m, 3H), 3.29-3.19 (m, 2H), 3.17- 3.13 (m, 0.5H), 3.00 (dd, J= 11.8, 7.3 Hz, 0.5H), 2.41-2.34 (m, 1H), 2.02-1.84 (m, 4H), 1.73- 1.49 (m, 1H); LC-MS: 95.89%; 396.0 (M++l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 μιη); RT 1.87 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 97.29%; (column; Eclipse XDB C-18 (150 x 4.6 mm, 5.0 μιη); RT 7.05 min. ACN: 5 mM Aq. NH4OAc; 1.0 mL/min).
Example 33: Synthesis of Compound 1654
Figure imgf000299_0001
1654
[000381] Synthesis of tert-butyl 3-((ll-oxo-10, 11-dihydrodibenzo [ϋ,β [1, 4] thiazepine-8- carboxamido) methyl) azetidine-l-carboxylate (461): To a stirred solution of compound 6 (600 mg, 2.21 mmol) in DMF (5 mL) under argon atmosphere were added EDCI.HC1 (634 mg, 3.32 mmol), HOBt (435 mg, 3.32 mmol), tert-butyl 3-(aminomethyl) azetidine-l-carboxylate 460 (453 mg, 2.43 mmol) and diisopropyl ethyl amine (1.14 mL, 6.64 mmol) at RT and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH/ CH2C12 to afford compound 461 (600 mg, 61%) as an off-white solid. TLC: 10% MeOH/ CH2C12 (Rf. 0.6); 1H NMR (DMSO-</6, 400 MHz): δ 10.76 (s, 1H), 8.64 (t, J= 5.6 Hz, 1H), 7.71-7.64 (m, 3H), 7.59-7.43 (m, 4H), 3.84 (t, J= 7.0 Hz, 2H), 3.66-3.50 (m, 2H), 3.41 (t, J = 6.3 Hz, 2H), 2.72-2.64 (m, 1H), 1.33 (s, 9H).
[000382] Synthesis of ll-oxo-7V-((l-(2, 2, 2-trifluoroacetyl)-114-azetidin-3-yl) methyl)-10, 11-dihydrodibenzo [b,j\ [1, 4] thiazepine-8-carboxamide (1654): To a stirred solution of 461 (350 mg, 0.79 mmol) in CH2C12 (10 mL) under argon atmosphere were added BF3.Et20 (0.18 mL, 1.59 mmol), molecular sieves (20 mg) at 0 °C; warmed to RT and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with CH2C12 (2 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified using preparative HPLC purification to afford compound 1654 (20 mg, 7%) as an off-white solid. TLC: 10% MeOH/ CH2C12 (Rf. 0.6); 1H NMR (DMSO-</6, 400 MHz): δ 10.79 (s, 1H), 8.70 (t, J= 5.6 Hz, 1H), 8.62-8.39 (m, 1H), 7.73-7.66 (m, 3H), 7.59 (dd, J= 8.1, 1.7 Hz, 1H), 7.57-7.43 (m, 3H), 3.99-3.88 (m, 2H), 3.80-3.69 (m, 2H), 3.45 (t, J= 6.1 Hz, 2H), 3.04-2.94 (m, 1H); LC-MS: 99.41%; 339.9 (M++l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 μιη); RT 1.70 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 98.60%; (column; Zorbax SB C-18 (150 x 4.6 mm, 3.5 μιη); RT 6.54 min. ACN : 0.05% TFA (Aq); 1.0 mL/min). Example 34: Synthesis of Compounds 1601 and 1609
Figure imgf000301_0001
1609 1601
[000383] Synthesis of tert-butyl 4-((ll-oxo-10, 11-dihydrodibenzo [ϋ,β [1, 4] thiazepine-8- carboxamido) methyl) piperidine-l-carboxylate (463): Using Procedure A the title compound was prepared with compound 6 (200 mg, 0.73 mmol), tert-butyl 4-(aminomethyl) piperidine-l- carboxylate 462 (0.17 mL, 0.81 mmol) and was obtained in 86% yield as pale brown solid;
TLC: 5% MeOH/ CH2C12 (Rf. 0.5); 1H NMR (DMSO-< , 400 MHz): δ 10.75 (br s, 1H), 8.52 (t, J= 5.6 Hz, 1H), 7.72-7.61 (m, 3H), 7.60-7.42 (m, 4H), 3.93-3.88 (m, 2H), 3.12 (t, J= 6.0 Hz, 2H), 2.71-2.59 (m, 2H), 1.74-1.57 (m, 3H), 1.38 (s, 9H), 1.06-0.92 (m, 2H)
[000384] Synthesis of ll-oxo- V-(piperidin-4-ylmethyl)-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide hydrochloride (1609): To a stirred solution of compound 463 (300 mg, 0.64 mmol) in CH2C12 (5 mL) under argon atmosphere was added 4 N HCI in 1, 4-dioxane (1 mL) at 0 °C; warmed to RT and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to afford compound 1609 (200 mg, 85%; HCI salt) as pale brown solid. TLC: 5% MeOH/ CH2C12 (Rf. 0.2); 1H-NMR (DMSO- d6, 400 MHz): δ 10.77 (s, 1H), 8.67-8.58 (m, 2H), 8.32 (br s, 1H), 7.71 -7.64 (m, 3H), 7.61-7.43 (m, 4H), 3.27-3.20 (m, 2H), 3.18-3.12 (m, 2H), 2.89-2.76 (m, 2H), 1.82-1.72 (m, 3H), 1.38-1.23 (m, 2H); LC-MS: 98.23%; 368.0 (M++l) (-HC1); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 μιη); RT 1.67 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); UPLC (purity): 97.67%; (column; Acquity UPLC BEH C-18 (50 x 2.1 mm, 1.7 μ); RT 1.59 min. ACN : 0.025% TFA (Aq); 0.5 mL/min).
[000385] Synthesis of V-((l-acetylpiperidin-4-yl) methyl)-ll-oxo-10, 11-dihydrodibenzo [b,j\ [1, 4] thiazepine-8-carboxamide (1601): To a stirred solution of compound 1609 (100 mg, 0.24 mmol) in CH2CI2 (5 mL) under argon atmosphere were added triethylamine (0.1 mL, 0.74 mmol), acetyl chloride (0.02 mL, 0.29 mmol) at 0 °C; warmed to RT, stirred for 12 h. The reaction was monitored by TLC; after completion the reaction, the reaction the volatiles were removed in vacuo; the residue was basified with saturated NaHC03 solution and extracted with CH2CI2 (2 x 15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 1% MeOH/ CH2CI2 to afford 1601 (20 mg, 20%>) as an off- white solid. TLC: 10% MeOH/ CH2C12 (Rf. 0.5); 1H-NMR (DMSO-< , 400 MHz): δ 10.75 (s, 1H), 8.53 (t, J= 5.5 Hz, 1H), 7.71-7.63 (m, 3H), 7.61-7.43 (m, 4H), 4.36-4.29 (m, 1H), 3.81-3.73 (m, 1H), 3.19-3.06 (m, 2H), 3.00-2.91 (m, 1H), 2.53-2.46 (m, 1H), 1.96 (s, 3H), 1.82-1.58 (m, 3H), 1.14- 0.89 (m, 2H); LC-MS: 99.33%; 410.0 (M++l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 μιη); RT 1.99 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); UPLC (purity): 99.57%; (column; Acquity UPLC BEH C-18 (50 x 2.1 mm, 1.7 μ); RT 1.79 min. ACN: 0.025% TFA (Aq); 0.5 mL/min).
Example 35: Synthesis of Compounds 1357, 1655, and 1367
Figure imgf000302_0001
[000386] Synthesis of methyl ll-oxo-10, 11-dihydrodibenzo [b, [1, 4] thiazepine-8- carboxylate (474): To a stirred solution of compound 6 (500 mg, 1.84 mmol) in MeOH: CH2CI2 (1 : 1 , 20 mL) under argon atmosphere was added CH2N2 (insitu prepared using N-nitrosomethyl urea (0.95 g, 9.2 mmol) + KOH (0.51 g, 9.22 mmol) ) at 0 °C; warmed to RT and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 474 (450 mg, 86%) as white solid. TLC: 30% EtOAc/ hexanes (Rf. 0.5); 1H-NMR (DMSO-< , 500 MHz): δ 10.82 (s, 1H), 7.82 (s, 1H), 7.75-7.69 (m, 3H), 7.58-7.63 (m, 3H), 3.82 (s, 3H).
[000387] Synthesis of 8-(hydroxymethyl) dibenzo [b,f\ [1, 4] thiazepin-ll(10H)-one (474-
A): To a stirred solution of compound 474 (500 mg, 1.75 mmol) in dry THF (3 mL) under argon atmosphere was added diisobutylaluminium hydride (1 M sol. in Toluene, 5 mL, 5.26 mmol) dropwise for 5 min at -25 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was cooled to 0 °C, quenched with saturated sodium potassium tartrate solution (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude, which was titurated with MeOH: diethyl ether (1 : 4, 5 mL) to afford 474-A
(300 mg, 66%) as an off-white solid. TLC: 70% EtOAc/ hexanes (Rf. 0.4); 1H NMR (DMSO-</6, 400 MHz): δ 10.66 (s, 1H), 7.67 (dd, J = 7.5, 1.6 Hz, 1H), 7.55-7.38 (m, 4H), 7.19 (s, 1H), 7.07 (dd, J= 7.9, 1.7 Hz, 1H), 5.26 (t, J = 5.7 Hz, 1H), 4.44 (d, J = 5.6 Hz, 2H); LC-MS: 97.26%; 257.8 (M++l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 μιη); RT 1.94 min. 0.025% Aq. TFA + 5% ACN: ACN +; 5% 0.025% Aq. TFA, 1.2 mL/min); UPLC (purity): 96.65%; (column; Acquity BEH C-18 (50 x 2.1 mm, 1.7 μ); RT 1.80 min. ACN: 0.025% TFA (Aq); 0.5 mL/min).
[000388] Synthesis of ll-oxo-10, 11-dihydrodibenzo [b,j\ [1, 4] thiazepine-8-carbaldehyde (475): To a stirred solution of compound 474-A (60 mg, 0.23 mmol) in CH2CI2 (5 mL) under argon atmosphere was added Dess-Martin periodinane (300 mg, 0.70 mmol) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with CH2CI2 (50 mL) and washed with saturated hypo solution (20 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified using silicagel column chromatography using 30% EtOAc/ hexanes to afford compound 475 (41 mg, 68%) as an off-white solid. TLC: 70% EtOAc/ hexanes (Rf. 0.8); 1H NMR (DMSO-< , 400 MHz): δ 10.89 (s, 1H), 9.96 (s, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.73-7.66 (m, 3H), 7.59-7.45 (m, 3H).
[000389] Synthesis of 8-((phenethylamino) methyl) dibenzo [b,f\ [1, 4] thiazepin-ll(lOH)- one (1357): To a stirred solution of compound 475 (100 mg, 0.39 mmol) in MeOH (4 mL) under argon atmosphere were added 2-phenylethan-l -amine 211 (57 mg, 0.47 mmol) and acetic acid (1 mL) at RT and stirred for 1 h. To this was added sodium cyanoborohydride (72 mg, 1.16 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water with EtOAc (100 mL), washed with saturated sodium bicarbonate solution (20 mL) and water (20 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified using silicagel column chromatography using 2% MeOH/ CH2C12 to afford compound 1357 (25 mg, 18%) as an off-white solid. TLC: 100% EtOAc (Rf. 0.3); 1H NMR (DMSO-< , 400 MHz): δ 10.65 (s, 1H), 7.67 (dd, J = 7.4, 1.6 Hz, 1H), 7.54-7.39 (m, 4H), 7.28-7.23 (m, 2H), 7.21-7.14 (m, 4H), 7.10 (d, J = 7.2 Hz, 1H), 3.70 (br s, 2H), 2.72 (br s, 4H); LC-MS: 95.70%; 361.0 (M++l); (column; X-select CSH C 18, (50 x 3.0 mm, 3.5 μιη); RT 2.65 min. 0.05% Aq. TFA: ACN; 0.8 mL/min); UPLC (purity): 95.01%; (column; Acquity BEH C-18 (50 x 2.1 mm, 1.7 μ); RT 1.87 min. ACN: 0.025% TFA (Aq); 0.5 mL/min).
[000390] Synthesis of 7V-((ll-oxo-10, 11-dihydrodibenzo [b,j\ [1, 4] thiazepin-8-yl) methyl)- V-phenethyl acetamide (1367): To a stirred solution of compound 1357 (40 mg, 0.1 1 mmol) in CH2C12 (2 mL) under argon atmosphere were added pyridine (0.013 mL, 0.16 mmol), acetic anhydride (0.01 1 mL, 0.12 mmol) at 0-5 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion the reaction, the reaction mixture was diluted with CH2C12 (20 mL) washed with 1 N HC1 (5 mL) and brine (10 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% EtOAc/ hexanes to afford 1367 (25 mg, 57%) as an off-white solid. TLC: 70% EtOAc/ hexanes (Rf. 0.8); 1H NMR (DMSO-</6, 500 MHz): δ 10.62-10.60 (m, 1H), 7.67-7.64 (m, 1H), 7.57-7.38 (m, 4H), 7.29-6.94 (m, 7H), 4.45 (d, J= 9.8 Hz, 2H), 3.41-3.35 (m, 2H), 2.82-2.66 (m, 2H), 1.97-1.87 (m, 3H); LC-MS: 92.67%; 403.5 (M++l); (column; X-select CSH C18, (50 x 3.0 mm, 3.5 μπι); RT 4.37 min. 5 mM
Aq.NH4OAc: ACN; 0.8 mL/min); UPLC (purity): 93.63%; (column; Acquity BEH C-18 (50 x 2.1 mm, 1.7 μ); RT 2.41 min. ACN: 0.025% TFA (Aq); 0.5 mL/min).
Example 36: Synthesis of Compound 1501
Figure imgf000305_0001
477 479
Figure imgf000305_0002
1501
[000391] Synthesis of 8-(hydroxymethyl)-10-(4-methoxybenzyl) dibenzo [ϋ,β [1, 4] thiazepin-ll(10H)-one (476): To a stirred solution of 1655 (1 g, 3.89 mmol) in THF (50 mL) were added Benzyltriethylammonium chloride (88 mg, 0.38 mmol), 50%> aqueous sodium hydroxide solution (4 mL) at 0-5 °C and stirred for 20 min. To this was added 4-methoxybenzy chloride (0.52 mL, 3.89 mmol) at 0-5 °C and heated to reflux for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice water (40 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified using silicagel column chromatography using 2% MeOH/ CH2CI2 to afford compound 476 (800 mg, 57%) as white solid. TLC: 5% MeOH/ CH2C12 (Rf. 0.6); 1H NMR (DMSO-< , 500 MHz): δ 7.64-7.59 (m, 1H), 7.53 (s, 1H), 7.51-7.44 (m, 2H), 7.41-7.35 (m, 2H), 7.22 (d, J = 8.7 Hz, 2H), 7.06 (d, J= 7.8 Hz, 1H), 6.81 (d, J= 8.7 Hz, 2H), 5.67 (d, J= 15.3 Hz, 1H), 5.21 ( br s, 1H), 4.85 (d, J = 15.3 Hz, 1H), 4.41 (s, 2H), 3.68 (s, 3H).
[000392] Synthesis of 8-(bromomethyl)-10-(4-methoxybenzyl) dibenzo [b,f\ [1, 4] thiazepin-ll(10H)-one (477): To a stirred solution of compound 476 (800 mg, 2.12 mmol) in CH2CI2 (20 mL) under argon atmosphere were added triphenyl phosphine (1.1 g, 4.24 mmol), CBr4 (0.3 mL, 3.18 mmol) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 50% EtOAc/ hexanes to afford compound 477 (600 mg, 66%) as an off-white solid. TLC: 5% MeOH/ CH2C12 (Rf 0.8); 1H NMR (DMSO-</6, 500 MHz): δ 7.73 (s, 1H), 7.63 (dd, J= 7.1 , 1.9 Hz, 1H), 7.53-7.44 (m, 2H), 7.43-7.36 (m, 2H), 7.22-7.15 (m, 3H), 6.79 (d, J= 8.7 Hz, 2H), 5.77-5.71 (m, 1H), 4.80 (d, J = 15.0 Hz, 1H), 4.60 (s, 2H), 3.67 (s, 3H).
[000393] Synthesis of 10-(4-methoxybenzyl)-8-(phenethoxymethyl)dibenzo [b,fl [1, 4] thiazepin-ll(10H)-one (479): To a stirred solution of 2-phenylethan-l-ol 477 (100 mg, 0.81 mmol) in THF (10 mL) inert atmosphere was added was added sodium hydride (60%>, 49 mg, 2.5 mmol) under portion wise for 5 min at 0 °C; warmed to RT and stirred for 2 h. To this was added compound 478 (359 mg, 0.81 mmol) at RT; heated to 65 °C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude compound 479 (150 mg) as yellow solid. TLC: 70% EtOAc/ hexanes (Rf 0.5); LC-MS: 58.75%; 482.0 (M++l); (column; Ascentis Express C 18, (50 x 3.0 mm, 2.7 μιη); RT 3.25 min. 0.025% Aq. TFA + 5% ACN: ACN +; 5% 0.025% Aq. TFA, 1.2 mL/min).
[000394] Synthesis of 8-(phenethoxymethyl) dibenzo [b,f\ [1, 4] thiazepin-ll(10H)-one (1501): A mixture of compound 479 (140 mg, crude) and trifluoro acetic acid (2 mL) under inert atmosphere at RT was heated to 80 °C and stirred for 6 h in a sealed tube. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo, the residue was quenched with 20%> aqueous sodium bicarbonate solution (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified using silicagel column chromatography using 70% EtOAc/ hexanes to afford compound 1501 (35 mg, 33%) as white solid. TLC: 70% EtOAc/ hexanes (Rf. 0.4); 1H NMR (DMSO-</6, 400 MHz): δ 10.65 (s, 1H), 7.67 (dd, J= 7.5, 1.6 Hz, 1H), 7.54-7.40 (m, 4H), 7.29-7.13 (m, 6H), 7.04 (dd, J= 7.9, 1.7 Hz, 1H), 4.44 (s, 2H), 3.63 (t, J= 6.9 Hz, 2H), 2.84 (t, J= 6.9 Hz, 2H); LC-MS: 96.49%; 361.9 (M++l); (column; Ascentis Express C18, (50 3.0 mm, 2.7 μπι); RT 2.79 min. 0.025% Aq. TFA + 5% ACN: ACN +; 5% 0.025% Aq. TFA, 1.2 mL/min); HPLC (purity): 96.59%; (column; Eclipse XDB-C-18 (150 x 4.6 mm, 5.0 μπι); RT 10.25 min. ACN: 0.025% TFA (Aq); 1.0 mL/min).
Example 37: Synthesis of 10-methyl-ll-oxo-lO, ll-dihydrodibenzo \b, f] [1, 41 thiazepine-8- carboxylic acid (486) - a common intermediate
Figure imgf000307_0001
6 486
[000395] To a stirred solution of compound 6 (500 mg, 1.84 mmol) in DMF (10 mL) was added sodium hydride (60%>, 442 mg, 18.45 mmol) under inert atmosphere at 0 °C and stirred for 1 h. To this was methyl iodide (1.14 mL, 18.45 mmol) at 0-5 °C, warmed to RT and stirred for 1.5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and washed with EtOAc (2 x 20 mL). The aqueous layer was separated and the pH was adjusted to ~2 with 4 N HC1. The precipitated solid was filtered, washed with n-hexane (10 mL) and dried in vacuo to obtain the compound 486 (400 mg, 76%) a white solid. TLC: 10% MeOH/ CH2C12 (Rf. 0.2); 1H-NMR (DMSO-</6, 500 MHz): δ 13.31 (br s, 1H), 7.99 (s, 1H), 7.75-7.68 (m, 2H), 7.65-7.61 (m, 1H), 7.54-7.49 (m, 1H), 7.44-7.39 (m, 2H), 3.53 (s, 3H).
Example 38: Synthesis of compounds from compound 486 and various commercially available amines
[000396] Compound 486 was converted to final products using commercially available or by employing Procedure A and the results are captured in the Table 2:
Figure imgf000308_0001
Table 2: Synthesis of compounds from compound 486 and various commercially available amines
Figure imgf000308_0002
Figure imgf000309_0001
Example 39: Synthesis of Compounds 1342 and 1361
Figure imgf000310_0001
[000397] Synthesis of methyl (Z)-2-((terf-butoxycarbonyl) amino)-3-(pyrimidin-5-yl) acrylate (507): To a stirred solution of methyl 2-((tert-butoxycarbonyl) amino)-2- (dimethoxyphosphoryl) acetate 506 (3.3 g, 11.11 mmol) in CH2CI2 (15 mL) under inert atmosphere was added potassium t-butoxide (13.8 mL, 13.88 mmol, 1M solution in THF), portion wise for 15 min at -30 °C. To this was added pyrimidine-5-carbaldehyde 505 (1 g, 9.25 mmol) in CH2CI2 (5 mL) drop wise for 10 min at -30 °C, stirred for 2 h; warmed to 0 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with CH2CI2 (2 x 100 mL). The combined organic extracts were washed with water (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 50% EtOAc/ hexanes to afford compound 507 (1.8 g, 72%) as an off- white solid. TLC: 70% EtOAc/ hexanes (R/. 0.8); 1H NMR (500MHz, DMSO-< ): δ 9.11 (s, 1H), 9.02 (brs, 1H), 8.98 (s, 2H), 6.46 (s, 1H), 3.76 (s, 3H), 1.42-1.38 (m, 9H).
[000398] Synthesis of methyl 2-((terf-butoxycarbonyl) amino)-3-(pyrimidin-5-yl) propanoate (508): To a stirred solution of compound 507 (1.8 g, 6.45 mmol) in MeOH (25 mL) under inert atmosphere was added 5% Pd/C (500 mg) at RT and stirred under hydrogen atmosphere (at 100 psi) for 16 h in a steel bomb. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and washed with 10% MeOH/ CH2CI2 (2 x 50 mL). The filtrate was concentrated in vacuo to obtain the crude compound 508 (1.3 g, 72%) as colorless syrup. TLC: 5% MeOH/ CH2C12 (Rf. 0.5); 1H NMR (DMSO-</6, 500 MHz): δ 9.03 (s, 1H), 8.68 (s, 2H), 7.40 (d, J= 7.8 Hz, 1H), 4.33-4.25 (m, 1H),
3.65 (s, 3H), 3.09 (dd, J= 14.4, 4.4 Hz, 1H), 2.89-2.81 (m, 1H), 1.33-1.22 (m, 9H).
[000399] Synthesis of methyl 2-amino-3-(pyrimidin-5-yl) propanoate hydrochloride (509):
To a stirred solution of compound 508 (1.3 g, 4.62 mmol) in CH2C12 (5 mL) under argon atmosphere was added 4 N HC1 in 1, 4-dioxane (5 mL) at 0 °C; warmed to RT and stirred for 3.5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to afford compound 509 (850 mg) as an off-white solid. TLC: 5% MeOH/ CH2C12 (Rf. 0.2); 1H NMR (DMSO-< , 400 MHz): δ 9.15-9.08 (m, 1H), 8.75 (s, 4H), 4.45-4.44 (m, 1H), 3.73 (s, 3H), 3.22 (dd, J= 6.6, 2.4 Hz, 2H).
[000400] Synthesis of methyl 2-(2-fluoro-ll-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamido)-3-(pyrimidin-5-yl) propanoate (1342): Using Procedure B the title compound was prepared with compound 35 (200 mg, 0.69 mmol), compound 509 (165 mg, 0.76 mmol) and was obtained in 67% yield as an off-white solid; TLC: 5% MeOH/ CH2C12 (Rf. 0.5); 1H NMR (DMSO-</6, 500 MHz): δ 10.89 (s, 1H), 8.99 (t, J= 4.0 Hz, 2H), 8.69 (s, 2H),
7.66 (d, J= 8.1 Hz, 1H), 7.61-7.56 (m, 2H), 7.52 (dd, J= 8.1, 1.4 Hz, 1H), 7.46 (dd, J= 9.1, 2.7 Hz, 1H), 7.36 (td, J= 8.4, 2.9 Hz, 1H), 4.81-4.70 (m, 1H), 3.64 (s, 3H), 3.22 (dd, J= 14.2, 4.9 Hz, 1H), 3.05 (dd, J= 14.0, 10.6 Hz, 1H); LC-MS: 98.59%; 453.4 (M++l); (column; X-select CSH CI 8, (50 x 3.0 mm, 3.5 μιη); RT 3.45 min. 0.05% Aq. TFA: ACN; 0.8 mL/min); UPLC (purity): 99.40%; (column; Acquity BEH C-18 (50 x 2.1 mm, 1.7 μ); RT 1.89 min. ACN:
0.025% TFA (Aq); 0.5 mL/min).
[000401] Synthesis of 2-fluoro- V-(l-hydroxy-3-(pyrimidin-5-yl) propan-2-yl)-ll-oxo-10, 11-dihydrodibenzo [b,j\ [1, 4] thiazepine-8-carboxamide (1361): To a stirred solution of 1342 (200 mg, 0.44 mmol) in MeOH (5 mL) under inert atmosphere was added sodium borohydride (65 mg, 1.76 mmol) at 0 °C; warmed to RT and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with ice cold water (25 mL) and extracted with 5% MeOH/ CH2CI2 (5 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 8% MeOH/ CH2CI2 to afford compound 1361 (140 mg, 75%) as an off-white solid. TLC: 10% MeOH/ CH2C12 (Rf. 0.4); 1H NMR (DMSO-</6, 400 MHz): δ 10.87 (s, 1H), 8.96 (s, 1H), 8.64 (s, 2H), 8.30 (d, J= 8.7 Hz, 1H), 7.66-7.63 (m, 1H), 7.61-7.57 (m, 2H), 7.53 (dd, J= 8.1, 1.8 Hz, 1H), 7.47 (dd, J= 9.2, 2.9 Hz, 1H), 7.37 (td, J= 8.5, 3.0 Hz, 1H), 4.93 (t, J= 5.6 Hz, 1H), 4.22-4.11 (m, 1H), 3.53-3.40 (m, 2H), 2.98 (dd, J= 13.9, 4.2 Hz, 1H), 2.73 (dd, J= 14.0, 10.1 Hz, 1H); LC-MS: 99.82%; 425.4 (M++l); (column; X-select CSH C18, (50 x 3.0 mm, 3.5 μιη); RT 3.68 min. 0.05% Aq. TFA: ACN; 0.8 mL/min); UPLC (purity): 99.77%; (column; Acquity BEH C-18 (50 x 2.1 mm, 1.7 μ); RT 1.65 min. ACN: 0.025% TFA (Aq.); 0.5 mL/min).
Example 40: Synthesis of Compound 1346
Figure imgf000312_0001
[000402] Synthesis of 2-(2-fluoro-ll-oxo-10, 11-dihydrodibenzo [b,fl [1, 4] thiazepine-8- carboxamido)-3-(pyrimidin-5-yl) propanoic acid (510): To a stirred solution of compound 1342 (150 mg, 0.33 mmol) in a mixture of THF: ¾0 (4: 1, 5 mL) was added lithium hydroxide monohydrate (35 mg, 0.82 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (3 mL) and the pH was adjusted to ~5 with 1 N HC1. The precipitated solid was filtered and dried in vacuo to afford compound 510 (75 mg, 52%>) as white solid. TLC: 10%> MeOH/ CH2CI2 (R/. 0.2); 1H NMR (DMSO </6, 400 MHz): δ 10.90 (s, 1H), 8.98 (s, 1H), 8.78 (d, J= 7.6 Hz, 1H), 8.68 (s, 2H), 7.66 (d, J= 8.0 Hz, 1H), 7.62-7.57 (m, 2H), 7.53 (dd, J= 8.1, 1.7 Hz, 1H), 7.47 (dd, J= 9.2, 2.9 Hz, 1H), 7.37 (dt, J= 8.5, 2.9 Hz, 1H), 7.40-7.34 (m, 1H), 4.69- 4.58 (m, 1H), 3.23 (dd, J= 14.1, 4.6 Hz, 1H), 3.03 (dd, J= 14.0, 10.3 Hz, 1H).
[000403] Synthesis of tert-butyl 2-(2-fluoro-ll-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamido)-3-(pyrimidin-5-yl) propanoate (1346): To a stirred solution of compound 510 (70 mg, 0.15 mmol) in t-butanol (4 mL) under inert atmosphere were added Boc- anhydride (0.11 mL, 0.47 mmol) and DMAP (30 mg, 0.03 mmol) at 5 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with CH2CI2 (2 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through preparative TLC (50% EtOAc/ hexanes) to afford 1346 (25 mg, 32%) as an off-white solid. TLC: 70% EtOAc/ hexanes (R/. 0.4); 1H NMR (DMSO-< , 400 MHz): δ 10.91 (s, 1H), 9.01 (s, 1H), 8.89 (d, J= 7.8 Hz, 1H), 8.71 (s, 2H), 7.67 (d, J= 8.0 Hz, 1H), 7.64-7.58 (m, 2H), 7.55 (dd, J = 8.0, 1.9 Hz, 1H), 7.48 (dd, J= 9.2, 2.9 Hz, 1H), 7.38 (td, J= 8.5, 2.9 Hz, 1H), 4.65-4.59 (m, 1H), 3.21-3.13 (m, 1H), 3.09-2.99 (m, 1H), 1.39-1.31 (m, 9H); LC-MS: 98.60%; 495.6 (M++l); (column; X-select CSH C18, (50 x 3.0 mm, 3.5 μιη); RT 3.91 min. 0.05% Aq. TFA: CAN; 0.8 mL/min); UPLC (purity): 98.29%; (column; Acquity BEH C-18 (50 x 2.1 mm, 1.7 μ); RT 2.15 min. CAN: 0.025% TFA (Aq); 0.5 mL/min).
Example 41: Synthesis of Compounds 1420 and 1419
Figure imgf000314_0001
[000404] Synthesis of methyl 3'-nitro-[l, l'-biphenyl]-4-carboxylate (512): To a stirred solution of methyl 4-bromobenzoate 511 (2.5 g, 14.97 mmol) and (3-nitrophenyl) boronic acid 382 (3.8 g, 17.96 mmol) in Toluene (20 mL) under inert atmosphere were added sodium carbonate (3.17 g, 29.96 mmol in 25 mL of H20) at RT and purged under argon atmosphere for 20 min. To this was added Pd(PPh3)4 (691 mg, 0.59 mmol) and heated to 80 °C for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with EtOAc (200 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% EtOAc/ hexanes to afford compound 512 (800 mg, 21 >) as yellow liquid. TLC: 15% EtOAc/ hexanes (Rf. 0.5); 1H NMR (400 MHz, CD3OD): δ 8.54-8.52 (m, 1H), 8.29-8.26 (m, 1H), 8.15 (d, J= 8.7 Hz, 2H), 8.12-8.09 (m, 1H), 7.84 (d, J= 8.6 Hz, 2H), 7.74 (t, J= 8.0 Hz, 1H), 3.94 (s, 3H).
[000405] Synthesis of methyl 3'-amino-[l, l'-biphenyl]-4-carboxylate (513): To a stirred solution of compound 512 (800 mg, 3.11 mmol) in EtOH (50 mL) under inert atmosphere was added 10% Pd/C (500 mg, wet) under argon atmosphere and stirred under H2 atmosphere (balloon pressure) for 5 h. After completion of the reaction, the reaction mixture was filtered through celite, washed with 50% MeOH/ CH2C12 (150 mL). The filtrate was concentrated in vacuo to obtain the crude which was purified through silicagel column chromatography in 5% MeOH/ CH2C12 to afford compound 513 (600 mg, 67%) as an off-white solid. The crude was carried for next step without further purification. TLC: 5% MeOH/ CH2C12 (R/. 0.4).
[000406] Synthesis of methyl 3'-(2-fluoro-ll-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamido)-[l, l'-biphenyl]-4-carboxylate (1420): Using Procedure A the title compound was prepared with 35 (50 mg, 0.17 mmol), compound 513 (43 mg, 0.19 mmol) and was obtained in 58% yield as white solid; TLC: 5% MeOH/ CH2C12 (Rf: 0.5); 1H NMR
(DMSO-< , 400 MHz): δ 10.99 (s, 1H), 10.43 (s, 1H), 8.14 (s, 1H), 8.07 (d, J= 7.9 Hz, 2H), 7.85-7.72 (m, 6H), 7.63 (dd, J= 8.6, 5.3 Hz, 1H), 7.54-7.45 (m, 3H), 7.40 (td, J= 8.5, 3.0 Hz, 1H), 3.88 (s, 3H); LC-MS: 98.86%; 498.1 (M++l); (column; X-select CSH C18, (50 x 3.0 mm, 3.5 μιη); RT 4.15 min. 0.05% Aq. TFA: ACN; 0.8 mL/min); UPLC (purity): 95.09%; (column; Acquity BEH C-18 (50 x 2.1 mm, 1.7 μ); RT 2.75 min. ACN : 0.025% TFA (Aq); 0.5 mL/min).
[000407] Synthesis of 3'-(2-fluoro-ll-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8- carboxamido)-[l, l'-biphenyl]-4-carboxylic acid (1419): To a stirred solution of 1420 (50 mg, 0.10 mmol) in MeOH: H20 (3: 1, 8 mL) was added potassium hydroxide (56 mg, 1.00 mmol) at RT in a sealed tube and heated to 90 °C and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the pH of the reaction mixture was acidified with 4 N HCl to pH ~2. The obtained solid was filtered, triturated with 10% EtOAc/ hexanes (10 mL) and dried in vacuo and to afford compound 1419 (20 mg, 41%) as an off-white solid. TLC: 70% EtOAc/ hexanes (R/. 0.2); 1H NMR (400 MHz, DMSO-< ): δ 12.98 (br s, 1H), 11.00 (s, 1H), 10.51 (s, 1H), 8.15 (s, 1H), 8.04 (d, J= 8.4 Hz, 2H), 7.87-7.70 (m, 6H), 7.63 (dd, J= 8.6, 5.3 Hz, 1H), 7.54-7.46 (m, 3H), 7.40 (td, J= 8.5,2.9 Hz, 1H); LC-MS: 91.15%; 485.0 (M++l); (column; Ascentis Express CI 8, (50 x 3.0 mm, 2.7 μπι); RT 2.48 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); UPLC (purity): 93.75%; (column; Acquity BEH C-18 (50 x 2.1 mm, 1.7 μ); RT 2.43 min. ACN : 0.025% TFA (Aq); 0.5 mL/min). Example 42: Synthesis of Compounds 1422 and 1421
Figure imgf000316_0001
[000408] Synthesis of methyl 3'-nitro-[l, l'-biphenyl]-3-carboxylate (515): To a stirred solution of methyl 3-bromobenzoate 514 (2.5 g, 14.99 mmol) and (3-nitrophenyl) boronic acid 382 (3.8 g, 17.99 mmol) in toluene (20 mL) under inert atmosphere were added sodium carbonate (3.17 g, 29.99 mmol in 20 mL of H20) at RT and purged under argon atmosphere for 20 min. To this was added Pd(PPh3)4 (693 mg, 0.59 mmol) and heated to 80 °C for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with EtOAc (200 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% EtOAc/ hexanes to afford compound 515 (1 g, 26%) as yellow liquid. TLC: 15% EtOAc/ hexanes (Rf. 0.5); 1H NMR (400 MHz, DMSO-< ): δ 8.48-8.46 (m, 1H), 8.30-8.25 (m, 2H), 8.22-8.18 (m, 1H), 8.11-8.07 (m, 1H), 8.04 (dt, J= 7.8, 1.3 Hz, 1H), 7.80 (t, J= 8.0 Hz, 1H), 7.69 (t, J= 7.8 Hz, 1H), 3.91 (s, 3H).
[000409] Synthesis of methyl 3'-amino-[l, l'-biphenyl]-3-carboxylate (516): To a stirred solution of compound 515 (1 g, 3.89 mmol) in EtOH (100 mL) under inert atmosphere was added 10% Pd/C (600 mg, wet) under argon atmosphere and stirred under H2 atmosphere (balloon pressure) for 16 h. After completion of the reaction, the reaction mixture was filtered through celite and the celite pad was washed with 50% MeOH/ CH2CI2 (150 mL). The filtrate was evaporated in vacuo to obtain the crude which was purified through silicagel column chromatography in 20% EtOAc/ hexanes to afford compound 516 (600 mg, 67%) as an off- white solid. TLC: 40% EtOAc/ hexanes (Rf 0.3); 1H NMR (400 MHz, DMSO-</6): δ 8.15- 8.08 (m, 1H), 7.92 (d, J= 7.7 Hz, 1H), 7.84 (d, J= 8.2 Hz, 1H), 7.59 (t, J= 7.7 Hz, 1H), 7.13 (t, J= 7.8 Hz, 1H), 6.90-6.87 (m, 1H), 6.81 (d, J= 7.6 Hz, 1H), 6.60 (dd, J= 8.0, 1.4 Hz, 1H), 5.22 (s, 2H), 3.32 (s, 3H).
[000410] Synthesis of methyl 3'-(2-fluoro-ll-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamido)-[l, l'-biphenyl]-3-carboxylate (1422): Using Procedure A the title compound was prepared with compound 35 (70 mg, 0.24 mmol), compound 516 (55 mg, 0.24 mmol) and was obtained in 41% yield as white solid; TLC: 5% MeOH/ CH2C12 (Rf 0.5); 1H
NMR (400 MHz, DMSO-</6): δ 10.99 (s, 1H), 10.43 (s, 1H), 8.12-8.19 (m, 1H), 8.10-8.08 (m, 1H), 7.96 (dd, J= 12.8, 7.9 Hz, 2H), 7.85 (dt, J= 7.1, 1.8 Hz, 1H), 7.81-7.73 (m, 3H), 7.69-7.59 (m, 2H), 7.54-7.45 (m, 3H), 7.40 (td, J= 8.5, 2.9 Hz, 1H), 3.90 (s, 3H); LC-MS: 99.82%; 499.0 (M+l)+; (column; X-select CSH C18, (50 x 3.0 mm, 3.5 μιη); RT 4.10 min. 0.05% Aq. TFA: ACN; 0.8 mL/min); UPLC (purity): 98.72%; (column; Acquity BEH C-18 (50 x 2.1 mm, 1.7 μ); RT 2.78 min. ACN : 0.025% TFA (Aq); 0.5 mL/min).
[000411] Synthesis of 3'-(2-fluoro-ll-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8- carboxamido)-[l, l'-biphenyl]-3-carboxylic acid (1421): To a stirred solution of 1422 (35 mg, 0.07 mmol) in MeOH: H20 (3: 1, 5 mL) under inert atmosphere was added potassium hydroxide (40 mg, 0.70 mmol) at RT in a sealed tube and heated to 80 °C and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the pH of the reaction mixture was acidified with 4 N HCl to pH ~2 and extracted with EtOAc (2 x 10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The obtained solid was filtered, dried in vacuo and triturated with 10%> EtOAc/ hexanes (10 mL) to afford compound 1421 (20 mg, 58%) as white solid. TLC: 70% EtOAc/ hexanes (Rf 0.2); 1H NMR (400 MHz, DMSO-< ): δ 12.99 (br s, 1H), 10.98 (s, 1H), 10.43 (s, 1H), 8.21-8.19 (m, 1H), 8.11-8.09 (m, 1H), 7.96 (d, J= 7.7 Hz, 1H), 7.87 (dd, J= 19.5, 7.3 Hz, 2H), 7.82-7.73 (m, 3H), 7.66-7.58 (m, 2H), 7.54-7.44 (m, 3H), 7.40 (td, J= 8.5, 2.9 Hz, 1H); LC-MS: 99.07%; 484.9 (M++l); (column; X-select CSH C18, (50 x 3.0 mm, 3.5 μπι); RT 3.73 min. 0.05% Aq. TFA: ACN; 0.8 mL/min); UPLC (purity): 96.90%; (column; Acquity BEH C-18 (50 x 2.1 mm, 1.7 μ); RT 2.46 min. ACN : 0.025% TFA (Aq); 0.5 mL/min).
Example 43: Synthesis of Compounds 1436 and 1435
Figure imgf000318_0001
[000412] Synthesis of methyl 3'-nitro-[l, l'-biphenyl]-2-carboxylate (518): To a stirred solution of methyl 2-bromobenzoate 517 (2.5 g, 14.97 mmol) and (3-nitrophenyl) boronic acid 382 (3.8 g, 17.96 mmol) in toluene (20 mL) under inert atmosphere were added sodium carbonate (3.17 g, 29.94 mmol in 20 mL of H20) at RT and purged under argon atmosphere for 20 min. To this was added Pd(PPh3)4 (691 mg, 0.59 mmol) and heated to 80 °C for 6 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with EtOAc (200 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 15% EtOAc/ hexanes to afford compound 518 (600 mg, 17%) as yellow solid. TLC: 30% EtOAc/ hexanes (Rf: 0.6); 1H NMR (400 MHz, DMSO-</6): δ 8.27-8.23 (m, 1H), 8.11-8.09 (m, 1H), 7.89 (dd, J= 7.7, 1.3 Hz, 1H), 7.79-7.67 (m, 3H), 7.59 (td, J= 7.6, 1.1 Hz, 1H), 7.52 (dd, J= 7.6, 0.6 Hz, 1H), 3.31 (s, 3H). [000413] Synthesis of methyl 3'-amino-[l, l'-biphenyl]-2-carboxylate (519): To a stirred solution of compound 518 (600 mg, 2.33 mmol) in EtOH (50 mL) under inert atmosphere was added 10% Pd/C (300 mg, wet) under argon atmosphere and stirred under H2 atmosphere (balloon pressure) for 16 h. After completion of the reaction, the reaction mixture was filtered through celite and the celite pad was washed with 50% MeOH/ CH2CI2 (100 mL). The filtrate was evaporated in vacuo to afford compound 519 (500 mg, 87%) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf 0.6); 1H NMR (400 MHz, DMSO-< ): δ 7.63 (dd, J= 7.7, 1.0 Hz, 1H), 7.56 (td, J = 9.0, 1.8 Hz, 1H), 7.43 (td, J= 7.6, 1.1 Hz, 1H), 7.37 (dd, J= 7.7, 0.8 Hz, 1H), 7.03 (t, J= 7.7 Hz, 1H), 6.57-6.52 (m, 1H), 6.52-6.49 (m, 1H), 6.39 (d, J= 7.5 Hz, 1H), 5.14 (br s, 2H), 3.59 (s, 3H).
[000414] Synthesis of methyl 3'-(2-fluoro-ll-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamido)-[l, l'-biphenyl]-2-carboxylate (1436): Using Procedure A the title compound was prepared with compound 35 (100 mg, 0.34 mmol), compound 519 (78 mg, 0.34 mmol) and was obtained in 35% yield as white solid; TLC: 5% MeOH/ CH2C12 (Rf 0.5); 1H
NMR (400 MHz, DMSO-< ): δ 10.97 (s, 1H), 10.37 (s, 1H), 7.78-7.72 (m, 6H), 7.66-7.60 (m, 2H), 7.54-7.48 (m, 2H), 7.46-7.36 (m, 3H), 7.04 (d, J= 7.3 Hz, 1H), 3.61 (s, 3H); LC-MS: 93.05%; 499.0 (M++l); (column; Ascentis Express C18, (50 x 3.0 mm, 2.7 μιη); RT 2.74 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); UPLC (purity): 91.54%; (column; Acquity BEH C-18 (50 x 2.1 mm, 1.7 μ); RT 2.72 min. ACN : 0.025% TFA (Aq); 0.5 mL/min).
[000415] Synthesis of 3'-(2-fluoro-ll-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8- carboxamido)-[l, l'-biphenyl]-2-carboxylic acid (1435): To a stirred solution of 1436 (35 mg, 0.07 mmol) in MeOH: H20 (3: 1, 8 mL) was added potassium hydroxide (40 mg, 0.70 mmol) at RT in a sealed tube and heated to 80 °C and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the pH of the reaction mixture was acidified with 4 N HCl to pH ~2 and extracted with EtOAc (2 x 10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The obtained solid was filtered, triturated with 10% EtOAc/ hexanes (5 mL) and dried in vacuo to afford compound 1435 (20 mg, 58%) as white solid. TLC: 70% EtOAc/ hexanes (Rf 0.2); 1H NMR (400 MHz, DMSO-</6): δ 11.00 (br s, 1H), 10.36 (s, 1H), 7.81-7.69 (m, 5H), 7.67-7.59 (m, 2H), 7.54-7.48 (m, 2H), 7.44-7.31 (m, 4H), 7.07 (d, J= 7.8 Hz, 1H); LC-MS: 91.40%; 484.9 (M++l); (column; Ascentis Express CI 8, (50 x 3.0 mm, 2.7 μπι); RT 2.49 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); UPLC (purity): 92.47%; (column; Acquity BEH C-18 (50 x 2.1 mm, 1.7 μ); RT 2.36 min. ACN : 0.025% TFA (Aq); 0.5 mL/min).
Example 44: Synthesis of ll-oxo-10, 11-dihydrodibenzo \b, f\ [1, 41 thiazepine-8- sulfonamide compounds
HCOONa, Pd(OAc)2, TPP,
Figure imgf000320_0001
491
[000416] To a stirred solution of compound 491 (80 mg, 0.26 mmol) in DMSO (1.5 mL) under inert atmosphere were added potassium metabisulfate (116 mg, 0.52 mmol), tetraethyl ammonium bromide (60 mg, 0.28 mmol), sodium formate (40 mg, 0.57 mmol), palladium acetate (18 mg, 0.026 mmol) and 1, 10-phenanthroline (14 mg, 0.078 mmol) at RT in a microwave vial and purged under argon atmosphere for 10 min; heated to 90 °C for 4 h. The reaction was monitored by TLC; after completion of the reaction, the crude compound was carried forward to next step. TLC: 30% EtOAc/ hexanes (R/. 0.4).
[000417] The above crude compound and commercially available amines were converted to corresponding sulfonamide employing the Procedure L and the results are captured in the Table 3.
Procedure L:
To a stirred solution of above crude compound (100 mg, crude) in THF (2 mL) under argon atmosphere were added piperidine 521 (0.05 mL, 0.54 mmol) in THF (1 mL), N- bromosuccinimide (96 mg, 0.54 mmol) in THF (1 mL) at 0 °C; warmed to RT and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with brine (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography to afford the desired compound.
Commercially available amines used for the preparation of compounds:
Figure imgf000321_0001
Table 3: Synthesis of compounds from compound 520 and various commercially available amines
Figure imgf000321_0002
Figure imgf000322_0001
Figure imgf000323_0001
Figure imgf000324_0001
Synthesis of ll-oxo-10, 11-dihydrodibenzo [ϋ,β [1, 4] thiazepine-8-sulfonyl chloride (520):
Figure imgf000325_0001
[000418] Synthesis of 8-(benzylthio) dibenzo [b,fl [1, 4] thiazepin-ll(10H)-one (527): To a stirred solution of compound 491 (1 g, 3.26 mmol) in 1, 4-dioxane (20 mL) under argon atmosphere were added phenylmethanethiol 526 (0.4 mL, 3.59 mmol), CS2CO3 (921 mg, 3.92 mmol) at RT, purged under argon atmosphere for 20 min. To this were added Pd2(dba)3 (75 mg, 0.081 mmol), Xantphos (94 mg, 1.06 mmol) at RT and heated to 110-120 °C and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered and the filtrate was removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5-40% EtOAc/ hexanes to afford compound 527 (700 mg, 61%) as pale yellow solid. TLC: 30% EtOAc/ hexanes (R/. 0.4); 1H NMR
(DMSO-< , 400 MHz): δ 10.63 (s, 1H), 7.68-7.65 (m, 1H), 7.53-7.41 (m, 4H), 7.39-7.34 (m, 2H), 7.32-7.20 (m, 3H), 7.17 (s, 1H), 7.10 (dd, J= 8.2, 2.1 Hz, 1H), 4.24 (s, 2H).
[000419] Synthesis of ll-oxo-10, 11-dihydrodibenzo [b,j [1, 4] thiazepine-8-sulfonyl chloride (520): To a stirred solution of 527 (700 mg, 2.00 mmol) in acetic acid: H20 (3: 1, 16 mL) under was added N-chlorosuccinimide (668 mg, 5.61 mmol) at 0 °C; warmed to RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with diethyl ether (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 520 (700 mg) as yellow solid. The crude compound was carried forward for next step without further purification. TLC: 20% EtOAc/ hexanes (R/. 0.6); LC-MS:
68.55%; 325.9 (M++l); column; Ascentis Express C18, (50 3.0 mm, 2.7 μπι); RT 2.51 min. 0.025% Aq. TFA + 5% ACN: ACN +; 5% 0.025% Aq. TFA, 1.2 mL/min).
Example 45: Synthesis of compounds from compound 520 and various commercially available amines
Figure imgf000326_0001
520
[000420] Compound 520 and commercially available amines were converted to corresponding sulfonamides employing Procedure M and the results are captured in Table 4.
Procedure M:
[000421] To a stirred solution of 2, 4-difluoroaniline 228 (100 mg, 0.77 mmol) in CH2C12 (5 mL) under argon atmosphere were added compound 6 (252 mg, crude), pyridine (3.87 mL, 5.26 mmol) at 0 °C; warmed to RT and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with CH2C12 (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography to afford the desired compound.
Commercially available amines used for the synthesis of compounds
Figure imgf000326_0002
Table 4: Synthesis of compounds from compound 520 and various commercially available amines
Figure imgf000326_0003
Figure imgf000327_0001
Figure imgf000328_0001
Example 46: Synthesis of Compound 1228
Figure imgf000329_0001
532 1228
[000422] Synthesis of 4-chloro- V-(2-cyclohexylethyl)-3-nitrobenzenesulfonamide (529): To a stirred solution of 2-cyclohexylethan-l -amine 261 (500 mg, 3.93 mmol) in CH2CI2 (10 mL) under inert atmosphere were added pyridine (0.9 mL), 4-chloro-3-nitrobenzenesulfonyl chloride 528 (1 g, 3.93 mmol) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with CH2CI2 (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 15% EtOAc/ hexanes to afford compound 529 (1.36 g, 52%) as yellow solid. TLC: 30% EtOAc/ hexanes (R/. 0.6); 1H-NMR (CDC13, 400 MHz): δ 8.33 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.71 (d, J= 8.4 Hz, 1H), 4.52 (t, J= 5.6 Hz, 1H), 3.03 (q, 2H), 1.69-1.56 (m, 4H), 1.40-1.35 (m, 2H), 1.28-1.08 (m, 5H), 0.89-0.83 (m, 2H).
[000423] Synthesis of methyl 2-((4-( V-(2-cyclohexylethyl) sulfamoyl)-2-nitrophenyl) thio) benzoate (530): To a stirred solution of compound 529 (200 mg, 0.57 mmol) in DMF (4 mL) under inert atmosphere was added cesium carbonate (281 mg, 0.86 mmol) at RT; heated to 40 °C, then added methyl thio salicylate (106 mg, 0.63 mmol) and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with water (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 530 (210 mg, 76%) as yellow syrup. TLC: 30%> EtOAc/ hexanes (Rf. 0.4); 1H-NMR (CDC13, 400 MHz): δ 8.67 (s, 1H), 7 '.99-7.97 (m, 1H), 7.73 (d, J= 8.4 Hz, 1H), 7.65-7.59 (m, 3H), 6.97 (d, J= 8.8 Hz, 1H), 4.44 (t, J= 6.0 Hz, 1H), 3.81 (s, 3H), 3.03-2.98 (m, 2H), 1.67-1.58 (m, 5H), 1.42-1.33 (m, 3H), 1.29-1.09 (m, 3H), 0.91-0.87 (m, 2H).
[000424] Synthesis of methyl 2-((2-amino-4-(7V-(2-cyclohexylethyl) sulfamoyl) phenyl) thio) benzoate (531): To a stirred solution of compound 530 (200 mg, 0.41 mmol) in MeOH (10 mL) under inert atmosphere was added 10%> Pd/ C (60 mg) at RT and stirred under hydrogen atmosphere (balloon pressure) for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10%) EtOAc/ Hexanes to afford compound 531 (120 mg, 64%>) as an off- white solid. TLC: 30% EtOAc/ Hexanes (Rf. 0.3); 1H-NMR (CDC13, 400 MHz): δ 8.03 (d, J = 7.6 Hz, 1H), 7.59 (d, J= 8.4 Hz, 1H), 7.30-7.29 (m, 2H), 7.21-7.16 (m, 2H), 6.71 (d, J= 8.0 Hz, 1H), 4.36 (br s, 1H), 3.97 (s, 3H), 3.04 (t, J = 6.4 Hz, 2H), 1.68-1.61 (m, 5H), 1.39-1.35 (m, 2H), 1.29-1.13 (m, 4H), 0.90-0.84 (m, 2H).
[000425] Synthesis of 2-((2-amino-4-(7V-(2-cyclohexylethyl) sulfamoyl) phenyl) thio) benzoic acid (532): To a stirred solution of compound 531 (1 10 mg, 0.24 mmol) in THF: H20 (2: 1 , 6 mL) was added lithium hydroxide monohydrate (20 mg, 0.49 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (15 mL), acidified with dil. HC1. The obtained precipitate was filtered, washed with ether (2 x 5 mL) and dried in vacuo to afford compound 532 (85 mg, 80%) as white solid. TLC: 30% EtOAc/ hexanes (Rf. 0.2); 1H-NMR (DMSO-</6, 400 MHz): δ 13.19 (br s, 1H), 7.94 (d, J= 7.6 Hz, 1H), 7.50-7.47 (m, 2H), 7.34 (t, J = 7.2 Hz, 1H), 7.24-7.18 (m, 2H), 6.94 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 5.82 (br s, 2H), 2.85-2.80 (m, 2H), 1.59-1.52 (m, 5H), 1.27-1.23 (m, 3H), 1.16-1.1 1 (m, 3H), 0.83-0.78 (m, 2H). [000426] Synthesis of V-(2-cyclohexylethyl)-ll-oxo-10, 11-dihydrodibenzo [ϋ,β [1, 4] thiazepine-8-sulfonamide (1228): To a stirred solution of compound 532 (80 mg, 0.18 mmol) in THF (5 mL) under inert atmosphere was added CDI (89 mg, 0.55 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (20 mL), acidified with dil.HCl. The obtained precipitate was filtered, washed with ether (2 x 5 mL) and dried in vacuo to afford 1228 (35 mg, 46%) as white solid. TLC: 5% MeOH/ CH2C12 (Rf. 0.6); 1H-NMR (DMSO-< , 400 MHz): δ 10.89 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.71-7.69 (m, 1H), 7.64-7.62 (m, 2H), 7.56-7.45 (m, 4H), 2.78-2.73 (m, 2H), 1.48-1.42 (m, 5H), 1.19-1.07 (m, 6H), 0.71-0.66 (m, 2H); LC-MS: 98.00%; 417.6 (M++l); (column; X-Select CSH C-18, (50 3.0 mm, 3.5 μιη); RT 4.76 min. 0.05% TFA (Aq) : ACN; 0.8 mL/min); UPLC (purity): 95.34%; (column :
Acquity BEH C-18 (50 2.1 mm, 1.7 μ); RT 2.74 min. ACN : 0.025% TFA (Aq.); 0.5 mL/min).
Example 47: Synthesis of Compound 1289
Figure imgf000331_0001
[000427] Synthesis of 4-chloro-3-nitro- V-phenethylbenzenesulfonamide (533): To a stirred solution of 2-phenylethan-l -amine 211 (250 mg, 2.06 mmol) in CH2C12 (5 mL) under inert atmosphere were added 4-chloro-3-nitrobenzenesulfonyl chloride 528 (528 mg, 2.06 mmol), pyridine (0.5 mL) at 0 °C; warmed to RT and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with CH2CI2 (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 15% EtOAc/ hexanes to afford compound 533 (410 mg, 58%) as colorless syrup. TLC: 30% EtOAc/ hexanes (Rf. 0.6); 1H-NMR (CDC13, 400 MHz): δ 8.21 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.64 (d, J= 8.4 Hz, 1H), 7.27 (s, 1H), 7.25-7.22 (m, 2H), 7.08 (d, J= 8.0 Hz, 2H), 4.59 (t, J= 6.0 Hz, 1H), 3.32 (q, 2H), 2.81 (t, J = 6.8 Hz, 2H).
[000428] Synthesis of methyl 2-((2-nitro-4-(7V-phenethylsulfamoyl) phenyl) thio) benzoate (534): To a stirred solution of compound 533 (100 mg, 0.29 mmol) in DMF (3 mL) under inert atmosphere were added methyl thio salicylate (54 mg, 0.32 mmol), cesium carbonate (143 mg, 0.44 mmol) at RT; heated to 40 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with water (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20% EtOAc/ hexanes to afford compound 534 (90 mg, 65%) as yellow solid. TLC: 30% EtOAc/ hexanes (Rf. 0.4); 1H-NMR (CDCI3, 400 MHz): δ 8.56 (s, 1H), 7.98 (t, J = 6.8 Hz, 1H), 7.64-7.60 (m, 4H), 7.23-7.20 (m, 3H), 7.07 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.4 Hz, 1H), 4.50 (t, J = 6.0 Hz, 1H), 3.80 (s, 3H), 3.28 (q, 2H), 2.79 (t, J = 6.8 Hz, 2H).
[000429] Synthesis of methyl 2-((2-amino-4-(7V-phenethylsulfamoyl) phenyl) thio) benzoate (535): To a stirred solution of compound 534 (330 mg, 0.69 mmol) in MeOH (15 mL) under inert atmosphere was added 10%> Pd/ C (100 mg) at RT and stirred under hydrogen atmosphere (balloon pressure) for 12 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite, washed with CH2CI2 (2 x 5 mL) and the filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 15%> EtOAc/ hexanes to afford compound 535 (210 mg, 68%>) as an off-white solid. TLC: 30% EtOAc/ hexanes (Rf. 0.3); 1H-NMR (CDCI3, 400 MHz): δ 8.03 (d, J= 8.0 Hz, 1H), 7.56 (d, J= 8.0 Hz, 1H), 7.28 (d, J= 8.0 Hz, 3H), 7.25-7.23 (m, 1H), 7.19- 7.1 1 (m, 5H), 6.69 (d, J = 8.0 Hz, 1H), 4.37 (t, J = 6.4 Hz, lH), 4.12 (q, 1H), 3.97 (s, 3H), 3.31 (q, 2H), 2.81 (t, J = 6.8 Hz, 2H), 2.04 (s, 1H).
[000430] Synthesis of 2-((2-amino-4-( V-phenethylsulfamoyl) phenyl) thio) benzoic acid (536): To a stirred solution of compound 535 (200 mg, 0.45 mmol) in THF: H20 (2: 1 , 6 mL) was added lithium hydroxide monohydrate (38 mg, 0.90 mmol) at RT and stirred for 16 h; heated to 40 °C and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (15 mL), acidified with dil. HC1. The obtained precipitate was filtered, washed with ether (2 x 5 mL) and dried in vacuo to afford compound 536 (130 mg, 67%) as white solid. TLC: 40%> EtOAc/ hexanes (R/. 0.2); 1H-NMR (DMSO-</6, 400 MHz): δ 7.93 (d, J= 7.6 Hz, 1H), 7.68 (t, J= 6.0 Hz, 1H), 7.47 (d, J= 8.0 Hz, 1H), 7.32-7.25 (m, 4H), 7.21-7.16 (m, 4H), 6.95 (d, J= 8.0 Hz, 1H), 6.60 (d, J = 8.4 Hz, 1H), 5.81 (br s, 2H), 3.03 (q, 2H), 2.70 (t, J = 8.0 Hz, 2H).
[000431] Synthesis of ll-oxo- V-phenethyl-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8- sulfonamide (1289): To a stirred solution of compound 536 (100 mg, 0.23 mmol) in THF (5 mL) under inert atmosphere was added CDI (1 13 mg, 0.70 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (20 mL), acidified with IN HC1. The obtained precipitate was filtered, washed with ether (2 x 5 mL) and dried in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 3-5% MeOH/ CH2C12 to afford 1289 (35 mg, 37%) as white solid. TLC: 5% MeOH/ CH2C12 (R/. 0.6); 1H-NMR (DMSO-< , 400 MHz): δ 10.86 (s, 1H), 7.81 (br s, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.71 (s, 1H), 7.59-7.45 (m, 4H), 7.18-7.14 (m, 2H), 7.1 1-7.07 (m, 3H), 2.97 (q, 2H), 2.64 (t, J= 7.6 Hz, 2H); LC-MS: 97.83%; 41 1.5 (M++l); (column; X-Select CSH C-18, (50 3.0 mm, 3.5 μπι); RT 4.33 min. 0.05% TFA (Aq): ACN; 0.8 mL/min); UPLC (purity): 98.00%; (column: Acquity BEH C-18 (50 x 2.1 mm, 1.7 μ); RT 2.43 min. ACN: 0.025% TFA (Aq); 0.5 mL/min).
Example 48: Synthesis of Compounds 1277 and 1282
Figure imgf000334_0001
1277
[000432] Synthesis of 3-(methoxycarbonyl)-ll-oxo-10, 11-dihydrodibenzo [ϋ,β [1, 4] thiazepine-8-carboxylic acid (537): To a stirred solution of dimethyl 2-((2-amino-4-(tert- butoxycarbonyl) phenyl) thio) terephthalate 130 (200 mg, 0.47 mmol) in 1, 2-dichloro ethane (10 mL) under inert atmosphere was added trifluoro acetic acid (1.09 g, 9.59 mmol) at RT; heated to 80 °C and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 6% MeOH/ CH2CI2 to afford compound 537 (60 mg, 38%) as an off-white solid. TLC: 10% MeOH/ CH2C12 (R/. 0.3); 1H-NMR (DMSO-</6, 400 MHz): δ 13.17 (br s, 1H), 10.99 (s, 1H), 8.02 (s, 1H), 7.97 (d, J= 8.0 Hz, 1H), 7.82 (d, J= 8.0 Hz, 1H), 7.79 (s, 1H), 7.70-7.65 (m, 2H), 3.86 (s, 3H).
[000433] Synthesis of methyl 8-((2-cyclohexylethyl) carbamoyl)-ll-oxo-10, 11- dihydrodibenzo [b,j\ [1, 4] thiazepine-3-carboxylate (538): To a stirred solution of compound 537 (60 mg, 0.18 mmol) in DMF (2.4 mL) under inert atmosphere were added 2- cyclohexylethan-1 -amine 261 (28 mg, 0.21 mmol), HOBt (37 mg, 0.27 mmol), EDCI. HC1 (52 mg, 0.27 mmol), diisopropyl ethyl amine (0.08 mL, 0.36 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL). The obtained solid was filtered and dried in vacuo to afford compound 538 (45 mg, 56%) as an off-white solid. TLC: 10% MeOH/ CH2C12 (Rf. 0.6); 1H- NMR (DMSO-< , 400 MHz): δ 10.94 (s, 1H), 8.46-8.45 (m, 1H), 8.02 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.81 (d, J= 8.0 Hz, 1H), 7.68 (d, J= 7.6 Hz, 2H), 7.57 (d, J= 8.4 Hz, 1H), 3.87 (s, 3H), 3.26-3.21 (m, 2H), 1.70-1.62 (m, 5H), 1.40-1.35 (m, 2H), 1.26-1.09 (m, 4H), 0.91-0.83 (m, 2H).
[000434] Synthesis of 8-((2-cyclohexylethyl) carbamoyl)-ll-oxo-10, 11-dihydrodibenzo [b, f\ [1, 4] thiazepine-3-carboxylic acid (1282): To a stirred solution of compound 538 (125 mg, 0.28 mmol) in THF: H20 (4: 1 , 5 mL) was added lithium hydroxide monohydrate (59.9 mg, 1.42 mmol) at RT and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was diluted with water (20 mL), neutralized with HC1, the obtained solid was filtered and dried in vacuo to afford 1282 (90 mg, 74%) as white solid. TLC: 10% MeOH/ CH2C12 (Rf. 0.3); 1H-NMR (DMSO-</6, 400 MHz): δ 13.44 (br s, 1H), 10.92 (s, 1H), 8.45 (t, J = 5.6 Hz, 1H), 8.00 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.79 (d, J= 8.0 Hz, 1H), 7.68-7.66 (m, 2H), 7.58-7.56 (m, 1H), 3.26-3.21 (m, 2H), 1.70-1.58 (m, 5H), 1.40-1.35 (m, 2H), 1.30-1.22 (m, 4H), 0.91 -0.83 (m, 2H). LC-MS: 99.29%; 425.9 (M++l); (column; X-Select CSH C-18, (50 3.0 mm, 3.5 μπι); RT 4.40 min. 0.05% TFA (Aq) : ACN; 0.8 mL/min); UPLC (purity): 98.94%; (column : Acquity BEH C-18 (50 x 2.1 mm, 1.7 μ); RT 2.32 min. ACN : 0.025% TFA (Aq); 0.5 mL/min).
[000435] Synthesis of V8-(2-cyclohexylethyl)- V3-methyl-ll-oxo-10, 11-dihydrodibenzo [b, β [1, 4] thiazepine-3, 8-dicarboxamide (1277): To a stirred solution of 1282 (30 mg, 0.07 mmol) in DMF (1.2 mL) under inert atmosphere were added methyl amine 306 (2 M in THF, 0.07 mL, 0.14 mmol), HATU (54.7 mg, 0.14 mmol), diisopropyl ethyl amine (0.05 mL, 0.28 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice water (10 mL). The obtained solid was filtered, washed with EtOAc (2 x 5 mL) and dried in vacuo to afford 1277 (1 1 mg, 35%) as white solid. TLC: 7% MeOH/ CH2C12 (Rf. 0.8); 1H-NMR (DMSO-< , 400 MHz): δ 10.86 (s, 1H), 8.63-8.62 (m, 1H), 8.44 (t, J = 5.2 Hz, 1H), 7.95 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.58-7.55 (m, 1H), 3.26-3.21 (m, 2H), 2.77 (s, 3H), 1.70-1.58 (m, 5H), 1.40-1.35 (m, 2H), 1.26-1.14 (m, 4H), 0.91 -0.83 (m, 2H); LC- MS: 94.12%; 438.8 (M++l); (column; X-Select CSH C-18, (50 3.0 mm, 3.5 μπι); RT 4.05 min. 0.05% TFA (Aq) : ACN; 0.8 mL/min); UPLC (purity): 98.69%; (column : Acquity BEH C-18 (50 x 2.1 mm, 1.7 μ); RT 2.28 min. ACN : 0.025% TFA (Aq); 0.5 mL/min).
Example 49: Synthesis of Compound 1278
Figure imgf000336_0001
1282 1278
[000436] Synthesis of V8-(2-cyclohexylethyl)- V3, V3-dimethyl-ll-oxo-10, 11- dihydrodibenzo [b,j\ [1, 4] thiazepine-3, 8-dicarboxamide (1278): To a stirred solution of 1282 (40 mg, 0.09 mmol) in DMF (2 mL) under inert atmosphere were added dimethylamine hydrochloride (23 mg, 0.28 mmol), HATU (73 mg, 0.18 mmol), diisopropyl ethyl amine (0.09 mL, 0.47 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (15 mL). The obtained solid was filtered, triturated with EtOAc (2 x 5 mL) and dried in vacuo to afford 1278 (19 mg, 48%) as an off-white solid. TLC: 5% MeOH/ CH2C12 (Rf. 0.6); 1H-NMR (DMSO-< , 400 MHz): δ 10.84 (s, 1H), 8.44 (t, J= 5.2 Hz, 1H), 7.72 (d, J= 8.0 Hz, 1H), 7.67-7.63 (m, 2H), 7.58-7.47 (m, 2H), 7.45 (d, J= 8.0 Hz, 1H), 3.27-3.22 (m, 2H), 2.96 (s, 3H), 2.88 (s, 3H), 1.70- 1.58 (m, 5H), 1.41-1.35 (m, 2H), 1.28-1.26 (m, 1H), 1.25-1.14 (m, 3H), 0.91-0.83 (m, 2H); LC- MS: 98.41%; 452.7 (M++l); (column; X-Select CSH C-18, (50 3.0 mm, 3.5 μπι); RT 4.11 min. 0.05% TFA (Aq) : ACN; 0.8 mL/min); UPLC (purity): 99.60%; (column : Acquity BEH C-18 (50 x 2.1 mm, 1.7 μ); RT 2.33 min. ACN : 0.025% TFA (Aq); 0.5 mL/min).
Example 50: Synthesis of Compounds 1280 and 1281
Figure imgf000337_0001
[000437] Synthesis of methyl ll-oxo-8-(phenethylcarbamoyl)-10, 11-dihydrodibenzo [ϋ,β
[1, 4] thiazepine-3-carboxylate (539): To a stirred solution of compound 537 (75 mg, 0.22 mmol) in DMF (3 mL) under inert atmosphere were added 2-phenylethan-l -amine 211 (30 mg, 0.25 mmol), HOBt (46 mg, 0.34 mmol), EDCI. HC1 (65 mg, 0.34 mmol), diisopropyl ethyl amine (0.08 mL, 0.45 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice water (20 mL). The obtained solid was filtered, washed with 20% EtOAc/ Hexanes (2 x 5 mL) and dried in vacuo to afford compound 539 (80 mg, 81%) as white solid. TLC: 7%> MeOH/ CH2C12 (Rf. 0.8); 1H-NMR (DMSO-</6, 400 MHz): δ 10.96 (s, 1H), 8.61 (t, J= 5.6 Hz, 1H), 8.02 (s, 1H), 7.97 (d, J= 8.0 Hz, 1H), 7.82 (d, J= 8.4 Hz, 1H), 7.68 (d, J= 8.0 Hz, 2H), 7.57- 7.54 (m, 1H), 7.29-7.25 (m, 2H), 7.22-7.16 (m, 3H), 3.87 (s, 3H), 3.47-3.42 (m, 2H), 2.80 (t, J = 7.2 Hz, 2H).
[000438] Synthesis of ll-oxo-8-(phenethylcarbamoyl)-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-3-carboxylic acid (540): To a stirred solution of compound 539 (80 mg, 0.18 mmol) in THF: H20 (4: 1, 3 mL) was added lithium hydroxide monohydrate (39 mg, 0.92 mmol) at RT and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (15 mL), acidified with HC1, the obtained solid was filtered, washed with 20% EtOAc/ hexanes (2 x 5 mL) and dried in vacuo to afford compound 540 (65 mg, 84%) as white solid. TLC: 10% MeOH/ CH2C12 (Rf. 0.2); 1H-NMR (DMSO-< , 400 MHz): δ 13.44 (br s, 1H), 10.94 (s, 1H), 8.62 (t, J = 5.6 Hz, 1H), 8.00 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.79 (d, J= 8.0 Hz, 1H), 7.68 (d, J= 8.0 Hz, 2H), 7.57- 7.54 (m, 1H), 7.29-7.25 (m, 2H), 7.22-7.16 (m, 3H), 3.47-3.42 (m, 2H), 2.80 (t, J = 7.2 Hz, 2H).
[000439] Synthesis of TV^methyl-ll-oxo-TV^phenethyl-lO, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-3, 8-dicarboxamide (1280): To a stirred solution of compound 540 (35 mg, 0.08 mmol) in DMF (2 mL) under inert atmosphere were added methyl amine (2 M in THF, 0.24 mL, 0.50 mmol), HATU (130 mg, 0.32 mmol), diisopropyl ethyl amine (0.10 mL, 0.50 mmol) at 0 °C; warmed to RT and stirred for 44 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice water (15 mL). The obtained solid was filtered, washed with EtOAc (2 x 5 mL) and dried in vacuo to afford 1280 (12 mg, 28%>) as white solid. TLC: 10% MeOH/ CH2C12 (Rf. 0.4); 1H-NMR (DMSO-</6, 400 MHz): δ 10.89 (s, 1H), 8.63-8.60 (m, 2H), 7.96 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.66-7.65 (m, 2H), 7.56-7.54 (m, 1H), 7.29-7.26 (m, 2H), 7.22-7.16 (m, 3H), 3.47-3.42 (m, 2H), 2.88-2.73 (m, 5H); LC-MS: 95.22%; 432.6 (M++l); (column; X-Select CSH C-18, (50 3.0 mm, 3.5 μπι); RT 3.61 min. 0.05% TFA (Aq) : ACN; 0.8 mL/min); UPLC (purity): 94.66%; (column : Acquity BEH C-18 (50 x 2.1 mm, 1.7 um); RT 1.97 min. ACN : 0.025% TFA (Aq); 0.5 mL/min).
[000440] Synthesis of TV3, TV^dimethyl-ll-oxo-TV^phenethyl-lO, 11-dihydrodibenzo [b,f\
[1, 4] thiazepine-3, 8-dicarboxamide (1281): To a stirred solution of 540 (30 mg, 0.07 mmol) in DMF (2 mL) under inert atmosphere were added dimethyl amine hydrochloride 310 (17.5 mg, 0.21 mmol), HATU (55.5 mg, 0.14 mmol), diisopropyl ethyl amine (0.07 mL, 0.35 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (10 mL). The obtained solid was filtered, washed with EtOAc (2 x 5 mL) and dried in vacuo to afford 1281 (17 mg, 53%) as an off-white solid. TLC: 5% MeOH/ CH2C12 (R/. 0.6); 1H-NMR (DMSO-< , 400 MHz): δ 10.86 (s, 1H), 8.61 (t, J = 5.2 Hz, 1H), 7.72 (d, J= 8.0 Hz, 1H), 7.67-7.64 (m, 2H), 7.57-7.53 (m, 2H), 7.46 (d, J= 8.0 Hz, 1H), 7.29-7.26 (m, 2H), 7.20-7.16 (m, 3H), 3.48-3.43 (m, 2H), 2.96 (s, 3H), 2.86 (s, 3H), 2.82-2.79 (m, 2H); LC-MS: 97.1 1%; 446.7 (M++l); (column; X-Select CSH C-18, (50 3.0 mm, 3.5 μπι); RT 3.68 min. 0.05% TFA (Aq) : ACN; 0.8 mL/min); UPLC (purity): 98.02%; (column : Acquity BEH C-18 (50 x 2.1 mm, 1.7 μ); RT 2.03 min. ACN : 0.025% TFA (Aq); 0.5 mL/min).
Example 51: Synthesis of Compounds 1225 and 1224
Figure imgf000339_0001
1225
[000441] Synthesis of phenyl (ll-oxo-10, 11-dihydrodibenzo [b,fl [1, 4] thiazepin-8-yl) carbamate (542): To a stirred solution of compound 145 (40 mg, 0.16 mmol) in CH2CI2 (3 mL) under inert atmosphere were added diisopropyl ethyl amine (0.06 mL, 0.33 mmol), phenyl carbonochloridate 541 (28 mg, 0.18 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (15 mL) and extracted with CH2CI2 (2 x 25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was triturated with 15%> EtOAc/ hexanes to afford compound 542 (50 mg, 83%>) as an off-white solid. TLC: 70% EtOAc/ Hexanes (Rf: 0.8); 1H-NMR (DMSO-< , 400 MHz): δ 10.73 (s, 1H), 10.45 (s, 1H), 7.68-7.65 (m, 1H), 7.52-7.40 (m, 7H), 7.28-7.24 (m, 2H), 7.21 (d, J = 7.6 Hz, 2H).
[000442] Synthesis of l-(2-cyclohexylethyl)-3-(ll-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepin-8-yl) urea (1225): To a stirred solution of compound 542 (50 mg, 0.13 mmol) in DMSO (3 mL) under inert atmosphere were added 2-cyclohexylethan-l -amine 161 (21 mg, 0.16 mmol), triethyl amine (0.04 mL, 0.27 mmol) at 0 °C; warmed to RT and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (15 mL). The obtained solid was filtered, washed with EtOAc (2 x 5 mL) and dried in vacuo to afford 1225 (17 mg, 31%) as white solid. TLC: 5% MeOH/ CH2C12 (Rf. 0.5); 1H-NMR (DMSO-</6, 500 MHz): δ 10.58 (s, 1H), 8.58 (s, 1H), 7.64 (d, J= 7.5 Hz, 1H), 7.48- 7.40 (m, 3H), 7.34 (d, J= 7.5 Hz, 2H), 7.13-7.11 (m, 1H), 6.10-6.07 (m, 1H), 3.08-3.04 (m, 2H), 1.67-1.57 (m, 5H), 1.31-1.11 (m, 6H), 0.86-0.84 (m, 2H); LC-MS: 95.28%; 396.4 (M++l); (column; X-Bridge C-18, (50 3.0 mm, 3.5 urn); RT 3.76 min. 0.05% TFA (Aq) : ACN; 0.8 mL/min); UPLC (purity): 96.65%; (column : Acquity UPLC BEH C-18 (2.1 x 50 mm, 1.7 μ); RT 2.65 min. ACN : 0.025% TFA (Aq); 0.5 mL/min).
Figure imgf000340_0001
[000443] In a similar manner 1224 (l-(ll-oxo-10,ll-dihydrodibenzo[b,f| [l,4]thiazepin-8- yl)-3-phenethylurea) was prepared. Yield: 27% LC-MS: 390.3 (M++l); 1H-NMR (DMSO-^, 400 MHz): δ 10.59 (s, 1H), 8.69 (s, 1H), 7.65 (d, J= 7.2 Hz, 1H), 7.49-7.41 (m, 3H), 7.35 (d, J = 7.6 Hz, 2H), 7.29 (d, J= 7.2 Hz, 2H), 7.22-7.13 (m, 4H), 6.14 (t, J= 6.0 Hz, 1H), 3.30 (s, 2H), 2.73 (t, J= 6.8 Hz, 2H).
Example 52: Synthesis of Compounds 1535 and 1536
Figure imgf000340_0002
1388 1535 1536
[000444] The racemic compound of 1388 (18 mg) was separated using a CHIRALPAK-IC column (250 x 20 mm x 5 μιη) (10 mg loading; 0.1% DEA in n-hexane: CH2C12: MeOH (50: 50) (A: B = 25: 75) as mobile phase) HPLC to afford 1535 (2.5 mg) and 1536 (2.5 mg) as off-white solids.
Compound 1535 analytical data (Fr-I):
[000445] LC-MS: 99.81%; 383.9 (M++l); (column; Ascentis Express C-18, (50 x 3.0 mm, 2.7 μπι); RT 1.69 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min). UPLC (purity): 96.76%; (column; Acquity UPLC BEH C-18 (50 x 2.1 mm, 1.7 μ); RT 1.49 min. ACN: 0.025% TFA (Aq); 0.5 mL/min). Chiral HPLC: 99.16%, Rt= 99.16 min (Chiralpak- IC, 250 x 4.6 mm, 5 μπι); mobile phase (A) 0.1% DEA in n-Hexane (B) CH2C12: MeOH (50: 50) (A: B:: 25: 75); Flow Rate: 1.0 mL/min).
Compound 1536 analytical data (Fr-II):
[000446] LC-MS: 99.39%; 383.9 (M++l); (column; Ascentis Express C-18, (50 x 3.0 mm, 2.7 μπι); RT 1.70 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min). UPLC (purity): 99.56%; (column; Acquity UPLC BEH C-18 (50 x 2.1 mm, 1.7 μ); RT 1.49 min. ACN: 0.025% TFA (Aq); 0.5 mL/min). Chiral HPLC: 98.30%, Rt= 13.33 min (Chiralpak- IC, 250 x 4.6 mm, 5 μπι); mobile phase (A) 0.1% DEA in n-Hexane (B) CH2C12: MeOH (50: 50) (A: B:: 25: 75); Flow Rate: 1.0 mL/min).
Example 53: Synthesis of Compound 1206
Figure imgf000341_0001
1206
[000447] Synthesis of V-(2-cyclohexylethyl)-ll-oxo-10, 11-dihydrodibenzo [ϋ,β [1, 4] thiazepine-8-carboxamide (545): To a stirred solution of 6 (100 mg, 0.36 mmol) in DMF (6 mL) under argon atmosphere were added EDCI.HC1 (105 mg, 0.54 mmol), HOBt (74 mg, 0.54 mmol), 2-cyclohexylethan-l -amine 261 (56 mg, 0.44 mmol), and diisopropyl ethyl amine (95 mg, 0.73 mmol) at 0-5 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water (20 mL), filtered and washed with water (2 x 5 mL) to obtain the crude. The crude was triturated with EtOAc (2 x 5 mL) to afford 545 (70 mg, 50%) as white solid. TLC: 5% MeOH/ CH2C12 (Rf. 0.5); 1H-NMR (DMSO-</6, 400 MHz): δ 10.75 (s, 1H), 8.43 (t, J= 5.6 Hz, 1H), 7.69-7.62 (m, 3H), 7.56-7.43 (m, 4H), 3.26-3.21 (m, 2H), 1.70-1.58 (m, 5H), 1.40-1.35 (m, 2H), 1.28-1.09 (m, 4H), 0.91-0.83 (m, 2H).
[000448] Synthesis of 7V-(2-cyclohexylethyl)-ll-oxo-10, 11-dihydrodibenzo [b,f\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (1206): To a stirred solution of 545 (40 mg, 0.10 mmol) in chloroform (20 mL) under inert atmosphere was added m-chloro perbenzoic acid (36.3 mg, 0.21 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with saturated sodium bicarbonate solution (15 mL) and extracted with CH2C12 (2 x 20 mL). The combined organic extracts were washed with water (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 30%> EtOAc/ hexanes to afford 1206 (16 mg, 37%) as white solid. TLC: 5% MeOH/ CH2C12 (Rf. 0.4); 1H-NMR
(DMSO-</6, 400 MHz): δ 11.49 (s, 1H), 8.63 (t, J= 4.8 Hz, 1H), 8.04-7.96 (m, 3H), 7.91-7.83 (m, 2H), 7.77 (t, J= 6.4 Hz, 2H), 3.25-3.24 (m, 2H), 1.71-1.58 (m, 5H), 1.42-1.37 (m, 2H), 1.28- 1.14 (m, 4H), 0.92-0.84 (m, 2H); LC-MS: 97.31%; 413.2 (M++l); (column; X-bridge C-18, (50 3.0 mm, 3.5 μιη); RT 3.78 min. 0.05% TFA in water: ACN; 0.8 mL/min); UPLC (purity): 96.73%; (column : Acquity UPLC BEH C-18 (2.1 x 50 mm, 1.7 μ); RT 2.52 min. ACN : 0.025% TFA (Aq); 0.5 mL/min).
Example 54: Synthesis of Compound 1656
Figure imgf000343_0001
1656
[000449] Synthesis of tert-butyl (4-bromophenethyl) carbamate (547): To a stirred solution of 2-(4-bromophenyl) ethan-1 -amine 546 (500 mg, 2.50 mmol) in CH2CI2 (5 mL) under argon atmosphere were added Boc-anhydride (594 mg, 2.75 mmol), diisopropyl ethyl amine (1 mL, 7.50 mmol) at RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with CH2CI2 (2 x 35 mL). The combined organic extracts were washed with water (25 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5-8% EtOAc/ hexanes to afford compound 547 (500 mg, 65%) as white solid. TLC: 10% EtOAc/ hexanes (R/. 0.5); 1H-NMR (DMSO-< , 400 MHz): δ 7.46 (d, J= 8.0 Hz, 2H), 7.12 (d, J= 8.0 Hz, 2H), 6.86-6.82 (m, 1H), 3.12-3.08 (m, 2H), 2.68-2.64 (m, 2H), 1.32 (s, 9H).
[000450] Synthesis of tert-buty\ (4-((trimethylsilyl) ethynyl) phenethyl) carbamate (548):
To a stirred solution of compound 547 (500 mg, 1.66 mmol) in DMF (10 mL) under argon atmosphere were added ethynyltrimethylsilane (1.8 mL, 16.66 mmol), triethyl amine (2.32 mL, 16.66 mmol) and purged under argon for 15 min. To this were added Pd(PPh3)2Cl2 (118 mg, 0.16 mmol), copper iodide (33 mg, 0.16 mmol) and purged under argon for 15 min; heated to 70 °C and stirred for 48 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude which was purified through silica gel column chromatography using 10% EtOAc/ hexanes to afford compound 548 (500 mg, 95%>) as brown syrup. TLC: 10% EtOAc/ hexanes (Rf. 0.6); 1H-NMR (DMSO-< , 400 MHz): δ 7.38 (d, J= 8.0 Hz, 2H), 7.18 (d, J= 8.0 Hz, 2H), 6.85 (t, J= 7.2 Hz, 1H), 3.16-3.11 (m, 2H), 2.70-2.66 (m, 2H), 1.34 (s, 9H), 0.23 (s, 9H).
[000451] Synthesis of terf-butyl (4-ethynylphenethyl) carbamate (549): To a stirred solution of compound 548 (500 mg, 1.70 mmol) in THF (5 mL) under argon atmosphere was added TBAF (2.08 mL, 2.08 mmol) in THF (3 mL) at RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude which was purified through silica gel column chromatography using 5-10% EtOAc/ hexanes to afford compound 549 (450 mg, 95%>) as brown syrup. TLC: 10%> EtOAc/ hexanes (Rf. 0.4); 1H-NMR (DMSO-< , 500 MHz): δ 7.39 (d, J= 7.5 Hz, 2H), 7.20 (d, J= 7.5 Hz, 2H), 6.87-6.85 (m, 1H), 4.10 (s, 1H), 3.15-3.12 (m, 2H), 2.71-2.69 (m, 2H), 1.30 (s, 9H).
[000452] Synthesis of terf-butyl (4-(l-benzyl-lH-l, 2, 3-triazol-5-yl) phenethyl) carbamate (551): To a stirred solution of compound 549 (200 mg, 0.82 mmol) in MeOH: DMF (1 : 1, 20 mL) under argon atmosphere were added (azidomethyl) benzene 550 (410 mg, 3.06 mmol), copper iodide (202 mg, 1.02 mmol) at RT; heated to reflux and stirred for 18 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude which was purified through silica gel column chromatography using 30%> EtOAc/ hexanes to afford compound 551 (200 mg, 68%) as white solid. TLC: 30% EtOAc/ hexanes (Rf. 0.3); 1H-NMR (DMSO-</6, 500 MHz): δ 8.59 (s, 1H), 7.75 (d, J= 8.5 Hz, 2H), 7.41-7.34 (m, 5H), 7.25 (d, J= 8.0 Hz, 2H), 6.90-6.88 (m, 1H), 5.64 (s, 2H), 3.17-3.13 (m, 2H), 2.70 (t, J= 7.5 Hz, 2H), 1.36 (s, 9H).
[000453] Synthesis of 2-(4-(l-benzyl-lH-l, 2, 3-triazol-5-yl) phenyl) ethan-l-amine (552):
To a stirred solution of compound 551 (190 mg, 0.50 mmol) in CH2C12 (4 mL) under argon atmosphere was added trifluoro acetic acid (1 mL) at RT and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude to obtain compound 552 (180 mg, crude) as dark brown syrup which was carried to the next step without any purification. TLC: 100% EtOAc (R/. 0.2); 1H-NMR
(DMSO-</6, 400 MHz): δ 8.61 (s, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.78-7.76 (m, 3H), 7.39-7.32 (m, 6H), 5.64 (s, 2H), 3.09-3.04 (m, 2H), 2.87 (t, J = 7.6 Hz, 2H).
[000454] Synthesis of V-(4-(l-benzyl-lH-l, 2, 3-triazol-5-yl) phenethyl)-ll-oxo-10, 11- dihydrodibenzo [b,j\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (553): To a stirred solution compound 552 (200 mg, 0.66 mmol) in DMF (10 mL) under argon atmosphere were added EDCI. HC1 (189 mg, 0.98 mmol), HOBt (189 mg, 0.98 mmol), compound 6 (297 mg, 0.79 mmol), diisopropyl ethyl amine (0.35 mL, 1.98 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with EtOAc (2 x 50 mL) washed with water (50 mL), brine, dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude compound was purified through column chromatography using 2% MeOH/ CH2CI2 to afford compound 553 (180 mg, 49%) as an off-white solid. TLC: 5% MeOH/ CH2C12 (Rf. 0.5); 1H NMR (DMSO-< , 400 MHz): δ 1 1.46 (br s, 1H), 8.80 (t, J = 5.5 Hz, 1H), 8.56 (s, 1H), 8.03 (d, J = 8.3 Hz, 1H), 8.00- 7.95 (m, 2H), 7.92-7.83 (m, 2H), 7.79 (s, 1H), 7.75 (d, J = 8.2 Hz, 3H), 7.42-7.31 (m, 5H), 7.29 (d, J= 8.3 Hz, 2H), 5.63 (s, 2H), 3.50 (q, J = 6.8 Hz, 2H), 2.85 (t, J= 7.2 Hz, 2H).
[000455] Synthesis of V-(4-(lH-l, 2, 3-triazol-5-yl) phenethyl)-ll-oxo-10, 11- dihydrodibenzo [b,j\ [1, 4] thiazepine-8-carboxamide 5, 5-dioxide (1656): To a stirred solution of compound 553 (180 mg, 0.31 mmol) in DMSO (10 mL) under argon atmosphere was added potassium tertiary butoxide (1 M in THF, 2.5 mL, 2.55 mmol) at RT. The reaction mixture was stirred under oxygen atmosphere (balloon pressure) for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude compound was purified through column chromatography using 2% MeOH/ CH2C12, lyophilized and washed EtOAc (5 mL), filtered , washed with n-pentane (5 mL)and dried in vacuo to afford 1656 (20 mg, 13%) as white solid. TLC: 5% MeOH/ CH2C12 (R/. 0.3); 1H NMR (DMSO-</6, 400 MHz): δ 14.91 (br s, 1H), 11.52 (br s, 1H), 8.81 (t, J= 5.5 Hz, 1H), 8.21 (br s, 1H), 8.04 (d, J= 8.3 Hz, 1H), 8.01- 7.95 (m, 2H), 7.92-7.85 (m, 2H), 7.82-7.73 (m, 4H), 7.31 (d, J = 7.9 Hz, 2H), 3.51 (q, J = 6.6 Hz, 2H), 2.86 (t, J = 7.1 Hz, 2H); LC-MS: 96.04%; 473.9 (M++l); (column; Ascentis Express C-18, (50 x 3.0 mm, 2.7 μιη); RT 2.01 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min). HPLC (purity): 95.54%; (column; Zorbax SB C-18 (150 x 4.6 mm, 3.5 μιη); RT 7.59 min. ACN: 0.05% TFA (Aq); 1.0 mL/min).
Example 55: Synthesis of compounds from compound 575 using various commercially available amines
[000456] Readily available acids similar to 575, 576 and 577 were converted to the desired compounds using commercially available amines employing Procedures A and B and the results are captured in Tables 5 and 6.
Carbon bridged compounds:
Figure imgf000346_0001
Table 5: Synthesis of compounds from compound 575 using various commercially available amines
Figure imgf000346_0002
Figure imgf000347_0001
1H), 7.43 (d, J
= 7.9 Hz, 1H), 7.38 (d, .7= 6.9 Hz, 1H), 7.33 (td, /= 7.6, 1.6 Hz, 1H), 4.64 (d, .7= 5.7 Hz, 2H), 3.96 (s, 2H);
Oxygen-bridged compounds:
Figure imgf000348_0001
Table 6: Synthesis of compounds from compound 576 and various commercially available amines
Figure imgf000348_0002
Figure imgf000349_0001
Nitrogen-bridged compounds:
Figure imgf000349_0002
577 1602
[000457] Synthesis of ll-oxo- V-(thiazol-5-ylmethyl)-10, ll-dihydro-5H-dibenzo [b, e] [1, 4] diazepine-8-carboxamide (1602): Using Procedure A the title compound was prepared using compound 577 (35 mg, 0.13 mmol) and thiazol-5-ylmethanamine hydrochloride 213 (20 mg, 0.13 mmol) and diisopropyl ethyl amine (0.05 mL, 0.27 mmol) and was obtained in 31% yield as an off-white solid; TLC: 5% MeOH/ CH2C12 (Rf. 0.5); 1H-NMR (DMSO-</6, 400 MHz): δ 9.89 (s, IH), 8.99-8.94 (m, 2H), 8.15 (s, IH), 7.79 (s, IH), 7.69 (dd, J = 7.8, 1.3 Hz, IH), 7.50 -7.42 (m, 2H), 7.38-7.32 (m, IH), 7.00 (dd, J = 10.9, 8.3 Hz, 2H), 6.91 (t, J = 7.4 Hz, IH), 4.63 (d, J = 5.6 Hz, 2H); LC-MS: 93.15%; 351.0 (M++l); column; Ascentis Express C18, (50 x 3.0 mm, 2.7 μιη); RT 1.76 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); UPLC (purity): 93.21%; (column; Acquity BEH C-18 (50 x 2.1 mm, 1.7 μ); RT 1.57 min.
ACN: 0.025% TFA (Aq); 0.5 mL/min).
Example 56: Assay Measuring Activity of Compounds on Viral Production in and on Viability of AD38 Cells
[000458] AD38 cells grown in a 175 cm flask with "Growth Medium" (DMEM/F12 (1 : 1) (cat# SH30023.01, Hyclone, IX Pen/step (cat#: 30-002-CL, Mediatech, Inc), 10% FBS (cat#: 101, Tissue Culture Biologies), 250 μg/mL G418 (cat#: 30-234-CR, Mediatech, Inc), 1 μg/mL Tetracycline (cat#: T3325, Teknova)) were detached with 0.25% trypsin. Tetracycline-free "treatment medium" (15 mL DMEM/F12 (1 : 1) (cat# SH30023.01, Hyclone, lx Pen/step (cat#: 30-002-CL, Mediatech, Inc), with 2% FBS, Tet-system approved (cat#: 631106, Clontech) were then added to mix and spun at 1300 rpm for 5 min. Pelleted cells were then re- suspended/washed with 50 mL of IX PBS 2 times and 10 mL Treatment Medium one time. AD38 cells were then re-suspended with 10 mL of Treatment Medium and counted. Wells of a collagen coated 96-well NUNC microtiter plate were seeded at 50,000/well in 180 μΐ, of
Treatment Medium, and 20 μΐ^ of in treatment media with either 10% DMSO (Control) or a 10X solution of compound in 10%> DMSO was added. Plates were incubated for 6 days at 37 °C.
[000459] Viral load production was assayed by quantitative PCR of the core sequence. Briefly, 5 μΐ^ of clarified supernatant was added to a PCR reaction mixture that contained forward primers HBV-f 5'-CTGTGCCTTGGGTGGCTTT-3', Reverse primers HBV-r 5*- AAGGAAAGAAGTC AGAAGGC AAAA-3 ' and Fluorescent TaqMan™ Probes HBV-probe 5'- FAM/AGCTCCAAA/ZEN/TTCTTTATAAGGGTCGATGTCCATG/3IABkFQ -3' in Quanta Biosciences PerfeCTa® qPCR Toughmix®, and was subsequently on an Applied Biosystems VIIA7 in a final volume of 20 μΐ^. The PCR mixture was incubated at 45 °C for 5 minutes, then 95 °C for 10 min, followed by 40 cycles of 10 seconds at 95 °C and 20 seconds at 60 °C. Viral load was quantitated against known standards by using ViiA™ 7 Software. Viral load in the supernatant from wells with treated cells were compared against viral load in supernatant from DMSO control wells (> 3 per plate).
[000460] At the end of compound treatment period cell viability was assessed using a Promega CellTiter-Glo protocol. All supernatant was removed the previously treated 96-well microtiter plate, and 50 μΐ^ Tetracycline-free treatment medium (DMEM/F12 (1 : 1), lx Pen/step (cat#: 30- 002-CL, Mediatech, Inc), with 2% FBS, Tet-system approved (cat#: 631 106, Clontech), and 1% DMSO was added back to each well. Another 50 of CellTiter-Glo reagent solution
(Promega, G7573) was then added at room temperature and the contents mixed for 2 minutes on an orbital shaker to induce cell lysis. This was followed by incubation at room temperature for 10 minutes to stabilize the luminescent signal. The luminescence was recorded for 0.2 seconds per well on a Tecan multimode platereader (Infinite Ml 000 pro). The luminescent signal from each well was normalized against that of untreated (DMSO) control wells. All results were reported percent viability (with controls being 100%).
Table 7
Figure imgf000351_0001
1120 7 94
1121 6 109
1122 21 86
1123 62 95
1124 80 99
1125 20 108
1127 22 94
1130 2 101
1133 94 99
1149 5 118
1150 1 22
1151 1 50
1152 1 45
1154 90 50
1155 18 103
1156 16 106
1157 1 48
1158 37 120
1159 8 92
1160 2 105
1161 1 99
1162 61 99
1163 3 104
1164 27 103
1165 5 82
1166 10 119
1167 57 124
1168 10 117 1169 39 107
1170 1 95
1171 49 103
1172 51 107
1173 39 105
1174 35 109
1175 30 123
1176 2 104
1177 47 118
1182 13 55
1183 2 36
1184 1 0
1185 1 0
1186 1 39
1187 1 73
1188 4 83
1189 1 85
1190 1 70
1191 14 121
1192 3 81
1193 4 90
1194 1 45
1195 0 48
1196 2 95
1197 1 88
1198 3 60
1199 19 109
1200 18 125 1201 1 50
1202 7 107
1203 3 89
1204 2 97
1205 2 89
1206 10 106
1207 24 99
1208 1 1 103
1209 1 102
1210 25 1 16
121 1 1 106
1212 1 72
1213 2 55
1214 2 94
1216 1 125
1217 1 37
1218 12 104
1219 5 100
1220 2 94
1221 19 106
1222 32 100
1223 2 28
1224 3 65
1225 10 87
1226 1 80
1227 10 92
1228 22 101
1229 45 76 1230 46 102
1231 12 93
1232 42 94
1233 1 93
1234 3 79
1235 6 61
1237 4 66
1238 26 104
1239 33 106
1240 26 92
1241 12 86
1242 91 78
1243 20 1 18
1244 14 103
1245 1 101
1246 6 96
1247 8 103
1248 3 106
1249 34 108
1250 14 1 13
1251 8 99
1252 14 94
1253 15 103
1256 1 102
1257 26 1 13
1258 12 105
1259 1 1 84
1260 8 100 1264 8 104
1266 1 74
1267 77 93
1268 77 106
1269 63 107
1270 1 94
1271 6 100
1272 24 102
1273 6 96
1274 1 1 88
1275 3 93
1276 24 89
1277 43 89
1278 3 88
1279 55 84
1280 74 94
1281 29 86
1282 102 105
1283 1 97
1285 3 108
1286 36 1 14
1287 1 1 96
1288 5 49
1289 40 96
1290 33 94
1291 1 102
1293 95 97
1308 1 99 1309 1 107
1310 1 89
131 1 8 95
1312 5 83
1313 17 108
1314 69 101
1315 4 103
1316 32 89
1317 50 95
1318 14 70
1319 16 83
1320 43 93
1321 15 74
1322 28 94
1323 96 60
1324 10 24
1325 26 90
1326 23 95
1328 54 105
1329 62 109
1330 41 109
1331 43 88
1332 70 103
1333 20 73
1334 33 83
1335 87 104
1336 70 90
1337 77 91 1338 70 1 18
1339 113 70
1340 64 1 16
1342 113 95
1343 8 91
1344 96 102
1345 115 93
1346 105 97
1347 3 94
1348 0 107
1349 12 102
1353 50 97
1354 98 70
1356 3 101
1357 39 1 15
1358 15 72
1361 79 1 13
1362 19 98
1364 1 102
1365 2 105
1366 12 93
1367 33 88
1370 5 94
1371 6 94
1372 60 103
1373 10 100
1374 1 98
1375 1 1 89 1376 3 63
1377 5 65
1381 40 93
1382 47 1 17
1383 1 87
1384 4 79
1385 26 51
1386 61 95
1387 2 78
1388 5 71
1389 15 89
1390 2 92
1391 2 71
1392 2 85
1393 41 87
1394 55 94
1395 64 79
1396 63 95
1397 73 95
1398 5 60
1399 105 92
1400 34 105
1401 31 79
1402 12 81
1403 15 82
1405 14 94
1407 3 103
1408 17 94 1409 4 83
1410 35 50
141 1 66 91
1412 48 87
1413 92 78
1414 39 89
1415 27 77
1417 1 1 75
1418 12 73
1419 113 89
1420 29 86
1421 78 95
1422 64 95
1423 37 91
1424 65 96
1427 7 85
1428 28 93
1429 38 90
1430 56 92
1431 115 92
1432 79 91
1433 82 94
1434 85 96
1435 77 99
1436 10 104
1440 71 91
1441 28 90
1442 65 99 1443 64 95
1444 6 65
1445 24 38
1446 3 84
1447 1 85
1448 3 85
1449 2 86
1450 73 94
1451 30 92
1452 15 62
1453 48 97
1454 27 95
1455 3 89
1456 15 101
1457 28 92
1458 12 49
1459 4 92
1462 35 99
1463 31 97
1464 49 98
1465 39 106
1466 7 88
1467 1 92
1468 76 97
1471 16 97
1472 37 95
1473 81 97
1474 51 101 1475 47 107
1476 1 86
1477 67 16
1478 2 94
1480 72 95
1481 46 100
1482 46 98
1483 65 98
1484 26 100
1485 30 96
1486 53 94
1487 15 96
1488 84 97
1490 7 79
1491 39 80
1492 39 79
1493 51 80
1494 115 60
1495 9 77
1496 2 18
1497 9 49
1498 1 82
1499 2 84
1501 37 71
1503 40 87
1505 81 85
1506 72 85
1507 1 1 96 1508 31 81
1509 15 29
1510 62 82
151 1 38 85
1512 27 99
1513 2 82
1514 13 84
1515 2 82
1516 30 82
1517 2 78
1518 67 85
1519 73 81
1520 1 81
1521 1 22
1522 1 82
1523 1 70
1524 2 18
1525 78 85
1526 57 92
1527 19 1 16
1528 4 85
1529 12 1 1 1
1530 70 93
1531 53 96
1532 17 1 12
1533 2 105
1534 5 109
1535 108 85 1536 2 120
1537 36 98
1540 12 87
1541 1 1 1 17
1542 34 95
1543 72 90
1544 40 97
1545 59 88
1546 65 89
1547 16 90
1548 28 85
1549 7 109
1550 1 87
1551 51 91
1552 64 93
1553 86 93
1555 36 81
1556 67 86
1557 54 86
1558 51 88
1559 68 92
1560 13 92
1561 8 1 18
1562 25 89
1563 41 93
1564 10 1 19
1565 4 103
1566 31 91 1567 1 109
1568 1 100
1569 1 114
1570 2 115
1571 35 117
1572 5 116
1573 46 126
1574 78 109
1575 90 108
1576 8 108
1577 6 120
1578 33 100
1580 59 89
1581 3 97
1582 8 112
1583 41 121
1584 52 95
1585 66 87
1586 23 112
1587 78 92
1588 0 98
1589 1 85
1590 1 96
1591 13 111
1592 50 102
1593 3 133
1594 4 109
1595 3 108 1597 64 87
1598 61 93
1599 72 101
1600 12 108
1601 62 106
1602 38 116
1603 6 91
1604 0 105
1605 25 106
1606 7 104
1607 14 93
1608 63 103
1609 68 99
1611 0 130
1612 0 112
1613 0 122
1614 2 45
1615 32 123
1616 5 115
1617 1 118
1618 0 44
1619 12 122
1620 3 111
1621 1 117
1622 0 120
1623 1 128
1624 1 136
1625 2 111 1626 0 1 18
1627 5 1 15
1628 17 138
1629 3 95
1631 9 1 12
1632 2 122
1633 66 124
1634 45 125
1635 1 93
1636 0 1 1 1
1637 32 123
INCORPORATION BY REFERENCE
[000461] All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.
EQUIVALENTS
[000462] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.
[000463] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention.

Claims

1. A compound represented by:
Figure imgf000368_0001
Formula wherein:
T is selected from the group consisting of -C(O)-, -CH2-C(0)-, -N(C(0)-CH3)-, -NH-, - 0-, and -S(0)z-, where z is 0, 1 or 2;
Y is C(RU)2 , S(0)y, NRY and O wherein y is 0, 1 , or 2;
RY is selected from the group consisting of H, methyl, ethyl, propyl, phenyl and benzyl;
RL is selected from the group consisting of H, methyl, and -C(0)-Ci_3alkyl;
L is a bond or Ci_4 straight chain alkylene optionally substituted by one or two substituents each independently selected from the group consisting of methyl (optionally substituted by halogen or hydroxyl), ethenyl, hydroxyl, NR'R", phenyl, heterocycle, and halogen and wherein the Ci_4 straight chain alkylene may be interrupted by an -0-;
R is selected from the group consisting of H, phenyl or naphthyl (wherein the phenyl or naphthyl may be optionally substituted with one, two , three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R" , -C(O)- NR'R" , - C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, phenyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R" , C(O)- NR'R" , -C(0)-Ci_6alkyl, -C(O)- Ci_6alkoxy, -S(0)w-Ci_6alkyl (where w is 1 , 2 or 3), S(0)W-NR'R" (where w is 1 , 2 or 3),-NR'- S(0)w, and -S(0)W-NR'R" (where w is 1 , 2 or 3)), heteroaryl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", C(O)- NR'R", -C(0)-Ci_6alkyl, -C(O)- Ci_6alkoxy, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), NR'-S(0)w, and -S(0)w-NR'R"(where w is 1, 2 or 3)), C3-6cycloalkyl, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), -S(0)w-NR'R" (where w is 1, 2 or 3), and -NR'-S(0)w, (where w is 1, 2 or 3)),
5-6 membered heteroaryl having one, two, or three heteroatoms each independently selected from O, N and S (wherein the 5-6 membered heteroaryl may be optionally substituted on a carbon with one, two , three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, phenyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", C(O)- NR'R", -C(0)-Ci_6alkyl, -C(0)-OH, -C(0)-Ci_6alkoxy, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), -NR'-S(0)w, and -S(0)w-NR'R"(where w is 1, 2 or 3)), heteroaryl, heterocycle, NR'R", - C(O)- NR'R", -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), -NR'- S(0)w, and -S(0)w-NR'R"(where w is 1, 2 or 3), and on a nitrogen by R'),
Ci_6alkyl, Ci_6alkoxy, C2_6alkenyl, C3_iocycloalkyl (optionally substituted with one, two , three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, NR'R", -C(O)- NR'R", =CNR', Ci_6alkyl, Ci_6alkoxy, -C(0)-Ci_6alkyl, and -C(0)-Ci_ 6alkoxy, and wherein the C3_iocycloalkyl may optionally be a bridged cycloalkyl)), and a 4-6 membered heterocycloalkyl having one or two heteroatoms each independently selected from O, N and S (wherein the 4-6 membered heterocycloalkyl may be optionally substituted with one, two , three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, NR'R", -C(O)- NR'R", Ci_6alkyl, Ci_6alkoxy, -C(0)-Ci_6alkyl, and -C(0)-Ci_ 6alkoxy);
R' is selected, independently for each occurrence, from H, methyl, ethyl, propyl, phenyl, and benzyl;
R' ' is selected, independently for each occurrence, from H, methyl, ethyl, propyl, butyl, carboxybenzyl, -C(0)-methyl and -C(0)-ethyl, or R' and R' ' taken together may form a 4-6 membered heterocycle; each of moieties R4, R5, R6, R7, R8, R9, R10, and R11 are independently selected for each occurrence from the group consisting of hydrogen, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, halogen, hydroxyl, nitro, cyano, NR'R", -C(O)- NR'R", -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), -NR'- S(0)w> and -S(0)w-NR'R"(where w is 0, 1 or 2), Ci_6alkoxy,-C(0)-OH, -C(0)-Ci_6alkyl, and - C(0)-Ci_6alkoxy; wherein for each occurrence, Ci_6alkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C2-6alkenyl, C2-6alkynyl, Ci_6alkoxy, phenyl, NR'R", -C(O)- NR'R", S(0)w-methyl (where w is 1, 2 or 3), -NR'-S(0)w, and S(0)w-NR'R"(where w is 0, 1 or 2); Ci_6alkoxy may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, phenyl, NR'R", -C(O)- NR'R", S(0)w-Ci_6alkyl (where w is 1, 2 or 3), -NR'-S(0)w, and S(0)w-NR'R" (where w is 0, 1 or 2); and C3_6cycloalkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, Ci_ ealkoxy, -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, and NR'R"; and pharmaceutically acceptable salts thereof.
2. The compound of claim 1, wherein L is -CH2-.
3. The compound of claim 1, wherein L is C2_3alkylene.
4. The compound of claim 1, wherein L is selected from the group consisting of-CH2-CH2- , -CH2(CH2)-CH2-, -CH2-CH2(OH)-, -CH2-CH2(CH3OH)-, and -CH2-CH2(OH)-CH2-.
5. The compound of claim 1, wherein L is a bond.
6. The compound of claim 1, wherein L is - C2_3alkylene-0-.
7. The compound of claim 1, wherein L is -0-.
8. The compound of any one of claims 1-7, wherein Y is S(0)y or NRy.
9. The compound of any one of claims 1-8, wherein Y is S(0)y.
10. The compound of any one of claims 1-9, wherein Y is S. 2
11. The compound of any one of claims 1-10, wherein R is phenyl or 5-6 membered
heteroaryl.
12. The compound of any one of claims 1-11, wherein R is phenyl.
13. The compound of any one of claims 1-12, wherein R is phenyl substituted by one or two substituents each selected from the group consisting of fluorine, chlorine, Ci_6alkyl (optionally substituted by one, two or three fluorines), Ci_6alkoxy (optionally substituted by one, two or three fluorines), hydroxyl, NR'R", -S(0)2-NR'R", heteroaryl, and phenyl (optionally substituted by halogen or hydroxyl).
14. The compound of claim 12, wherein R is phenyl substituted by an 5-6 membered
heteroaryl selected from the group consisting of:
Figure imgf000371_0001
2
15. The compound of claim 14, wherein R is phenyl substituted by
Figure imgf000371_0002
2
16. The compound of any one of claims 1-11, wherein R is a 5-6 membered heteroaryl.
2
17. The compound of claim 16, wherein R is selected from the group consisting of:
Figure imgf000372_0001
2
18. The compound of claim 16 or 17 wherein R is selected from the group consisting of:
Figure imgf000372_0002
wherein
R 32 is selected from the group consisting of H, halogen, phenyl, and Ci_6alkyl (optionally substituted by one, two or three halogens);
R 52 is selected from the group consisting of H, halogen, phenyl, and Ci_6alkyl (optionally substituted by one, two or three halogens);
R 42 is selected from the group consisting of H, halogen, phenyl, Ci_6alkyl (optionally substituted by one, two or three halogens), Ci_6alkoxy (optionally substituted by one, two or three halogens), NH2, -OCH3, NHCH3, and N(CH3)2.
42
19. The compound of claim 18, wherein R is independently selected for each occurrence from the group consisting of H, methyl, ethyl, propyl, -CF3, -CH2CH3, CI, F, phenyl, - NH2, -OCH3, NHCH3, and N(CH3)2.
20. The compound of claim 17 or 18, wherein R is optionally substituted on a carbon by a substitutent selected from the group consisting of fluorine, chlorine, phenyl, -NH2, NH Ci_6alkyl, and N(Ci_6alkyl)2, Ci_6alkyl, and Ci_6alkoxy. 2
21. The compound of any one of claims 1-10, wherein R is a 4-6 membered
heterocycloalkyl or C4_6cycloalkyl.
22. The compound of claim 21, wherein R is selected from the group of: tetrahydropyranyl, tetrahydrofuran, cyclopentane, cyclohexane, and cyclobutane.
23. The compound of claim 22, wherein R2 is selected from the group consisting of:
Figure imgf000373_0001
Y is S(0)y, wherein y is 0, 1, 2;
L is a bond or Ci_4 straight chain alkylene optionally substituted by one or two substituents each independently selected from the group consisting of methyl (optionally substituted by halogen or hydroxyl), hydroxyl and halogen;
R is selected from phenyl optionally substituted with one, two , three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_ 6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", -C(O)- NR'R", -C(0)-Ci_6alkyl, -C(0)-Ci_ 6alkoxy, phenyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_ ealkoxy, NR'R", C(O)- NR'R", -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), NR'-S(0)w, and -S(0)w-NR'R"(where w is 1, 2 or 3)), 5-6 membered heteroaryl having one, two, or three heteroatoms each independently selected from O, N and S (optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, Ci_6alkyl, C2-6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", C(O)- NR'R", -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, -S(0)w-Ci_6alkyl (where w is 1 , 2 or 3), -NR'-S(0)w, and -S(0)w-NR'R"(where w is 1 , 2 or 3)), C3_6cycloalkyl, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), S(0)w-NR'R" (where w is 1 , 2 or 3),-and -NR'-S(0)w, (where w is 1 , 2 or 3)), and a 5-6 membered heteroaryl having one, two, or three heteroatoms each independently selected from O, N and S (wherein the 5-6 membered heteroaryl may be optionally substituted on a carbon with one, two , three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, phenyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", C(O)- NR'R", -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, -S(0)w-Ci_6alkyl (where w is 1 , 2 or 3), S(0)w- NR'R" (where w is 1 , 2 or 3),-NR'-S(0)w, and -S(0)w-NR'R"(where w is 1 , 2 or 3)), heteroaryl, heterocycle, NR'R", -C(O)- NR'R", -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, -S(0)w-Ci_ 6alkyl (where w is 1 , 2 or 3),-NR'-S(0)w, and -S(0)w-NR'R"(where w is 1 , 2 or 3), and on a nitrogen by R');
R' is selected, independently for each occurrence, from H, methyl, ethyl, and propyl,
R' ' is selected, independently for each occurrence, from H, methyl, ethyl, propyl, butyl, - C(0)-methyl and -C(0)-ethyl, or R' and R' ' taken together may form a 4-6 membered heterocycle; each of moieties R4, R5, R6, R7, R8, R9, R10, and R11 are independently selected for each occurrence from the group consisting of hydrogen, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, halogen, hydroxyl, nitro, cyano, NR'R", -C(O)- NR'R", -S(0)w-Ci_6alkyl (where w is 1 , 2 or 3), NR'- S(0)w, and S(0)w-NR'R" (where w is 0, 1 or 2), Ci_6alkoxy,-C(0)-OH, -C(0)-Ci_6alkyl, and - C(0)-Ci_6alkoxy; wherein for each occurrence, Ci_6alkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, phenyl, NR'R", -C(O)- NR'R", S(0)w-methyl (where w is 1, 2 or 3), -NR'-S(0)w, and S(0)w-NR'R"(where w is 0, 1 or 2); Ci_6alkoxy may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, phenyl, NR'R", -C(O)- NR'R", S(0)w-Ci_6alkyl (where w is 1, 2 or 3), -NR'-S(0)w, and S(0)w-NR'R" (where w is 0, 1 or 2); and C3_6cycloalkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, Ci_ 6alkoxy, -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, and NR'R".
25. The compound of any one of claims 1-24, wherein R7 is selected from H and F.
26. The compound of any one of claims 1-25, wherein R6 is selected from H and F.
27. The compound of any one of claims 1-26, wherein R5 is selected from H and F.
28. The compound of any one of claims 1-27, wherein R10 is selected from the group
consisting of H, methyl and F.
29. The compound of any one of claims 1-28, wherein each of R4, R5, R6, R7, R8, R9, R10, and R11 are H.
30. A compound represented by:
Figure imgf000375_0001
wherein
Rm and Rm are each independently selected from the group consisting of H, halogen, Ci_ 6alkyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), NR'R", and hydroxyl;
22
R is selected for each occurrence from the group consisting of H, halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, C2-6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", -C(0)-Ci_6alkyl, - C(0)-Ci_6alkoxy, phenyl, heteroaryl, C3_6cycloalkyl, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), - S(0)w-NR'R" (where w is 1, 2 or 3), and -NR'-S(0)w, (where w is 1, 2 or 3));
R' is selected, independently for each occurrence, from H, methyl, ethyl, and propyl; R' ' is selected, independently for each occurrence, from H, methyl, ethyl, propyl, butyl, - C(0)-methyl and -C(0)-ethyl, or R' and R' ' taken together with the nitrogen to which they are attached may form a 4-6 membered heterocycle; each of moieties R4, R5, R6, R7, R8, R9, and R10 is independently selected for each occurrence from the group consisting of hydrogen, Ci_6alkyl, C2-6alkynyl, C2-6alkenyl, halogen, hydroxyl, nitro, cyano, and NR'R"; wherein for each occurrence, Ci_6alkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", -NR'-S(0)w, and S(0)w-NR'R"; Ci_ 6alkoxy may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, NR'R", -NR'-S(0)w, and S(0)w-NR'R"; C3-6cycloalkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_ 6alkyl, Ci_6alkoxy, -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, and NR'R"; phenyl may be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, Ci_6alkyl, C2_6alkenyl, C2-6alkynyl, Ci_6alkoxy, NR'R", C(O)- NR'R", -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), NR'-S(0)w, and -S(0)w-NR'R"(where w is 1 , 2 or 3), and heteroaryl may be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, Ci_6alkyl, C2-6alkenyl, C3-6cycloalkyl, C2-6alkynyl, Ci_6alkoxy, NR'R", C(O)- NR'R", -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), NR'-S(0)w, and - S(0)w-NR'R"(where w is 1, 2 or 3)), C3-6cycloalkyl; and pharmaceutically acceptable salts thereof.
31. The compound of claim 30, wherein R7 is selected from H and F.
32. The compound of claim 30 and 31, wherein R6 is selected from H and F.
33. The compound of any one of claims 30-32, wherein R5 is selected from H and F.
34. The compound of any one of claims 30-33, wherein R10 is selected from the group
consisting of H, methyl and F.
35. The compound of any one of claims 30-34 wherein each of R4, R5, R6, R7, R8, R9, R10, and Ru are H.
36. The compound of claim 30, wherein the compound is represented by:
Figure imgf000377_0001
37. The compound of claim 30, wherein the compound is represented by:
Figure imgf000377_0002
38. The compound of any one of claims 30-37, wherein R is selected from the group consisting of:
Figure imgf000377_0003
22
39. The compound of any one of claims 30-38, wherein R is phenyl.
40. A compound represented by:
Figure imgf000378_0001
wherein
Y is C(RU)2 , S(0)y, NRY and O wherein y is 0, 1, or 2;
RY is selected from the group consisting of H, methyl, ethyl, propyl, phenyl and benzyl;
Rm and Rm are each independently selected from the group consisting of H, halogen, Ci_ 6alkyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), C2_6alkenyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), NR'R", and hydroxyl;
R62 is selected for each occurrence from the group consisting of H, halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", -C(0)-Ci_6alkyl, - C(0)-Ci_6alkoxy, phenyl, heteroaryl, C3_6cycloalkyl, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), - S(0)w-NR'R" (where w is 1, 2 or 3), and -NR'-S(0)w, (where w is 1, 2 or 3));
R' is selected, independently for each occurrence, from H, methyl, ethyl, and propyl;
R' ' is selected, independently for each occurrence, from H, methyl, ethyl, propyl, butyl, - C(0)-methyl and -C(0)-ethyl, or R' and R' ' taken together with the nitrogen to which they are attached may form a 4-6 membered heterocycle; each of moieties R4, R5, R6, R7, R8, R9, and R10 is independently selected for each occurrence from the group consisting of hydrogen, Ci_6alkyl, C2_6alkynyl, C2_6alkenyl, halogen, hydroxyl, nitro, cyano, and NR'R"; wherein for each occurrence, Ci_6alkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", -NR'-S(0)w, and S(0)w-NR'R"; Ci_ 6alkoxy may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, NR'R", -NR'-S(0)w, and S(0)w-NR'R"; C3_6cycloalkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_ 6alkyl, Ci_6alkoxy, -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, and NR'R"; phenyl may be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, Ci_6alkyl, C2-6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", C(O)- NR'R", -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), NR'-S(0)w and -S(0)w-NR'R"(where w is 1 , 2 or 3), and heteroaryl may be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", C(O)- NR'R", -C(0)-Ci_ ealkyl, -C(0)-Ci_6alkoxy, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), NR'-S(0)w, and -S(0)w- NR'R"(where w is 1, 2 or 3)), and C3_6cycloalkyl; and pharmaceutically acceptable salts thereof.
41. The compound of claim 40, wherein R7 is selected from H and F.
42. The compound of claim 40 or 41, wherein R6 is selected from H and F.
43. The compound of any one of claims 40-42, wherein R5 is selected from H and F.
44. The compound of any one of claims 40-43, wherein R10 is selected from the group
consisting of H, methyl and F.
45. The compound of any one of claims 40-44 wherein each of R4, R5, R6, R7, R8, R9, R10, and R11 are H.
46. The compound of any one of claims 40-45, wherein Y is S.
47. A compound represented by:
Figure imgf000379_0001
wherein
Y is C(RU)2 , S(0)Y, NRY and O wherein y is 0, 1, or 2;
RY is selected from the group consisting of H, methyl, ethyl, propyl, phenyl and benzyl;
RM and RM are each independently selected from the group consisting of H, halogen, Ci_ 6alkyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), C2_6alkenyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), NR'R", and hydroxyl;
RC is H or Ci_6alkyl;
72
R is selected for each occurrence from the group consisting of H, halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R" , -C(0)-Ci_6alkyl, - C(0)-Ci_6alkoxy, phenyl, heteroaryl, C3_6cycloalkyl, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), - S(0)W-NR'R" (where w is 1, 2 or 3), and -NR' -S(0)W, (where w is 1, 2 or 3));
R' is selected, independently for each occurrence, from H, methyl, ethyl, and propyl;
R' ' is selected, independently for each occurrence, from H, methyl, ethyl, propyl, butyl, - C(0)-methyl and -C(0)-ethyl, or R' and R' ' taken together with the nitrogen to which they are attached may form a 4-6 membered heterocycle; each of moieties R4, R5, R6, R7, R8, R9, and R10 is independently selected for each occurrence from the group consisting of hydrogen, Ci_6alkyl, C2_6alkynyl, C2_6alkenyl, halogen, hydroxyl, nitro, cyano, and NR'R" ; wherein for each occurrence, Ci_6alkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R" , -NR'-S(0)W, and S(0)W-NR'R" ; Ci_ 6alkoxy may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, NR'R", -NR'-S(0)W, and S(0)W-NR'R"; C3_6cycloalkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_ 6alkyl, Ci_6alkoxy, -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, and NR'R" ; phenyl may be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, Ci_6alkyl, C2-6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", C(O)- NR'R", -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), NR'-S(0)w and -S(0)w-NR'R"(where w is 1 , 2 or 3), and heteroaryl may be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", C(O)- NR'R", -C(0)-Ci_ ealkyl, -C(0)-Ci_6alkoxy, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), NR'-S(0)w, -S(0)w- NR'R"(where w is 1, 2 or 3)), and C3_6cycloalkyl, and pharmaceutically acceptable salts thereof.
48. The compound of claim 47, wherein Rc is H or methyl.
49. The compound of claim 47 or 48, wherein Rc is H.
50. The compound of any one of claims 47-49, wherein R7 is selected from H and F.
51. The compound of any one of claims 47-50, wherein R6 is selected from H and F.
52. The compound of any one of claims 47-51, wherein R5 is selected from H and F.
53. The compound of any one of claims 47-52, wherein R10 is selected from the group
consisting of H, methyl and F.
54. The compound of any one of claims 47-53 wherein each of R4, R5, R6, R7, R8, R9, R10, and R11 are H.
55. The compound of any one of claims 47-54, wherein Y is S.
56. A compound represented by:
Figure imgf000381_0001
wherein Y is C(RU)2 , S(0)y, NRY and O wherein y is 0, 1, or 2;
RY is selected from the group consisting of H, methyl, ethyl, propyl, phenyl and benzyl;
Rm and Rm are each independently selected from the group consisting of H, halogen, Ci_ 6alkyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), C2_6alkenyl (optionally substituted by one, two or three substituents each independently selected from halogen and hydroxyl), NR'R", and hydroxyl;
Rc is H or Ci_6alkyl;
78
R is selected from the group consisting of H, halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, phenyl, heteroaryl, C3_6cycloalkyl, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), -S(0)w-NR'R" (where w is 1, 2 or 3), and -NR'-S(0)w, (where w is 1, 2 or 3));
79
R is selected from the group consisting of H, halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, phenyl, heteroaryl, C3_6cycloalkyl, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), -S(0)w-NR'R" (where w is 1, 2 or 3), and -NR'-S(0)w, (where w is 1, 2 or 3));
R' is selected, independently for each occurrence, from H, methyl, ethyl, and propyl;
R' ' is selected, independently for each occurrence, from H, methyl, ethyl, propyl, butyl, - C(0)-methyl and -C(0)-ethyl, or R' and R' ' taken together with the nitrogen to which they are attached may form a 4-6 membered heterocycle; each of moieties R4, R5, R6, R7, R8, R9, and R10 is independently selected for each occurrence from the group consisting of hydrogen, Ci_6alkyl, C2_6alkynyl, C2_6alkenyl, halogen, hydroxyl, nitro, cyano, and NR'R"; wherein for each occurrence, Ci_6alkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, C2_6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", -NR'-S(0)w, and S(0)w-NR'R"; Ci_ 6alkoxy may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_6alkyl, NR'R", -NR'-S(0)w, and S(0)w-NR'R"; C3_6cycloalkyl may be optionally substituted with one, two, three or more substituents selected from the group consisting of halogen, hydroxyl, nitro, cyano, carboxy, Ci_ 6alkyl, Ci_6alkoxy, -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, and NR'R"; phenyl may be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, Ci_6alkyl, C2-6alkenyl, C2_6alkynyl, Ci_6alkoxy, NR'R", C(O)- NR'R", -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), NR'-S(0)w, and -S(0)w-NR'R"(where w is 1, 2 or 3), and heteroaryl may be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, Ci_6alkyl, C2_6alkenyl, C2_6alkynyl, C3-6cycloalkyl, Ci_6alkoxy, NR'R", C(O)- NR'R", -C(0)-Ci_6alkyl, -C(0)-Ci_6alkoxy, -S(0)w-Ci_6alkyl (where w is 1, 2 or 3), NR'-S(0)w, and - S(0)w-NR'R"(where w is 1, 2 or 3), and pharmaceutically acceptable salts thereof.
57. The compound of claim 56, wherein Rc is H or methyl.
58. The compound of claim 56 or 57, wherein Rc is H.
59. The compound of any one of claims 56-58, wherein R7 is selected from H and F.
60. The compound of any one of claims 56-59, wherein R6 is selected from H and F.
61. The compound of any one of claims 56-60, wherein R5 is selected from H and F.
62. The compound of any one of claims 56-61, wherein R10 is selected from the group
consisting of H, methyl and F.
63. The compound of any one of claims 56-62 wherein each of R4, R5, R6, R7, R8, R9, R10, and R11 are H.
64. A compound selected from the group consisting of compounds in Table 1, 2, 3, 4, 5, and 6, and pharmaceutically acceptable salts thereof.
65. A pharmaceutically acceptable composition comprising a compound of any one of claims 1-64, and a pharmaceutically acceptable excipient.
66. A method of treating a hepatitis B infection in a patient in need thereof, comprising
administering an effective amount of a compound of any one of claims 1-64.
67. A method of treating a hepatitis B infection in a patient in need thereof, comprising administering a first compound selected from a compound of claims 1-64, and optionally administering a one or more additional compounds each selected from a compound of claims 1-63.
68. A method of treating a hepatitis B infection in patient in need thereof, comprising
administering an amount of a compound of any one of claims 1-64, and administering another HBV capsid assembly promoter.
69. A method of treating a hepatitis B infection in a patient in need thereof, comprising administering a first compound selected from any one of claims 1-64, and one or more other HBV agent each selected from the group consisting of HBV capsid assembly promoters, HBF viral polymerase interfering nucleosides, viral entry inhibitors, HBsAg secretion inhibitors, disruptors of nucleocapsid formation, cccDNA formation inhibitors, antiviral core protein mutant, HBc directed transbodies, R Ai targeting HBV R A, immunostimulants, TLR-7/9 agonists, cyclophilin inhibitors, HBV vaccines, SMAC mimetics, epigenetic modulators, kinase inhibitors, and STING agonists.
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