WO2017015496A1 - Methods of preparing cytotoxic benzodiazepine derivatives - Google Patents

Methods of preparing cytotoxic benzodiazepine derivatives Download PDF

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Publication number
WO2017015496A1
WO2017015496A1 PCT/US2016/043406 US2016043406W WO2017015496A1 WO 2017015496 A1 WO2017015496 A1 WO 2017015496A1 US 2016043406 W US2016043406 W US 2016043406W WO 2017015496 A1 WO2017015496 A1 WO 2017015496A1
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Prior art keywords
formula
compound
reacting
reagent
protecting group
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PCT/US2016/043406
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French (fr)
Inventor
Baudouin GÉRARD
Manami Shizuka
Michael Louis Miller
Richard A. Silva
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Immunogen Inc
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Immunogen Inc
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Priority to DK16745961.9T priority Critical patent/DK3325483T3/en
Priority to AU2016297608A priority patent/AU2016297608B2/en
Priority to ES16745961T priority patent/ES2764548T3/en
Priority to EP16745961.9A priority patent/EP3325483B1/en
Priority to EP22195446.4A priority patent/EP4163284A1/en
Priority to HRP20192289TT priority patent/HRP20192289T1/en
Priority to CA2992082A priority patent/CA2992082A1/en
Priority to PL16745961T priority patent/PL3325483T3/en
Priority to LTEP16745961.9T priority patent/LT3325483T/en
Priority to SI201630578T priority patent/SI3325483T1/en
Priority to CN201680053093.1A priority patent/CN108026103B/en
Priority to RU2018105756A priority patent/RU2727151C2/en
Priority to IL294651A priority patent/IL294651B2/en
Priority to EP19200626.0A priority patent/EP3653628B1/en
Priority to KR1020247012991A priority patent/KR20240055903A/en
Application filed by Immunogen Inc filed Critical Immunogen Inc
Priority to IL283355A priority patent/IL283355B/en
Priority to KR1020187005041A priority patent/KR102660070B1/en
Priority to JP2018502791A priority patent/JP6787995B2/en
Priority to IL305989A priority patent/IL305989A/en
Priority to SM20200004T priority patent/SMT202000004T1/en
Priority to RS20191647A priority patent/RS59806B1/en
Publication of WO2017015496A1 publication Critical patent/WO2017015496A1/en
Priority to IL256861A priority patent/IL256861B/en
Anticipated expiration legal-status Critical
Priority to CY20191101364T priority patent/CY1122553T1/en
Priority to IL276630A priority patent/IL276630B/en
Priority to AU2021202403A priority patent/AU2021202403B2/en
Priority to AU2023201339A priority patent/AU2023201339A1/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • 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
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to novel methods for preparing cytotoxic indolinobenzodiazepine derivatives .
  • cell-binding agent conjugates of indolinobenzodiazepine dimers that have one imine functionality and one amine functionality display a much higher therapeutic index (ratio of maximum tolerated dose to minimum effective dose) in vivo compared to previously disclosed benzodiazepine derivatives having two imine functionalities.
  • the previously disclosed method for making the indolinobenzodiazepine dimers with one imine functionality and one amine functionality involves partial reduction of indolinobenzodiazepine dimers having two imine functionalities.
  • the partial reduction step generally leads to the formation of fully reduced by-product and unreacted starting material, which requires cumbersome purification step and results in low yield.
  • indolinobenzodiazepine dimers that are more efficient and suitable for large scale manufacturing process.
  • the present invention provides various methods for preparing
  • indolinobenzodiazepine dimer compounds and their synthetic precursors Compared to the previously disclosed method, the methods of the present invention can produce the desired dimer compounds with higher yield without the need of cumbersome purification steps. These methods are more suitable for large scale manufacturing process.
  • the present invention provides a method of preparing a compound of formula (2d),
  • said method comprising introducing an alcohol protecting group onto one of the primary alcohols of a compound of formula (Id) by reacting the compound of formula (Id) with an alcohol protecting reagent,
  • Pi is the alcohol protecting group; and Rioo is (Ci-C 3 )alkoxy.
  • the present invention provides a method of preparing a compound of formula (3d),
  • Pi is an alcohol protecting group
  • Xi is a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester, and an activated ester (preferably, Xi is -Br, -I, or a sulfonate ester); and Rioo is (Ci-C3)alkoxy.
  • the present invention provides a method of preparing a compound of formula (4d),
  • Pi is an alcohol protecting group
  • X 1 is a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester, and an activated ester (preferably, X 1 is -Br, -I, or a sulfonate ester); and Rioo is (Ci-C 3 )alkoxy.
  • the present invention provides a method of preparing a compound of formula (5d),
  • the present invention provides method of preparing a compound of formula (6d),
  • the present invention provides a method of preparing a compound of formula (7d),
  • X 2 is a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester, and an activated ester (preferably, X 2 is -Br, -I, or a sulfonate ester); and Rioo is (Ci-C 3 )alkoxy.
  • the present invention provides a method of preparing a compound of formula (7d")
  • Pi' is an acid labile alcohol protecting group
  • X 2 ' is -Br or -I
  • Rioo is (Ci-C 3 )alkoxy.
  • the present invention provides a method of preparing a compound of formula (Id'),
  • a pharmaceutically acceptable salt thereof comprising reacting a compound of formula (7d) with a monomer compound of the formula (ai), wherein Rioo is (Ci-C3)alkoxy; and, X 2 is a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester, and an activated ester (preferably, X 2 is -I, or a sulfonate ester).
  • the present invention provides a method of forming compound of formula (Id'),
  • Xi and X 2 are each independently a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester, and an activated ester (preferably, X 1 and X 2 are each independently -Br, -I, or a sulfonate ester); and Rioo is (Ci-C 3 )alkoxy.
  • the present invention provides a method of preparing a compound of formula (Id'),
  • the present invention provides a method of preparing a compound of formula (9d),
  • the present invention provides a method of preparing a compound of formula (lOd),
  • X 2 is -Br, -I, -CI, a sulfonate ester, and an activated ester (preferably, X 2 is -Br, -I, or a sulfonate ester); and Rioo is (Ci-C3)alkoxy.
  • the present invention provides a method of preparing a compound of formula (18d),
  • X 2 is a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester, and an activated ester (preferably, X 2 is -Br, -I, or a sulfonate ester);
  • P 3 is H or P 2 ;
  • P 2 is an amine protecting group; and
  • Rioo is (Ci-C 3 )alkoxy.
  • the present invention provides a method of preparing a compound of formula (Id'),
  • the present invention provides a method of preparing a compound of formula (Id'),
  • Xi is -Br, -I, a sulfonate ester or an activated ester (preferably, X 1 is -Br, -I, or a sulfonate ester); and Rioo is (Ci-C 3 )alkoxy.
  • the present invention provides a method of preparing a compound of formula (10d'),
  • Xi is -Br, -I, -CI, a sulfonate ester, and an activated ester (preferably, Xi is -Br,
  • the present invention provides a method of preparing a compound of formula (7d'),
  • the present invention provides a method of preparing a compound of formula (Id'),
  • the present invention provides a method of preparing a compound of formula (Id'),
  • the present invention provides a method of preparing a compound of formula (Id'),
  • X 1 is -Br, -I, -CI, a sulfonate ester, or an activated ester (preferably, X 1 is -Br, I, or a sulfonate ester);
  • P 3 is H or an amine protecting group; and
  • Rioo is (Ci-C 3 )alkoxy.
  • the present invention provides a method of preparing a compound of formula (13d),
  • Pi is an alcohol protecting group
  • X 3 is -CI
  • Rioo is (Ci-C 3 )alkoxy.
  • the present invention provides a method of preparing a compound of formula (14d),
  • the present invention provides a method of preparing a compound of formula (15d):
  • X 3 is -CI;
  • X 4 is a sulfonate ester or an activated ester (preferably, X 4 is a sulfonate ester); and
  • Rioo is (Ci-C 3 )alkoxy.
  • the present invention provides a method of preparing a compound of formula (20d):
  • the present invention provides a method of preparing a compound of formula (16d):
  • X 3 is -CI;
  • X 4 is a sulfonate ester or an activated ester (preferably, X 4 is a sulfonate ester); and
  • Rioo is (Ci-C 3 )alkoxy.
  • the present invention provides a method of preparing a compound of formula (16d),
  • the present invention provides a method of preparing a compound of formula (16d),
  • the present invention provides a method of preparing a compound of formula (18d):
  • the present invention provides a method for preparing a compound of formula (17d):
  • X 3 is -CI
  • X 4 is a sulfonate ester or an activated ester (preferably, X 4 is a sulfonate ester)
  • P 3 is H or an amine protecting group
  • Rioo is (Ci-C 3 )alkoxy.
  • the present invention provides a method of preparing a compound of formula (17d),
  • the present invention provides a method of preparing a compound of formula (17d):
  • the present invention provides a method of preparing a compound of formula (17d'):
  • the present invention provides a method of preparing a compound of formula (18d),
  • the present invention provides a thirty-fifth embodiment
  • X 3 is -CI
  • X 4 is a sulfonate ester or an activated ester (preferably, a sulfonate ester)
  • Pi is an alcohol protecting group
  • P 3 is H or an amine protecting group
  • Rioo is (Ci-C 3 )alkoxy.
  • the present invention provides a method of preparing a compound of formula (18d),
  • the present invention provides a method of preparing a com ound of formula (18d),
  • the present invention provides a method of preparing a compound of formula (18d),
  • X 3 is -CI
  • X 4 is a sulfonate ester or an activated ester (preferably, a sulfonate ester)
  • Pi is an alcohol protecting group
  • P 3 is H or an amine protecting group
  • Rioo is (Ci-C 3 )alkoxy.
  • the present invention provides method of preparing a compound of formula 18d),
  • the present invention provides a method of preparing a compound of formula (18d),
  • the present invention provides a method of preparing a compound of formula (Id'),
  • the present invention provides a method of preparing a compound of formula (Id'),
  • the present invention provides a method of preparing a com ound of formula (Id'),
  • the present invention provides a method of
  • FIGs. 1-13 show exemplary schemes for the methods of the present invention.
  • Alkyl refers to a saturated linear or branched-chain monovalent hydrocarbon radical of one to twenty carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-methyl-l -propyl, - CH 2 CH(CH 3 )2), 2-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl 3-pentyl, 2-methyl-2- butyl, 3-methyl-2-butyl, 3 -methyl- 1 -butyl, 2-methyl-l -butyl, 1-hexyl), 2-hexyl, 3-hexyl,
  • the alkyl has one to ten carbon atoms. More preferably, the alkyl has one to four carbon atoms.
  • Aryl means a monovalent aromatic hydrocarbon radical of 6-18 carbon atoms derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Some aryl groups are represented in the exemplary structures as "Ar.” Aryl includes bicyclic radicals comprising an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic carbocyclic or heterocyclic ring.
  • Typical aryl groups include, but are not limited to, radicals derived from benzene (phenyl), substituted benzenes, naphthalene, anthracene, indenyl, indanyl, 1,2-dihydronapthalene, 1,2,3,4-tetrahydronapthyl, and the like.
  • aryl is phenyl group.
  • halo or halogen refers to F, CI, Br or I. In one embodiment, the halogen is Br or I.
  • cytotoxic dimer compound are used interchangeably. They are intended to include compounds for which a structure or formula or any derivative thereof has been disclosed in the present invention or a structure or formula or any derivative thereof that has been incorporated by reference.
  • the term also includes, stereoisomers, geometric isomers, tautomers, solvates, metabolites, salts (e.g. , pharmaceutically acceptable salts) and prodrugs, and prodrug salts of a compound of all the formulae disclosed in the present invention.
  • the term also includes any solvates, hydrates, and polymorphs of any of the foregoing.
  • precursor of a given group refers to any group which may lead to that group by any deprotection, a chemical modification, or a coupling reaction.
  • chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • stereoisomer refers to compounds which have identical chemical constitution and connectivity, but different orientations of their atoms in space that cannot be interconverted by rotation about single bonds.
  • Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as crystallization, electrophoresis and chromatography.
  • Enantiomers refer to two stereoisomers of a compound which are non- superimposable mirror images of one another.
  • the compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention.
  • Many organic compounds exist in optically active forms, i.e. , they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s).
  • d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory.
  • these stereoisomers are identical except that they are mirror images of one another.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereo selection or stereospecificity in a chemical reaction or process.
  • racemic mixture and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • tautomer or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • the term "imine reducing reagent” refers to a reagent that is capable of reducing an imine functional group to an amine functional group.
  • the imine reducing reagent is a hydride reducing reagent.
  • examples of such imine reducing reagents include, but are not limited to, borohydrides (e.g.
  • the imine reducing reagent is sodium triacetoxy borohydride.
  • protecting group refers to a substituent that is commonly employed to block or protect a particular functionality while reacting other functional groups on the compound, a derivative thereof, or a conjugate thereof.
  • an "amine protecting group” or an “amino-protecting moiety” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound.
  • Such groups are well known in the art (see for example P. Wuts and T. Greene, 2007, Protective Groups in Organic Synthesis, Chapter 7, J.
  • carbamates such as methyl and ethyl carbamate, FMOC, substituted ethyl carbamates, carbamates cleaved by l,6-P-elimination (also termed "self immolative"), ureas, amides, peptides, alkyl and aryl derivatives.
  • Suitable amino- protecting groups include, but are not limited to, acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethylenoxycarbonyl (Fmoc), 2- trimethylsilylethyl,(2-phenyl-2-trimethylsilyl)ethyl, triisopropylsiloxy, 2- (trimethylsilyl)ethoxymethyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2- (trimethylsilyl)ethoxycarbonyl, or 2, 2,2,2-trichloroethoxycarbonyl.
  • protecting groups and their use see P. G.M. Wuts & T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 2007.
  • an "alcohol protecting group” or an “alcohol-protecting moiety” is a substituent attached to an alcohol group that blocks or protects the alcohol functionality in the compound.
  • Such groups are well known in the art (see for example, P. Wuts and T. Greene, 2007, Protective Groups in Organic Synthesis, Chapter 2, J. Wiley & Sons, NJ).
  • Suitable alcohol protecting group include, but are not limited to, pivaloyl, methoxymethyl, 2-methoxyethoxymethyl, /?-methoxybenzyl, 3,4-dimethyoxybenzyl, 2,6-dimethyoxybenzyl, diphenylmethyl, benzyloxymethyl, 2,2,2- trichloroethoxycarbonyl, tetrahydrofuranyl, tetrahydropyranyl, benzyl, benzoyl, para- phenylbenzoyl, 2,4,6-trimethylbenzoyl, /?ara-bromobenzoyl, /?ara-nitrobenzoyl, picolinoyl, nicotinoyl, 5-dibenzosuberyl, trityl/triphenylmethyl, or tris(4-ie/ - butylphenyl)methyl and various silyl protecting groups (for example,
  • the alcohol protecting group is sterically hindered.
  • the alcohol protecting group is preferably methoxymethyl, tetrahydropyranyl, 2-methoxyethoxymethyl, p-methoxybenzyl, benzyloxymethyl, or 2,2,2-trichloroethoxycarbonyl. More preferably, the alcohol protecting group is 2,2,2-trichloroethoxycarbonyl.
  • the alcohol protecting group is a silyl protecting group, preferably, triethylsilyl, triisopropylsilyl, or tert-butyldimethylsilyl. More preferably, the alcohol protecting group is tert- butyldimethylsilyl.
  • alcohol protecting reagent refers to a reagent that introduces an alcohol protecting group onto an alcohol group.
  • an “acid labile alcohol protecting group” is an alcohol protecting group that is not stable under acidic condition and releases the alcohol protecting group to form free alcohol.
  • Examples of an acid labile alcohol protecting group include, but are not limited to, acetate, allyl, methoxymethyl, tetrahydrofuranyl, tetrahydropyranyl, 5- dibenzosuberyl, 1-ethoxyethyl, 1 -methyl- lmethoxylethyl, 2-(phenylselenyl)ethyl, trityl/triphenylmethyl, tris(4-ie/ -butyrphenyl)methyl, and various silyl protecting group (for example, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tribenzylsilyl, triphenylsilyl, 2-
  • the alcohol protecting group is a silyl protecting group, preferably, triethylsilyl, triisopropylsilyl, or tert-butyldimethylsilyl. More preferably, the alcohol protecting group is tert-butyldimethylsilyl.
  • alcohol deprotecting reagent refers to a reagent that is capable of cleaving an alcohol protecting group to form free alcohol.
  • Such reagents are well known in the art (see for example P. Wuts and T. Greene, 2007, Protective Groups in Organic Synthesis, Chapter 2, J. Wiley & Sons, NJ).
  • alcohol deprotecting reagents include, but are not limited to, tetra-n-butylammonium fluoride, tris(dimethylamino)sulfonium difluorotrimethylsilicate, hydrogen fluoride or a solvate thereof, hydrogen fluoride pyridine, silicon tetrafluoride, hexafluorosilicic acid, cesium fluoride, hydrochloric acid, acetic acid, trifluoroacetic acid, pyridinium p- toluensulfonate, p-toluenesulfonic acid (p-TsOH), formic acid, periodic acid.
  • tetra-n-butylammonium fluoride tris(dimethylamino)sulfonium difluorotrimethylsilicate
  • hydrogen fluoride or a solvate thereof hydrogen fluoride pyridine, silicon tetrafluoride, hexafluorosilicic acid, cesium flu
  • the alcohol deprotecting reagent is hydrochloric acid or tetra-n- butylammonium fluoride (TBAF). In certain embodiments, the alcohol deprotecting agent is hydrogen fluoride-pyridine (HF-pyridine).
  • amine deprotecting group refers a reagent that is capable of cleaving an amine protecting group to form free amine.
  • reagents are well known in the art (see for example P. Wuts and T. Greene, 2007, Protective Groups in Organic Synthesis, Chapter 7, J. Wiley & Sons, NJ).
  • Examples of such amine deprotecting reagents include, but are not limited to, tetra-n-butylammonium fluoride, acetic acid, hydrogen fluoride pyridine, cesium fluoride, piperidine, morpholine, or trifluoroacetic acid.
  • alcohol activating agent refers a reagent that increases the reactivity of a hydroxyl group thereby making the hydroxyl group a better leaving group.
  • examples of such alcohol activating agents include p-toluenesulfonyl chloride, thionyl chloride, triflic anhydride, mesyl chloride, mesyl anhydride, triphenylphosphine, acyl chloride, 4-dimethylaminopyridine, and others.
  • the alcohol activating agent is thionyl chloride.
  • the alcohol activating agent is triphenylphosphine.
  • phrases "pharmaceutically acceptable salt” as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound of the invention.
  • Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate "mesylate,” ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e.
  • a pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion.
  • the counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound.
  • a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion.
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid,
  • hydrobromic acid sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
  • an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • amino acids such as glycine and arginine
  • ammonia such as glycine and arginine
  • primary, secondary, and tertiary amines such as piperidine, morpholine and piperazine
  • inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • phrases "pharmaceutically acceptable” indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • leaving group refers to a group of charged or uncharged moiety that departs during a nucleophilic substitution or displacement.
  • leaving groups include, but not limited to, halogens, esters, alkoxy, hydroxyl, tosylates, triflates, mesylates, nitriles, azide, carbamate, disulfides, thioesters, thioethers and diazonium compounds.
  • halogenating reagent refers to a reagent that converts an alcohol group to a halide group.
  • a "brominating reagent” is a reagent that converts an alcohol group to a bromide group.
  • a "iodinating reagent” is a reagent that converts an alcohol group to a iodide group.
  • a “chlorinating reagent” is a reagent that converts an alcohol group to a chloride group.
  • Exemplary brominating reagents include, but are not limited to, bromine, hydrobromic acid, carbon tetrabromide, phosphorus tribromide, and potassium bromide.
  • Exemplary iodinating reagent include, but are not limited to, hydroiodic acid, iodine, carbon tetraiodide, phosphorus triiodide, sodium iodide, or potassium iodide.
  • Exemplary chlorinating reagent include, but are not limited to, carbon tetrachloride, methanesulfonyl chloride, sulfuryl chloride, thionyl chloride, cyanuric chloride, N-chlorosuccinimide, phosphorus(V) oxychloride, phosphorus pentachloride, and phosphorus trichloride.
  • the chlorinating reagent is methanesulfonyl chloride.
  • a "sulfonating reagent” refers to a reagent that converts an alcohol group to a sulfonate ester group.
  • the sulfonating reagent is a sulfonic anhydride, such as methanesulfonic anhydride, or a sulfonic chloride, such as methanesulfonyl chloride (MsCl).
  • an "activated ester” refers to an ester group that is readily displaced by a hydroxyl or an amine group.
  • exemplary activated esters include, but are not limited to nitrophenyl (e.g. , 2 or 4-nitrophenyl) ester, dinitrophenyl (e.g. , 2,4- dinitrophenyl) ester, sulfo-tetraflurophenyl (e.g. , 4-sulfo-2,3,5,6-tetrafluorophenyl) ester, pentafluorophenyl ester, nitropyridyl (e.g. , 4-nitropyridyl) ester, trifluoroacetate, and acetate.
  • nitrophenyl e.g. , 2 or 4-nitrophenyl
  • dinitrophenyl e.g. , 2,4- dinitrophenyl
  • sulfo-tetraflurophenyl e.g
  • an "esterification reagent” refers to a reagent that converts an alcohol group to an ester group.
  • exemplary esterification reagent include, but are not limited to, nitrobenzoid acid (e.g. , 2 or 4-nitrobenzoic acid), dinitrobenzoid acid (e.g. , 2,4-dinitrobenzoic acid), sulfo-tetraflurobenzoid acid (e.g. , 4-sulfo-2,3,5,6- tetrafluorobenzoic acid), pentafluorobenzoic acid, nitropyridine carboxylic acid (e.g. , 4- nitro-2-pyridine carboxylic acid, trifluoroacetic acid, and acetic acid, or acyl chloride, acid anhydride or other activated carboxylic acid derivatives thereof.
  • nitrobenzoid acid e.g. , 2 or 4-nitrobenzoic acid
  • dinitrobenzoid acid e.g. , 2,4
  • the present invention provides novel methods for preparing
  • indolinobenzodiazepine dimer compounds that have one imine functionality and one amine functionality.
  • the present methods can produce the desired dimer compounds with higher yield and without the use of HPLC purification.
  • the present invention provides a method of preparing a compound of formula (2d),
  • (2d) or a salt thereof said method comprising introducing an alcohol protecting group onto one of the primary alcohols of a compound of formula (Id) by reacting the compound of formula (Id) with an alcohol protecting reagent,
  • Pi is the alcohol protecting group; and Rioo is (Ci-C 3 )alkoxy.
  • Also provided in the first embodiment is a method of preparing a compound of formula (2A),
  • (2A) or a salt thereof comprising introducing an alcohol protecting group onto one of the primary alcohols of a compound of formula (1A) by reacting the compound of formula (1A) with an alcohol protecting reagent,
  • the alcohol protecting group is sterically hindered.
  • the alcohol protecting group is pivaloyl, methoxymethyl, 2-methoxyethoxymethyl, /?-methoxybenzyl, 3,4-dimethyoxybenzyl, 2,6-dimethyoxybenzyl, diphenylmethyl, benzyloxymethyl, 2,2,2- trichloroethoxycarbonyl, tetrahydrofuranyl, tetrahydropyranyl, benzyl, benzoyl, para- phenylbenzoyl, 2,4,6-trimethylbenzoyl, /?ara-bromobenzoyl, /?ara-nitrobenzoyl, picolinoyl, nicotinoyl, 5-dibenzosuberyl, trityl/triphenylmethyl, or tris(4-ie/ - butylphenyl)methyl.
  • the alcohol protecting group is methoxymethyl, tetrahydropyranyl, 2-methoxyethoxymethyl, p-methoxybenzyl, benzyloxymethyl, or 2,2,2-trichloroethoxycarbonyl. Even more preferably, the alcohol protecting group is 2,2,2-trichloroethoxycarbonyl.
  • the alcohol protecting group is a silyl protecting group.
  • the silyl protecting group is dimethylisopropylsilyl,
  • the silyl protecting group is triethylsilyl, triisopropylsilyl, or tert-butyldimethylsilyl. More preferably, the silyl protecting group is tert-butyldimethylsilyl.
  • the silyl protecting group can be introduced by reacting the compound of formula (Id) or (1A) with R 3 -C1, R 3 -Br, R 3 -I or R 3 -OS0 2 CF 3 (collectively the alcohol protecting reagent) in the presence of a base, wherein R is dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl, trimethylsilyl, triisopropylsilyl, tribenzylsilyl, triphenylsilyl, 2-norbornyldimethylsilyl, ie/t-butyldimethylsilyl, ie/t-butyldiphenylsilyl or [2-(trimethylsilyl)ethoxy]methyl.
  • the molar ratio of the alcohol protecting reagent to the compound of formula (Id) or (1A) is between 0.8-1.2, between 1 to 5, between 1 to 2, between 1 to 1.5, between 1 to 1.4, between 1 to 1.3, between 1 to 1.2, or between 1 to 1.1. In certain embodiment, less than 2 molar equivalents of the alcohol protecting reagent is used relative to the compound of formula (Id) or (1A). Preferably, 1.5, 1.4, 1.3, 1.2, 1.1 or 1.0 molar equivalent of the alcohol protecting reagent relative to the compound of formula (Id) or (1A) is used.
  • the base can be a non-nucleophilic base.
  • non- nucleophilic base include, but are not limited to, imidazole, triethylamine,
  • the non-nucleophilic base is imidazole. Molar excess amount of the base can be used. In certain embodiments, more than 2 molar equivalents of the base (e.g. non-nucleophilic base) are used relative to the compound of formula (Id) or (lA).
  • Exemplary catalysts include, but are not limited to, 4-dimethylaminopyridine (DMAP), 1,1,3,3-tetramethylguanidine and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
  • DMAP 4-dimethylaminopyridine
  • DBU 1,1,3,3-tetramethylguanidine
  • Any suitable organic solvents can be used for the methods of the first embodiment.
  • Exemplary solvents include, but are not limited to, DMF, CH 2 CI 2 , dichloroethane, THF, dimethylacetamide, etc. In certain embodiments, DMF is used as the solvent.
  • the method of preparing the compound of formula (2d) or (2A) comprising reacting the compound of (Id) or (1A) with TBSC1 in the presence of a non-nucleophilic base.
  • the base is imidazole or DIPEA.
  • the base is imidazole.
  • the base is DIPEA.
  • the present invention provides a method of preparing a compound of formula (3d
  • Pi is an alcohol protecting group
  • Xi is a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester, and an activated ester
  • R 100 is (Q- C 3 )alkoxy.
  • Also provided in the second embodiment is a method of preparing a compound of formula (3A),
  • Pi and Rioo are as defined in the first embodiment, and Xi is a leaving group selected from the group consisting of: -Br, -I, -CI a sulfonate ester, and an activated ester.
  • Xi is -Br, -I or a sulfonate ester.
  • Xi is mesylate, tosylate, brosylate, or triflate.
  • Xi is mesylate.
  • the method of the second embodiment comprises reacting the compound of formula (2d) or (2A) with a halogenating reagent.
  • exemplary halogenating reagents include, but are not limited to, bromine, hydrobromic acid, carbon tetrabromide, phosphorus tribromide, potassium bromide, hydroiodic acid, iodine, carbon tetraiodide, phosphorus triiodide, sodium iodide, or potassium iodide.
  • the method of the second embodiment comprises reacting the compound of formula (2d) or (2A) with a sulfonating reagent.
  • the sulfonating reagent is a sulfonic anhydride, such as methanesulfonic anhydride, or a sulfonic chloride, such as methane sulfonyl chloride (MsCl).
  • the reaction between the compound of formula (2d) or (2A) and the sulfonating reagent can be carried out in the presence of a base.
  • the base is a non-nucleophilic base.
  • Exemplary non-nucleophilic bases include, but are not limited to, triethylamine, imidazole, triethylamine,
  • diisopropylethylamine pyridine, 2,6-lutidine, dimethylformamide, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), or tetramethylpiperidine.
  • the base is triethylamine or diisopropylethylamine.
  • any suitable organic solvents can be used in the method of the second embodiment.
  • the solvent is dichloromethane.
  • the present invention provides a method of preparing a compound of formula (4d),
  • Pi is an alcohol protecting group
  • Xi is a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester and an activated ester
  • Rioo is (Ci- C 3 )alkoxy.
  • Also provided in the third embodiment is a method of preparing a compound of formula (4A),
  • ai a monomer compound of the formula (ai), wherein Pi is an alcohol protecting group; and X 1 is a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester and an activated ester.
  • Xi is -Br, -I, or a sulfonate ester.
  • the compound of formula (3d) or (3A) is reacted with the monomer compound of formula (ai) in the presence of a base.
  • a base Any suitable base can used.
  • Exemplary bases include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride. In one embodiment, the base is potassium carbonate.
  • the solvent is dimethylacetamide (DMA).
  • the method of preparing compound of formula (4d) or (4A) described above comprises reacting the compound of formula (3d) or (3A) with the monomer compound (ai) in the presence of potassium carbonate in DMA. In one embodiment, the reaction is carried out in the presence of potassium iodide.
  • the present invention provides a method of preparing a compound of formula (5d),
  • Also provided in the fourth embodiment is a method of preparing a compound of formula (5A),
  • the imine reducing reagent is a hydride reducing reagent.
  • the imine reducing reagent is sodium
  • the imine reducing reagent is sodium triacetoxy borohydride (NaBH(OAc) 3 ).
  • any suitable solvents can be use in the method of fourth embodiment.
  • the solvent is dichloroethane.
  • the present invention provides a method of preparing a compound of formula (6d),
  • Also provided in the fifth embodiment is a method of preparing a compound of formula (6A),
  • the alcohol deprotecting reagent is tetra-n-butylammonium fluoride, tris(dimethylamino)sulfonium difluorotrimethylsilicate, hydrogen fluoride or a solvate thereof, hydrogen fluoride pyridine, silicon tetrafluoride, hexafluorosilicic acid, cesium fluoride, hydrochloric acid, acetic acid, trifluoroacetic acid, pyridinium p- toluensulfonate, p-toluenesulfonic acid (p-TsOH), formic acid, or periodic acid.
  • p-TsOH p-toluenesulfonic acid
  • the alcohol deprotecting reagent is hydrochloric acid or tetra-n- butylammonium fluoride.
  • the alcohol deprotecting reagent is aqueous hydrochloric acid.
  • any suitable solvents can be used in the deprotection reaction described above.
  • the solvent is THF.
  • the present invention provides a method of preparing a compound of formula (7d),
  • X 2 is a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester and an activated ester; and Rioo is (Ci-C3)alkoxy.
  • Also provided in the sixth embodiment is a method of preparing a compound of formula (7 A),
  • X 2 is -Br, -I, -CI, a sulfonate ester or an activated ester; and the remaining variables are as described above in the fifth embodiment.
  • X 2 is -Br, -I or a sulfonate ester.
  • X 2 is mesylate, tosylate, brosylate, or triflate.
  • X 2 is mesylate.
  • the method of the sixth embodiment comprises reacting the compound of formula (6d) or (6A) with a halogenating reagent.
  • exemplary halogenating reagent include, but are not limited to, bromine, hydrobromic acid, carbon tetrabromide, phosphorus tribromide, potassium bromide, hydroiodic acid, iodine, carbon tetraiodide, phosphorus triiodide, sodium iodide, or potassium iodide.
  • the method of the sixth embodiment comprises reacting the compound of formula (6d) or (6A) with a sulfonating reagent.
  • the sulfonating reagent is a sulfonic anhydride , such as methanesulfonic anhydride, or a sulfonic chloride, such as methane sulfonyl chloride (MsCl).
  • the reaction between the compound of formula (6d) or (6A) and the sulfonating reagent is carried out in the presence of a base.
  • the base is a non-nucleophiclic base.
  • Exemplary non-nucleophic base include, but are not limited to, triethylamine, imidazole, triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, dimethylformamide, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or
  • the base is triethylamine or diisopropylethylamine.
  • the solvent is dichloromethane.
  • the solvent is DMF.
  • the solvent is a mixture of dichloromethane and DMF.
  • the present invention provides a method of preparing a compound of formula (7d")
  • Pi' is an acid labile alcohol protecting group
  • X 2 ' is -Br or -I
  • Rioo is (Ci-C3)alkoxy.
  • Also provided in the seventh embodiment is a method of preparing a compound of formula (7A"):
  • the method of the seventh embodiment combines the alcohol deprotection step described in the fifth embodiment and the halogenation reaction of the resulting alcohol described in the sixth embodiment into one step.
  • the compound of formula (7d) is represented by the following formula:
  • the com ound of formula (7 A') is represented by the following formula:
  • the acid labile alcohol protecting group is acetate, allyl, methoxymethyl, tetrahydrofuranyl, tetrahydropyranyl, 5-dibenzosuberyl, 1-ethoxyethyl, 1 -methyl- lmethoxylethyl, 2- (phenylselenyl)ethyl, trityl/triphenylmethyl, or tris(4-tert-butylphenyl)methyl.
  • the acid labile alcohol protecting group is a silyl protecting group.
  • silyl protecting groups include, but are not limited to, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tribenzylsilyl, triphenylsilyl, 2-norbornyldimethylsilyl, ie/t-butyldimethylsilyl, ie/t-butyldiphenylsilyl, 2-trimethyethylsilyl (TEOC), or [2- (trimethylsilyl)ethoxy]methyl.
  • the silyl protecting group is triethylsilyl, triisopropylsilyl, or tert-butyldimethylsilyl. More preferably, the silyl protecting group is tert-butyldimethylsilyl.
  • the alcohol deprotecting reagent is tetra-n-butylammonium fluoride, tris(dimethylamino)sulfonium difluorotrimethylsilicate, hydrogen fluoride or a solvate thereof, hydrogen fluoride pyridine, silicon tetrafluoride, hexafluorosilicic acid, cesium fluoride, hydrochloric acid, acetic acid, pyridinium p-toluensulfonate, formic acid, periodic acid, trifluoroacetic acid, or .p-toluenesulfonic acid (p-TsOH).
  • the alcohol deprotecting reagent is acetic acid.
  • the bromination reagent is HBr.
  • the methods of the seventh embodiment comprises reacting the compound of formula (5d") with a mixture of acetic acid and HBr to give the compound of formula (7d"').
  • the methods of the seventh embodiment comprises reacting the compound of formula (5A") with a mixture of acetic acid and HBr to give the compound of formula (7 A')
  • the present invention provides a method of preparing a compound of formula (Id'),
  • ai monomer compound of the formula (ai), wherein Rioo is (Ci-C3)alkoxy; and, X 2 is a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester, and an activated ester.
  • Also provided in the eighth embodiment is a method of preparing a compound of formula (IA),
  • ai monomer compound of the formula (ai), wherein Rioo is (Ci-C3)alkoxy; and, X 2 is a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester, and an activated ester.
  • X 2 is -Br, -I or a sulfonate ester.
  • the compound of formula (7d) or (7 A) is reacted with the monomer compound of formula (ai) in the presence of a base.
  • a base include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride.
  • the base is potassium carbonate.
  • any suitable solvents can be used in the methods of eighth embodiment described above.
  • the solvent is DMF. In another embodiment, the solvent is DMA.
  • the present invention provides a method of preparing a compound of formula (Id'),
  • Also provided in the ninth embodiment is a method of preparing a compound of formula (IA):
  • Xi and X 2 are each independently -Br, -CI or a sulfonate ester.
  • reaction conditions and reagents for each step in the method of the ninth embodiment are as described in the first, second, third, fourth, fifth, sixth and/or eighth embodiment or any specific embodiments described therein.
  • the present invention provides a method of preparing a compound of formula (Id'),
  • the present invention provides a method of preparing a compound of formula (9d),
  • the alcohol deprotecting reagent is tetra-n-butylammonium fluoride
  • tris(dimethylamino)sulfonium difluorotrimethylsilicate hydrogen fluoride or a solvate thereof, hydrogen fluoride pyridine, silicon tetrafluoride, hexafluorosilicic acid, cesium fluoride, hydrochloric acid, acetic acid, pyridinium p-toluensulfonate, formic acid, periodic acid, trifluoroacetic acid, or p-toluenesulfonic acid (p-TsOH). More
  • the alcohol deprotecting reagent is hydrochloric acid or tetra-n- butylammonium fluoride.
  • the present invention provides a method of preparing a compound of formula (lOd),
  • X 2 is -Br, -I, -CI, a sulfonate ester or an activated ester; and Rioo is (Ci- C 3 )alkoxy.
  • X 2 is -Br, -I, -CI, a sulfonate ester or an activated ester.
  • X 2 is -Br, -I or a sulfonate ester. In a specific embodiment, for the methods of the twelfth embodiment, X 2 is mesylate, tosylate, brosylate, or triflate. Preferably, X 2 is mesylate.
  • the method described in the twelfth embodiment comprises reacting the compound of formula (9d) or (9A) with a halogenating reagent.
  • a halogenating reagent include, but are not limited to, bromine, hydrobromic acid, carbon tetrabromide, phosphorus tribromide, potassium bromide, hydroiodic acid, iodine, carbon tetraiodide, phosphorus triiodide, sodium iodide, or potassium iodide.
  • the method of the twelfth embodiment comprises reacting the compound of formula (9d) or (9A) with a sulfonating reagent.
  • the sulfonating reagent is a sulfonic anhydride , such as methanesulfonic anhydride, or a sulfonic chloride, such as methane sulfonyl chloride (MsCl).
  • the reaction between the compound of formula (9d) or (9 A) and the sulfonating reagent is carried out in the presence of a base.
  • the base is a non-nucleophiclic base.
  • Exemplary non-nucleophic base include, but are not limited to, triethylamine, imidazole, triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, dimethylformamide, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or
  • the base is triethylamine or diisopropylethylamine.
  • the present invention provides a method of preparing a compound of formula 18d),
  • X 2 is a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester and an activated ester; P 3 is H or P 2 ; P 2 is an amine protecting group; and Rioo is (Ci-C 3 )alkoxy.
  • X 2 is -Br, -I, or a sulfonate ester.
  • Also provided in the thirteenth embodiment is a method of preparing a compound of formula 18A):
  • X 2 is a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester or an activated ester; and P 3 is H or P 2 ; and P 2 is an amine protecting group. In one embodiment, X 2 is -Br, -I, or a sulfonate ester.
  • P 3 is H and the compound of (lOd) or (10A) is reacted with the monomer compound of (di) to form a compound of (Id') or (IA), respectively:
  • P 3 is an amine protecting group represented by P 2 ; the monomer compound is represented by formula (ci):
  • the amine protecting group is 2- trimethylsilylethyl,(2-phenyl-2-trimethylsilyl)ethyl, triisopropylsiloxy, 2- (trimethylsilyl)ethoxymethyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2- (trimethylsilyl)ethoxycarbonyl, or 2, 2,2,2-trichloroethoxycarbonyl.
  • the compound of formula (lOd) or (10A) is reacted with the monomer compound of formula (di) or (ci) in the presence of a base.
  • the base include, but are not limited to sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride.
  • any suitable solvents can be used in the reaction described above.
  • the solvent is DMF.
  • the present invention provides a method of preparing a compound of formula (Id'),
  • Also provided in the fourteenth embodiment is a method of preparing a compound of formula (IA):
  • the amine deprotecting reagent is tetra-n-butylammonium fluoride, acetic acid, hydrogen fluoride pyridine, cesium fluoride, piperidine, morpholine, or trifluroacetic acid.
  • the present invention provides a method of preparing a compound of formula (Id'),
  • X 1 and X 2 are each independently -Br, -I or a sulfonate ester.
  • P 3 is H and the compound of (lOd) or (10A) is reacted with the monomer compound of (di) to form a compound of (Id') or (IA), respectively.
  • P 3 is P 2 ; the monomer compound is represented by formula (ci):
  • P 2 is an amine protecting group
  • the present invention provides a method of preparing a compound of formula (12d),
  • halogenating reagent or a sulfonating reagent wherein Xi is -Br, -I, -CI, a sulfonate ester or an activated ester; and Rioo is (Ci-C3)alkoxy.
  • Also provided in the sixteenth embodiment is a method of preparing a compound of formula (12A):
  • X 1 is -Br, -I, -CI, a sulfonate ester or an activated ester.
  • Xi is -
  • X 1 is -Br or -I.
  • X 1 is a sulfonate ester, preferably mesylate.
  • Xi is -CI.
  • the halogenating reagent reacts with the primary alcohols of the compound of formula (Id) or (1 A) in the presence of an alcohol activating agent.
  • the alcohol activating agent is thionyl chloride.
  • halogenating reagent is lithium bromide, sodium bromide, potassium bromide, potassium iodide, or sodium iodide.
  • the halogenating reagent is carbon tetrachloride/triphenylphosphine, methanesulfonyl (mesyl) chloride/lithium chloride, or methanesulfonyl (mesyl) chloride/pyridine.
  • the methods of the sixteenth embodiment comprise reacting the compound of formula (Id) or (1 A) with LiBr in the presence of thionyl chloride.
  • Any suitable solvents can be used in the methods of the sixteenth embodiment described above.
  • Exemplary solvents include, but are not limited to, DMF, CH 2 CI 2 , THF, dichloroethane, etc.
  • the present invention provides a method of preparing a compound of formula (10d'),
  • Also provided in the seventeenth embodiment is a method of preparing a compound of formula ( ⁇ ')
  • Also provided in the seventeenth embodiment is a method of preparing a compound of formula (7dl'),
  • Also provided in the seventeenth embodiment is a method of preparing a compound of formula (7 ⁇ ),
  • P 3 is H. In another specific embodiment, P 3 is an amine protecting group as described herein.
  • X 1 is -Br, -I, or a sulfonate ester.
  • Xi is a sulfonate ester.
  • Xi is mesylate.
  • the compound of formula (12d) or (12A) is reacted with the monomer compound of formula (ai) in the presence of a base.
  • suitable base include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride.
  • the base is potassium carbonate.
  • the compound of formula (12d) or (12A) is reacted with the monomer compound of formula (di) in the presence of a base.
  • Suitable base include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride.
  • the base is potassium carbonate.
  • any suitable solvents can be used.
  • the solvent is DMF.
  • the present invention provides a method of preparing a compound of formula (7d'),
  • Also provided in the eighteenth embodiment is a method of preparing a compound of formula (7 A'),
  • Xi is -Br, -I, or a sulfonate ester. In another specific embodiment, Xi is a sulfonate ester.
  • Xi is mesylate.
  • the imine reducing reagent is a hydride reducing reagent.
  • the imine reducing reagent is sodium borohydride, sodium triacetoxy borohydride, sodium cyanoborohydride, lithium aluminum hydride, hydrogen gas, ammonium formate, borane, 9-borabicyclo[3.3.1]nonane (9-BBN), diisobutylaluminium hydride (DIBAL), lithium borohydride (LiBH 4 ), potassium borohydride (KBH 4 ), or sodium bis(2-methoxyethoxy)aluminumhydride (Red-Al).
  • the imine reducing reagent is sodium triacetoxy borohydride (NaBH(OAc)3).
  • any suitable solvents can be used in the methods of the eighteenth embodiment.
  • the solvent is dichloroethane.
  • the present invention provides a method of preparing a com ound of formula (Id'),
  • Also provided in the nineteenth embodiment is a method of preparing a compound of formula (IA),
  • Xi is -Br, -I, or a sulfonate ester.
  • P 3 is H and the compound of (10d') or (10A) is reacted with the monomer compound of (di) to form a compound of (Id') or (IA), respectively.
  • P 3 is P 2 ; the monomer compound is represented by formula (ci):
  • P 2 is an amine protecting group
  • the present invention provides a method of preparing a compound a compound of formula (Id'),

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Abstract

The invention relates to novel methods for preparing indolinobenzodiazepine dimer compounds and their synthetic precursors.

Description

METHODS OF PREPARING CYTOTOXIC BENZODIAZEPINE
DERIVATIVES
REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the filing date, under 35 U.S.C. § 119(e), of
U.S. Provisional Application No. 62/327,973, filed on April 26, 2016, and
U.S. Provisional Application No. 62/195,023, filed on July 21, 2015. The entire contents of each of the above-referenced applications are incorporated herein by reference. FIELD OF THE INVENTION
The present invention relates to novel methods for preparing cytotoxic indolinobenzodiazepine derivatives .
BACKGROUND OF THE INVENTION
It has been shown that cell-binding agent conjugates of indolinobenzodiazepine dimers that have one imine functionality and one amine functionality display a much higher therapeutic index (ratio of maximum tolerated dose to minimum effective dose) in vivo compared to previously disclosed benzodiazepine derivatives having two imine functionalities. See, for example, WO 2012/128868. The previously disclosed method for making the indolinobenzodiazepine dimers with one imine functionality and one amine functionality involves partial reduction of indolinobenzodiazepine dimers having two imine functionalities. The partial reduction step generally leads to the formation of fully reduced by-product and unreacted starting material, which requires cumbersome purification step and results in low yield.
Thus, there exists a need for improved methods for preparing the
indolinobenzodiazepine dimers that are more efficient and suitable for large scale manufacturing process.
SUMMARY OF THE INVENTION
The present invention provides various methods for preparing
indolinobenzodiazepine dimer compounds and their synthetic precursors. Compared to the previously disclosed method, the methods of the present invention can produce the desired dimer compounds with higher yield without the need of cumbersome purification steps. These methods are more suitable for large scale manufacturing process.
In a first embodiment, the present invention provides a method of preparing a compound of formula (2d),
Figure imgf000003_0001
(2d)
or a salt thereof, said method comprising introducing an alcohol protecting group onto one of the primary alcohols of a compound of formula (Id) by reacting the compound of formula (Id) with an alcohol protecting reagent,
Figure imgf000003_0002
(1d)
wherein Pi is the alcohol protecting group; and Rioo is (Ci-C3)alkoxy.
In a second embodiment, the present invention provides a method of preparing a compound of formula (3d),
Figure imgf000003_0003
(3d)
or a salt thereof, said method comprising reacting a halogenating reagent, a sulfonating reagent or an esterification reagent with a compound of formula (2d),
Figure imgf000003_0004
(2d)
wherein Pi is an alcohol protecting group; Xi is a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester, and an activated ester (preferably, Xi is -Br, -I, or a sulfonate ester); and Rioo is (Ci-C3)alkoxy.
In a third embodiment, the present invention provides a method of preparing a compound of formula (4d),
Figure imgf000004_0001
(Ad)
or a salt thereof, said method comprising reacting a compound of formula (3d)
Figure imgf000004_0002
(3d)
with a monomer compound of the formula (ai),
Figure imgf000004_0003
wherein Pi is an alcohol protecting group; X1 is a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester, and an activated ester (preferably, X1 is -Br, -I, or a sulfonate ester); and Rioo is (Ci-C3)alkoxy.
In a fourth embodiment, the present invention provides a method of preparing a compound of formula (5d),
Figure imgf000004_0004
(5d)
or a salt thereof, said method comprising reacting a compound of formula (4d),
Figure imgf000005_0001
(4d)
with an imine reducing agent, wherein Pi is an alcohol protecting group; and Rioo is C3)alkoxy.
In a fifth embodiment, the present invention provides method of preparing a compound of formula (6d),
Figure imgf000005_0002
(6d)
or a salt thereof, said method comprising reacting a compound of formula (5d),
Figure imgf000005_0003
(5d)
with an alcohol deprotecting reagent, wherein Pi is an alcohol protecting group; and Rioo is (Ci-C3)alkoxy.
In a sixth embodiment, the present invention provides a method of preparing a compound of formula (7d),
Figure imgf000005_0004
(7d)
or a salt thereof, said method comprising reacting a halogenating reagent, a sulfonating reagent or an esterification reagent with the primary alcohol compound of formula (6d),
Figure imgf000006_0001
(6d)
wherein X2 is a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester, and an activated ester (preferably, X2 is -Br, -I, or a sulfonate ester); and Rioo is (Ci-C3)alkoxy.
In a seventh embodiment, the present invention provides a method of preparing a compound of formula (7d")
Figure imgf000006_0002
(7d")
or a salt thereof, said method comprising reacting a compound of formula (5d")
Figure imgf000006_0003
(5d")
with an alcohol deprotecting reagent and a halogenating reagent, wherein Pi' is an acid labile alcohol protecting group; X2' is -Br or -I; and Rioo is (Ci-C3)alkoxy.
In a eighth embodiment, the present invention provides a method of preparing a compound of formula (Id'),
Figure imgf000006_0004
or a pharmaceutically acceptable salt thereof, said method comprising reacting a compound of formula (7d)
Figure imgf000007_0001
with a monomer compound of the formula (ai),
Figure imgf000007_0002
wherein Rioo is (Ci-C3)alkoxy; and, X2 is a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester, and an activated ester (preferably, X2 is -I, or a sulfonate ester).
In a ninth embodiment, the present invention provides a method of forming compound of formula (Id'),
Figure imgf000007_0003
(Id')
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) introducing an alcohol protecting group onto one of the primary alcohols of a compound of formula (Id),
Figure imgf000007_0004
(1 d)
to form a compound of formula (2d),
Figure imgf000007_0005
(2d) (2) reacting the compound of formula (2d) with a halogenating reagent, a sulfonating reagent or an esterification reagent to form a compound of formula (3d),
Figure imgf000008_0001
(3d)
(3) reacting the compound of formula (3d) with a monomer compound of the formula (ai),
Figure imgf000008_0002
(ai)
to form a compound of formula (4d),
Figure imgf000008_0003
(4d)
(4) reacting the compound of formula (4d) with an imine reducing agent to form a compound of formula (5d),
Figure imgf000008_0004
(5d)
(5) reacting the compound of formula (5d) with an alcohol deprotecting reagent to form a compound of formula (6d),
Figure imgf000008_0005
(6d) (6) reacting the compound of formula (6d) with a second halogenating reagent, a second sulfonating reagent, or a second esterification reagent to form a compound of formula (7d),
Figure imgf000009_0001
(7d) ; and
(7) reacting the compound of formula (7d) with a monomer compound of the formula (ai),
Figure imgf000009_0002
to form the compound of formula (Id'); wherein Pi is an alcohol protecting group; Xi and X2 are each independently a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester, and an activated ester (preferably, X1 and X2 are each independently -Br, -I, or a sulfonate ester); and Rioo is (Ci-C3)alkoxy.
In a tenth embodiment, the present invention provides a method of preparing a compound of formula (Id'),
Figure imgf000009_0003
(Id')
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) introducing an alcohol protecting group onto one of the primary alcohols of a compound of formula (Id),
Figure imgf000009_0004
(1d)
to form a compound of formula (2d"),
Figure imgf000010_0001
(2d")
(2) reacting the compound of formula (2d") with a halogenating reagent, a sulfonating reagent or an esterification reagent to form a compound of formula (3d"),
Figure imgf000010_0002
(3d")
(3) reacting the compound of formula (3d") with a monomer compound of the formula (a ,
Figure imgf000010_0003
to form a compound of formula (4d"),
Figure imgf000010_0004
(4d")
(4) reacting the compound of formula (4d") with an imine reducing agent to form a compound of formula (5d"),
Figure imgf000010_0005
(5d")
(5) reacting the compound of formula (5d") with an alcohol deprotecting reagent and a halogenating reagent to form a compound of formula (7d"),
Figure imgf000011_0001
(7d")
(6) reacting a compound of formula (7d") with a monomer compound of the formula (ai),
Figure imgf000011_0002
to form the compound of formula (Id'), wherein X2' is -Br or -I; and the remaining variables are as described above in the ninth embodiment.
In a eleventh embodiment, the present invention provides a method of preparing a compound of formula (9d),
Figure imgf000011_0003
(9d)
or a salt thereof, said method comprising reacting a compound of formula (4d),
Figure imgf000011_0004
(4d)
with an alcohol deprotecting reagent, wherein Pi is an alcohol protecting group; and Rioo is (Ci-C3)alkoxy..
In a twelfth embodiment, the present invention provides a method of preparing a compound of formula (lOd),
Figure imgf000012_0001
(10d)
or a salt thereof, said method comprising reacting the compound of formula (9d) with a halogenating reagent, a sulfonating reagent or an esterification reagent ,
Figure imgf000012_0002
(9d)
wherein X2 is -Br, -I, -CI, a sulfonate ester, and an activated ester (preferably, X2 is -Br, -I, or a sulfonate ester); and Rioo is (Ci-C3)alkoxy.
In a thirteenth embodiment, the present invention provides a method of preparing a compound of formula (18d),
Figure imgf000012_0003
(18d)
or a salt thereof, said method comprising reacting a compound of formula (lOd)
Figure imgf000012_0004
(10d)
with a monomer compound of the formula (di),
Figure imgf000012_0005
wherein X2 is a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester, and an activated ester (preferably, X2 is -Br, -I, or a sulfonate ester); P3 is H or P2; P2 is an amine protecting group; and Rioo is (Ci-C3)alkoxy.
In a fourteenth embodiment, the present invention provides a method of preparing a compound of formula (Id'),
Figure imgf000013_0001
(Id')
or a pharmaceutically acceptable salt thereof, said method comprising reacting a compound of formula l id),
Figure imgf000013_0002
(11d)
with an amine deprotecting reagent, wherein P2 is an amine protecting group; and Rioo is (Ci-C3)alkoxy.
In a fifteenth embodiment, the present invention provides a method of preparing a compound of formula (Id'),
Figure imgf000013_0003
(Id')
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) introducing an alcohol protecting group onto one of the primary alcohols of the compound of formula (Id),
Figure imgf000014_0001
(1 d)
to form a compound of formula (2d),
Figure imgf000014_0002
(2d)
(2) reacting the compound of formula (2d) with a halogenating reagent, a sulfonating reagent or an esterification reagent to form a compound of formula (3d),
Figure imgf000014_0003
(3d)
(3) reacting the compound of formula (3d) with a monomer compound of the formula (ai),
Figure imgf000014_0004
to form a compound of formula (4d),
Figure imgf000014_0005
(4d)
(4) reacting the compound of formula (4d) with an alcohol deprotecting reagent to form a compound of formula (9d),
Figure imgf000015_0001
(9d)
(5) reacting the compound of formula (9d) with a second halogenating reagent, a second sulfonating reagent or a second esterification reagent to form a compound of formula (lOd),
Figure imgf000015_0002
(10d)
(6) reacting the compound of formula (lOd) with a monomer compound of the formula (di)
Figure imgf000015_0003
(di)
to form a compound of formula (18d),
Figure imgf000015_0004
( 8d) ; and
(7) when P3 is an amine protecting group, reacting the compound of formula (18d) to an amine deprotecting reagent to form the compound of formula (Id'), wherein Pi is an alcohol protecting group; Xi and X2 are each independently a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester, and an activated ester (preferably, Xi is -Br, -I, or a sulfonate ester); P3 is H or an amine protecting group; and Rioo is (Ci-C3)alkoxy. In a sixteenth embodiment, the present invention provides a method of preparing a compound of formula (12d),
Figure imgf000016_0001
(12d)
or a salt thereof, said method comprising reacting a compound of formula (Id),
Figure imgf000016_0002
< d>
with a halogenating reagent, a sulfonating reagent or an esterification reagent, wherein
Xi is -Br, -I, a sulfonate ester or an activated ester (preferably, X1 is -Br, -I, or a sulfonate ester); and Rioo is (Ci-C3)alkoxy.
In a seventeenth embodiment, the present invention provides a method of preparing a compound of formula (10d'),
Figure imgf000016_0003
(10d')
or a salt thereof, said method comprising reacting a compound of formula (12d),
Figure imgf000016_0004
(12d)
with a monomer compound of the formula (ai),
Figure imgf000016_0005
<ai)
wherein Xi is -Br, -I, -CI, a sulfonate ester, and an activated ester (preferably, Xi is -Br,
-I, or a sulfonate ester); and Rioo is (Ci-C3)alkoxy. In a eighteenth embodiment, the present invention provides a method of preparing a compound of formula (7d'),
Figure imgf000017_0001
(7d') or a salt thereof, said method comprising reacting a compound of formula (10d'),
Figure imgf000017_0002
(i od') or a salt thereof, with an imine reducing agent, wherein X1 is -Br, -I, -CI, a sulfonate ester, and an activated ester (preferably, Xi is -Br, -I, or a sulfonate ester); and Rioo is (Ci-C3)alkoxy.
In a nineteenth embodiment, the present invention provides a method of preparing a compound of formula (Id'),
Figure imgf000017_0003
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a compound of formula (Id) with a halogenating reagent, a sulfonating reagent or an esterification reagent,
Figure imgf000018_0001
(1d)
to form a compound of formula (12d),
Figure imgf000018_0002
(12d)
(2) reacting the compound of formula (12d) with a monomer compound of the formula (ai),
Figure imgf000018_0003
to form a compound of a formula (10d'),
Figure imgf000018_0004
(10d')
(3) reacting the compound of formula (10d') with a monomer compound of the formula (di),
Figure imgf000018_0005
to form a compound of formula (18d),
Figure imgf000018_0006
; and (4) when P3 is an amine protecting group, reacting the compound of formula (18d) with an amine deprotecting reagent to form the compound of formula (Id'), wherein Xi is -Br, -I, -CI, a sulfonate ester, and an activated ester (preferably, Xi is -Br, -I, or a sulfonate ester); P3 is H or an amine protecting group; and Rioo is (Ci-C3)alkoxy.
In a twentieth embodiment, the present invention provides a method of preparing a compound of formula (Id'),
Figure imgf000019_0001
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a halogenating reagent, a sulfonating reagent or an esterification reagent with a compound of formula (Id),
Figure imgf000019_0002
(1d)
to form a compound of formula (12d),
Figure imgf000019_0003
(12d)
(2) reacting the compound of formula (12d) with a monomer compound of the formula (ai),
Figure imgf000019_0004
to form a compound of a formula (10d'),
Figure imgf000020_0001
(10d')
(3) reacting the compound (10d') with an imine reducing reagent to form a compound (7d'),
Figure imgf000020_0002
(7d')
(4) reacting the compound of formula (7d') with a monomer compound of the formula (ai),
Figure imgf000020_0003
to form a compound of formula (Id'), or a pharmaceutically acceptable salt thereof, wherein Xi is -Br, -I, -CI, a sulfonate ester, or an activated ester (preferably, Xi is -Br, -I, or a sulfonate ester); and Rioo is (Ci-C3)alkoxy.
In a twenty-first embodiment, the present invention provides a method of preparing a compound of formula (Id'),
Figure imgf000020_0004
(Id') or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a halogenating reagent, a sulfonating reagent or an esterification reagent with a compound of formula (Id),
Figure imgf000021_0001
(1d)
to form a compound of formula (12d),
Figure imgf000021_0002
(12d)
(2) reacting the compound of formula (12d) with a monomer compound of the formula (di),
Figure imgf000021_0003
to form a compound of a formula (7d 1 ' )
Figure imgf000021_0004
(7d1 ')
(3) reacting the compound of formula (7dl ') with a monomer compound of the formula (ai),
Figure imgf000022_0001
to form a compound of formula (18d)
Figure imgf000022_0002
(18d) ; and
(4) when P3 is an amine protecting group, reacting the compound of formula (18d) with an amine deprotecting reagent to form the compound of formula (Id');
wherein X1 is -Br, -I, -CI, a sulfonate ester, or an activated ester (preferably, X1 is -Br, I, or a sulfonate ester); P3 is H or an amine protecting group; and Rioo is (Ci-C3)alkoxy.
In a twenty- second embodiment, the present invention provides a method of preparing a compound of formula (13d),
Figure imgf000022_0003
(13d)
or a salt thereof, said method comprising reacting a chlorinating reagent with a compound of formula (2d),
Figure imgf000022_0004
(2d)
wherein Pi is an alcohol protecting group; X3 is -CI; and Rioo is (Ci-C3)alkoxy.
In a twenty-third embodiment, the present invention provides a method of preparing a compound of formula (14d),
Figure imgf000023_0001
(14d)
or a salt thereof, said method comprising reacting a compound of formula (13d)
Figure imgf000023_0002
(13d)
with an alcohol deprotecting reagent, wherein Pi is an alcohol protecting group; X3 -CI; and Rioo is (Ci-C3)alkoxy.
In a twenty-fourth embodiment, the present invention provides a method of preparing a compound of formula (15d):
Figure imgf000023_0003
(15d)
or a salt thereof, said method comprising reacting a sulfonating reagent or an esterification reagent with a compound of formula (14d),
Figure imgf000023_0004
(14d)
wherein X3 is -CI; X4 is a sulfonate ester or an activated ester (preferably, X4 is a sulfonate ester); and Rioo is (Ci-C3)alkoxy.
In a twenty-fifth embodiment, the present invention provides a method of preparing a compound of formula (20d):
Figure imgf000023_0005
(20d) or a salt thereof, said method comprising reacting a brominating or iodinating reagent with a compound of formula (14d),
Figure imgf000024_0001
(14d)
wherein X3 is -CI; X5 is -Br or -I; and Rioo is (Ci-C3)alkoxy. In a twenty- sixth embodiment, the present invention provides a method of preparing a compound of formula (16d):
Figure imgf000024_0002
(16d)
or a salt thereof, said method comprising reacting a compound of formula (15d)
Figure imgf000024_0003
(15d)
with a monomer compound of formula (ai),
Figure imgf000024_0004
wherein X3 is -CI; X4 is a sulfonate ester or an activated ester (preferably, X4 is a sulfonate ester); and Rioo is (Ci-C3)alkoxy.
In a twenty- seventh embodiment, the present invention provides a method of preparing a compound of formula (16d),
Figure imgf000025_0001
(16d)
or a salt thereof, said method comprising reacting a compound of formula (20d)
Figure imgf000025_0002
(20d)
with a monomer compound of formula (ai),
Figure imgf000025_0003
wherein X3 is -CI; X5 is -Br or -I; and R100 is (Ci-C3)alkoxy.
In a twenty-eighth embodiment, the present invention provides a method of preparing a compound of formula (16d),
Figure imgf000025_0004
(16d) or a salt thereof, said method comprising reacting a compound of formula (14d)
Figure imgf000025_0005
(14d) with a monomer compound of formula (ai),
Figure imgf000026_0001
wherein X3 is -CI; and Rioo is (Ci-C3)alkoxy.
In a twenty-ninth embodiment, the present invention provides a method of preparing a compound of formula (18d):
Figure imgf000026_0002
(18d)
a pharmaceutically acceptable salt thereof, said method comprising reacting a compound of formula of (16d):
Figure imgf000026_0003
(16d)
with a reduced monomer of formula (di):
Figure imgf000026_0004
wherein X3 is -CI; P3 is H or an amine protecting group; and Rioo is (Ci-C3)alkoxy.
In a thirtieth embodiment, the present invention provides a method for preparing a compound of formula (17d):
Figure imgf000026_0005
(17d) or a salt thereof, said method com rising reacting a compound of formula (15d)
Figure imgf000027_0001
(15d)
with a monomer compound of formula (di),
Figure imgf000027_0002
wherein X3 is -CI; X4 is a sulfonate ester or an activated ester (preferably, X4 is a sulfonate ester); P3 is H or an amine protecting group; and Rioo is (Ci-C3)alkoxy.
In a thirty-first embodiment, the present invention provides a method of preparing a compound of formula (17d),
Figure imgf000027_0003
(17d)
or a salt thereof, said method comprising reacting a compound of formula (14d)
Figure imgf000027_0004
(14d) with a monomer compound of formula (di),
Figure imgf000027_0005
wherein X3 is -CI; P3 is H or an amine protecting group; and Rioo is (Ci-C3)alkoxy. In a thirty- second embodiment, the present invention provides a method of preparing a compound of formula (17d):
Figure imgf000028_0001
(17d)
or a salt thereof, said method comprising reacting a compound of formula (20d)
Figure imgf000028_0002
(20d)
with a monomer compound of formula (di),
Figure imgf000028_0003
wherein X3 is -CI; X5 is -Br or -I; P3 is H or an amine protecting group; and R100 is (Ci- C3)alkoxy.
In a thirty-third embodiment, the present invention provides a method of preparing a compound of formula (17d'):
Figure imgf000028_0004
(17d')
or a salt thereof, said method comprising reacting a compound of formula (16d)
Figure imgf000029_0001
(16d) with an imine reducing agent, wherein X3 is -CI; and Rioo is (Ci-C3)alkoxy.
In a thirty-fourth embodiment, the present invention provides a method of preparing a compound of formula (18d),
Figure imgf000029_0002
(18d)
or a pharmaceutically acceptable salt thereof, said method comprising reacting a compound of formula of (17d):
Figure imgf000029_0003
(17d)
with a monomer of formula (ai):
Figure imgf000029_0004
wherein X3 is -CI; P3 is H or an amine protecting group; and Rioo is (Ci-C3)alkoxy.
In a thirty-fifth embodiment, the present invention provides a
method of preparing a compound of formula (18d),
Figure imgf000030_0001
(18d)
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a sulfonating reagent or an esterification reagent with the compound of formula (14d):
Figure imgf000030_0002
(14d)
or a salt thereof, to form a compound of formula (15d):
Figure imgf000030_0003
(15d)
or a salt thereof;
(2) reacting the compound of formula (15a) with a monomer compound of formula (a ,
Figure imgf000030_0004
to form a compound of formula (16d):
Figure imgf000030_0005
(16d) or a salt thereof; and
(3) reacting the compound of formula of (16d) with a reduced monomer of formula (di):
Figure imgf000031_0001
to form a compound of formula (18d), or a pharmaceutically acceptable salt thereof, wherein X3 is -CI; X4 is a sulfonate ester or an activated ester (preferably, a sulfonate ester); Pi is an alcohol protecting group; P3 is H or an amine protecting group; and Rioo is (Ci-C3)alkoxy.
In a thirty- sixth embodiment, the present invention provides a method of preparing a compound of formula (18d),
Figure imgf000031_0002
(18d)
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting the compound of formula (14d):
Figure imgf000031_0003
(14d)
or a salt thereof, with a monomer compound of formula (ai),
Figure imgf000031_0004
to form a compound of formula (16d):
Figure imgf000032_0001
(16d)
or a salt thereof; and
(2) reacting the compound of formula of (16d) with a reduced monomer of formula (di):
Figure imgf000032_0002
to form a compound of formula (18d), or a pharmaceutically acceptable salt thereof, wherein X3 is -CI; Pi is an alcohol protecting group; P3 is H or an amine protecting group; and Rioo is (Ci-C3)alkoxy.
In a thirty- seventh embodiment, the present invention provides a method of preparing a com ound of formula (18d),
Figure imgf000032_0003
(18d)
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a halogenating reagent with the compound of formula (14d):
Figure imgf000032_0004
(14d)
or a salt thereof, to form a compound of formula (20d):
Figure imgf000033_0001
(20d)
or a salt thereof;
(2) reacting a compound of formula (20d) or a salt thereof with a monomer compound of formula (ai),
Figure imgf000033_0002
to form a compound of formula (16d):
Figure imgf000033_0003
(16d)
or a salt thereof; and
(3) reacting the compound of formula of (16d) with a reduced monomer of formula (di):
Figure imgf000033_0004
to form a compound of formula (18d), or a pharmaceutically acceptable salt thereof, wherein X3 is -CI; X5 is -Br or -I; P3 is H or an amine protecting group; and R100 is (Q- C3)alkoxy.
In a thirty-eighth embodiment, the present invention provides a method of preparing a compound of formula (18d),
Figure imgf000034_0001
(18d)
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a sulfonating reagent or an esterification reagent with the compound of formula (14d):
Figure imgf000034_0002
(14d)
or a salt thereof, to form a compound of formula (15d):
Figure imgf000034_0003
(15d)
or a salt thereof;
(2) reacting the compound of formula (15d) with a reduced monomer compound of formula (di),
Figure imgf000034_0004
to form a compound of formula (17d):
Figure imgf000034_0005
(17d)
or a salt thereof; and (3) reacting the compound of formula of (17d) with a monomer of formula (ai):
Figure imgf000035_0001
to form a compound of formula (18d), or a pharmaceutically acceptable salt thereof, wherein X3 is -CI; X4 is a sulfonate ester or an activated ester (preferably, a sulfonate ester); Pi is an alcohol protecting group; P3 is H or an amine protecting group; and Rioo is (Ci-C3)alkoxy.
In a thirty-ninth embodiment, the present invention provides method of preparing a compound of formula 18d),
Figure imgf000035_0002
(18d)
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting the compound of formula (14d):
Figure imgf000035_0003
(14d)
or a salt thereof, with a reduced monomer compound of formula (di),
Figure imgf000035_0004
to form a compound of formula (17d)
Figure imgf000035_0005
(17d) or a salt thereof; and
(2) reacting the compound of formula of 17d) with a monomer of formula (ai):
Figure imgf000036_0001
to form a compound of formula (18d), or a pharmaceutically acceptable salt thereof, wherein X3 is -CI; Pi is an alcohol protecting group; P3 is H or an amine protecting group; and Rioo is (Ci-C3)alkoxy.
In a fortieth embodiment, the present invention provides a method of preparing a compound of formula (18d),
Figure imgf000036_0002
(18d)
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a brominating or iodinating reagent with the compound of formula
(14d):
Figure imgf000036_0003
(14d)
or a salt thereof, to form a compound of formula (20d):
Figure imgf000036_0004
(20d)
or a salt thereof;
(2) reacting the compound of formula (20d) with a reduced monomer compound of formula (di),
Figure imgf000037_0001
to form a compound of formula (17d):
Figure imgf000037_0002
(17d)
or a salt thereof; and
(3) reacting the compound of formula of (17d) with a monomer of formula (ai):
Figure imgf000037_0003
to form a compound of formula (18d), or a pharmaceutically acceptable salt thereof, wherein X3 is -CI; X5 is -Br or -I; Pi is an alcohol protecting group; P3 is H or an amine protecting group; and R100 is (Ci-C3)alkoxy.
In a forty-first embodiment, the present invention provides a method of preparing a compound of formula (Id'),
Figure imgf000037_0004
(Id')
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a sulfonating reagent or an esterification reagent with the compound of formula (14d):
Figure imgf000037_0005
(14d) or a salt thereof, to form a compound of formula (15d):
Figure imgf000038_0001
(15d)
or a salt thereof;
(2) reacting the compound of formula (15d) with a monomer compound of formula (ai),
Figure imgf000038_0002
to form a compound of formula (16d):
Figure imgf000038_0003
(16d)
or a salt thereof;
(3) reacting the compound of formula (16d) with an imine reducing agent to form a compound of formula (17d'):
Figure imgf000038_0004
(17d')
or a salt thereof; and
(4) reacting the compound of formula (17d') with a monomer of formula (ai):
Figure imgf000038_0005
to form the compound of formula (Id'); wherein X3 is -CI; X4 is a sulfonate ester or an activated ester (preferably, a sulfonate ester); Pi is an alcohol protecting group; P2 is an amine protecting group; and Rioo is (Ci-C3)alkoxy.
In a forty- second embodiment, the present invention provides a method of preparing a compound of formula (Id'),
Figure imgf000039_0001
(Id')
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting the compound of formula (14d):
Figure imgf000039_0002
(14d)
or a salt thereof, with a monomer compound of formula (ai),
Figure imgf000039_0003
to form a compound of formula (16d):
Figure imgf000039_0004
(16d)
or a salt thereof;
(2) reacting the compound of formula (16d) with an imine reducing agent to form a compound of formula (17d'):
Figure imgf000040_0001
(17d')
or a salt thereof; and
(3) reacting the compound of formula (17d') with a monomer of formula (ai):
Figure imgf000040_0002
to form the compound of formula (Id'); wherein X3 is -CI; Pi is an alcohol protecting group; and Rioo is (Ci-C3)alkoxy.
In a forty-third embodiment, the present invention provides a method of preparing a com ound of formula (Id'),
Figure imgf000040_0003
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a brominating or iodinating reagent with the compound of formula (14d):
Figure imgf000040_0004
(14d)
or a salt thereof, to form a compound of formula (20d):
Figure imgf000040_0005
(20d) or a salt thereof;
(2) reacting a compound of formula (20d) or a salt thereof with a monomer compound of formula (ai),
Figure imgf000041_0001
to form a compound of formula (16d):
Figure imgf000041_0002
(16d)
(3) reacting the compound of formula (16d) with an imine reducing agent to form a compound of formula (17d'):
Figure imgf000041_0003
(17d')
or a salt thereof; and
(4) reacting the compound of formula (17d') with a monomer of formula (ai):
Figure imgf000041_0004
to form the compound of formula (Id'); wherein X3 is -CI; Pi is an alcohol protecting group; and Rioo is (Ci-C3)alkoxy. In a forty-fourth embodiment, the present invention provides a method of
Figure imgf000042_0001
(Id')
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a compound of formula (IA):
Figure imgf000042_0002
with a reducing agent to form a compound of formula (IB):
Figure imgf000042_0003
(2) reacting the compound of formula (IB) with a compound of formula (LI):
Figure imgf000042_0004
to form the compound of formula (Id), wherein E is -OH, halide or -C(=0)E is an activated ester; and Rioo is (Ci-C3)alkoxy.
Also included in the present invention are compounds described in the methods of the present invention.
BRIEF DESCRIPTION OF THE FIGURES
FIGs. 1-13 show exemplary schemes for the methods of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents which may be included within the scope of the present invention as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention.
It should be understood that any of the embodiments described herein can be combined with one or more other embodiments of the invention, unless explicitly disclaimed or improper. Combination of embodiments are not limited to those specific combinations claimed via the multiple dependent claims.
DEFINITIONS
"Alkyl" as used herein refers to a saturated linear or branched-chain monovalent hydrocarbon radical of one to twenty carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-methyl-l -propyl, - CH2CH(CH3)2), 2-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl 3-pentyl, 2-methyl-2- butyl, 3-methyl-2-butyl, 3 -methyl- 1 -butyl, 2-methyl-l -butyl, 1-hexyl), 2-hexyl, 3-hexyl,
2- methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-
3- pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl, and the like. Preferably, the alkyl has one to ten carbon atoms. More preferably, the alkyl has one to four carbon atoms.
"Aryl" means a monovalent aromatic hydrocarbon radical of 6-18 carbon atoms derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Some aryl groups are represented in the exemplary structures as "Ar." Aryl includes bicyclic radicals comprising an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic carbocyclic or heterocyclic ring. Typical aryl groups include, but are not limited to, radicals derived from benzene (phenyl), substituted benzenes, naphthalene, anthracene, indenyl, indanyl, 1,2-dihydronapthalene, 1,2,3,4-tetrahydronapthyl, and the like. Preferably, aryl is phenyl group.
The term "halo" or "halogen" refers to F, CI, Br or I. In one embodiment, the halogen is Br or I.
The term "compound" or "cytotoxic compound," "cytotoxic dimer" and
"cytotoxic dimer compound" are used interchangeably. They are intended to include compounds for which a structure or formula or any derivative thereof has been disclosed in the present invention or a structure or formula or any derivative thereof that has been incorporated by reference. The term also includes, stereoisomers, geometric isomers, tautomers, solvates, metabolites, salts (e.g. , pharmaceutically acceptable salts) and prodrugs, and prodrug salts of a compound of all the formulae disclosed in the present invention. The term also includes any solvates, hydrates, and polymorphs of any of the foregoing. The specific recitation of "stereoisomers," "geometric isomers," "tautomers," "solvates," "metabolites," "salt" "prodrug," "prodrug salt," "conjugates," "conjugates salt," "solvate," "hydrate," or "polymorph" in certain aspects of the invention described in this application shall not be interpreted as an intended omission of these forms in other aspects of the invention where the term "compound" is used without recitation of these other forms.
The term "precursor" of a given group refers to any group which may lead to that group by any deprotection, a chemical modification, or a coupling reaction.
The term "chiral" refers to molecules which have the property of non- superimposability of the mirror image partner, while the term "achiral" refers to molecules which are superimposable on their mirror image partner.
The term "stereoisomer" refers to compounds which have identical chemical constitution and connectivity, but different orientations of their atoms in space that cannot be interconverted by rotation about single bonds.
"Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as crystallization, electrophoresis and chromatography.
"Enantiomers" refer to two stereoisomers of a compound which are non- superimposable mirror images of one another.
Stereochemical definitions and conventions used herein generally follow S . P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic
Compounds," John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e. , they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereo selection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.
As used herein, the term "imine reducing reagent" refers to a reagent that is capable of reducing an imine functional group to an amine functional group. In certain embodiments, the imine reducing reagent is a hydride reducing reagent. Examples of such imine reducing reagents include, but are not limited to, borohydrides (e.g. , sodium borohydride, sodium triacetoxy borohydride, sodium cyanoborohydride, lithium borohydride (LiBH4), potassium borohydride (KBH4)), hydrogen gas, and lithium aluminum hydride, ammonium formate, borane, 9-borabicyclo[3.3.1]nonane (9-BBN), diisobutylaluminium hydride (DIBAL), and sodium bis(2- methoxyethoxy)aluminumhydride (Red-Al). In certain embodiments, the imine reducing reagent is sodium triacetoxy borohydride.
The term "protecting group" or "protecting moiety" refers to a substituent that is commonly employed to block or protect a particular functionality while reacting other functional groups on the compound, a derivative thereof, or a conjugate thereof. For example, an "amine protecting group" or an "amino-protecting moiety" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Such groups are well known in the art (see for example P. Wuts and T. Greene, 2007, Protective Groups in Organic Synthesis, Chapter 7, J. Wiley & Sons, NJ) and exemplified by carbamates such as methyl and ethyl carbamate, FMOC, substituted ethyl carbamates, carbamates cleaved by l,6-P-elimination (also termed "self immolative"), ureas, amides, peptides, alkyl and aryl derivatives. Suitable amino- protecting groups include, but are not limited to, acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethylenoxycarbonyl (Fmoc), 2- trimethylsilylethyl,(2-phenyl-2-trimethylsilyl)ethyl, triisopropylsiloxy, 2- (trimethylsilyl)ethoxymethyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2- (trimethylsilyl)ethoxycarbonyl, or 2, 2,2,2-trichloroethoxycarbonyl. For a general description of protecting groups and their use, see P. G.M. Wuts & T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 2007.
An "alcohol protecting group" or an "alcohol-protecting moiety" is a substituent attached to an alcohol group that blocks or protects the alcohol functionality in the compound. Such groups are well known in the art (see for example, P. Wuts and T. Greene, 2007, Protective Groups in Organic Synthesis, Chapter 2, J. Wiley & Sons, NJ). Suitable alcohol protecting group include, but are not limited to, pivaloyl, methoxymethyl, 2-methoxyethoxymethyl, /?-methoxybenzyl, 3,4-dimethyoxybenzyl, 2,6-dimethyoxybenzyl, diphenylmethyl, benzyloxymethyl, 2,2,2- trichloroethoxycarbonyl, tetrahydrofuranyl, tetrahydropyranyl, benzyl, benzoyl, para- phenylbenzoyl, 2,4,6-trimethylbenzoyl, /?ara-bromobenzoyl, /?ara-nitrobenzoyl, picolinoyl, nicotinoyl, 5-dibenzosuberyl, trityl/triphenylmethyl, or tris(4-ie/ - butylphenyl)methyl and various silyl protecting groups (for example,
dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl, trimethylsilyl, triisopropylsilyl, tribenzylsilyl, triphenylsilyl, 2-norbornyldimethylsilyl, tert- butyldimethylsilyl, ie/t-butyldiphenylsilyl, 2-trimethyethylsilyl (TEOC), or [2- (trimethylsilyl)ethoxy] methyl). In certain embodiments, the alcohol protecting group is sterically hindered. In certain embodiments, the alcohol protecting group is preferably methoxymethyl, tetrahydropyranyl, 2-methoxyethoxymethyl, p-methoxybenzyl, benzyloxymethyl, or 2,2,2-trichloroethoxycarbonyl. More preferably, the alcohol protecting group is 2,2,2-trichloroethoxycarbonyl. In certain embodiments, the alcohol protecting group is a silyl protecting group, preferably, triethylsilyl, triisopropylsilyl, or tert-butyldimethylsilyl. More preferably, the alcohol protecting group is tert- butyldimethylsilyl.
An "alcohol protecting reagent" as used herein refers to a reagent that introduces an alcohol protecting group onto an alcohol group.
An "acid labile alcohol protecting group" is an alcohol protecting group that is not stable under acidic condition and releases the alcohol protecting group to form free alcohol. Examples of an acid labile alcohol protecting group include, but are not limited to, acetate, allyl, methoxymethyl, tetrahydrofuranyl, tetrahydropyranyl, 5- dibenzosuberyl, 1-ethoxyethyl, 1 -methyl- lmethoxylethyl, 2-(phenylselenyl)ethyl, trityl/triphenylmethyl, tris(4-ie/ -butyrphenyl)methyl, and various silyl protecting group (for example, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tribenzylsilyl, triphenylsilyl, 2- norbornyldimethylsilyl, ie/t-butyldimethylsilyl, ie/ -butyldiphenylsilyl, 2- trimethyethylsilyl (TEOC), or [2-(trimethylsilyl)ethoxy] methyl). In certain
embodiments, the alcohol protecting group is a silyl protecting group, preferably, triethylsilyl, triisopropylsilyl, or tert-butyldimethylsilyl. More preferably, the alcohol protecting group is tert-butyldimethylsilyl.
As used herein, the term "alcohol deprotecting reagent" refers to a reagent that is capable of cleaving an alcohol protecting group to form free alcohol. Such reagents are well known in the art (see for example P. Wuts and T. Greene, 2007, Protective Groups in Organic Synthesis, Chapter 2, J. Wiley & Sons, NJ). Examples of such alcohol deprotecting reagents include, but are not limited to, tetra-n-butylammonium fluoride, tris(dimethylamino)sulfonium difluorotrimethylsilicate, hydrogen fluoride or a solvate thereof, hydrogen fluoride pyridine, silicon tetrafluoride, hexafluorosilicic acid, cesium fluoride, hydrochloric acid, acetic acid, trifluoroacetic acid, pyridinium p- toluensulfonate, p-toluenesulfonic acid (p-TsOH), formic acid, periodic acid. In certain embodiments, the alcohol deprotecting reagent is hydrochloric acid or tetra-n- butylammonium fluoride (TBAF). In certain embodiments, the alcohol deprotecting agent is hydrogen fluoride-pyridine (HF-pyridine).
As used herein, "amine deprotecting group" refers a reagent that is capable of cleaving an amine protecting group to form free amine. Such reagents are well known in the art (see for example P. Wuts and T. Greene, 2007, Protective Groups in Organic Synthesis, Chapter 7, J. Wiley & Sons, NJ). Examples of such amine deprotecting reagents include, but are not limited to, tetra-n-butylammonium fluoride, acetic acid, hydrogen fluoride pyridine, cesium fluoride, piperidine, morpholine, or trifluoroacetic acid.
As used herein, "alcohol activating agent" refers a reagent that increases the reactivity of a hydroxyl group thereby making the hydroxyl group a better leaving group. Examples of such alcohol activating agents include p-toluenesulfonyl chloride, thionyl chloride, triflic anhydride, mesyl chloride, mesyl anhydride, triphenylphosphine, acyl chloride, 4-dimethylaminopyridine, and others. In certain embodiments, the alcohol activating agent is thionyl chloride. In certain embodiment,the alcohol activating agent is triphenylphosphine.
The phrase "pharmaceutically acceptable salt" as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound of the invention. Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate "mesylate," ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e. , l,l '-methylene-bis-(2-hydroxy-3-naphthoate)) salts, alkali metal (e.g. , sodium and potassium) salts, alkaline earth metal (e.g. , magnesium) salts, and ammonium salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion. The counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion.
If the compound of the invention is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
If the compound of the invention is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
The phrase "pharmaceutically acceptable" indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
The term "leaving group" refers to a group of charged or uncharged moiety that departs during a nucleophilic substitution or displacement. Such leaving groups are well known in the art and include, but not limited to, halogens, esters, alkoxy, hydroxyl, tosylates, triflates, mesylates, nitriles, azide, carbamate, disulfides, thioesters, thioethers and diazonium compounds.
As used herein, the term "halogenating reagent" refers to a reagent that converts an alcohol group to a halide group. A "brominating reagent" is a reagent that converts an alcohol group to a bromide group. A "iodinating reagent" is a reagent that converts an alcohol group to a iodide group. A "chlorinating reagent" is a reagent that converts an alcohol group to a chloride group. Exemplary brominating reagents include, but are not limited to, bromine, hydrobromic acid, carbon tetrabromide, phosphorus tribromide, and potassium bromide. Exemplary iodinating reagent include, but are not limited to, hydroiodic acid, iodine, carbon tetraiodide, phosphorus triiodide, sodium iodide, or potassium iodide. Exemplary chlorinating reagent include, but are not limited to, carbon tetrachloride, methanesulfonyl chloride, sulfuryl chloride, thionyl chloride, cyanuric chloride, N-chlorosuccinimide, phosphorus(V) oxychloride, phosphorus pentachloride, and phosphorus trichloride. In a specific embodiment, the chlorinating reagent is methanesulfonyl chloride.
As used herein, a "sulfonating reagent" refers to a reagent that converts an alcohol group to a sulfonate ester group. Preferably, the sulfonating reagent is a sulfonic anhydride, such as methanesulfonic anhydride, or a sulfonic chloride, such as methanesulfonyl chloride (MsCl).
As used herein, an "activated ester" refers to an ester group that is readily displaced by a hydroxyl or an amine group. Exemplary activated esters include, but are not limited to nitrophenyl (e.g. , 2 or 4-nitrophenyl) ester, dinitrophenyl (e.g. , 2,4- dinitrophenyl) ester, sulfo-tetraflurophenyl (e.g. , 4-sulfo-2,3,5,6-tetrafluorophenyl) ester, pentafluorophenyl ester, nitropyridyl (e.g. , 4-nitropyridyl) ester, trifluoroacetate, and acetate.
As used herein, an "esterification reagent" refers to a reagent that converts an alcohol group to an ester group. Exemplary esterification reagent include, but are not limited to, nitrobenzoid acid (e.g. , 2 or 4-nitrobenzoic acid), dinitrobenzoid acid (e.g. , 2,4-dinitrobenzoic acid), sulfo-tetraflurobenzoid acid (e.g. , 4-sulfo-2,3,5,6- tetrafluorobenzoic acid), pentafluorobenzoic acid, nitropyridine carboxylic acid (e.g. , 4- nitro-2-pyridine carboxylic acid, trifluoroacetic acid, and acetic acid, or acyl chloride, acid anhydride or other activated carboxylic acid derivatives thereof.
METHODS OF THE PRESENT INVENTION
The present invention provides novel methods for preparing
indolinobenzodiazepine dimer compounds that have one imine functionality and one amine functionality. As compared to the methods known in the art, the present methods can produce the desired dimer compounds with higher yield and without the use of HPLC purification.
In a first embodiment, the present invention provides a method of preparing a compound of formula (2d),
Figure imgf000050_0001
(2d) or a salt thereof, said method comprising introducing an alcohol protecting group onto one of the primary alcohols of a compound of formula (Id) by reacting the compound of formula (Id) with an alcohol protecting reagent,
Figure imgf000051_0001
(1d)
wherein Pi is the alcohol protecting group; and Rioo is (Ci-C3)alkoxy.
Also provided in the first embodiment is a method of preparing a compound of formula (2A),
Figure imgf000051_0002
(2A) or a salt thereof, comprising introducing an alcohol protecting group onto one of the primary alcohols of a compound of formula (1A) by reacting the compound of formula (1A) with an alcohol protecting reagent,
Figure imgf000051_0003
(1A)
wherein Pi is the alcohol protecting group.
In a specific embodiment, for methods of preparing compound of formula (2d) or (2A) described above the alcohol protecting group is sterically hindered.
In another specific embodiment, the alcohol protecting group is pivaloyl, methoxymethyl, 2-methoxyethoxymethyl, /?-methoxybenzyl, 3,4-dimethyoxybenzyl, 2,6-dimethyoxybenzyl, diphenylmethyl, benzyloxymethyl, 2,2,2- trichloroethoxycarbonyl, tetrahydrofuranyl, tetrahydropyranyl, benzyl, benzoyl, para- phenylbenzoyl, 2,4,6-trimethylbenzoyl, /?ara-bromobenzoyl, /?ara-nitrobenzoyl, picolinoyl, nicotinoyl, 5-dibenzosuberyl, trityl/triphenylmethyl, or tris(4-ie/ - butylphenyl)methyl. Preferably, the alcohol protecting group is methoxymethyl, tetrahydropyranyl, 2-methoxyethoxymethyl, p-methoxybenzyl, benzyloxymethyl, or 2,2,2-trichloroethoxycarbonyl. Even more preferably, the alcohol protecting group is 2,2,2-trichloroethoxycarbonyl. In another specific embodiment, the alcohol protecting group is a silyl protecting group. For example, the silyl protecting group is dimethylisopropylsilyl,
diethylisopropylsilyl, dimethylhexylsilyl, trimethylsilyl, triisopropylsilyl, tribenzylsilyl, triphenylsilyl, 2-norbornyldimethylsilyl, ie/t-butyldimethylsilyl, ie/ -butyldiphenylsilyl, 2-trimethyethylsilyl (TEOC), or [2-(trimethylsilyl)ethoxy]methyl. Preferably, the silyl protecting group is triethylsilyl, triisopropylsilyl, or tert-butyldimethylsilyl. More preferably, the silyl protecting group is tert-butyldimethylsilyl.
The silyl protecting group can be introduced by reacting the compound of formula (Id) or (1A) with R3-C1, R3-Br, R3-I or R3-OS02CF3 (collectively the alcohol protecting reagent) in the presence of a base, wherein R is dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl, trimethylsilyl, triisopropylsilyl, tribenzylsilyl, triphenylsilyl, 2-norbornyldimethylsilyl, ie/t-butyldimethylsilyl, ie/t-butyldiphenylsilyl or [2-(trimethylsilyl)ethoxy]methyl. In certain embodiments, the molar ratio of the alcohol protecting reagent to the compound of formula (Id) or (1A) is between 0.8-1.2, between 1 to 5, between 1 to 2, between 1 to 1.5, between 1 to 1.4, between 1 to 1.3, between 1 to 1.2, or between 1 to 1.1. In certain embodiment, less than 2 molar equivalents of the alcohol protecting reagent is used relative to the compound of formula (Id) or (1A). Preferably, 1.5, 1.4, 1.3, 1.2, 1.1 or 1.0 molar equivalent of the alcohol protecting reagent relative to the compound of formula (Id) or (1A) is used.
In one embodiment, the base can be a non-nucleophilic base. Examples of non- nucleophilic base include, but are not limited to, imidazole, triethylamine,
diisopropylethylamine, pyridine, 2,6-lutidine, l,8-diazabicycloundec-7-ene, or tetramethylpiperidine. Preferably, the non-nucleophilic base is imidazole. Molar excess amount of the base can be used. In certain embodiments, more than 2 molar equivalents of the base (e.g... non-nucleophilic base) are used relative to the compound of formula (Id) or (lA).
In another embodiment, the reaction between the compound of formula (Id) or
(1A) and R 3 -CI, R 3 -Br, R 3 -I or R 3 -OS02CF3 is carried out in the presence of a catalyst that facilitates the introduction of the silyl protecting group. Any suitable catalysts known in the art (see, for example, P. Wuts and T. Greene, 2007, Protective Groups in Organic Synthesis, Chapter 2, J. Wiley & Sons, NJ) can be used in the reaction.
Exemplary catalysts include, but are not limited to, 4-dimethylaminopyridine (DMAP), 1,1,3,3-tetramethylguanidine and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Any suitable organic solvents can be used for the methods of the first embodiment. Exemplary solvents include, but are not limited to, DMF, CH2CI2, dichloroethane, THF, dimethylacetamide, etc. In certain embodiments, DMF is used as the solvent.
In another specific embodiment, the method of preparing the compound of formula (2d) or (2A) comprising reacting the compound of (Id) or (1A) with TBSC1 in the presence of a non-nucleophilic base. In one embodiment, the base is imidazole or DIPEA. In a specific embodiment, the base is imidazole. In another specific embodiment, the base is DIPEA.
In a second embodiment, the present invention provides a method of preparing a compound of formula (3d
Figure imgf000053_0001
(3d)
or a salt thereof, said method comprising reacting a halogenating reagent, a sulfonating reagent or an esterification rea ent with a compound of formula (2d),
Figure imgf000053_0002
wherein Pi is an alcohol protecting group; Xi is a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester, and an activated ester; and R100 is (Q- C3)alkoxy.
Also provided in the second embodiment is a method of preparing a compound of formula (3A),
Figure imgf000053_0003
(3A)
or a salt thereof, comprising reacting the compound of formula (2A) with a halogenating reagent, a sulfonating reagent or an esterification reagent,
Figure imgf000054_0001
(2A)
wherein Pi and Rioo are as defined in the first embodiment, and Xi is a leaving group selected from the group consisting of: -Br, -I, -CI a sulfonate ester, and an activated ester.
In a specific embodiment, for methods of preparing compound of formula (3d) or
(3A) described above, Xi is -Br, -I or a sulfonate ester.
In a specific embodiment, for methods of making compound of formula (3d) or (3A) described above, Xi is mesylate, tosylate, brosylate, or triflate. Preferably, Xi is mesylate.
In another specific embodiment, the method of the second embodiment comprises reacting the compound of formula (2d) or (2A) with a halogenating reagent. Exemplary halogenating reagents include, but are not limited to, bromine, hydrobromic acid, carbon tetrabromide, phosphorus tribromide, potassium bromide, hydroiodic acid, iodine, carbon tetraiodide, phosphorus triiodide, sodium iodide, or potassium iodide.
In yet another specific embodiment, the method of the second embodiment comprises reacting the compound of formula (2d) or (2A) with a sulfonating reagent. Preferably, the sulfonating reagent is a sulfonic anhydride, such as methanesulfonic anhydride, or a sulfonic chloride, such as methane sulfonyl chloride (MsCl).
In certain embodiment, the reaction between the compound of formula (2d) or (2A) and the sulfonating reagent can be carried out in the presence of a base. In one embodiment, the base is a non-nucleophilic base. Exemplary non-nucleophilic bases include, but are not limited to, triethylamine, imidazole, triethylamine,
diisopropylethylamine, pyridine, 2,6-lutidine, dimethylformamide, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), or tetramethylpiperidine. Preferably, the base is triethylamine or diisopropylethylamine.
Any suitable organic solvents can be used in the method of the second embodiment. In one embodiment, the solvent is dichloromethane.
In a third embodiment, the present invention provides a method of preparing a compound of formula (4d),
Figure imgf000055_0001
(4d)
or a salt thereof, said method comprising reacting a compound of formula (3d)
Figure imgf000055_0002
(3d)
with a monomer compound of the formula ai),
Figure imgf000055_0003
wherein Pi is an alcohol protecting group; Xi is a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester and an activated ester; and Rioo is (Ci- C3)alkoxy.
Also provided in the third embodiment is a method of preparing a compound of formula (4A),
Figure imgf000055_0004
(4A)
or a salt thereof, said method comprising reacting a compound of formula (3 A)
Figure imgf000055_0005
(3A)
with a monomer compound of the formula (ai),
Figure imgf000055_0006
wherein Pi is an alcohol protecting group; and X1 is a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester and an activated ester.
In a specific embodiment, for methods of the third embodiment, Xi is -Br, -I, or a sulfonate ester.
In a specific embodiment, for method of preparing compound of formula (4d) or
(4A), the compound of formula (3d) or (3A) is reacted with the monomer compound of formula (ai) in the presence of a base. Any suitable base can used. Exemplary bases include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride. In one embodiment, the base is potassium carbonate.
Any suitable solvents can be use in the method of third embodiment. In one embodiment, the solvent is dimethylacetamide (DMA).
In a specific embodiment, the method of preparing compound of formula (4d) or (4A) described above comprises reacting the compound of formula (3d) or (3A) with the monomer compound (ai) in the presence of potassium carbonate in DMA. In one embodiment, the reaction is carried out in the presence of potassium iodide.
In a fourth embodiment, the present invention provides a method of preparing a compound of formula (5d),
Figure imgf000056_0001
(5d)
or a salt thereof, said method comprising reacting a compound of formula (4d),
Figure imgf000056_0002
(4d)
with an imine reducing agent, wherein Pi is an alcohol protecting group; and Rioo is (Q- C3)alkoxy.
Also provided in the fourth embodiment is a method of preparing a compound of formula (5A),
Figure imgf000057_0001
or a salt thereof, said method comprising reacting a compound of formula (4A),
Figure imgf000057_0002
with an imine reducing agent, wherein the variables are as described above in the third embodiment.
In a specific embodiment, for methods of preparing compound of formula (5d) or (5A) described above, the imine reducing reagent is a hydride reducing reagent.
In another specific embodiment, the imine reducing reagent is sodium
borohydride, sodium triacetoxy borohydride, sodium cyanoborohydride, lithium aluminum hydride, hydrogen gas, ammonium formate, borane, 9- borabicyclo[3.3.1]nonane (9-BBN), diisobutylaluminium hydride (DIBAL), lithium borohydride (LiBH4), potassium borohydride (KBH4), or sodium bis(2- methoxyethoxy)aluminumhydride (Red-Al). Preferably, the imine reducing reagent is sodium triacetoxy borohydride (NaBH(OAc)3).
Any suitable solvents can be use in the method of fourth embodiment. In one embodiment, the solvent is dichloroethane.
In a fifth embodiment, the present invention provides a method of preparing a compound of formula (6d),
Figure imgf000057_0003
(6d)
or a salt thereof, said method comprising reacting a compound of formula (5d),
Figure imgf000058_0001
(5d)
with an alcohol deprotecting reagent, wherein Pi is an alcohol protecting group; and Rioo is (Ci-C3)alkoxy.
Also provided in the fifth embodiment is a method of preparing a compound of formula (6A),
Figure imgf000058_0002
or a salt thereof, said method comprising reacting a compound of formula (5A),
Figure imgf000058_0003
with an alcohol deprotecting reagent, wherein the variables are as described above in the fourth embodiment
In a specific embodiment, for methods of preparing a compound of formula (6d) or (6A) described above, the alcohol deprotecting reagent is tetra-n-butylammonium fluoride, tris(dimethylamino)sulfonium difluorotrimethylsilicate, hydrogen fluoride or a solvate thereof, hydrogen fluoride pyridine, silicon tetrafluoride, hexafluorosilicic acid, cesium fluoride, hydrochloric acid, acetic acid, trifluoroacetic acid, pyridinium p- toluensulfonate, p-toluenesulfonic acid (p-TsOH), formic acid, or periodic acid.
Preferably, the alcohol deprotecting reagent is hydrochloric acid or tetra-n- butylammonium fluoride. In a more specific embodiment, the alcohol deprotecting reagent is aqueous hydrochloric acid.
Any suitable solvents can be used in the deprotection reaction described above. In one embodiment, the solvent is THF.
In a sixth embodiment, the present invention provides a method of preparing a compound of formula (7d),
Figure imgf000059_0001
(7d)
or a salt thereof, said method comprising reacting a halogenating reagent, a sulfonating reagent or an esterification reagent with the primary alcohol compound of formula (6d),
Figure imgf000059_0002
(6d)
wherein X2 is a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester and an activated ester; and Rioo is (Ci-C3)alkoxy.
Also provided in the sixth embodiment is a method of preparing a compound of formula (7 A),
Figure imgf000059_0003
(7A)
or a salt thereof, said method comprising reacting a halogenating reagent, a sulfonating reagent or an esterification reagent with the primary alcohol compound of formula (6A),
Figure imgf000059_0004
(6A)
wherein X2 is -Br, -I, -CI, a sulfonate ester or an activated ester; and the remaining variables are as described above in the fifth embodiment.
In a specific embodiment, for methods of preparing a compound of formula (7d) or (7A), X2 is -Br, -I or a sulfonate ester. In a specific embodiment, for methods of preparing a compound of formula (7d) or (7 A), X2 is mesylate, tosylate, brosylate, or triflate. Preferably, X2 is mesylate.
In another specific embodiment, the method of the sixth embodiment comprises reacting the compound of formula (6d) or (6A) with a halogenating reagent. Exemplary halogenating reagent include, but are not limited to, bromine, hydrobromic acid, carbon tetrabromide, phosphorus tribromide, potassium bromide, hydroiodic acid, iodine, carbon tetraiodide, phosphorus triiodide, sodium iodide, or potassium iodide.
In yet another specific embodiment, the method of the sixth embodiment comprises reacting the compound of formula (6d) or (6A) with a sulfonating reagent. Preferably, the sulfonating reagent is a sulfonic anhydride , such as methanesulfonic anhydride, or a sulfonic chloride, such as methane sulfonyl chloride (MsCl).
In one embodiment, the reaction between the compound of formula (6d) or (6A) and the sulfonating reagent is carried out in the presence of a base. Preferably, the base is a non-nucleophiclic base. Exemplary non-nucleophic base include, but are not limited to, triethylamine, imidazole, triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, dimethylformamide, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or
tetramethylpiperidine. Preferably, the base is triethylamine or diisopropylethylamine.
Any suitable solvents can be used in the reactions described in the sixth embodiment above. In one embodiment, the solvent is dichloromethane. In another embodiment, the solvent is DMF. In yet another embodiment, the solvent is a mixture of dichloromethane and DMF.
In a seventh embodiment, the present invention provides a method of preparing a compound of formula (7d")
Figure imgf000060_0001
(7d")
or a salt thereof, said method comprising reacting a compound of formula (5d")
Figure imgf000061_0001
(5d")
with an alcohol deprotecting reagent and a halogenating reagent, wherein Pi' is an acid labile alcohol protecting group; X2' is -Br or -I; and Rioo is (Ci-C3)alkoxy.
Also provided in the seventh embodiment is a method of preparing a compound of formula (7A"):
Figure imgf000061_0002
(7A")
or a salt thereof, said method comprising reacting a compound of formula (5A")
Figure imgf000061_0003
(5A")
with an alcohol deprotecting reagent and a halogenating reagent, wherein Pi' is an acid labile alcohol protecting group; X2' is -Br or -I; and the remaining variables are as described above in the sixth embodiment.
The method of the seventh embodiment combines the alcohol deprotection step described in the fifth embodiment and the halogenation reaction of the resulting alcohol described in the sixth embodiment into one step.
In a specific embodiment, for the method of the seventh embodiment, the compound of formula (7d") is represented by the following formula:
Figure imgf000061_0004
(7d"') and the method comprising reacting the compound of formula (5d") with an alcohol deprotecting reagent and a bromination reagent.
In another specific embodiment, for the method of the seventh embodiment, the com ound of formula (7 A'") is represented by the following formula:
Figure imgf000062_0001
and the method comprising reacting the compound of formula (5A"),
Figure imgf000062_0002
(5A")
with an alcohol deprotecting reagent and a bromination reagent.
In one embodiment, for the methods described in the seventh embodiment, the acid labile alcohol protecting group is acetate, allyl, methoxymethyl, tetrahydrofuranyl, tetrahydropyranyl, 5-dibenzosuberyl, 1-ethoxyethyl, 1 -methyl- lmethoxylethyl, 2- (phenylselenyl)ethyl, trityl/triphenylmethyl, or tris(4-tert-butylphenyl)methyl.
In another embodiment, the acid labile alcohol protecting group is a silyl protecting group. Exemplary silyl protecting groups include, but are not limited to, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tribenzylsilyl, triphenylsilyl, 2-norbornyldimethylsilyl, ie/t-butyldimethylsilyl, ie/t-butyldiphenylsilyl, 2-trimethyethylsilyl (TEOC), or [2- (trimethylsilyl)ethoxy]methyl. Preferably, the silyl protecting group is triethylsilyl, triisopropylsilyl, or tert-butyldimethylsilyl. More preferably, the silyl protecting group is tert-butyldimethylsilyl.
In one embodiment, the alcohol deprotecting reagent is tetra-n-butylammonium fluoride, tris(dimethylamino)sulfonium difluorotrimethylsilicate, hydrogen fluoride or a solvate thereof, hydrogen fluoride pyridine, silicon tetrafluoride, hexafluorosilicic acid, cesium fluoride, hydrochloric acid, acetic acid, pyridinium p-toluensulfonate, formic acid, periodic acid, trifluoroacetic acid, or .p-toluenesulfonic acid (p-TsOH). Preferably, the alcohol deprotecting reagent is acetic acid. In yet another embodiment, the bromination reagent is HBr.
In one specific embodiment, the methods of the seventh embodiment comprises reacting the compound of formula (5d") with a mixture of acetic acid and HBr to give the compound of formula (7d"').
In another specific embodiment, the methods of the seventh embodiment comprises reacting the compound of formula (5A") with a mixture of acetic acid and HBr to give the compound of formula (7 A'")
In a eighth embodiment, the present invention provides a method of preparing a compound of formula (Id'),
Figure imgf000063_0001
(Id')
or a pharmaceutically acceptable salt thereof, said method comprising reacting ;
compound of formula (7d)
Figure imgf000063_0002
(7d)
with a monomer compound of the formula (ai),
Figure imgf000063_0003
wherein Rioo is (Ci-C3)alkoxy; and, X2 is a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester, and an activated ester.
Also provided in the eighth embodiment is a method of preparing a compound of formula (IA),
Figure imgf000064_0001
Figure imgf000064_0002
(7A)
with a monomer compound of the formula (ai),
Figure imgf000064_0003
wherein Rioo is (Ci-C3)alkoxy; and, X2 is a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester, and an activated ester.
In one embodiment, for methods of the eighth embodiment, X2 is -Br, -I or a sulfonate ester.
In one embodiment, for methods of the eighth embodiment, the compound of formula (7d) or (7 A) is reacted with the monomer compound of formula (ai) in the presence of a base. Examples of the base include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride. In one embodiment, the base is potassium carbonate.
Any suitable solvents can be used in the methods of eighth embodiment described above. In one embodiment, the solvent is DMF. In another embodiment, the solvent is DMA.
In a ninth embodiment, the present invention provides a method of preparing a compound of formula (Id'),
Figure imgf000065_0001
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) introducing an alcohol protecting group onto one of the primary alcohols of a compound of formula (Id),
Figure imgf000065_0002
(1d)
to form a compound of formula (2d),
Figure imgf000065_0003
(2d)
(2) reacting the compound of formula (2d) with a halogenating reagent, a sulfonating reagent or an esterification reagent to form a compound of formula (3d),
Figure imgf000065_0004
(3d)
(3) reacting the compound of formula (3d) with a monomer compound of the formula (ai),
Figure imgf000065_0005
to form a compound of formula (4d),
Figure imgf000066_0001
(4d)
(4) reacting the compound of formula (4d) with an imine reducing agent to form a compound of formula d),
Figure imgf000066_0002
(5d)
(5) reacting the compound of formula (5d) with an alcohol deprotecting reagent to form a compound of formu (6d),
Figure imgf000066_0003
(6d)
(6) reacting a second halogenating reagent, a second sulfonating reagent or a second esterification reagent with the compound of formula (6d) to form a compound of formula (7d),
Figure imgf000066_0004
<7d) ; and
(7) reacting the compound of formula (7d) with a monomer compound of the formula (ai),
Figure imgf000067_0001
to form the compound of formula (Id'), wherein Pi is an alcohol protecting group; Xi and X2 are each independently a leaving group selected from the group consisting of: - Br, -I, -CI, a sulfonate ester and an activated ester; and Rioo is (Ci-C3)alkoxy.
Also provided in the ninth embodiment is a method of preparing a compound of formula (IA):
Figure imgf000067_0002
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) introducing an alcohol protecting group onto one of the primary alcohols of a compound of formula (1A),
Figure imgf000067_0003
(1A)
to form a compound of formula (2A),
Figure imgf000067_0004
(2A)
(2) reacting the compound of formula (2A) with a halogenating reagent, a sulfonating reagent or an esterification reagent to form a compound of formula (3A),
Figure imgf000067_0005
(3A)
(3) reacting the compound of formula (3A) with a monomer compound of the formula (ai),
Figure imgf000068_0001
to form a compound of formula (4A),
Figure imgf000068_0002
(4) reacting the compound of formula (4A) with an imine reducing agent to form a compound of formula (5A),
Figure imgf000068_0003
(5A)
(5) reacting the compound of formula (5A) with an alcohol deprotecting reagent to form a compound of formula (6A),
Figure imgf000068_0004
(6A)
(6) reacting a second halogenating reagent, a second sulfonating reagent or an esterification reagent with the compound of formula (6A) to form a compound of formula (7 A),
Figure imgf000068_0005
(7A) ; and
(7) reacting the compound of formula (7 A) with a monomer compound of the formula (ai),
Figure imgf000069_0001
to form the compound of formula (IA), wherein Pi is an alcohol protecting group; and Xi and X2 are each independently a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester and an activated ester.
In one embodiment, for methods of the ninth embodiment, Xi and X2 are each independently -Br, -CI or a sulfonate ester.
The reaction conditions and reagents for each step in the method of the ninth embodiment are as described in the first, second, third, fourth, fifth, sixth and/or eighth embodiment or any specific embodiments described therein.
In a tenth embodiment, the present invention provides a method of preparing a compound of formula (Id'),
Figure imgf000069_0002
(Id')
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) introducing an alcohol protecting group onto one of the primary alcohols of z compound of formula (Id),
Figure imgf000069_0003
(1d)
to form a compound of formula (2d"),
Figure imgf000069_0004
(2d")
(2) reacting the compound of formula (2d") with a halogenating reagent, a sulfonating reagent or an esterification reagent to form a compound of formula (3d"),
Figure imgf000070_0001
(3d")
(3) reacting the compound of formula (3d") with a monomer compound of the formula (ai),
Figure imgf000070_0002
to form a compound of formula (4d"),
Figure imgf000070_0003
(4d")
(4) reacting the compound of formula (4d") with an imine reducing agent to form a compound of formula (5d"),
Figure imgf000070_0004
(5d")
(5) reacting the compound of fonnula (5d") with an alcohol deprotecting reagent and a halogenating reagent to form a compound of formula (7d"),
Figure imgf000070_0005
(7d")
(6) reacting a compound of formula (7d") with a monomer compound of the formula (ai),
Figure imgf000071_0001
to form the compound of formula (Id'), wherein X2' is -Br or -I; and the remaining variables are as described above in the ninth embodiment.
Also provided in the tenth embodiment is a method of preparing a compound of formula (IA):
Figure imgf000071_0002
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) introducing an alcohol protecting group onto one of the primary alcohols of a compound of formula (1A),
Figure imgf000071_0003
(1A)
to form a compound of formula (2A"),
Figure imgf000071_0004
(2A")
(2) reacting the compound of formula (2A") with a halogenating reagent, a sulfonating reagent or an esterification reagent to form a compound of formula (3A"),
Figure imgf000071_0005
(3A")
(3) reacting the compound of formula (3A") with a monomer compound of the formula (ai),
Figure imgf000071_0006
to form a compound of formula (4 A"),
Figure imgf000072_0001
(4) reacting the compound of formula (4A") with an imine reducing agent to form a compound of formula (5 A"),
Figure imgf000072_0002
(5A")
(5) reacting the compound of formula (5 A") with an alcohol deprotecting reagent and a halogenating reagent to form a compound of formula (7 A"),
Figure imgf000072_0003
(7A")
(6) reacting a compound of formula (7 A") with a monomer compound of the formula (ai),
Figure imgf000072_0004
to form the compound of formula (IA), wherein X2' is -Br or -I; and the remaining variables are as described above in the ninth embodiment.
The conditions and reagents for the methods of tenth embodiment are as described above in the first, second, third, fourth, seventh and/or eighth embodiment(s) and any specific embodiments described therein.
In a eleventh embodiment, the present invention provides a method of preparing a compound of formula (9d),
Figure imgf000073_0001
(9d)
or a salt thereof, said method comprising reacting a compound of formula (4d),
Figure imgf000073_0002
(4d)
with an alcohol deprotecting reagent, wherein Pi is an alcohol protecting group; and Rioo is (Ci-C3)alkoxy.
Also provided in the eleventh embodiment is a method of preparing a compound of (9A):
Figure imgf000073_0003
or a salt thereof, said method comprising reacting a compound of formula (4A),
Figure imgf000073_0004
with an alcohol deprotecting reagent, wherein Pi is an alcohol protecting group.
In a specific embodiment, for the methods of the eleventh embodiment, the alcohol deprotecting reagent is tetra-n-butylammonium fluoride,
tris(dimethylamino)sulfonium difluorotrimethylsilicate, hydrogen fluoride or a solvate thereof, hydrogen fluoride pyridine, silicon tetrafluoride, hexafluorosilicic acid, cesium fluoride, hydrochloric acid, acetic acid, pyridinium p-toluensulfonate, formic acid, periodic acid, trifluoroacetic acid, or p-toluenesulfonic acid (p-TsOH). More
specifically, the alcohol deprotecting reagent is hydrochloric acid or tetra-n- butylammonium fluoride. In a twelfth embodiment, the present invention provides a method of preparing a compound of formula (lOd),
Figure imgf000074_0001
(10d)
or a salt thereof, said method comprising reacting the compound of formula (9d) with a halogenating reagent, a sulfonating reagent or an esterification reagent,
Figure imgf000074_0002
(9d)
wherein X2 is -Br, -I, -CI, a sulfonate ester or an activated ester; and Rioo is (Ci- C3)alkoxy.
Also provided in the twelfth embodiment is a method of preparing a compound of formula (10A):
Figure imgf000074_0003
(10A)
or a salt thereof, said method comprising reacting the compound of formula (9A) with a halogenating reagent, a sulfonating reagent or an esterification reagent,
Figure imgf000074_0004
wherein X2 is -Br, -I, -CI, a sulfonate ester or an activated ester.
In a specific embodiment, for the methods of the twelfth embodiment, X2 is -Br, -I or a sulfonate ester. In a specific embodiment, for the methods of the twelfth embodiment, X2 is mesylate, tosylate, brosylate, or triflate. Preferably, X2 is mesylate.
In another specific embodiment, the method described in the twelfth embodiment comprises reacting the compound of formula (9d) or (9A) with a halogenating reagent. Exemplary halogenating reagent include, but are not limited to, bromine, hydrobromic acid, carbon tetrabromide, phosphorus tribromide, potassium bromide, hydroiodic acid, iodine, carbon tetraiodide, phosphorus triiodide, sodium iodide, or potassium iodide.
In yet another specific embodiment, the method of the twelfth embodiment comprises reacting the compound of formula (9d) or (9A) with a sulfonating reagent. Preferably, the sulfonating reagent is a sulfonic anhydride , such as methanesulfonic anhydride, or a sulfonic chloride, such as methane sulfonyl chloride (MsCl).
In one embodiment, the reaction between the compound of formula (9d) or (9 A) and the sulfonating reagent is carried out in the presence of a base. Preferably, the base is a non-nucleophiclic base. Exemplary non-nucleophic base include, but are not limited to, triethylamine, imidazole, triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, dimethylformamide, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or
tetramethylpiperidine. Preferably, the base is triethylamine or diisopropylethylamine.
In a thirteenth embodiment, the present invention provides a method of preparing a compound of formula 18d),
Figure imgf000075_0001
(18d)
or a salt thereof, said method comprising reacting a compound of formula (lOd)
Figure imgf000075_0002
(10d)
with a monomer compound of the formula (di),
Figure imgf000076_0001
wherein X2 is a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester and an activated ester; P3 is H or P2; P2 is an amine protecting group; and Rioo is (Ci-C3)alkoxy. In one embodiment, X2 is -Br, -I, or a sulfonate ester.
Also provided in the thirteenth embodiment is a method of preparing a compound of formula 18A):
Figure imgf000076_0002
(18A)
or a salt thereof, said method comprising reacting a compound of formula (10A)
Figure imgf000076_0003
with a monomer compound of the formula (di),
Figure imgf000076_0004
herein X2 is a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester or an activated ester; and P3 is H or P2; and P2 is an amine protecting group. In one embodiment, X2 is -Br, -I, or a sulfonate ester.
In a specific embodiment, for methods of the thirteenth embodiment, P3 is H and the compound of (lOd) or (10A) is reacted with the monomer compound of (di) to form a compound of (Id') or (IA), respectively:
Figure imgf000077_0001
(ΙΑ)
In another specific embodiment, P3 is an amine protecting group represented by P2; the monomer compound is represented by formula (ci):
Figure imgf000077_0002
and the compound of formula (18d) or (18A) is represented by formula (l id) respectively,
Figure imgf000077_0003
(1 1A)
Any suitable amine protecting group can be used in the methods of the thirteenth embodiment described above. In one embodiment, the amine protecting group is 2- trimethylsilylethyl,(2-phenyl-2-trimethylsilyl)ethyl, triisopropylsiloxy, 2- (trimethylsilyl)ethoxymethyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2- (trimethylsilyl)ethoxycarbonyl, or 2, 2,2,2-trichloroethoxycarbonyl. In a specific embodiment, the compound of formula (lOd) or (10A) is reacted with the monomer compound of formula (di) or (ci) in the presence of a base. Examples of the base include, but are not limited to sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride.
Any suitable solvents can be used in the reaction described above. In one embodiment, the solvent is DMF.
In a fourteenth embodiment, the present invention provides a method of preparing a compound of formula (Id'),
Figure imgf000078_0001
(Id')
or a pharmaceutically acceptable salt thereof, said method comprising reacting a compound of formula (l id),
Figure imgf000078_0002
(11 d)
with an amine deprotecting reagent, wherein P2 is an amine protecting group; and Rioo is (Ci-C3)alkoxy.
Also provided in the fourteenth embodiment is a method of preparing a compound of formula (IA):
Figure imgf000078_0003
(IA)
or a pharmaceutically acceptable salt thereof, said method comprising reacting a compound of formula (l id),
Figure imgf000079_0001
(11 A)
with an amine deprotecting reagent, wherein P2 is an amine protecting group.
Any suitable amine deprotecting reagent can be used in the method described above. In one embodiment, the amine deprotecting reagent is tetra-n-butylammonium fluoride, acetic acid, hydrogen fluoride pyridine, cesium fluoride, piperidine, morpholine, or trifluroacetic acid.
In a fifteenth embodiment, the present invention provides a method of preparing a compound of formula (Id'),
Figure imgf000079_0002
(Id')
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) introducing an alcohol protecting group onto one of the primary alcohols of the compound of formula (Id),
Figure imgf000079_0003
(1d)
to form a compound of formula (2d),
Figure imgf000079_0004
(2d)
(2) reacting the compound of formula (2d) with a halogenating reagent, a sulfonating reagent or an esterification reagent to form a compound of formula (3d),
Figure imgf000080_0001
(3d)
(3) reacting the compound of formula (3d) with a monomer compound of the formula (ai).
Figure imgf000080_0002
to form a compound of formula (4d),
Figure imgf000080_0003
(4d)
(4) reacting the compound of formula (4d) with an alcohol deprotecting reagent to form a compound of formula (9d),
Figure imgf000080_0004
(9d)
(5) reacting the compound of formula (9d) with a second halogenating reagent, second sulfonating reagent or a second esterification reagent to form a compound of formula (lOd),
Figure imgf000080_0005
(10d) (6) reacting the compound of formula (lOd) with a monomer compound of the formula (di)
Figure imgf000081_0001
to form a compound of formula (18d),
Figure imgf000081_0002
(18d) . and
(7) when P3 is an amine protecting group, reacting the compound of formula (18d) to an amine deprotecting reagent to form the compound of formula (Id'), wherein Pi is an alcohol protecting group; Xi and X2 are each independently a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester and an activated ester; P3 is H or an amine protecting group; and Rioo is (Ci-C3)alkoxy.
Also included in the fifteenth embodiment is a method of preparing a compound of formula (IA):
Figure imgf000081_0003
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) introducing an alcohol protecting group onto one of the primary alcohols of the compound of formula (1A),
Figure imgf000081_0004
(1A)
to form a compound of formula (2A),
Figure imgf000082_0001
(2A)
(2) reacting the compound of formula (2A) with a halogenating reagent, a sulfonating reagent or an esterification reagent to form a compound of formula (3 A),
Figure imgf000082_0002
(3A)
(3) reacting the compound of formula (3A) with a monomer compound of the formula (ai),
Figure imgf000082_0003
to form a compound of formula (4A),
Figure imgf000082_0004
(4) reacting the compound of formula (4 A) with an alcohol deprotecting reagent to form a compound of formula (9A),
Figure imgf000082_0005
(9A)
(5) reacting the compound of formula (9A) with a second halogenating reagent , a second sulfonating reagent or a second esterification reagent to form a compound of formula (10A),
Figure imgf000082_0006
(10A) (6) reacting the compound of formula (10A) with a monomer compound of the formula (di)
Figure imgf000083_0001
to form a compound of formula (18A),
Figure imgf000083_0002
(18A) ; and
(7) reacting the compound of formula (18A) to an amine deprotecting reagent to form the compound of formula (IA), wherein Pi is an alcohol protecting group; X1 and X2 are each independently a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester and an activated ester; and P3 is H or an amine protecting group.
In a specific embodiment, for methods of the fifteenth embodiment, X1 and X2 are each independently -Br, -I or a sulfonate ester.
In a specific embodiment, for methods of the fifteenth embodiment, P3 is H and the compound of (lOd) or (10A) is reacted with the monomer compound of (di) to form a compound of (Id') or (IA), respectively.
In another specific embodiment, for methods of the fifteenth embodiment, P3 is P2; the monomer compound is represented by formula (ci):
Figure imgf000083_0003
and the compound of formula (18d) or (18A) is represented by formula (l id) respectively:
Figure imgf000084_0001
Figure imgf000084_0002
wherein P2 is an amine protecting group.
The conditions and reagents for the methods of the fifteenth embodiment are as described above in the first, second, third, eleventh, twelfth, thirteenth, and/or fourteenth, embodiment(s) and any specific embodiments described therein.
In a sixteenth embodiment, the present invention provides a method of preparing a compound of formula (12d),
Figure imgf000084_0003
(12d)
or a salt thereof, said method comprising reacting a compound of formula (Id),
Figure imgf000084_0004
(1d)
with a halogenating reagent or a sulfonating reagent, wherein Xi is -Br, -I, -CI, a sulfonate ester or an activated ester; and Rioo is (Ci-C3)alkoxy.
Also provided in the sixteenth embodiment is a method of preparing a compound of formula (12A):
Figure imgf000084_0005
(12A) or a salt thereof, said method comprising reacting a compound of formula (1A),
Figure imgf000085_0001
(1A)
with a halogenating reagent or a sulfonating reagent, wherein X1 is -Br, -I, -CI, a sulfonate ester or an activated ester.
In a specific embodiment, for the methods of the sixteenth embodiment, Xi is -
Br, -I, or a sulfonate ester. In another specific embodiment, X1 is -Br or -I. In yet another specific embodiment, X1 is a sulfonate ester, preferably mesylate. In another specific embodiment, Xi is -CI.
In another specific embodiment, the halogenating reagent reacts with the primary alcohols of the compound of formula (Id) or (1 A) in the presence of an alcohol activating agent. In one embodiment, the alcohol activating agent is thionyl chloride. In another specific embodiment, halogenating reagent is lithium bromide, sodium bromide, potassium bromide, potassium iodide, or sodium iodide. In another specific embodiment, the halogenating reagent is carbon tetrachloride/triphenylphosphine, methanesulfonyl (mesyl) chloride/lithium chloride, or methanesulfonyl (mesyl) chloride/pyridine.
In yet another specific embodiment, the methods of the sixteenth embodiment comprise reacting the compound of formula (Id) or (1 A) with LiBr in the presence of thionyl chloride.
Any suitable solvents can be used in the methods of the sixteenth embodiment described above. Exemplary solvents include, but are not limited to, DMF, CH2CI2, THF, dichloroethane, etc.
In a seventeenth embodiment, the present invention provides a method of preparing a compound of formula (10d'),
Figure imgf000085_0002
(10d')
or a salt thereof, said method comprising reacting a compound of formula (12d),
Figure imgf000086_0001
(12d)
with a monomer compound of th
Figure imgf000086_0002
wherein Xi is -Br, -I, -CI, a sulfonate ester or an activated ester; and Rioo is (Ci- C3)alkoxy.
Also provided in the seventeenth embodiment is a method of preparing a compound of formula (ΙΟΑ')
Figure imgf000086_0003
or a salt thereof, said method comprising reacting a compound of formula (12A),
Figure imgf000086_0004
( 2A)
with a monomer compound of the formula (ai),
Figure imgf000086_0005
wherein Xi is -Br, -I, -CI, a sulfonate ester or an activated ester.
Also provided in the seventeenth embodiment is a method of preparing a compound of formula (7dl'),
Figure imgf000087_0001
(7d1 ')
or a salt thereof, said method comprising reacting a compound of formula (12d) with a monomer compound of formula (di), wherein X1 is -Br, -I, -CI, a sulfonate ester or an activated ester; P3 is H or an amine protecting group; and Rioo is a (Ci-C3)alkoxy.
Also provided in the seventeenth embodiment is a method of preparing a compound of formula (7Α ),
Figure imgf000087_0002
(7Α-Γ)
or a salt thereof, said method comprising reacting a compound of formula (12A) with a monomer compound of formula (di), wherein X1 is -Br, -I, -CI, a sulfonate ester or an activated ester; and P3 is H or an amine protecting group.
In a specific embodiment, for formula (7dl') or (7Α ), P3 is H. In another specific embodiment, P3 is an amine protecting group as described herein.
In a specific embodiment, for methods of the seventeenth embodiment, X1 is -Br, -I, or a sulfonate ester. In another specific embodiment, Xi is a sulfonate ester. In a more specific embodiment, Xi is mesylate.
In a specific embodiment, the compound of formula (12d) or (12A) is reacted with the monomer compound of formula (ai) in the presence of a base. Examples of suitable base include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride. In one embodiment, the base is potassium carbonate.
In another specific embodiment, the compound of formula (12d) or (12A) is reacted with the monomer compound of formula (di) in the presence of a base.
Examples of suitable base include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride. In one
embodiment, the base is potassium carbonate. For the methods of the seventeenth embodiment, any suitable solvents can be used. In one embodiment, the solvent is DMF.
In another specific embodiment, excess molar equivalent of the compound of formula (12d) or (12A) relative to the monomer compound of formula (ai) or (di) is used in the reaction.
In a eighteenth embodiment, the present invention provides a method of preparing a compound of formula (7d'),
Figure imgf000088_0001
(7d') or a salt thereof, said method comprising reacting a compound of formula (10d'),
Figure imgf000088_0002
(10d') or a salt thereof, with an imine reducing agent, wherein Xi is -Br, -I, -CI, a sulfonate ester or an activated ester; and Rioo is (Ci-C3)alkoxy.
Also provided in the eighteenth embodiment is a method of preparing a compound of formula (7 A'),
Figure imgf000088_0003
<7A'>
or a salt thereof, said method comprising reacting a compound of formula (ΙΟΑ'),
Figure imgf000089_0001
(10Α') or a salt thereof, with an imine reducing agent, wherein Xi is -Br, -I, -CI, a sulfonate ester or an activated ester.
In a specific embodiment, for methods of the eighteenth embodiment, Xi is -Br, -I, or a sulfonate ester. In another specific embodiment, Xi is a sulfonate ester.
Preferably, Xi is mesylate.
In another specific embodiment, for methods of the eighteenth embodiment, the imine reducing reagent is a hydride reducing reagent. In a more specific embodiment, the imine reducing reagent is sodium borohydride, sodium triacetoxy borohydride, sodium cyanoborohydride, lithium aluminum hydride, hydrogen gas, ammonium formate, borane, 9-borabicyclo[3.3.1]nonane (9-BBN), diisobutylaluminium hydride (DIBAL), lithium borohydride (LiBH4), potassium borohydride (KBH4), or sodium bis(2-methoxyethoxy)aluminumhydride (Red-Al). Even more specifically, the imine reducing reagent is sodium triacetoxy borohydride (NaBH(OAc)3).
Any suitable solvents can be used in the methods of the eighteenth embodiment. In one embodiment, the solvent is dichloroethane.
In a nineteenth embodiment, the present invention provides a method of preparing a com ound of formula (Id'),
Figure imgf000089_0002
(Id')
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a compound of formula (Id) with a halogenating reagent, a sulfonating reagent or an esterification reagent,
Figure imgf000090_0001
(1d)
to form a compound of formula (12d),
Figure imgf000090_0002
(12d)
(2) reacting the compound of formula (12d) with a monomer compound of the formula (ai),
Figure imgf000090_0003
to form a compound of a formula (10d'),
Figure imgf000090_0004
(10d')
(3) reacting the compound of formula (10d') with a monomer compound of the formula (di),
Figure imgf000090_0005
to form a compound of formula (18d),
Figure imgf000090_0006
; and (4) when P3 is an amine protecting group, reacting the compound of formula (18d) with an amine deprotecting reagent to form the compound of formula (Id'), wherein Xi is -Br, -I, -CI, a sulfonate ester or an activated ester; P3 is H or an amine protecting group; and Rioo is (Ci-C3)alkoxy.
Also provided in the nineteenth embodiment is a method of preparing a compound of formula (IA),
Figure imgf000091_0001
(IA)
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a compound of formula (IA) with a halogenating reagent, a sulfonating reagent or an esterification reagent,
Figure imgf000091_0002
(1A)
to form a compound of formula (12
Figure imgf000091_0003
(12A)
(2) reacting the compound of formula (12A) with a monomer compound of the formula (ai),
Figure imgf000091_0004
to form a compound of a formula (ΙΟΑ'),
Figure imgf000091_0005
(3) reacting the compound of formula (ΙΟΑ') with a monomer compound of the formula (di),
Figure imgf000092_0001
to form a compound of formula (18A),
Figure imgf000092_0002
(18A) ; and
(4) reacting the compound of formula (11A) with an amine deprotecting reagent to form the compound of formula (IA), wherein Xi is -Br, -I, -CI, a sulfonate ester or an activated ester; P3 is H or an amine protecting group.
In a specific embodiment, for methods of the nineteenth embodiment, Xi is -Br, -I, or a sulfonate ester.
In a specific embodiment, for methods of the nineteenth embodiment, P3 is H and the compound of (10d') or (10A) is reacted with the monomer compound of (di) to form a compound of (Id') or (IA), respectively.
In another specific embodiment, for methods of the nineteenth embodiment, P3 is P2; the monomer compound is represented by formula (ci):
Figure imgf000092_0003
and the compound of formula (18d) or (18A) is represented by formula (l id) respectively:
Figure imgf000092_0004
Figure imgf000093_0001
wherein P2 is an amine protecting group.
The conditions and reagents for the method of nineteenth embodiment are as described above in the sixteenth, seventeenth, thirteenth and/or fourteenth
embodiment(s) and any specific embodiments described therein.
In a twentieth embodiment, the present invention provides a method of preparing a compound a compound of formula (Id'),
Figure imgf000093_0002
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a halogenating reagent, a sulfonating reagent or an esterification reagent with a compound of formula (Id),
Figure imgf000093_0003
(1 d)
a compound of formula (12d),
Figure imgf000093_0004
(12d)
(2) reacting the compound of formula (12d) with a monomer compound of the formula (ai),
Figure imgf000094_0001
to form a compound of a formula (10d'),
Figure imgf000094_0002
(10d')
(3) reacting the compound (10d') with an imine reducing reagent to form a compound (7d'),
Figure imgf000094_0003
(7cT)
(4) reacting the compound of formula (7d') with a monomer compound of the formula (ai),
Figure imgf000094_0004
to form a compound of formula (Id'), or a pharmaceutically acceptable salt thereof, wherein X1 is -Br, -I, -CI, a sulfonate ester or an activated ester; and Rioo is (Q- C3)alkoxy.
Also provided in the twentieth embodiment is a method of preparing a compound of (IA),
Figure imgf000094_0005
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a halogenating reagent, a sulfonating reagent or a second esterification reagent with a compound of formula (1A),
Figure imgf000095_0001
(1A)
to form a compound of formula (12
Figure imgf000095_0002
(12A)
(2) reacting the compound of formula (12A) with a monomer compound of the formula (ai),
Figure imgf000095_0003
to form a compound of a formula (ΙΟΑ')
Figure imgf000095_0004
(10Α')
(3) reacting the compound (ΙΟΑ') with an imine reducing reagent to form a compound (7Α'),
Figure imgf000095_0005
(7A)
(4) reacting the compound of formula (7 A') with a monomer compound of the formula (ai),
Figure imgf000095_0006
to form a compound of formula (ΙΑ'), or a pharmaceutically acceptable salt thereof, wherein X1 is -Br, -I, -CI, a sulfonate ester or an activated ester.
In a specific embodiment, for methods of the twentieth embodiment, Xi is -Br, -I, or a sulfonate ester.
The conditions and reagents for the method of twentieth embodiment are as described above in the sixteenth, seventeenth, eighteenth and/or eighth embodiment(s) and any specific embodiments described therein.
In a twenty-first embodiment, the present invention provides a method of preparing a compound of formula (Id'),
Figure imgf000096_0001
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a halogenating reagent, a sulfonating reagent or an esterification reagent with a compound of formula (Id),
Figure imgf000096_0002
to form a compound of formula (12d),
Figure imgf000096_0003
(12d)
(2) reacting the compound of formula (12d) with a monomer compound of the formula (di),
Figure imgf000097_0001
to form a compound of a formula (7dl'),
Figure imgf000097_0002
(7d1 ')
(3) reacting the compound of formula (7dl ') with a monomer compound of the formula (ai),
Figure imgf000097_0003
to form a compound of formula (18d),
Figure imgf000097_0004
(4) when P3 is an amine protecting group, reacting the compound of formula (18d) with an amine deprotecting reagent to form the compound of formula (Id'); wherein Xi is -Br, -I, -CI, a sulfonate ester or an activated ester; P3 is H or an amine protecting group.
Also provided in the twenty-first embodiment is a method of preparing a compound of formula (IA),
Figure imgf000098_0001
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a halogenating reagent, a sulfonating reagent or an esterification reagent with a compound of formula (1A),
Figure imgf000098_0002
to form a compound of formula (12A),
Figure imgf000098_0003
(12A)
(2) reacting the compound of formula (12A) with a monomer compound of the formula (di),
Figure imgf000098_0004
to form a compound of a formula (7Α ),
Figure imgf000098_0005
(7Α1 ')
(3) reacting the compound of formula (7Α ) with a monomer compound of the formula (ai),
Figure imgf000099_0001
to form a compound of formula (18A),
Figure imgf000099_0002
(18A) ; and
(4) when P3 is an amine protecting group, reacting the compound of formula (18A) with an amine deprotecting reagent to form the compound of formula (IA); wherein X1 is -Br, -I, -CI, a sulfonate ester or an activated ester; P3 is H or an amine protecting group.
In one embodiment, for methods of the twenty-first embodiment, P3 is H.
In another embodiment, for methods of the twenty-first embodiment, Xi is -Br, -CI or a sulfonate ester.
The conditions and reagents for the methods of twenty-first embodiment are as described above in the sixteenth, seventeenth, eighteenth, eighth and/or fourteenth embodiment(s) and any specific embodiments described therein.
In a twenty- second embodiment, the present invention provides a method of preparing a compound of formula (13d),
Figure imgf000099_0003
(13d)
or a salt thereof, said method comprising reacting a chlorinating reagent with a compound of formula (2d),
Figure imgf000099_0004
(2d) wherein Pi is an alcohol protecting group; X3 is -CI; and Rioo is (Ci-C3)alkoxy.
Also provided in the twenty-second embodiment is a method of preparing a compound of formula (13 A),
Figure imgf000100_0001
(13A)
or a salt thereof, said method comprising reacting a chlorinating reagent with a compound of formula (2A),
Figure imgf000100_0002
(2A)
wherein Pi is an alcohol protecting group and X3 is -CI.
In another specific embodiment, for methods of the twenty- second embodiment, the alcohol protecting group is pivaloyl, methoxymethyl, 2-methoxyethoxymethyl, p- methoxybenzyl, 3,4-dimethyoxybenzyl, 2,6-dimethyoxybenzyl, diphenylmethyl, benzyloxymethyl, 2,2,2-trichloroethoxycarbonyl, tetrahydrofuranyl, tetrahydropyranyl, benzyl, benzoyl, /?ara-phenylbenzoyl, 2,4,6-trimethylbenzoyl, /¾zra-bromobenzoyl, /?ara-nitrobenzoyl, picolinoyl, nicotinoyl, 5-dibenzosuberyl, trityl/triphenylmethyl, or tris(4-ieri-butylphenyl)methyl. Preferably, the alcohol protecting group is
methoxymethyl, tetrahydropyranyl, 2-methoxyethoxymethyl, p-methoxybenzyl, benzyloxymethyl, or 2,2,2-trichloroethoxycarbonyl. Even more preferably, the alcohol protecting group is 2,2,2-trichloroethoxycarbonyl.
In another specific embodiment, the alcohol protecting group is a silyl protecting group. For example, the silyl protecting group is dimethylisopropylsilyl,
diethylisopropylsilyl, dimethylhexylsilyl, trimethylsilyl, triisopropylsilyl, tribenzylsilyl, triphenylsilyl, 2-norbornyldimethylsilyl, ie/t-butyldimethylsilyl, ie/ -butyldiphenylsilyl, 2-trimethyethylsilyl (TEOC), or [2-(trimethylsilyl)ethoxy]methyl. Preferably, the silyl protecting group is triethylsilyl, triisopropylsilyl, or tert-butyldimethylsilyl. More preferably, the silyl protecting group is tert-butyldimethylsilyl.
In one embodiment, the base is used. The base can be a non-nucleophilic base. Examples of non-nucleophilic base include, but are not limited to, triethylamine, imidazole, diisopropylethylamine (DIPEA), pyridine, 2,6-lutidine, dimethylformamide, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or tetramethylpiperidine . Preferably, the non-nucleophilic base is pyridine.
Any suitable organic solvents can be used for the methods of the twenty-second embodiment. Exemplary solvents include, but are not limited to, DMF, CH2CI2, dichloroethane, THF, dimethylacetamide, etc. In certain embodiments, DMF is used as the solvent.
In a twenty-third embodiment, the present invention provides a method of preparing a compound of formula (14d),
Figure imgf000101_0001
(14d)
or a salt thereof, said method comprising reacting a compound of formula (13d)
Figure imgf000101_0002
(13d)
with an alcohol deprotecting reagent, wherein Pi is an alcohol protecting group; X3 -CI; and R100 is (Ci-C3)alkoxy.
Also provided in the twenty-third embodiment is a method of preparing a compound of formula (14A),
Figure imgf000101_0003
(14A)
or a salt thereof, said method comprising reacting a compound of formula (13 A)
Figure imgf000101_0004
(13A)
with an alcohol deprotecting reagent, wherein Pi is an alcohol protecting group; and X3 is -CI.
In another specific embodiment, for methods of the twenty-third embodiment, the alcohol deprotecting reagent is tetra-n-butylammonium fluoride, tris(dimethylamino)sulfonium difluorotrimethylsilicate, hydrogen fluoride or a solvate thereof, hydrogen fluoride pyridine, silicon tetrafluoride, hexafluorosilicic acid, cesium fluoride, hydrochloric acid, acetic acid, trifluoroacetic acid, pyridinium p- toluensulfonate, p-toluenesulfonic acid (p-TsOH), formic acid, or periodic acid.
Preferably, the alcohol deprotecting reagent is hydrogen fluoride pyridine.
In a twenty-fourth embodiment, the present invention provides a method of preparing a compound of formula (15d):
Figure imgf000102_0001
(15d)
or a salt thereof, said method comprising reacting a sulfonating reagent or an
esterification reagent with a compound of formula (14d),
Figure imgf000102_0002
(14d)
wherein X3 is -CI; X4 is a sulfonate ester or an activated ester; and Rioo is (Ci-C3)alkoxy.
Also provided in the twenty-fourth embodiment is a method of preparing a compound of formula (15A),
Figure imgf000102_0003
< 5A)
or a salt thereof, said method comprising reacting a sulfonating reagent with a compound of formula (14A),
Figure imgf000102_0004
(14A)
wherein X3 is -CI; and X4 is a sulfonate ester or an activated ester.
In a specific embodiment, for methods of the twenty-fourth embodiment, X4 is a sulfonate ester. In another specific embodiment, for methods of the twenty-fourth embodiment, the sulfonating reagent is methanesufonyl anhydride, methanesufonyl chloride, p- toluenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, or trifluoromethanesulfonyl anhydride.
In another specific embodiment, for methods of the twenty-fourth embodiment, the sulfonate ester is mesylate, tosylate, brosylate, or triflate. Preferably, the sulfonate ester is mesylate.
In another embodiment, for methods of the twenty-fourth embodiment, a base is used. The base can be a non-nucleophilic base. Examples of non-nucleophilic base include, but are not limited to, triethylamine, imidazole, diisopropylethylamine, pyridine, 2,6-lutidine, dimethylformamide, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or tetramethylpiperidine. Preferably, the non-nucleophilic base is
diisopropylethylamine.
In a twenty-fifth embodiment, the present invention provides a method of preparing a compound of formula (20d):
Figure imgf000103_0001
(20d)
or a salt thereof, said method comprising reacting a brominating or iodinating reagent with a compound of formula (14d),
Figure imgf000103_0002
(14d)
wherein X3 is -CI; X5 is -Br or -I; and Rioo is (Ci-C3)alkoxy.
Also provided in the twenty-fifth embodiment is a method of preparing a compound of formula (20 A):
Figure imgf000103_0003
(20A) or a salt thereof, said method comprising reacting a brominating or iodinating reagent with a compound of formula (14A),
Figure imgf000104_0001
(14A)
wherein X3 is -CI; X5 is -Br or -I; and Rioo is (Ci-C3)alkoxy.
In a specific embodiment, for methods of the twenty-fifth embodiment, the brominating or iodinating reagent is bromine, hydrobromic acid, carbon tetrabromide, phosphorus tribromide, potassium bromide, hydroiodic acid, iodine, carbon tetraiodide, phosphorus triiodide, sodium iodide, or potassium iodide.
In a twenty- sixth embodiment, the present invention provides a method of preparing a compound of formula (16d):
Figure imgf000104_0002
(16d)
or a salt thereof, said method comprising reacting a compound of formula (15d)
Figure imgf000104_0003
(15d)
with a monomer compound of formula (ai),
Figure imgf000104_0004
wherein X3 is -CI; X4 is a sulfonate ester or an activated ester; and Rioo is (Ci-C3)alkoxy.
Also provided in the twenty-sixth embodiment is a method of preparing a compound of formula (16A),
Figure imgf000105_0001
(16A)
or a salt thereof, said method comprising reacting a compound of formula (15A)
Figure imgf000105_0002
(15A)
with a monomer compound of formula (ai),
Figure imgf000105_0003
wherein X3 is -CI; and X4 is a sulfonate ester or an activated ester.
In a specific embodiment, for methods of the twenty-sixth embodiment, X4 is a sulfonate ester.
In an embodiment, for methods of the twenty-sixth embodiment, a base is used. In specific embodiment, the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride. Preferably, the base is potassium carbonate.
Any suitable organic solvents can be used for the methods of the twenty-sixth embodiment. Exemplary solvents include, but are not limited to, DMF, CH2CI2, dichloroethane, THF, dimethylacetamide, etc. In certain embodiments,
dimethylacetamide is used as the solvent.
In a twenty- seventh embodiment, the present invention provides a method of preparing a com ound of formula (16d),
Figure imgf000105_0004
(16d)
or a salt thereof, said method comprising reacting a compound of formula (20d)
Figure imgf000106_0001
(20d)
with a monomer compound of formula (ai),
Figure imgf000106_0002
wherein X3 is -CI; X5 is -Br or -I; and R100 is (Ci-C3)alkoxy.
Also provided in the twenty-seventh embodiment is a method of preparing a compound of formula (16A),
Figure imgf000106_0003
(16A)
or a salt thereof, said method comprising reacting a compound of formula (20A)
Figure imgf000106_0004
(20A)
with a monomer compound of formula (ai),
Figure imgf000106_0005
wherein X3 is -CI and X5 is -Br or -I.
In a specific embodiment, for methods of the twenty-seventh embodiment, the compound of formula (20d) or (20A) is reacted with the monomer compound of formula (ai) in the presence of a base. Any suitable base can be used. In one embodiment, the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride. More specifically, the base is potassium carbonate.
In one embodiment, for methods of the twenty-seventh embodiment, any suitable solvent can be used for the reactions of compounds of formula (20d) or (20A) with the monomer compounds of formula (ai). In a specific embodiment, the reaction is carried out in a polar aprotic solvent. More specifically, the aprotic solvent is
dimethylacetamide.
In a twenty-eighth embodiment, the present invention provides a method of preparing a compound of formula (16d),
Figure imgf000107_0001
or a salt thereof, said method comprising reacting a compound of formula (14d)
Figure imgf000107_0002
with a monomer compound of formula (ai),
Figure imgf000107_0003
wherein X3 is -CI; and Rioo is (Ci-C3)alkoxy.
Also included in the twenty-eighth embodiment is a method of preparing a compound of formula (16A),
Figure imgf000107_0004
or a salt thereof, said method comprising reacting a compound of formula (14A)
Figure imgf000108_0001
(14A)
with a monomer compound of formula (ai),
Figure imgf000108_0002
wherein X3 is -CI.
In a specific embodiment, for methods of the twenty-eighth embodiment, the compound of formula (14d) or (14A) is reacted with a monomer of formula (ai) in the presence of an alcohol activating agent. In one embodiment, the alcohol activating agent is a trialkylphosphine, triarylphosphine, or triheteroarylphosphine. In a specific embodiment, the alcohol activating agent is trimethylphosphine, tributylphosphine, tri(o- tolyl)phosphine, tri(m-tolyl)phosphine, tri(p-tolyl)phosphine, tri(2-pyridyl)phosphine, tri(3-pyridyl)phosphine, tri(4-pyridyl)phosphine, or [4-
(3,3,4,4,5,5,6,6,7,7,8,8,9,9, 10, 10, 10-heptadecafluorodecyl)phenyl] diphenylphosphine. In another embodiment, the alcohol activating agent can be a phosphine-like reagent, such as (tributylphosphoranylidene)acetonitrile, (cyanomethylene)tributylphosphorane (CMBP), or (cyanomethylene)trimethylphosphorane (CMMP). In a more specific embodiment, the alcohol activating agent is triphenylphosphine. In one embodiment, the alcohol activating agent can be polymer-bound or polymer-supported, such as polymer- bound or polymer-supported trialkyl phosphine, triarylphosphine (e.g.,
triphenylphosphine), or triheteroarylphosphine.
In another specific embodiment, for methods of the twenty-eighth embodiment, the compound of formula (14d) or (14A) is reacted with a monomer of formula (ai) in the presence of an azodicarboxylate. In one embodiment, the azodicarboxylate is selected from the group consisting of: diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), l,l'-(azodicarbonyl)dipiperidine (ADDP), ditertbutyl azodicarboxylate (DTAD), 1 ,6-dimethyl- 1 ,5,7-hexahydro- 1 ,4,6,7-tetrazocin-2,5-dione (DHTD) , di-(4-chlorobenzyl)azodicarboxylate (DCAD), azodicarboxylic dimorpholide, Ν,Ν,Ν',Ν'- tetramethylazodicarboxamide (TMAD), Ν,Ν,Ν',Ν'- tetraisopropylazodicarboxamide (TIPA), 4,4'-azopyridine, bis (2,2,2-trichloroethyl) azodicarboxylate, o-(tert-Butyldimethylsilyl)-N-tosylhydroxylamine, di-(4- chlorobenzyl)azodicarboxylate, cyclic 1 ,6-dimethyl- 1 ,5,7-hexahydro- 1 ,4,6,7-tetrazocin- 2,5-dione (DHTD), dimethyl acetylenedicarboxylate (DMAD), di-2-methoxyethyl azodicarboxylate, di-(4-chlorobenzyl)azodicarboxylate and bis(4,4,5,5,6,6,7,7,8,8,9,9,9- tridecafluorononyl) azodicarboxylate. More specifically, the azodicarboxylate is DIAD. In one embodiment, the azodicarboxylate is polymer-bound or polymer supported, such as polymer- supported alkylazodicarboxylate (e.g. polymer-bound DEAD, DIAD, DTAD or ADDP).
In yet another specific embodiment, for methods of the twenty-eighth
embodiment, the compound of formula (14d) or (14A) is reacted with a monomer of formula (ai) in the presence of triphenylphosphine and an azodicarboxylate. In one embodiment, the azodicarboxylate is selected from the group consisting of: diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), 1, 1 '- (azodicarbonyl)dipiperidine (ADDP), and ditertbutyl azodicarboxylate (DTAD). More specifically, the azodicarboxylate is DIAD.
In a twenty-ninth embodiment, the present invention provides a method of preparing a compound of formula (18d):
Figure imgf000109_0001
(18d)
a pharmaceutically acceptable salt thereof, said method comprising reacting a compound of formula of (16d):
Figure imgf000109_0002
(16d)
with a reduced monomer of formula (di):
Figure imgf000110_0001
(di)
wherein X3 is -CI; P3 is H or an amine protecting group; and Rioo is (Ci-C3)alkoxy.
Also provided in the twenty-ninth embodiment is a method of preparing a compound of formula (18A),
Figure imgf000110_0002
(1 8A)
a pharmaceutically acceptable salt thereof, said method comprising reacting a compound of formula of 16A):
Figure imgf000110_0003
(di)
wherein X3 is -CI; and P3 is H or an amine protecting group.
In one embodiment, for methods of the twenty-ninth embodiment, the reaction between the compound of formula (16d) or (16A) and the reduced monomer of formula (di) is carried out in the presence of a base. In specific embodiment, the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride. Preferably, the base is potassium carbonate.
Any suitable organic solvents can be used for the methods of the twenty-ninth embodiment. In one embodiment, the solvent is a polar aprotic solvent. Exemplary solvents include, but are not limited to, dimethylformamide (DMF), CH2CI2, dichloroethane, THF, dimethylacetamide, etc. In certain embodiments,
dimethylformamide or dimethylacetamide is used as the solvent. In a specific embodiment of the twenty-ninth embodiment, the compound of formula (16d) or (16A) is reacted with reduced monomer of formula (di), wherein P3 is
H, to form a compound of formula (Id') or (IA), respectively:
Figure imgf000111_0001
In another specific embodiment of the twenty-ninth embodiment, P3 is an amine protecting group. Any suitable amine protecting group can be used in the method described above. In one embodiment, the amine protecting group is 2- trimethylsilylethyl,(2-phenyl-2-trimethylsilyl)ethyl, triisopropylsiloxy, 2- (trimethylsilyl)ethoxymethyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2- (trimethylsilyl)ethoxycarbonyl, or 2, 2,2,2-trichloroethoxycarbonyl.
When P3 is an amine protecting group, the compound of formula (18d) or (18A) is further reacted with an amine deprotecting reagent to form a compound of formula (Id') or (IA), respectively.
Examples of suitable amine deprotecting reagent include, but are not limited to, the amine deprotecting reagent is selected from the group consisting of tetra-n- butylammonium fluoride, acetic acid, hydrogen fluoride pyridine, cesium fluoride, piperidine, morpholine, or trifluroacetic acid.
In a thirtieth embodiment, the present invention provides a method for preparing a compound of formula (17d):
Figure imgf000111_0002
(17d) or a salt thereof, said method com rising reacting a compound of formula (15d)
Figure imgf000112_0001
(15d)
with a monomer compound of formula (di),
Figure imgf000112_0002
wherein X3 is -CI; X4 is a sulfonate ester or an activated ester; P3 is H or an amine protecting group; and Rioo is (Ci-C3)alkoxy. In one embodiment, X4 is an activated ester.
Also included in the thirtieth embodiment is a method of preparing a compound of formula (17 A),
Figure imgf000112_0003
( 7A)
or a salt thereof, said method comprising reacting a compound of formula (15A)
Figure imgf000112_0004
(15A)
with a monomer compound of formula (di),
Figure imgf000112_0005
wherein X3 is -CI; X4 is a sulfonate ester or an activated ester; and P3 is H or an amine protecting group. In one embodiment, X4 is an activated ester.
In an embodiment, for methods of the thirtieth embodiment, a base is used. In specific embodiment, the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride. Preferably, the base is potassium carbonate.
Any suitable organic solvents can be used for the methods of the thirtieth embodiment. Exemplary solvents include, but are not limited to, DMF, CH2CI2, dichloroethane, THF, dimethylacetamide, etc. In certain embodiments,
dimethylacetamide is used as the solvent.
In a specific embodiment of the thirtieth embodiment, P3 is H and the compound of formula (15d) or (15A) is reacted with the monomer compound of formula (di) to form a compound of formula (17d') or (17Α'), respectively.
Figure imgf000113_0001
(17d') (17Α')
In another specific embodiment of the thirtieth embodiment, P3 is an amine protecting group and the method further comprises the step of reacting the compound of formula (17d) or (17 A) with an amine deprotecting reagent to form a compound of formula (17d') or (17Α'), respectively.
Examples of suitable amine deprotecting reagent include, but are not limited to, the amine deprotecting reagent is selected from the group consisting of tetra-n- butylammonium fluoride, acetic acid, hydrogen fluoride pyridine, cesium fluoride, piperidine, morpholine, or trifluroacetic acid.
In a thirty-first embodiment, the present invention provides a method of preparing a compound of formula (17d),
Figure imgf000113_0002
(17d)
or a salt thereof, said method comprising reacting a compound of formula (14d)
Figure imgf000114_0001
(14d) with a monomer compound of formula (di),
Figure imgf000114_0002
wherein X3 is -CI; P3 is H or an amine protecting group; and Rioo is (Ci-C3)alkoxy.
Also included in the thirty-first embodiment is a method of preparing a compound of formula (17A
Figure imgf000114_0003
(17A)
or a salt thereof, said method comprising reacting a compound of formula (14A)
Figure imgf000114_0004
(14A) with a monomer compound of formula (di),
Figure imgf000114_0005
wherein X3 is -CI; and P3 is H or an amine protecting group.
In a specific embodiment, for methods of the thirty-first embodiment, the compound of formula (14d) or (14A) is reacted with a monomer of formula (di) in the presence of an alcohol activating agent. In a specific embodiment, the alcohol activating agent is trimethylphosphine, tributylphosphine, tri(o-tolyl)phosphine, tri(m- tolyl)phosphine, tri(p-tolyl)phosphine, tri(2-pyridyl)phosphine, tri(3-pyridyl)phosphine, tri(4-pyridyl)phosphine, or [4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10, 10,10- Heptadecafluorodecyl)phenyl] diphenylphosphine. In another embodiment, the alcohol activating agent can be a phosphine-like reagent, such as
(tributylphosphoranylidene)acetonitrile, (cyanomethylene)tributylphosphorane (CMBP), or (cyanomethylene)trimethylphosphorane (CMMP). In a more specific embodiment, the alcohol activating agent is triphenylphosphine. In one embodiment, the alcohol activating agent can be polymer-bound or polymer- supported, such as polymer-bound or polymer- supported trialkyl phosphine, triarylphosphine (e.g., triphenylphosphine), or trihetero ary lpho sphine .
In another specific embodiment, for methods of the thirty-first embodiment, the compound of formula (14d) or (14A) is reacted with a monomer of formula (di) in the presence of an azodicarboxylate. In one embodiment, the azodicarboxylate is selected from the group consisting of: diethyl azodicarboxylate (DEAD), diisopropyl
azodicarboxylate (DIAD), l,l '-(azodicarbonyl)dipiperidine (ADDP), ditertbutyl azodicarboxylate (DTAD), 1 ,6-dimethyl- 1 ,5,7-hexahydro- 1 ,4,6,7-tetrazocin-2,5-dione (DHTD) , di-(4-chlorobenzyl)azodicarboxylate (DCAD), azodicarboxylic dimorpholide, Ν,Ν,Ν',Ν'- tetramethylazodicarboxamide (TMAD), Ν,Ν,Ν',Ν'- tetraisopropylazodicarboxamide (TIPA), 4,4'-azopyridine, bis (2,2,2-trichloroethyl) azodicarboxylate, o-(tert-Butyldimethylsilyl)-N-tosylhydroxylamine, di-(4- chlorobenzyl)azodicarboxylate, cyclic 1 ,6-dimethyl- 1 ,5,7-hexahydro- 1 ,4,6,7-tetrazocin- 2,5-dione (DHTD), dimethyl acetylenedicarboxylate (DMAD), di-2-methoxyethyl azodicarboxylate, di-(4-chlorobenzyl)azodicarboxylate and bis(4,4,5,5,6,6,7,7,8,8,9,9,9- tridecafluorononyl) azodicarboxylate, . More specifically, the azodicarboxylate is DIAD. In one embodiment, the azodicarboxylate is polymer-bound or polymer supported, such as polymer-supported alkylazodicarboxylate (e.g. polymer-bound DEAD, DIAD, DTAD or ADDP).
In yet another specific embodiment, for methods of the thirty-first embodiment, the compound of formula (14d) or (14A) is reacted with a monomer of formula (di) in the presence of triphenylphosphine and an azodicarboxylate. In one embodiment, the azodicarboxylate is selected from the group consisting of: diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), l, l '-(azodicarbonyl)dipiperidine (ADDP), and ditertbutyl azodicarboxylate (DTAD). More specifically, the
azodicarboxylate is DIAD.
In a thirty- second embodiment, the present invention provides a method of preparing a compound of formula (17d):
Figure imgf000116_0001
(17d)
or a salt thereof, said method comprising reacting a compound of formula (20d)
Figure imgf000116_0002
(20d)
with a monomer compound of formula (di),
Figure imgf000116_0003
wherein X3 is -CI; X5 is -Br or -I; P3 is H or an amine protecting group; and R100 is (C\- C3)alkoxy.
Also provided in the thirty-second embodiment is a method of preparing a compound of formula (17A):
Figure imgf000116_0004
(17A)
or a salt thereof, said method comprising reacting a compound of formula (20A)
Figure imgf000117_0001
(20A)
with a monomer compound of formula (di),
Figure imgf000117_0002
wherein X3 is -CI; X5 is -Br or -I; and P3 is H or an amine protecting group.
In one embodiment, for methods of the thirty-second embodiment, the compound of formula (20d) or (20A) is reacted with the monomer compound of formula (di) in the presence of a base. Any suitable base can be used. In one embodiment, the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride. More specifically, the base is potassium carbonate.
In another embodiment, for methods of the thirty- second embodiment, any suitable solvent can be used for the reactions of compounds of formula (20d) or (20A) with the monomer compounds of formula (di). In a specific embodiment, the reaction is carried out in a polar aprotic solvent. More specifically, the aprotic solvent is dimethylacetamide.
In a specific embodiment of the thirty-second embodiment, P3 is H and the compound of formula (20d) or (20A) is reacted with the monomer compound of formula (di) to form a compound of formula (17d') or (17Α'), respectively,
Figure imgf000117_0003
In another specific embodiment of the thirty- second embodiment, P3 is an amine protecting group, the method further comprises the step of reacting the compound of formula (17d) or (17 A) with an amine deprotecting reagent to form a compound of formula (17d') or (17Α'), respectively. Examples of suitable amine deprotecting reagent include, but are not limited to, the amine deprotecting reagent is selected from the group consisting of tetra-n- butylammonium fluoride, acetic acid, hydrogen fluoride pyridine, cesium fluoride, piperidine, morpholine, or trifluroacetic acid.
In a thirty-third embodiment, the present invention provides a method of preparing a compound of formula (17d'):
Figure imgf000118_0001
(17d')
or a salt thereof, said method comprising reacting a compound of formula (16d)
Figure imgf000118_0002
(16d) with an imine reducing agent, wherein X3 is -CI; and Rioo is (Ci-C3)alkoxy.
Also included in the thirty-third embodiment is a method of preparing a compound of formula (17Α'):
Figure imgf000118_0003
(17Α')
or a salt thereof, said method comprising reacting a compound of formula (16A)
Figure imgf000118_0004
with an imine reducing agent, wherein X3 is -CI. In one specific embodiment, for methods of the thirty-third embodiment, the imine reducing agent is a hydride reducing agent. Examples of suitable hydride reducing agents include, but are not limited to, sodium borohydride, sodium triacetoxy borohydride, sodium cyanoborohydride, lithium aluminum hydride, hydrogen gas, ammonium formate, borane, 9-borabicyclo[3.3.1]nonane (9-BBN), diisobutylaluminium hydride (DIBAL), lithium borohydride (LiBH4), potassium borohydride (KBH4), or sodium bis(2-methoxyethoxy)aluminumhydride (Red-Al). In one particular embodiment, the hydride reducing agent is sodium triacetoxy borohydride
(NaBH(OAc)3).
In a thirty-fourth embodiment, the present invention provides a method of preparing a com ound of formula (18d),
Figure imgf000119_0001
(18d)
or a pharmaceutically acceptable salt thereof, said method comprising reacting a compound of formula of
Figure imgf000119_0002
with a monomer of formula (ai):
Figure imgf000119_0003
(ai)
wherein X3 is -CI; P3 is H or an amine protecting group; and Rioo is (Ci-C3)alkoxy.
Also provided in the thirty-fourth embodiment is a method of preparing a compound of formula (18A),
Figure imgf000120_0001
(18A)
or a pharmaceutically acceptable salt thereof, said method comprising reacting a compound of formula of (17 A
Figure imgf000120_0002
(17A)
with a monomer of formula (ai):
Figure imgf000120_0003
(ai)
wherein X3 is -CI; and P3 is H or an amine protecting group.
In one embodiment, for methods of the thirty-fourth embodiment, the reaction between the compound of formula (17d) or (17A) and the monomer of formula (ai) is carried out in the presence of a base. In specific embodiment, the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or
potassiumhydride. Preferably, the base is potassium carbonate.
Any suitable organic solvents can be used for the methods of the thirty-fourth embodiment. In one embodiment, the solvent is a polar aprotic solvent. Exemplary solvents include, but are not limited to, dimethylformamide (DMF), CH2CI2, dichloroethane, THF, dimethylacetamide, etc. In certain embodiments,
dimethylformamide or dimethylacetamide is used as the solvent.
In a specific embodiment of the thirty-fourth embodiment, the compound of formula (17d) or (17A) is reacted with the monomer of formula (& ), wherein P3 is H, to form a compound of formula (Id') or (IA), respectively.
In another specific embodiment of the thirty-fourth embodiment, P3 is an amine protecting group. Any suitable amine protecting group can be used in the method described above. In one embodiment, the amine protecting group is 2- trimethylsilylethyl,(2-phenyl-2-trimethylsilyl)ethyl, triisopropylsiloxy, 2- (trimethylsilyl)ethoxymethyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2- (trimethylsilyl)ethoxycarbonyl, or 2, 2,2,2-trichloroethoxycarbonyl.
When P3 is an amine protecting group, the compound of formula (18d) or (18A) is further reacted with an amine deprotecting reagent to form a compound of formula (Id') or (IA), respectively.
Examples of suitable amine deprotecting reagent include, but are not limited to, the amine deprotecting reagent is selected from the group consisting of tetra-n- butylammonium fluoride, acetic acid, hydrogen fluoride pyridine, cesium fluoride, piperidine, morpholine, or trifluroacetic acid.
In a thirty-fifth embodiment, the present invention provides a
method of preparin a compound of formula (18d),
Figure imgf000121_0001
(18d)
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a sulfonating reagent or an esterification reagent with the compound of formula (14d):
Figure imgf000121_0002
(14d)
or a salt thereof, to form a compound of formula (15d):
Figure imgf000121_0003
(15d)
or a salt thereof;
(2) reacting the compound of formula (15a) with a monomer compound of formula (ai),
Figure imgf000122_0001
to form a compound of formula (16d):
Figure imgf000122_0002
(16d)
or a salt thereof; and
(3) reacting the compound of formula of (16d) with a reduced monomer of formula (di):
Figure imgf000122_0003
to form a compound of formula (18d), or a pharmaceutically acceptable salt thereof, wherein X3 is -CI; X4 is a sulfonate ester or an activated ester; Pi is an alcohol protecting group; P3 is H or an amine protecting group; and Rioo is (Ci-C3)alkoxy. In one embodiment, X4 is a sulfonate ester.
Also included in the thirty-fifth embodiment is a method of preparing a compound of formula (18A),
Figure imgf000122_0004
(18A)
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a sulfonating reagent or an esterification reagent with the compound of formula (14A):
Figure imgf000123_0001
(14A)
or a salt thereof, to form a compound of formula (15A):
Figure imgf000123_0002
(15A)
or a salt thereof;
(2) reacting the compound of formula (15A) with a monomer compound of formula (ai),
Figure imgf000123_0003
to form a compound of formula (16A):
Figure imgf000123_0004
or a salt thereof; and
(3) reacting the compound of formula of (16A) with a reduced monomer of formula (di):
Figure imgf000123_0005
to form a compound of formula (18A), or a pharmaceutically acceptable salt thereof, wherein X3 is -CI; X4 is a sulfonate ester or an activated ester; Pi is an alcohol protecting group; and P3 is H or an amine protecting group. In one embodiment, X4 is a sulfonate ester. The conditions and reagents for the method of thirty-fifth embodiment are as described above in the twenty-fourth, twenty-sixth and/or twenty-ninth embodiment(s) and any specific embodiments described therein.
In a thirty- sixth embodiment, the present invention provides a method of preparing a compound of formula (18d),
Figure imgf000124_0001
(18d)
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting the compound of formula (14d):
Figure imgf000124_0002
(14d)
or a salt thereof, with a monomer compound of formula (ai),
Figure imgf000124_0003
to form a compound of formula (16d):
Figure imgf000124_0004
(16d)
or a salt thereof; and
(2) reacting the compound of formula of (16d) with a reduced monomer of formula (di):
Figure imgf000125_0001
to form a compound of formula (18d), or a pharmaceutically acceptable salt thereof, wherein X3 is -CI; Pi is an alcohol protecting group; P3 is H or an amine protecting group; and Rioo is (Ci-C3)alkoxy.
Also provided in the thirty- sixth embodiment is a method of preparing a compound of formula (18A),
Figure imgf000125_0002
(18A)
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting the compound of formula (14A):
Figure imgf000125_0003
(14A)
or a salt thereof, with a monomer compound of formula (& ),
Figure imgf000125_0004
to form a compound of formula (16A):
Figure imgf000125_0005
or a salt thereof; and
(2) reacting the compound of formula of (16A) with a reduced monomer of formula (di):
Figure imgf000126_0001
to form a compound of formula (18A), or a pharmaceutically acceptable salt thereof, wherein X3 is -CI; Pi is an alcohol protecting group; and P3 is H or an amine protecting group.
The conditions and reagents for the method of thirty-sixth embodiment are as described above in the twenty-eighth, and/or twenty-ninth embodiment(s) and any specific embodiments described therein.
In a thirty- seventh embodiment, the present invention provides a method of preparing a compound of formula (18d),
Figure imgf000126_0002
(18d)
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a halogenating reagent with the compound of formula (14d):
Figure imgf000126_0003
(14d)
salt thereof, to form a compound of formula (20d)
Figure imgf000126_0004
(20d)
or a salt thereof;
(2) reacting a compound of formula (20d) or a salt thereof with a monomer compound of formula (ai),
Figure imgf000127_0001
to form a compound of formula (16d):
Figure imgf000127_0002
(16d)
or a salt thereof; and
(3) reacting the compound of formula of (16d) with a reduced monomer of formula (di):
Figure imgf000127_0003
to form a compound of formula (18d), or a pharmaceutically acceptable salt thereof, wherein X3 is -CI; X5 is -Br or -I; P3 is H or an amine protecting group; and R100 is (C C3)alkoxy.
Also provided in the thirty- seventh embodiment is a method of preparing a compound of formula (18A),
Figure imgf000127_0004
(18A)
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a halogenating reagent with the compound of formula (14A):
Figure imgf000127_0005
(14A)
or a salt thereof, to form a compound of formula (20 A):
Figure imgf000128_0001
(20A)
or a salt thereof;
(2) reacting a compound of formula (20A) or a salt thereof with a monomer compound of formula (ai),
Figure imgf000128_0002
to form a compound of formula (16A):
Figure imgf000128_0003
or a salt thereof; and
(3) reacting the compound of formula of (16A) with a reduced monomer of formula (di):
Figure imgf000128_0004
to form a compound of formula (18A), or a pharmaceutically acceptable salt thereof, wherein X3 is -CI; X5 is -Br or -I; and P3 is H or an amine protecting group.
The conditions and reagents for the method of thirty-seventh embodiment are as described above in the twenty-fifth, twenty- seventh, and/or twenty-ninth embodiment(s) and any specific embodiments described therein.
In a specific embodiment, for the methods of the thirty-fifth, thirty-sixth and thirty-seventh embodiments, P3 is H, the compound of formula (16d) or (16A) is reacted with reduced monomer of formula (di) to form a compound of formula (Id') or (IA) respectively:
Figure imgf000129_0001
In another specific embodiment, for the methods of thirty-fifth, thirty- sixth and thirty-seventh embodiments, P3 is an amine protecting group and the methods further comprise reacting the compound of formula (18d) or (18A) with an amine deprotecting reagent to form a compound of formula (Id') or (IA) respectively.
In a thirty-eighth embodiment, the present invention provides a method of preparing a compound of formula (18d),
Figure imgf000129_0002
(18d)
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a sulfonating reagent or an esterification reagent with the compound of formula (14d):
Figure imgf000129_0003
(14d)
or a salt thereof, to form a compound of formula (15d):
Figure imgf000130_0001
(15d)
or a salt thereof;
(2) reacting the compound of formula (15d) with a reduced monomer compound of formula (di),
Figure imgf000130_0002
to form a compound of formula (17d):
Figure imgf000130_0003
(17d)
or a salt thereof; and
(3) reacting the compound of formula of (17d) with a monomer of formula (ai):
Figure imgf000130_0004
to form a compound of formula (18d), or a pharmaceutically acceptable salt thereof, wherein X3 is -CI; X4 is a sulfonate ester or an activated ester; Pi is an alcohol protecting group; P3 is H or an amine protecting group; and Rioo is (Ci-C3)alkoxy. In one embodiment, X4 is a sulfonate ester.
Also provided in the thirty-eighth embodiment is a method of preparing a compound of formula (18A),
(1) reacting a sulfonating reagent or an esterification reagent with the compound of formula (14A):
Figure imgf000131_0001
(14A)
or a salt thereof, to form a compound of formula (15A)
Figure imgf000131_0002
(15A)
or a salt thereof;
(2) reacting the compound of formula (15A) with a reduced monomer compound of formula (di),
Figure imgf000131_0003
to form a compound of formula (17A):
Figure imgf000131_0004
or a salt thereof; and
(3) reacting the compound of formula of (17A) with a monomer of formula (ai):
Figure imgf000131_0005
(ai)
to form a compound of formula (18A), or a pharmaceutically acceptable salt thereof, wherein X3 is -CI; X4 is a sulfonate ester or an activated ester; Pi is an alcohol protecting group; and P3 is H or an amine protecting group. In one embodiment, X4 is a sulfonate ester.
The conditions and reagents for the method of thirty-eighth embodiment are as described above in the twenty-fifth, thirtieth and/or thirty-fourth embodiment(s) and any specific embodiments described therein.
In a thirty-ninth embodiment, the present invention provides method of preparing a compound of formula (18d),
Figure imgf000132_0001
(18d)
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting the compound of formula (14d):
Figure imgf000132_0002
(14d)
or a salt thereof, with a reduced monomer compound of formula (di),
Figure imgf000132_0003
to form a compound of formula (17d):
Figure imgf000132_0004
(17d)
or a salt thereof; and
(2) reacting the compound of formula of (17d) with a monomer of formula (ai):
Figure imgf000132_0005
to form a compound of formula (18d), or a pharmaceutically acceptable salt thereof, wherein X3 is -CI; Pi is an alcohol protecting group; P3 is H or an amine protecting group; and Rioo is (Ci-C3)alkoxy. Also provided in the thirty-ninth embodiment is a method of preparing compound of formula (18A),
Figure imgf000133_0001
(18A)
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting the compound of formula (14A):
Figure imgf000133_0002
(14A)
or a salt thereof, with a reduced monomer compound of formula (di),
Figure imgf000133_0003
to form a compound of formula (17A):
Figure imgf000133_0004
< 7A>
or a salt thereof; and
(2) reacting the compound of formula of (17A) with a monomer of formula (ai):
Figure imgf000133_0005
to form a compound of formula (18A), or a pharmaceutically acceptable salt thereof, wherein X3 is -CI; Pi is an alcohol protecting group; and P3 is H or an amine protecting group.
The conditions and reagents for the method of thirty-ninth embodiment are as described above in the thirty-first and/or thirty-fourth embodiment(s) and any specific embodiments described therein. In a fortieth embodiment, the present invention provides a method of preparing a compound of formula 18d),
Figure imgf000134_0001
(18d)
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a brominating or iodinating reagent with the compound of formula
(14d):
Figure imgf000134_0002
(14d)
or a salt thereof, to form a compound of formula (20d):
Figure imgf000134_0003
(20d)
or a salt thereof;
(2) reacting the compound of formula (20d) with a reduced monomer compound of formula (di),
Figure imgf000134_0004
to form a compound of formula (17d):
Figure imgf000134_0005
(17d) or a salt thereof; and
(3) reacting the compound of formula of (17d) with a monomer of formula (ai):
Figure imgf000135_0001
to form a compound of formula (18d), or a pharmaceutically acceptable salt thereof, wherein X3 is -CI; X5 is -Br or -I; Pi is an alcohol protecting group; P3 is H or an amine protecting group; and R100 is (Ci-C3)alkoxy.
Also provided in the fortieth embodiment is a method of preparing a compound of formula (18A),
Figure imgf000135_0002
(18A)
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a brominating or iodinating reagent with the compound of formula
(14A):
Figure imgf000135_0003
(14A)
or a salt thereof, to form a compound of formula (20 A)
Figure imgf000135_0004
(20A)
or a salt thereof;
(2) reacting the compound of formula (20A) with a reduced monomer compound of formula (di),
Figure imgf000135_0005
to form a compound of formula (17A):
Figure imgf000136_0001
(17A)
or a salt thereof; and
(3) reacting the compound of formula of (17A) with a monomer of formula (ai):
Figure imgf000136_0002
to form a compound of formula (18A), or a pharmaceutically acceptable salt thereof, wherein X3 is -CI; X5 is -Br or -I; Pi is an alcohol protecting group; and P3 is H or an amine protecting group.
The conditions and reagents for the method of fortieth embodiment are as described above in the twenty-fifth, thirty-second and/or thirty-fourth embodiment(s) and any specific embodiments described therein.
In a specific embodiment, for the methods of the thirty-eighth, thirty-ninth and fortieth embodiments, P3 is H, the compound of formula (17d) or (17 A) is reacted with the monomer of formula (ai) to form a compound of formula (Id') or (IA) respectively.
In another specific embodiment, for the methods of thirty-eighth, thirty-ninth and fortieth embodiments, P3 is an amine protecting group and the methods further comprise reacting the compound of formula (18d) or (18A) with an amine deprotecting reagent to form a compound of formula (Id') or (IA) respectively.
In a forty-first embodiment, the present invention provides a method of preparing a compound of formula (Id'),
Figure imgf000136_0003
(Id')
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a sulfonating reagent or an esterification reagent with the compound of formula (14d):
Figure imgf000137_0001
(14d)
or a salt thereof, to form a compound of formula (15d):
Figure imgf000137_0002
(15d)
or a salt thereof;
(2) reacting the compound of formula (15d) with a monomer compound of formula (ai),
Figure imgf000137_0003
to form a compound of formula (16d):
Figure imgf000137_0004
(16d)
or a salt thereof;
(3) reacting the compound of formula (16d) with an imine reducing agent to form a compound of formula (17d'):
Figure imgf000137_0005
(17d')
or a salt thereof; and
(4) reacting the compound of formula (17d') with a monomer of formula (ai):
Figure imgf000138_0001
to form the compound of formula (Id'); wherein X3 is -CI; X4 is a sulfonate ester or an activated ester; Pi is an alcohol protecting group; P2 is an amine protecting group; and Rioo is (Ci-C3)alkoxy. In one embodiment, X4 is a sulfonate ester.
Also provided in the forty-first embodiment is a method of preparing a compound of formula IA),
Figure imgf000138_0002
(Id')
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a sulfonating reagent or an esterification reagent with the compound of formula (14A):
Figure imgf000138_0003
(14A)
or a salt thereof, to form a compound of formula (15A):
Figure imgf000138_0004
(15A)
or a salt thereof;
(2) reacting the compound of formula (15A) with a monomer compound of formula (ai),
Figure imgf000138_0005
to form a compound of formula (16d):
Figure imgf000139_0001
or a salt thereof;
(3) reacting the compound of formula (16A) with an imine reducing agent to form a compound of formula (17Α'):
Figure imgf000139_0002
or a salt thereof; and
(4) reacting the compound of formula (17Α') with a monomer of formula (ai):
Figure imgf000139_0003
to form the compound of formula (IA); wherein X3 is -CI; X4 is a sulfonate ester or an activated ester; Pi is an alcohol protecting group; and P2 is an amine protecting group. In one embodiment, X4 is a sulfonate ester.
The conditions and reagents for the method of forty-first embodiment are as described above in the twenty-fourth, twenty-sixth and/or thirty-fourth embodiment(s) and any specific embodiments described therein.
In a forty- second embodiment, the present invention provides a method of preparing a compound of formula (Id'),
Figure imgf000139_0004
(Id')
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting the compound of formula (14d):
Figure imgf000140_0001
(14d)
or a salt thereof, with a monomer compound of formula (ai),
Figure imgf000140_0002
(ai)
to form a compound of formula 16d):
Figure imgf000140_0003
(16d)
or a salt thereof;
(2) reacting the compound of formula (16d) with an imine reducing agent to form a compound of formula (17d'):
Figure imgf000140_0004
(17d')
or a salt thereof; and
(3) reacting the compound of formula (17d') with a monomer of formula (ai):
Figure imgf000140_0005
to form the compound of formula (Id'); wherein X3 is -CI; Pi is an alcohol protecting group; and Rioo is (Ci-C3)alkoxy.
Also provided in the forty-second embodiment is a method of preparing a compound of formula (IA),
Figure imgf000141_0001
(IA)
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting the compound of formula (14A):
Figure imgf000141_0002
(14A)
or a salt thereof, with a monomer compound of formula (ai),
Figure imgf000141_0003
to form a compound of formula (16A):
Figure imgf000141_0004
or a salt thereof;
(2) reacting the compound of formula (16A) with an imine reducing agent to form a compound of formula (17Α'):
Figure imgf000141_0005
(17Α')
or a salt thereof; and
(3) reacting the compound of formula (17Α') with a monomer of formula (ai):
Figure imgf000141_0006
to form the compound of formula (IA); wherein X3 is -CI; and Pi is an alcohol protecting group.
The conditions and reagents for the method of forty- second embodiment are as described above in the twenty-eighth, thirty-third and/or thirty-fourth embodiment(s) and any specific embodiments described therein.
In a forty-third embodiment, the present invention provides a method of preparing a com ound of formula (Id'),
Figure imgf000142_0001
(Id')
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a halogenating reagent with the compound of formula (14d):
Figure imgf000142_0002
(14d)
or a salt thereof, to form a compound of formula (20d):
Figure imgf000142_0003
(20d)
or a salt thereof;
(2) reacting a compound of formula (20d) or a salt thereof with a monomer compound of formula (ai),
Figure imgf000142_0004
to form a compound of formula (16d):
Figure imgf000143_0001
(16d)
(3) reacting the compound of formula (16d) with an imine reducing agent to form a compound of formula (17d'):
Figure imgf000143_0002
(17d')
or a salt thereof; and
(4) reacting the compound of formula (17d') with a monomer of formula (ai):
Figure imgf000143_0003
to form the compound of formula (Id'); wherein X3 is -CI; X5 is -Br or -I; and Rioo is (Ci-C3)alkoxy.
Also provided in the forty-third embodiment is a method of preparing a compound of formula (IA),
Figure imgf000143_0004
(IA)
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a halogenating reagent with the compound of formula (14A):
Figure imgf000143_0005
< 4A>
or a salt thereof, to form a compound of formula (20d):
Figure imgf000144_0001
(20A)
or a salt thereof;
(2) reacting a compound of formula (20A) or a salt thereof with a monomer compound of formula (ai),
Figure imgf000144_0002
to form a compound of formula (16A):
Figure imgf000144_0003
(3) reacting the compound of formula (16A) with an imine reducing agent to form a compound of formula (17Α'):
Figure imgf000144_0004
(17Α')
or a salt thereof; and
(4) reacting the compound of formula (17Α') with a monomer of formula (ai):
Figure imgf000144_0005
to form the compound of formula (IA); wherein X3 is -CI.
The conditions and reagents for the method of the forty-third embodiment are as described above in the twenty-fifth, twenty- seventh, thirty-third and/or thirty-fourth embodiment(s) and any specific embodiments described therein.
In one embodiment, for methods of the thirty-fifth, thirty- sixth, thirty- seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, forty- second and forty-third embodiments described above, the compound (14d) of a salt thereof is prepared a method comprising the following steps:
(1) reacting a chlorinating reagent with a compound of formula (2d),
Figure imgf000145_0001
(2d)
to form a compound a compound of formula (13d),
Figure imgf000145_0002
(13d)
or a salt thereof; and
(2) reacting the compound of formula (13d) with an alcohol deprotecting reagent to form the compound of formula (14d) or a salt thereof, wherein X3 is -CI; and Pi is an alcohol protecting group.
In another embodiment, for methods of the thirty-fifth, thirty-sixth, thirty- seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, forty- second and forty-third embodiments described above, the compound (14A) of a salt thereof is prepared a method comprising the following steps:
(1) reacting a chlorinating reagent with a compound of formula (2A),
Figure imgf000145_0003
(2A)
to form a compound a compound of formula (13 A),
Figure imgf000145_0004
(13A)
or a salt thereof; and
(2) reacting the compound of formula (13 A) with an alcohol deprotecting reagent to form the compound of formula (14A) or a salt thereof. The conditions and reagents for the method of preparing compound of formula (14d) or (14A) above are as described above in the twenty- second and/or twenty-third embodiment(s) and any specific embodiments described therein.
In another embodiment, for the methods described above, the compound of formula (2d) is prepared by reacting a compound of formula (Id) with an alcohol protecting reagent.
In another embodiment, for the methods described above, the compound of formula (2A) is prepared by reacting a compound of formula (1A) with an alcohol protecting reagent.
The conditions and reagents for the method of preparing compound of formula
(2d) or (2A) above are as described above in the first embodiment and any specific embodiments described therein.
In a forth-fourth embodiment the present invention provides a method of
Figure imgf000146_0001
(Id')
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a compound of formula (IA):
Figure imgf000146_0002
(IA)
with a reducing agent to form a compound of formula (IB):
Figure imgf000146_0003
(IB) ; and
(2) reacting the compound of formula (IB) with a compound of formula (LI):
Figure imgf000147_0001
to form the compound of formula (Id), wherein E is -OH, halide or -C(=0)E is an activated ester; and Rioo is (Ci-C3)alkoxy.
Any reducing reagent that can convert a nitro (-N02) group to an amine (-NH2) group can be used in step (1). In one embodiment, the reducing reagent is selected from the group consisting of: hydrogen gas, sodium hydrosulfite, sodium sulfide, stanneous chloride, titanium (II) chloride, zinc, iron and samarium iodide. In a specific
embodiment, the reducing reagent is Fe/NH4C1 or Zn/NH4C1.
In a specific embodiment, for the method of forty-fourth embodiment, E is -OH and the reaction of the compound of formula (IB) and the compound of formula (LI) is carried out in the presence of an activating agent.
In one embodiment, the activating agent is a carbodiimide, a uranium, an active ester, a phosphonium, 2-alkyl-l-alkylcarbonyl-l,2-dihydroquinoline, 2-alkoxy-l- alkoxycarbonyl-l,2-dihydroquinoline, or alkylchloroformate. In a specific embodiment, the activating agent is a carbodiimide. In a more specific embodiment, the activating agent is dicyclohexylcarbodiimide (DCC), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC), or diisopropylcarbodiimide (DIC). In another specific embodiment, the activating agent is N-ethoxycarbonyl-2-ethoxy- l,2- dihydroquinoline .
In one embodiment, for methods described above, Rioo is methoxy.
The method of the present invention can also be any combination of the methods described above (e.g. , methods in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty- second, twenty- third, twenty-fourth, twenty-fifth, twenty- sixth, twenty- seventh, twenty-eighth, twenty- ninth, thirtieth, thirty-first, thirty- second, thirty-third, thirty-fourth, thirty- fifth, thirty- sixth, thirty-seventh, thirty-eighty, thirty-ninth, fortieth, forty-first, forty-second, forty- third and forty-fourth embodiment). For example, the combination of the methods of the first and second embodiments, the combination of methods of the first, second, and third embodiments, the combination of the methods of the fourth and fifth embodiments, the combination of the methods of the fourth, fifth and sixth embodiments, the combination of the methods of the sixth and eighth embodiments, the combination of the methods of thirteenth and fourteenth embodiments, the combination of the methods of thirteenth, fourteenth and fifteenth embodiments, and the combination of the methods of the seventeenth and eighteenth embodiments are also included in the present invention. The variable definitions described in any of the specific embodiments below also apply to any combination of methods described above.
The reactions described herein in the methods of the present invention can be carried out in any suitable solvent(s). In one embodiment, the solvent is an organic solvent. Exemplary organic solvents include, but are not limited to, dichloromethane, dichloroethane, DMF, DMA, acetone, acetonitrile, THF, DMSO, ethyl acetate etc., or a combination thereof.
The reactions described herein in the methods of the present invention can be carried out at any suitable temperature. In one embodiment, the reaction can be carried out at room temperature. In another embodiment, the reaction can carried out at a low temperature, such as 0°C. In yet another embodiment, the reaction can be carried out at an elevated temperature, such as about 40°C, about 50 °C etc.
In certain embodiment, the indolinobenzodiazepine dimer compound of formula (Id') and (IA) can be prepared according to Schemes 1 -10 shown below, wherein L' is
O |_| = o o o for formula (Id'); and -NO2 for formula (IA). In one embodiment, R100 is -OMe.
Figure imgf000148_0001
K2C03, DMF
Figure imgf000148_0002
Figure imgf000149_0001
K2C03, DMF
Figure imgf000149_0002
reduced IGN monomer A K2C03, DMF
P2 = amine protecting group
3. TBAF or other deprotection conditions
Scheme 2
Figure imgf000149_0003
Scheme 3
Figure imgf000150_0001
Figure imgf000151_0001
Scheme 6
Figure imgf000151_0002
K2C03, DMF
Figure imgf000151_0003
Scheme 7
Figure imgf000151_0004
Scheme 8
Figure imgf000152_0001
Scheme 9
Figure imgf000152_0002
Scheme 10
Figure imgf000152_0003
Scheme 11
Figure imgf000153_0001
Scheme 12
COMPOUNDS OF THE INVENTION
The present invention also provides novel compounds described herein. In certain embodiments, the compounds of the present invention are compounds of formulas (Id), (1A), (2d), (2A), (2d"), (2A"), (3d), (3A), (3d"), (3A"), (4d), (4A), (4d"), (4A"), (5d), (5A), (5d"), (5A"), (6d), (6A), (7d), (7 A), (7d'), (7Α'), (7dl'), (7Α ), (7d"), (7 A"), (7d"'), (7 A'"), (9d), (9A), (lOd), (10A), (10d'), (ΙΟΑ'), (l id), (11 A), (12d), (12A), (13d), (13A), (14d), (14A), (15d), (15A), (16d), (16A), (17d), (17A), (17d'), (17Α'), (18d), (18A), (20d), (20A), (ci), (di), (Id'), (IA), and (IB), wherein the variables are as described above.
In a 1st specific embodiment, for compound of formula (Id), (2d), (2d"), (3d), (3d"), (4d), (4d"), (5d), (5d"), (6d), (7d), (7d'), (7dl'), (7d"), (7d"'), (9d), (lOd), (10d'), (l id), (12d), (13d), (14d), (15d), (16d), (17d), (17d'), (18d), (20d), or (Id'), R100 is - OMe.
In a 2nd specific embodiment, for compound of formula (2d), (3d), (4d), (5d), (13d), (2A), (3A), (4A), (5A), (13A), Pi is a silyl protecting group; and the remaining variables are as described in first to forty-fourth embodiments or the 1st specific embodiment above. More specifically, the silyl protecting group is
dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl, trimethylsilyl, triisopropylsilyl, tribenzylsilyl, triphenylsilyl, 2-norbornyldimethylsilyl, tert- butyldimethylsilyl, tert-butyldiphenylsilyl, 2-trimethyethylsilyl (TEOC), or [2- (trimethylsilyl)ethoxy]methyl. Even more specifically, the silyl protecting group is triethylsilyl, triisopropylsilyl, or tert-butyldimethyl silyl. In another even more specific embodiment, the silyl protecting group is tert-butyldimethylsilyl. In a 3r specific embodiment, for compound of formula (3d), (3d"), (7d'), (7dl '), (12d), (10d'),(3A), (3A"), (7 A'), (7A1 '),(12A), or (ΙΟΑ'), Xi is a sulfonate ester; and the remaining variables are as described above in the first to forty-fourth embodiments or in the 1st or 2nd specific embodiment. More specifically, the sulfonate ester is mesylate, tosylate, brosylate, or triflate. Even more specifically, the sulfonate ester is mesylate.
In a 4th specific embodiment, for compound of formula (3d), (3d"), (7d'), (7dl '), (12d), (10d'),(3A), (3A"), (7 A'), (7A1 '),(12A), or (ΙΟΑ'), Xi is -Br or -I; and the remaining variables are as described above in the first to forty-fourth embodiments or in the 1st or 2nd specific embodiment. More specifically, Xi is -Br.
In a 5th specific embodiment, for compound of formula (7d), (lOd), (7 A), or (10A), X2 is a sulfonate ester; and the remaining variables are as described above in the first to forty-fourth embodiments or in the 1st specific embodiment. More specifically, the sulfonate ester is mesylate, tosylate, brosylate, or triflate. Even more specifically, the sulfonate ester is mesylate.
In a 6th specific embodiment, for compound of (7d") or (7 A"), X2' is -Br or -I, and the remaining variables are as described above in the first to forty-fourth
embodiments or in the 1st specific embodiment.
In a 7th specific embodiment, for the compound of formula (2d"), (3d"), (4d"), (5d"), (2A"), (3 A"), (4 A"), or (5 A"), Pi' is acetate, allyl, methoxymethyl,
tetrahydrofuranyl, tetrahydropyranyl, 5-dibenzosuberyl, 1-ethoxyethyl, 1 -methyl- 1- methoxylethyl, 2-(phenylselenyl)ethyl, trityl/triphenylmethyl, or tris(4-ie/t- butylphenyl)methyl; and the remaining variables are as described above in the first to forty-fourth embodiments or in the 1st, 3rd, or 4th specific embodiment. In another specific embodiment, Pi' is a silyl protecting group; the remaining variables are as described above in the first to forty-fourth embodiments or in the 1st, 3rd, or 4th specific embodiment. In a more specific embodiment, Pi' is dimethylisopropylsilyl,
diethylisopropylsilyl, dimethylhexylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tribenzylsilyl, triphenylsilyl, 2-norbornyldimethylsilyl, ie/ -butyldimethylsilyl, tert- butyldiphenylsilyl, 2-trimethyethylsilyl (TEOC), or [2-(trimethylsilyl)ethoxy]methyl. Even more specifically, Pi' is triethylsilyl, triisopropylsilyl, or tert-butyldimethylsilyl. In another more specific embodiment, Pi' is tert-butyldimethylsilyl. In a 8th specific embodiment , for the compound of formula (13d), (14d), (15d), (16d), (17d), (17d'), (20d), (13A), (14A), (15A), (16A), (17A), (17Α'), or (20A), X3 is chlorine; and the remaining variables are as described above in the first to forty-fourth embodiments or in the 1st or 2nd specific embodiment.
In a 9th specific embodiment, for the compound of formula (15d) or (15A), X4 is a sulfonate ester; and the remaining variables are as described above in the first to forty- fourth embodiments or in the 1st or 8th specific embodiment. More specifically, the sulfonate ester is mesylate, tosylate, brosylate, or triflate. Even more specifically, the sulfonate ester is mesylate.
In a 10th specific embodiment, for the compound of formula (ci), (1 Id) or (11A),
P2 is an amine protecting group selected from 2-trimethylsilylethyl,(2-phenyl-2- trimethylsilyl)ethyl, triisopropylsiloxy, 2-(trimethylsilyl)ethoxymethyl,
allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, and 2, 2,2,2-trichloroethoxycarbonyl; and the remaining variables are as described above in the first to forty-fourth embodiments or in the 1st specific embodiment.
In a 11th specific embodiment, for the compound of formula (di), (7dl'), (17d), (18d), (7Α ), (17A) or (18A), P3 is H or an amine protecting group selected from 2- trimethylsilylethyl,(2-phenyl-2-trimethylsilyl)ethyl, triisopropylsiloxy, 2- (trimethylsilyl)ethoxymethyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2- (trimethylsilyl)ethoxycarbonyl, or 2, 2,2,2-trichloroethoxycarbonyl; and the remaining variables are as described above in the first to forty-fourth embodiments or in the 1st or 8th specific embodiment.
In a 12th specific embodiment, for the compound of (20d) or (20A), X5 is -Br; and the remaining variables are as described above in the first to forty-fourth
embodiments or in the 1st or 8th specific embodiment.
All references cited herein and in the examples that follow are expressly incorporated by reference in their entireties.
EXAMPLES
The invention will now be illustrated by reference to non-limiting examples. Unless otherwise stated, all percents, ratios, parts, etc. are by weight. All reagents were purchased from the Aldrich Chemical Co., New Jersey, or other commercial sources. Nuclear Magnetic Resonance (1H NMR) spectra were acquired on a Bruker 400 MHz instrument. Mass spectra were acquired on a Bruker Daltonics Esquire 3000 instrument and LCMS were acquired on an Agilent 1260 Infinity LC with an Agilent 6120 single quadrupole MS using electrospray ionization and UPLC were acquired on a Waters,
Acquity system with a single quadrupole MS Zspray™ (column: Acquity BEH C I 8, 2.1 x 50 mm, 1.7 μιη, method: 2.5 min, flow rate 0.8 mL/min, solvent A: water, solvent B: MeCN, 5 to 95% of MeCN over 2.0 min and 95% MeCN for 0.5 min).
The following solvents, reagents, protecting groups, moieties and other designations may be referred to by their abbreviations in parenthesis:
Me = methyl; Et = ethyl; Pr = propyl; z'-Pr = isopropyl; Bu = butyl; t- u = tert-butyl; Ph
= phenyl, and Ac = acetyl
AcOH or HO Ac = acetic acid
ACN or CH3CN = acetonitrile
Ala = alanine
Ar = argon
aq = aqueous
Bn = benzyl
Boc or BOC = tert-butoxycarbonyl
CBr4 = carbontetrabromide
Cbz or Z = benzyloxycarbonyl
DCM or CH2CI2 = dichloromethane
DCE = 1,2-dichloroethane
DMAP = 4-dimethylaminopyridine
DI water = deionized water
DIBAL = diisobutylaluminum hydride
DIEA or DIPEA = N,N-diisopropylethylamine
DMA = N,N-dimethylacetamide
DMF = N,N-dimethylformamide
DMSO = dimethyl sulfoxide
DTT = dithiothreitol
EDC = l-ethyl-3-(3-dimethylaminopropyl)carbodiimide
EEDQ = N-Ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline
ESI or ES = electrospray ionization
EtOAc = ethylacetate
Gly = glycine g = grams
h = hour
HATU = N,N,N'N'-tetramethyl-0-(7-azabenzotriazol-l-yl)uronium hexaphosphate
HPLC = high-performance liquid chromatography
HOBt or HOBT = 1-hydroxybenzotriazole
LAH = lithium aluminum hydride
LC = liquid chromatography
LCMS = liquid chromatography mass spectrometry
min = minutes
mg = miligrams
mL = mililiters
mmol = milimoles
μg = micrograms
μΐ. = microliters
μηιοΐ = micromoles
Me = methyl
MeOH : methanol
Mel = methyliodide
MS = mass spectrometry
MsCl = methanesulfonyl chloride (mesyl chloride)
Ms20 = methanesulfonic anhydride
MTBE = Methyl tert-butyl ether
NaBH(OAc)3 = sodium triacetoxyborohydride
NHS = N-hydroxysuccinamide
NMR = nuclear magnetic resonance spectroscopy
PPh3 = triphenylphosphine
PTLC = preparative thin layer chromatography
rac = racemic mixture
R = retardation factor
RPHPLC or RP-HPLC = reverse phase high-performance liquid chromarography
RT or rt = room temperature (ambient, about 25 °C)
sat or sat'd = saturated
STAB = sodium triacetoxyborohydride (NaBH(OAc)3) TBSC1 or TBDMSC1 = te/t-butyldimethylsilyl chloride
TBS = ie/ -butyldimethylsilyl
TCEP HC1 = ira(2-carboxyethyl)phosphine hydrochloride salt
TEA = triethylamine (Et3N)
TFA = trifluoroacetic acid
THF = tetrahydrofuran
TLC = thin layer chromatography
Example 1.
Figure imgf000158_0001
(S)-2-(((benzyloxy)carbonyl)amino)propanoic acid (5 g, 22.40 mmol) and (S)- tert-butyl 2-aminopropanoate hydrochloride (4.48 g, 24.64 mmol) were dissolved in anhydrous DMF (44.8 mL). EDC HC1 (4.72 g, 24.64 mmol), HOBt (3.43 g, 22.40 mmol), and DIPEA (9.75 mL, 56.0 mmol) were added. The reaction stirred under argon, at room temperature overnight. The reaction mixture was diluted with dichloromethane and then washed with saturated ammonium chloride, saturated sodium bicarbonate, water, and brine. The organic layer was dried over sodium sulfate and concentrated. The crude oil was purified by silica gel chromatography (Hexanes/Ethyl Acetate) to yield compound 2a (6.7 g, 85% yield). 1H NMR (400 MHz, CDC13): δ 7.38-7.31 (m, 5H), 6.53-6.42 (m, 1H), 5.42-5.33 (m, 1H), 5.14 (s, 2H), 4.48-4.41 (m, 1H), 4.32-4.20 (m, 1H), 1.49 (s, 9H), 1.42 (d, 3H, / = 6.8 Hz), 1.38 (d, 3H, / = 7.2 Hz).
Figure imgf000158_0002
Compound 2a (6.7 g, 19.12 mmol) was dissolved in methanol (60.7 mL) and water (3.03 mL). The solution was purged with argon for five minutes. Palladium on carbon (wet, 10%) (1.017 g, 0.956 mmol) was added slowly. The reaction was stirred overnight under an atmosphere of hydrogen. The solution was filtered through Celite, rinsed with methanol and concentrated. It was azeotroped with methanol and acetonitrile and the resulting oil was placed directly on the high vacuum to give compound 2b (4.02 g, 97% yield) which was used directly in the next step. 1H NMR (400 MHz, CDC13): δ 7.78-7.63 (m, 1H), 4.49-4.42 (m, 1H), 3.55-3.50 (m, 1H), 1.73 (s, 2H), 1.48 (s, 9H), 1.39 (d, 3H, J = 7.2 Hz), 1.36 (d, 3H, / = 6.8 Hz).
Figure imgf000159_0001
2b 2c
Compound 2b (4.02 g, 18.59 mmol) and mono methyladipate (3.03 mL, 20.45 mmol) were dissolved in anhydrous DMF (62.0 mL). EDC HC1 (3.92 g, 20.45 mmol), HOBt (2.85 g, 18.59 mmol) and DIPEA (6.49 mL, 37.2 mmol) were added. The mixture was stirred overnight at room temperature. The reaction was diluted with dichloromethane/methanol (150 mL, 5: 1) and washed with saturated ammonium chloride, saturated sodium bicarbonate, and brine. It was dried over sodium sulfate, filtered and concentrated. The compound was azeotroped with acetonitrile (5x), then pumped on the high vacuum at 35 °C to give compound 2c (6.66 g, 100% yield). The crude material was taken onto next step without purification. 1H NMR (400 MHz, CDC13): δ 6.75 (d, 1H, = 6.8 Hz), 6.44 (d, 1H, = 6.8 Hz), 4.52-4.44 (m, 1H), 4.43- 4.36 (m, 1H), 3.65 (s, 3H), 2.35-2.29 (m, 2H), 2.25-2.18 (m, 2H), 1.71- 1.60 (m, 4H), 1.45 (s, 9H), 1.36 (t, 6H, / = 6.0 Hz).
Figure imgf000159_0002
2c 2d
Compound 2c (5.91 g, 16.5 mmol) was stirred in TFA (28.6 mL, 372 mmol) and deionized water (1.5 mL) at room temperature for three hours. The reaction mixture was concentrated with acetonitrile and placed on high vacuum to give crude compound 2d as a sticky solid (5.88 g, 100% yield). 1H NMR (400 MHz, CDC13): δ 7.21 (d, 1H, = 6.8 Hz), 6.81 (d, 1H, J = 7.6 Hz), 4.69-4.60 (m, 1H), 4.59-4.51 (m, 1H), 3.69 (s, 3H), 2.40- 2.33 (m, 2H), 2.31-2.24 (m, 2H), 1.72-1.63 (m, 4H), 1.51- 1.45 (m, 3H), 1.42-1.37 (m, 3
Figure imgf000159_0003
Compound 2d (5.6 g, 18.52 mmol) was dissovled in anhydrous dichloromethane (118 mL) and anhydrous methanol (58.8 mL). (5-amino-l,3-phenylene)dimethanol (2.70 g, 17.64 mmol) and EEDQ (8.72 g, 35.3 mmol) were added and the reaction was stirred at room temperature overnight. The solvent was concentrated and ethyl acetate was added. The resulting slurry was filtered, washed with ethyl acetate and dried under vacuum/Ni to give compound 2e (2.79 g, 36% yield). 1H NMR (400 MHz, DMSO-i¾): δ 9.82 (s, 1H), 8.05, (d, 1H, 7 = 9.2 Hz), 8.01 (d, 1H, 7 = 7.2 Hz), 7.46 (s, 2H), 6.95 (3, 1H), 5.21-5.12 (m, 2H), 4.47-4.42 (m, 4H), 4.40-4.33 (m, 1H), 4.33-4.24 (m, 1H), 3.58 (s, 3H), 2.33-2.26 (m, 2H), 2.16-2.09 (m, 2H), 1.54-1.46 (m, 4H), 1.30 (d, 3H, 7 = 7.2 Hz), 1.22 (d, 3H, 7 = 4.4 Hz).
Figure imgf000160_0001
2e 2f
Diol 2e (1.0 g, 2.286 mmol) was dissolved in anhydrous DMF (7.6 mL). TBSCI (0.482 g, 3.20 mmol) and imidazole (0.467 g, 6.86 mmol) were added and the reaction was stirred at room temperature for 2 hrs. The reaction was quenched with saturated ammonium chloride and diluted with water and EtOAc. The aqueous layer was extracted once with EtOAc and the combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel flash chromatography (DCM/MeOH) to obtain compound 2f (360 mg, 28% yield). LCMS (8 min method, 40-98%) = 2.35 min. Mass observed (ESI+): 574.4 (M+Na)+.
Figure imgf000160_0002
2f 29
Compound 2f (360 mg, 0.652 mmol) was dissolved in anhydrous dichloromethane (6.52 mL) and cooled in an acetone/ice bath. Triethylamine (227 μί, 1.631 mmol) and methanesulfonic anhydride (146 mg, 0.816 mmol) were added. The reaction stirred at -10°C in the acetone/ice bath for 1 hr. The reaction was diluted with cold EtOAc and quenched with ice water. The organic layer was washed with ice water and then dried over sodium sulfate and magnesium sulfate, filtered and concentrated to give crude compound 2g as a fluffy solid (390 mg, 95% yield). LCMS (8 min method, 40-98%) = 2.81 min; 5.86 min (8 min method, 5-98%). Mass observed (ESI-): 628.0 (M-H)~.
Figure imgf000161_0001
Mesylate 2g (390 mg, 0.619 mmol) and IGN monomer A (264 mg, 0.897 mmol) were dissolved in anhydrous DMA (7.47 mL). Potassium carbonate (207 mg, 1.495 mmol) and potassium iodide (51.4 mg, 0.310 mmol) were added and the reaction was stirred overnight at room temperature. The reaction was precipitated with water, filtered and the filter cake washed with water. The solid was redissolved in DCM, washed with water, dried over magnesium sulfate and concentrated to give crude compound 2h (568 mg, 111% yield). The product was carried on without further purification. LCMS (8 min method, 5-98%) = 6.23 min. Mass observed (ESI+): 827.8 (M+H)+.
Figure imgf000161_0002
Compound 2h (0.513 g, 0.619 mmol) was dissolved in DCE (7.74 mL). NaBH(OAc)3 (0.276 g, 1.239 mmol) was added and the mixture stirred at room temperature for 1.5 h. The reaction was diluted with DCM, quenched with saturated ammonium chloride and washed with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to give compound 2i. LCMS (15 min
Figure imgf000161_0003
Compound 2i (514 mg, 0.619 mmol) was dissolved in THF (3.44 mL). 5 M aqueous HCl (1.24 mL, 6.19 mmol) was added at room temperature and the reaction stirred for 1 h. The reaction mixture was diluted with DCM/MeOH (20: 1) and the organic layer was washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (DCM/MeOH) to give compound 2j (210 mg, 47% yield). LCMS (8 min method, 5-98%) = 4.56 min. Mass observed (ESI+): 715.8 (M+H)+.
Figure imgf000162_0001
Compound 2j (210 mg, 0.293 mmol) was dissolved in DCM (3.95 mL) and DMF (500 μί) and cooled to -10°C (ice-acetone bath). TEA (57.2 μΐ,, 0.411 mmol) and methanesulfonic anhydride (46.6 mg, 0.260 mmol) were added and the reaction as stirred for 3 h under Ar. The reaction was quenched with cold water at -5°C and diluted with EtOAc. The aqueous layer was extracted with cold EtOAc (2x) and the combined organics were washed with cold water (2x). The organic layer was dried over anhydrous sodium/magnesium sulfate, filtered and concentrated. The crude product 2k was pumped on the high vacuum and taken onto next step without purification. LCMS (8 min method, 5-98%) = 5.06 min. Mass -H)~.
Figure imgf000162_0002
Compound 2k (233 mg, 0.293 mmol) was dissolved in DMA (1.95 mL). IGN monomer A (103 mg, 0.352 mmol) and potassium carbonate (60.7 mg, 0.440 mmol) were added at room temperature and the reaction stirred overnight. DI water was added to the reaction mixture and the resulting solid was filtered and washed with water. The solid was redissolved in DCM/MeOH (20: 1), washed with water, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by RPHPLC (ACN/H20) to give 21 (44 mg, 15% yield). LCMS (8 min method, 5-98%) = 5.4 min. Mass observed (ESI+): 991.7 (M+H)+. Example 2.
Figure imgf000163_0001
IGN monomer A reduced IGN monomer A
To a solution of IGN monomer A (1.0 g, 3.4 mmol) in DCE (10 mL) and DMF (4 mL) was added sodium triacetoxyborohydride (1.1 g, 5.1 mmol, 1.5 equiv) and the reaction was stirred until completion of starting material. Upon completion of the starting material after 2h at room temperature, the reaction was quenched with sat. ammonium chloride (10 mL), and then the layers were separated. The aqueous layer was extracted once with dichloromethane (10 mL) and the combined organic layers were washed with water (2 x 10 mL) and brine (10 mL). The organic layer was dried over magnesium sulfate, filtered and the solvent was removed in vacuo to give a white/brown powder. The powder was washed with EtOAc (2 x 10 mL) and dried under vaccum to give reduced IGN monomer A as a white solid (0.87 g, 2.9 mmol, 87% yield) which was used in the next step without further purification. UPLCMS (2.5 min method) = 1.34 min. Mass observed (ESI+): 297.4 (M+H)+. 1H NMR (400 MHz, DMSO- 6): δ 9.44 (s, 1H), 8.20 (d, = 8.1 Hz, 1H), 7.30 - 7.23 (m, 2H), 7.22 - 7.12 (m, 1H), 7.01 (td, = 7.4, 1.1 Hz, 1H), 6.21 (s, 1H), 6.17 (d, = 6.6 Hz, 1H), 4.37 (tdd, = 10.1, 4.4, 1.9 Hz, 1H), 3.70 (s, 3H), 3.58 - 3.39 (m, 2H), 3.31 - 3.15 (m, 2H), 2.88 (dd, = 16.9, 4.4 Hz, 1H).
Figure imgf000163_0002
2e 2m
A solution of 2e (5.53 g, 12.6 mmol) in DCM (81 mL) and DMF (64.9 mL) was cooled down to 0 °C and then DIPEA (6.13 mL, 37.9 mmol, 3.0 equiv.) was added followed by a solution of methanesulfonic anhydride (5.06 g, 29.1 mmol, 2.3 equiv.) in DCM (15 mL) / DMF (1 mL) dropwise. The reaction was stirred for lh before quenching with cold water. After washing with water and brine the solution was dried over magnesium sulfate, filtered, and the solvent was removed in vacuo to give an orange oil which was triturated in diethyl ether to give bis mesylate 2m (6.4 g, 10.8 mmol, 85% yield). LCMS (8 min method) = 4.019 min. Mass observed (ESI+): 594.8 (M+H)+. The crude material was carried on to the next step without further purification.
Figure imgf000164_0001
To a solution of 2m (0.52 g, 0.88 mmol) and IGN monomer A (0.18 g, 0.61 mmol, 0.7 equiv.) in DMF (7 mL) was added potassium carbonate (0.24 g, 1.75 mmol, 2.0 equiv.) and the reaction was stirred at room temperature for 12 h,. The reaction was quenched with water (30 mL) and was extracted with DCM (3 x 15 mL). Thehe organic layers were combined and washed with water (3 x 60 mL), brine (60 mL), dried over magnesium sulfate, filtered and the solvent was removed in vacuo to give a crude yellow oil. The material was purified by silica gel chromatography (DCM/(MeCN/MeOH (4/1) from 100/0 to 65/35) to give desired product 2n (0.09 g, 0.12 mmol, 13% yield).
UPLCMS (2.5 min method) = 1.46 min. Mass observed (ESI+): 792.6 (M+H)+.
Figure imgf000164_0002
To a solution of 2n (0.05 g, 0.06 mmol) in DMF (0.48 mL, 6.2 mmol) was added potassium carbonate (0.02 g, 0.12 mmol, 2.0 equiv.) followed by reduced IGN monomer A (0.02 g, 0.07 mmol, 1.1 equiv.). The reaction was stirred at room temperature for 12 h. The reaction was quenched with water and the resulting solid was filtered and washed with water. The solid was redissolved in DCM/MeOH (20: 1), washed with water, dried with magnesium sulfate, filtered and concentrated. The crude residue was purified by RPHPLC (ACN/H20) to give 21 (0.03 g, 0.04 mmol, 55% yield). LCMS (8 min method, 5-98%) = 5.4 min. Mass observed (ESI+): 991.7 (M+H)+. 1H NMR (400 MHz, DMSO-ifc, reported as a mixture of water adducts): δ 10.10 (d, 7 = 3.7 Hz, 1H), 8.27 (d, 7 = 8.0 Hz, 1H), 8.21 - 8.10 (m, 1H), 8.05 (d, 7 = 7.4 Hz, 1H), 7.78 (dt, 7 = 8.5, 1.8 Hz, 2H), 7.43 - 7.13 (m, 7H), 7.16 - 6.98 (m, 2H), 6.49 (s, 1H), 6.36 (d, 7 = 13.1 Hz, 0.4H), 6.16 (d, 7 = 6.2 Hz, 0.4H), 5.80 (s, 0.4H), 5.67 (s, 0.4H), 5.57 (d, 7 = 5.6 Hz, 0.4H), 5.35 - 5.09 (m, 2H), 5.03 (t, 7 = 5.9 Hz, 2H), 4.81 - 4.72 (m, 0.4H), 4.60 (dt, 7 = 9.7, 5.0 Hz, 0.2H), 4.51 - 4.36 (m, 2H), 4.39 - 4.23 (m, 1H), 4.17 (td, 7 = 9.7, 2.9 Hz, 0.4H), 3.93 (s, 0.4H), 3.83 - 3.74 (m, 5H), 3.62 (s, 2H), 3.75 - 3.44 (m, 2H), 3.32 (d, J = 11.6 Hz, 1H), 3.19 - 3.07 (m, 1H), 2.95 (dd, = 17.1, 4.3 Hz, 1H), 2.38 - 2.29 (m, 1H), 2.18 (m, 1H), 1.56 (m, J = 3.9 Hz, 4H), 1.41 - 1.31 (m, 3H), 1.30 - 1.14 (m, 3H).
Example 3.
Figure imgf000165_0001
To a solution of 2m (0.88 g, 1.47 mmol) in DMF (11 mL) was added reduced IGN monomer A (0.26 g, 0.88 mmol, 0.6 equiv.) followed by potassium carbonate (0.41 mg, 2.95 mmol, 2.0 equiv.). After the reaction was stirred for 12 h, the reaction was diluted with water (50 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over magnesium sulfate and filtered. The solvent was removed and the crude mixture was purified by silica gel chromatography (DCM/MeOH) to give desired product 2k (0.11 g, 0.14 mmol, 10% yield). LCMS (8 min method) = 5.013 min. Mass observed (ESI+): 794.3 (M+H)+.
Figure imgf000165_0002
To a solution of 2k (0.11 g, 0.14 mmol) in DMF (2 mL) was added potassium carbonate (0.04 g, 0.29 mmol, 2.0 equiv.) IGN monomer A (0.04 g, 0.14 mmol, 1.0 equiv.) was added and the reaction was stirred at rt for 12 h.The reaction was quenched with water (10 mL) and the resulting solid was filtered and washed with water. The solid was redissolved in DCM/MeOH (20: 1), washed with water (10 mL), dried with magnesium sulfate, filtered and concentrated. The crude residue was purified by RPHPLC (ACN/H20) to give 21 (0.08 g, 0.09 mmol, 59% yield). LCMS (8 min method, 5-98%) = 5.4 min. Mass observed (ESI+): 991.7 (M+H)+. Example 4.
Figure imgf000166_0001
To a solution of 2n (0.1 g, 0.13 mmol) in DCE (2 mL) was added sodium triacetoxyborohydride (0.03g , 0.13 mmol, 1.0 equiv.) and the reaction was stirred at rt for 2 h. The reaction was quenched with saturated ammonium chloride (2 mL) and the layers were separated. The aqueous layer was extracted with DCM (5 mL) and the combined organic layers were washed with water, brine, dried over magnesium sulfate and filtered. The crude yellow solid was purified using silica gel chromatography (EtOAc/MeOH (95/5)) to afford the desired reduced product 2k (0.035 g, 0.044 mmol, 35% yield). LCMS (8 min method) = 5.021 min. Mass observed (ESI+): 794.3 (M+H)+.
Figure imgf000166_0002
To a solution of 2k (0.035 g, 0.044 mmol) in DMF (1.0 mL) was added potassium carbonate (0.013 g, 0.09 mmol, 2.0 equiv.). IGN monomer A (0.013 g, 0.04 mmol, 1.0 equiv.) was added and the reaction was stirred at room temperature for 12 h. The reaction was quenched with water (10 mL) and the resulting solid was filtered and washed with water. The solid was redissolved in DCM/MeOH (20: 1, 20 mL), washed with water (20 mL), dried with magnesium sulfate, filtered and concentrated. The crude residue was purified by RPHPLC (ACN/H20) to give 21 (0.017 g, 0.01 mmol, 38% yield). LCMS (8 min method, 5-98%) = 5.4 min). Mass observed (ESI+): 991.7 (M+H)+.
Example 5.
Figure imgf000166_0003
To a solution of 2f (8.8 g, 16.0 mmol) in DMF (100 mL) was added pyridine (4.51 ml, 55.8 mmol, 3.5 equiv.). The reaction was cooled down to 0 °C then methanesulfonyl chloride (2.5 mL, 31.9 mmol, 2.0 equiv.) was added dropwise and reaction stirred for 2 h. The mixture was quenched with sat. sodium bicarbonate (30 mL), EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 50 mL) and the combined organic layers were washed with water, brine, dried over magnesium sulfate and filtered. The solvent was removed and the crude white solid 2o was used in the next step without purification (6.2 g, 10.9 mmol, 68%). UPLCMS (2.5 min method) = 1.96 min. Mass observed (ESI+): 570.7 (M+H)+.
Figure imgf000167_0001
To a solution of 2o (1.7 g, 2.98 mmol) in THF (36.6 mL) was added DIPEA (2.1 mL, 11.9 mmol, 4.0 equiv.) followed by HF-pyridine (0.84 mL, 6.0 mmol, 2.0 equiv.). The reaction was stirred at room temperature for 3 h. The reaction was quenched with sat. sodium bicarbonate (20 mL) and then the layers were separated. The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate, filtered and the solvent removed in vacuo to give a crude white oil which was purified by silica gel chromatography (DCM/MeOH) to give desired product 2p as a white solid (0.75 g, 1.6 mmol, 55% yield). UPLCMS (2.5 min method) = 1.23 min. Mass observed (ESI+): 456.4 (M+H)+.
Figure imgf000167_0002
To a solution of 2p (0.65 g, 1.43 mmol) in DCM (10 mL) and DMF (2 mL) was added DIPEA (0.51 mL, 2.85 mmol, 2.0 equiv.) and the reaction was cooled down to 0 °C. A solution of methanesulfonic anhydride (0.3 g, 1.71 mmol) in DCM (2 mL) was added slowly. The reaction was completed after 30 min, quenched with water (20 mL), the layers were extracted, aqueous layer washed with DCM (2 x 10 mL). Organic layers were combined, washed with water (20 mL), brine (10 mL), dried over magnesium sulfate and filtered. The solvent was removed in vacuo to give desired product 2q (0.76 g, 1.42 mmol, 100% yield) which was carried crude into the next step without further purification. UPLCMS (2.5 min method) = 1.37 min. Mass observed (ESI+): 534.4 (M+H)+.
Figure imgf000168_0001
To a solution of 2q (0.76 g, 1.42 mmol) in DMA (13 mL) was added potassium carbonate (0.59 g, 4.27 mmol) followed by a solution of IGN monomer A (0.5 g, 1.71 mmol) in DMA (1 mL). The reaction was stirred at room temperature for 12 h. The reaction was quenched with water (30 mL) and the mixture was stirred for 10 min. The solid was filtered and then dissolved in DCM/MeOH (9/1, 20 mL) and washed with brine (10 mL). The organic layer was separated and dried over magnesium sulfate, filtered and concentrated in vacuo to give a crude yellow solid 2r (0.76 g, 1.04 mmol, 73% yield) which was carried crude into the next step without further purification.
+): 732.9 (M+H)+.
Figure imgf000168_0002
To a solution of 2r (0.26 g, 0.36 mmol) in DMA (10 mL) was added potassium iodide (0.06 g, 0.355 mmol, 1.0 equiv.), reduced IGN monomer A (0.1 g, 0.37 mmol, 1.05 equiv.) and potassium carbonate (0.15 g, 1.06 mmol, 3.0 equiv.). The reaction was warmed up to 40 °C and stirred for 4 h.The reaction was quenched with water (20 mL) and the mixture stirred for 10 min. The resulting solid was filtered. The solid was redissolved in DCM/MeOH (20: 1, 20 mL), washed with water (20 mL), dried with magnesium sulfate, filtered and concentrated. The crude residue was purified by RPHPLC (ACN/H20) to give 21 (0.097 g, 0.097 mmol, 28% yield). LCMS (8 min method, 5-98%) = 5.4 min. Mass observed (ESI+): 991.7 (M+H)+.
Example 6.
Figure imgf000169_0001
To a solution of 2r (0.76 g, 1.04 mmol) in DCE (10 mL) was added DMF (3.0 mL) followed by addition of sodium triacetoxyborohydride (0.33 g, 1.56 mmol) at 0 °C. The reaction was stirred at room temperature for 4 h. The reaction was quenched with sat. ammonium chloride (20 mL) and the layers were separated. The aqueous layer was extracted with DCM (3 x 10 mL)and the combined organic layers were washed with water (10 mL), brine (10 mL), dried over magnesium sulfate, filtered and the solvent removed in vacuo to give the desired crude material 2s as an oil (0.65 g, 0.88 mmol, 85% yield) which was used in the next step without further purification. UPLCMS (2.5 min method) = 1.80 min. Mass observed (ESI+): 735.3 (M+H)+.
Figure imgf000169_0002
To a solution of 2s (0.65 g, 0.88 mmol) in DMA (15 mL) was added potassium carbonate (0.25 g, 1.78 mmol, 2.0 equiv.) followed by potassium iodide (0.073 g, 0.44 mmol, 0.5 equiv.) and a solution of IGN monomer A (0.29 g, 0.974 mmol, 1.1 equiv.) in DMA (2 mL) was added to the reaction mixture at room temperature. The reaction was heated at 40 °C for 5 h.. The reaction was quenched with water (30 mL) and then solid was filtered off. The solid was redissolved in DCM/MeOH (20: 1, 30 mL), washed with water (20 mL), dried with magnesium sulfate, filtered and concentrated. The crude residue (0.78 g) was purified by RPHPLC (ACN/H20) to give 21 (0.43 g, 0.43 mmol, 49% yield). LCMS (8 min method, 5-98%) = 5.4 min. Mass observed (ESI+): 991.7 (M+H)+.
Example 7.
Figure imgf000170_0001
To a solution of 2q (0.14 g, 0.27 mmol) in DMA (3 mL) was added potassium carbonate (0.11 g, 0.81 mmol) followed by a solution of reduced IGN monomer A (0.084 g, 0.28 mmol) in DMA (1 mL). The reaction was stirred at room temperature for 12 h. The reaction was quenched with water (20 mL) and the mixture stirred for 10 min. The solid was filtered and then dissolved in DCM/MeOH (9/1, 20 mL) and washed with brine (10 mL). The organic layer was separated and dried over magnesium sulfate, filtered and solvent removed in vacuo. The crude material was purified by silica gel chromatography using DCM (MeOH/EtOAc, 1/4) to give desired product 2s (0.08 g, 0.11 mmol, 40% yield). UPLCMS (2.5 min method) = 1.63 min. Mass observed (ESI+): 735.2 (M+H)+
Figure imgf000170_0002
To a solution of 2s (0.06 g, 0.09 mmol) in DMA (2 mL) was added potassium carbonate (0.025 g, 0.18 mmol) followed by potassium iodide (0.007 g, 0.044 mmol). A solution of IGN monomer A (0.03 g, 0.097 mmol) in DMA (1 mL) was added to the reaction mixture at room temperature. The reaction was heated at40 C for 5h., The reaction was cooled down and quenched with water (20 mL) and the solid was filtered off. The solid was redissolved in DCM/MeOH (20: 1, 20 mL), washed with water (10 mL), dried with magnesium sulfate, filtered and concentrated. The crude residue (0.07 g) was purified by RPHPLC (ACN/H20) to give 21 (0.035 g, 0.035 mmol, 51% yield). LCMS (8 min method, 5-98%) = 5.4 min. Mass observed (ESI+): 991.7 (M+H)+.
Figure imgf000171_0001
To a solution of 2h (0.85 g, 1.027 mmol) in THF (9 mL) was added DIPEA (0.54 mL, 3.1 mmol, 3.0 equiv.) followed by HF-pyridine (0.3 mL, 2.053 mmol, 2.0 equiv.) at room temperature. The reaction was stirred for 3 h at room temperature. The reaction was quenched with sat. sodium bicarbonate (10 mL), the layers were separated and the aqueous layer extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, and filtered. The solvent was removed in vacuo to give crude product as a solid which was washed with EtOAc to give the desired product 2t (0.64 g, 0.89 mmol, 87% yield). UPLCMS (2.5 min method) = +): 714.6 (M+H)+.
Figure imgf000171_0002
To a solution of 2t (0.23 g, 0.322 mmol) in dichloromethane (3 mL) was added DIPEA (0.11 ml, 0.644 mmol, 2.0 equiv.) followed by methanesulfonic anhydride (0.084 g, 0.48 mmol, 1.5 equiv.) as a solution in DCM (1 mL) at 0 °C. The reaction was stirred for 1 h. The reaction was quenched with water (3 mL) and diluted with DCM (3 mL). The layers were separated and the organic layer was washed with brine (3 mL), dried over magnesium sulfate and filtered. The solvent was removed in vacuo and the crude material 2n (0.25 g, 0.31 mmol, 98% yield) was used in the next step without further purification. UPLCMS (2.5 min method) = 1.45 min. Mass observed (ESI+): 792.5 (M+H)+.
Figure imgf000172_0001
To a solution of 2n (0.02 g, 0.027 mmol) in DMF (0.2 ml) was added potassium carbonate (0.007g, 0.053 mmol, 2.0 equiv.) followed by reduced IGN monomer A (0.009g, 0.029 mmol, 1.1 equiv.) and the reaction was stirred at room temperature for 18 h.Water (3 mL) was added to the reaction mixture and the resulting solid was filtered. The solid was redissolved in DCM/MeOH (20: 1, 5 mL), washed with water (5 mL), dried with magnesium sulfate, filtered and concentrated. The crude residue was purified by RPHPLC (ACN/H20) to give 21 (0.005 g, 0.005 mmol, 19% yield). LCMS (8 min method, 5-98%) = 5.4 min. Mass observed (ESI+): 991.7 (M+H)+.
Example 9.
Figure imgf000172_0002
To a solution of 2t (0.02 g, 0.031 mmol) in THF (2 mL) was added DIPEA (0.016 mL, 0.092 mmol, 3.0 equiv.) followed by a solution of dibromotriphenylphosphorane (0.03 g, 0.062 mmol, 2.0 equiv.) in THF (0.5 mL). The reaction was stirred at room temperature for 12 h., The reaction was stopped by evaporation of solvent and then the crude material was purified by silica gel chromatography to give 2u (0.006 g, 0.007 mmol, 25% yield). UPLCMS (2.5 min method) = 1.56 min. Mass observed (ESI+): 778.2 (M+H)+.
Figure imgf000172_0003
To a solution of 2u (0.006 g, 7.73 μιηοΐ) in DMA (1 mL) was added reduced IGN monomer A (0.003 g, 9.27 μιηοΐ) followed by potassium carbonate (0.002 g, 0.015 mmol) and the reaction was stirred at room temperature for 18 h. Water (3 mL) was added to the reaction mixture and the resulting solid was filtered and washed with water. The solid was redissolved in DCM/MeOH (20: 1, 5 mL), washed with water (5 mL), dried with magnesium sulfate, filtered and concentrated. The crude residue was purified by RPHPLC (ACN/H20) to give 21 (0.001 g, 0.001 mmol, 13% yield). LCMS (8 min method, 5-98%) = 5.4 min. Mass observed (ESI+): 991.7 (M+H)+.
Example 10.
Figure imgf000173_0001
3a 3b
To a solution of (5-nitro-l,3-phenylene)dimethanol 3a (4.0 g, 21.84 mmol) in DCM (40 mL) and DMF (5 mL) was added DIPEA (3.86 mL, 21.84 mmol, 1.0 equiv.) followed by TBSCI (3.29 g, 21.84 mmol, 1.0 equiv.) as a solution in DMF (5 mL). The reaction was stirred at 0 °C for 1 h.. The reaction was quenched with sat. ammonium chloride (20 mL) and the layers were separated. The aqueous layer was extracted with DCM (2 x 20 mL) and the combined organic layers were washed with water (2 x 50 mL), brine, dried over magnesium sulfate, filtered and solvent was removed in vacuo to give a crude yellow oil. The crude product was purified by silica gel chromatography (DCM/MeOH) to give desired product 3b (3.69 g, 12.41 mmol, 57% yield). UPLCMS (2.5 min method) = 1.96 min. Mass observed (ESI+): 298.5 (M+H)+.
Figure imgf000173_0002
3b 3c
To a solution of 3b (2.0 g, 6.72 mmol) in DMF (50 mL) was added pyridine (1.6 ml, 20.17 mmol, 3.0 equiv.) followed by methanesulfonyl chloride (1.1 mL, 13.45 mmol, 2.0 equiv.) at 0 °C. The reaction was warmed to rt and was stirred for 3 h. The reaction was quenched with sat. sodium bicarbonate (20 mL) and the layers were separated. The aqueous layer wasextracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (2 x 100 mL), brine (100 mL), dried over magnesium sulfate and filtered. The solvent removed in vacuo and the crude material 3c (2.0g, 6.7 mmol, 94% yield) was carried crude onto the next step. UPLCMS (2.5 min method) = 2.22 min. Mass observed (ESI+): 316.7 (M+H)+.
Figure imgf000174_0001
3c 3d
To a solution of 3c (2.0 g, 6.33 mmol) in THF (38.9 mL) was added DIPEA (5.5 mL, 31.6 mmol, 5.0 equiv.) followed by HF-pyridine (2.7 mL, 19.0 mmol, 3.0 equiv.) and the reaction was stirred at room temperature for 2 h. The reaction was then quenched with sat. sodium bicarbonate (100 mL). The layers were separated and then the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were then washed with water (30 mL), brine (30 mL), dried over magnesium sulfate and filtered. The excess of solvent was removed in vacuo to give desired product 3d (l. lg, 5.46 mmol, 86% yield). UPLCMS (2.5 min method) = 1.31 min. Mass observed (ESI+): 202.4 (M+H)+.
Figure imgf000174_0002
3d 3e
To a solution of 3d (1.0 g, 4.96 mmol) in DCM (10 mL) was added DIPEA (2.6 mL, 14.9 mmol, 3.0 equiv.) at 0 °C then a solution of methanesulfonic anhydride (1.1 g, 6.45 mmol, 1.3 equiv.) in DCM was added to the reaction mixture. The reaction was stirred for 1 h. The reaction was quenched with water (10 mL) and the layers were separated and the aqueous layer was extracted with DCM (2 x 20 mL). The combined organic layers were washed with sat. sodium bicarbonate (10 mL), brine (20 mL), dried over magnesium sulfate and filtered. The solvent was removed in vacuo and the crude material 3e (1.3 g, 4.65 mmol, 94% yield) was used in the next step without further purification. UPLCMS (2.5 min method) = 1.51 min. Mass observed (ESI+): 280.6 (M+H)+.
Figure imgf000174_0003
To a solution of 3e (0.4 g, 1.43 mmol) and potassium carbonate (0.6 g, 4.29 mmol, 3.0 equiv.) in DMA (13.4 mL) was added a solution of IGN monomer A (0.46 g, 1.57 mmol, 1.1 equiv.) in DMA (2 mL) at room tempertaure and the reaction was stirred for 5 h. The reaction was quenched with water (30 mL), the layers were separated and the aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over magnesium sulfate and the solvent was removed in vacuo. The crude oil was purified over silica gel chromatography using DCM / MeOH to give compound 3f (0.37g, 0.77 mmol, 54% yield). UPLCMS (2.5 min method) = 1.69 min. Mass observed (ESI+): 478.3 (M+H)+.
Figure imgf000175_0001
To a solution of 3f (0.11 g, 0.23 mmol) in DMA (3.0 mL) was added potassium carbonate (0.095 g, 0.69 mmol, 3.0 equiv.), followed by potassium iodide (0.02 g, 0.11 mmol, 0.5 equiv.). A solution of reduced IGN monomer A (0.07 g, 0.25 mmol, 1.1 equiv.) in DMA (1 mL) was added. The reaction was then gently heated at 35 °C for 5 h. The reaction was quenched with water, and the solid was filtered off. The solid was redissolved in DCM/MeOH (20: 1), washed with water, dried with magnesium sulfate, filtered and concentrated. The crude residue (0.13 g) was purified by RPHPLC (ACN/H20) to give 3g (0.063 g, 0.085 mmol, 36% yield). UPLCMS (2.5 min method) = 1.79 min. Mass observed (ESI+): 738.3 (M+H)+. 1H NMR (400 MHz, DMSO- 6, reported as a mixture of water adducts) 1H NMR (400 MHz, OMSO-d6): δ 8.43 - 8.36 (m, 2H), 8.27 (d, = 8.1 Hz, 1H), 8.13 - 8.02 (m, 2H), 7.44 - 7.14 (m, 6H), 7.14 - 6.99 (m, 2H), 6.79 (s, 0.5H), 6.56 (s, 0.5H), 6.50 (d, = 2.2 Hz, 1H), 6.39 (d, = 6.9 Hz, 1H), 6.17 (d, = 6.8 Hz, 0.5H), 5.69 (s, 0.5H), 5.59 (d, = 5.7 Hz, 0.5H), 5.47 - 5.27 (m, 4H), 5.03 (t, = 6.1 Hz, 0.5H), 4.77 (dd, / = 9.1, 6.8 Hz, 0.5H), 4.61 (dt, = 9.7, 5.1 Hz, 0.15H), 4.50 - 4.39 (m, 0.5H), 4.27 (dd, = 10.9, 4.2 Hz, 0.5H), 4.16 (td, = 9.6, 2.9 Hz, 0.5H), 3.95 (s, 0.5H), 3.89 - 3.76 (m, 6H), 3.76 - 3.44 (m, 4H), 3.20 - 3.08 (m, 1H), 2.96 (dd, = 17.0, 4.4 Hz, 1H). Example 11.
Figure imgf000176_0001
To a solution of 3e (0.45 g, 1.61 mmol) in DMA (15.1 mL) was added potassium carbonate (0.67 g, 4.83 mmol, 3.0 equiv.) followed by a solution of reduced IGN monomer A (0.5 g, 1.69 mmol, 1.1 equiv.) in DMA (2 mL). The reaction was stirred at room temperature for 5h.. The reaction was quenched with water (30 mL) and the mixture was stirred for 10 min. The solid was filtered and then dissolved in DCM/MeOH (9/1, 30 mL) and washed with brine (20 mL). The organic layer was separated and dried over magnesium sulfate, filtered and the solvent removed in vacuo. The crude material was purified by silica gel chromatography using Hexane/EtOAc to give compound 3h (0.28 g, 0.58 mmol, 36% yield) as colorless oil. UPLCMS (2.5 min meth = 1.82 min. Mass observed (ESI+): 480.3 (M+H)+.
Figure imgf000176_0002
To a solution of 3h (0.27 g, 0.56 mmol) in DMA (10 mL) was added potassium carbonate (0.16 g, 1.12 mmol, 2.0 equiv.) followed by potassium iodide (0.05 g, 0.28 mmol, 0.05 equiv.). A solution of IGN monomer A (0.18 g, 0.62 mmol, 1.1 equiv.) in DMA (2 mL) was added to the reaction mixture at room temperature. The reaction was then stirred at 40 °C for 3h. The reaction was quenched with water (20 mL) and the solid was filtered off and washed with water. The crude yellow solid was dissolved in DCM/MeOH (9/1, 30 mL) and then washed with water (10 mL), dried over magnesium sulfate and filtered. The solvent was removed in vacuo to give a crude yellow solid.The crude product was purified by silica gel chromatography using DCM/MeOH (0% to 5% MeOH/DCM) to give the product 3g as a yellow powder (0.35 g, 0.48 mmol, 86% yield). UPLCMS (2.5 min method) = 1.79 min (2.5 min method). Mass observed (ESI+): 738.4 (M+H)+. Example 12.
Figure imgf000177_0001
To a solution of 3f (0.15 g, 0.31 mmol) in DCE (2 mL) was added sodium triacetoxyborohydride (0.067 g, 0.31 mmol, 1.0 equiv.) and the reaction was stirred at room temperature for 1 h. The reaction was quenched with sat. ammonium chloride (1 mL) and then the layers were separated. The aqueous layer was extracted with DCM (3 x 10 mL) and the combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, filtered and the solvent removed in vacuo. The crude brown oil was purified by silica gel chromatography to give desired product 3h (0.08 g, 0.16 mmol, 52% yield). UPLCMS (2.5 min method) = 1.80 min. Mass observed (ESI+): 480.5 (M+ +.
Figure imgf000177_0002
To a solution of 3h (0.07g, 0.16 mmol) in DMA (2 mL) was added potassium carbonate (0.07 g, 0.47 mmol, 3.0 equiv.) followed by potassium iodide (0.013 g, 0.08 mmol, 0.05 equiv.) and then a solution of IGN monomer A (0.05 g, 0.17 mmol, 1.1 equiv.) in DMA (0.5 mL) was added. The reaction was stirred at room temperature for 12h.. Water (20 mL) was added to the mixture and the mixture was stirred for 10 min at which point the solid was filtered. The solid was solubilized in DCM (10 mL) and then washed with brine (10 mL). The organic layer was dried over magnesium sulfate and filtered. The solvent was removed to obtain a yellow oil (0.09 g, 0.12 mmol, 80% yield). UPLCMS (2.5 min method) = 1.79 min (2.5 min method). Mass observed (ESI+): 738.5 (M+H)+.
Example 13.
Figure imgf000177_0003
3b To a solution of 3b (1.00 g, 3.4 mmol) in DCM (33 mL) was added DIPEA (1.781 ml, 10.09 mmol, 3.0 equiv.), followed by a solution of methanesulfonic anhydride (0.703 g, 4.03 mmol, 1.2 equiv.) at 0 °C. The reaction was stirred for 1 h.The solvent was evaporated to give the crude product 3j (1.2 g, 3.2 mmol, 95% yield) which was used in the next step without further purification. UPLCMS (2.5 min method) = 2.04 min. Mas
Figure imgf000178_0001
To a solution of 3j (1.24 g, 3.30 mmol) in DMF (26 mL) was added potassium carbonate (0.91 g, 6.60 mmol, 2.0 equiv.) followed by IGN monomer A (0.97 g, 3.30 mmol, 1.0 equiv.) at room temperaturefor 12 h. The reaction was quenched with water
(60 mL) and the solid was filtered off and then dissolved in DCM/MeOH (20/1, 20 mL).
The organic layer was washed with brine, dried over magnesium sulfate and filtered.
The solvent was removed in vacuo and the crude material was purified over silica gel chromatography to give the desired product 3k (1.3 g, 2.27 mmol, 69% yield). UPLCMS
(2.5 min M+H)+.
Figure imgf000178_0002
3k (0.63 g, 1.1 mmol) was dissolved in anhydrous DCE (11 mL). Sodium triacetoxyborohydride (0.70 g, 3.3 mmol, 3.0 equiv.) was added and the reaction mixture was stirred for 1 h at room temperature.The mixture was quenched with sat. ammonium chloride (10 mL). The layers were separated and the aqueous layer was extracted with DCM (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to obtain 31 (0.58 g, 1.0 mmol, 92% yield). UPLCMS (8.0 min method) = 7.797 min (8.0 min method). Mass observed (ESI+): 576.3 (M+H)+.
Figure imgf000179_0001
A solution of 31 (0.58 g, 1.0 mmol) was dissolved in anhydrous THF (5 mL) and 5 M aqueous hydrochloride acid solution (2.01 mL, 10.07 mmol) was added. The mixture was stirred at room temperature for 2 h. The reaction was quenched with sat. sodium bicarbonate (5 mL) and the layers were separated and the aqueous layer was extracted with DCM (2 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over magnesium sulfate and concentrated to give a bright orange solid. The resulting solid was purified by silica gel chromatography (DCM/MeOH) to give compound 3m (0.33 g, 0.71 mmol, 71% yield). UPLCMS (8.0 min method) = 5.166 min. Mass observed (ESI+): 462.1 (M+H)+.
Figure imgf000179_0002
3m (0.1 g, 0.22 mmol) was dissolved in anhydrous DCM (1.5 mL) and anhydrous DMF (0.7 mL). The reaction was cooled to 0 °C and triethylamine (0.12 mL, 0.88 mmol) and methanesulfonic anhydride (0.08 g, 0.44 mmol) were added. The reaction was stirred at 0 °C for 1 h. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water (2 x 20 mL), dried over magnesium sulfate, filtered and concentrated. The compound was initially purified by silica gel chromatography (DCM/EtOAc) followed by additional purification by RPPHPLC (MeCN/water) to give the desired product 3n (0.041 g, 0.076 mmol, 34% yield). Mass observed (ESI+): 540.3 (M+ +.
Figure imgf000179_0003
Compound 3n (0.041 g, 0.076 mmol) and IGN monomer A (0.027 g, 0.091 mmol) were dissolved in anhydrous DMA (0.5 mL). Potassium carbonate (0.012 g, 0.091 mmol) and potassium iodide (0.006 g, 0.038 mmol) were added and the mixture stirred for 12 h. . Water (5 mL) was added to the reaction mixture. The solid was filtered off and then redis solved in DCM (20 mL) and washed with water (10 mL). After drying over magnesium sulfate, filtration and concentration, the solid was purified by RPHPLC (ACN/H20) to give 3g (0.012 g, 0.016 mmol, 21% yield). UPLCMS (2.5 min method) =
+): 738.5 (M+H)+.
Figure imgf000180_0001
Compound 3g (0.017 g, 0.023 mmol) was dissolved in anhydrous THF (1 mL), anhydrous MeOH (0.5 mL) and water (0.1 mL). Ammonium chloride (0.012 g, 0.23 mmol, 10.0 equiv.) and iron (0.006 g, 0.115 mmol, 5.0 equiv.) were added. The mixture was stirred at 60 °C for 2 h.. The reaction mixture was cooled to room temp, filtered through Celite and rinsed with 20% MeOH/DCM (10 mL). The filtrate was concentrated and the crude product was purified by silica gel chromatography (DCM/MeOH) to give compound 3o as a white solid (0.012 g, 0.018 mmol, 76% yield). UPLCMS (2.5 min method) = 1.84 min. Mass observed (ESI+): 708.5 (M+H)+. 1H NMR (400 MHz, OMSO-d6, reported as a mixture of water adducts, T = 330K): δ 8.26 (d, = 7.9 Hz, 1H), 8.17 (d, = 7.8 Hz, 1H), 8.03 (d, = 4.5 Hz, 1H), 7.49 (s, 1H), 7.42 - 7.33 (m, 2H), 7.36 - 7.08 (m, 4H), 7.09 - 6.95 (m, 2H), 6.76 - 6.64 (m, 3H), 6.47 (s, 1H), 6.15 (d, = 6.5 Hz, 1H), 5.11 (m, 2H), 4.98 (m, 2H), 4.58 (dt, = 9.9, 4.7 Hz, 1H), 4.47 - 4.36 (m, 1H), 3.87 (m, 1H), 3.76 (s, 3H). 3.71 - 3.46 (m, 4H), 3.39 - 3.28 (m, 1H), 2.93 (dd, = 16.8, 4.7 Hz, 1H).
Example 14.
Figure imgf000180_0002
Compound 2p (0.03 g, 0.066 mmol, 1.0 equiv.) and IGN monomer A (0.021 g, 0.072 mmol, 1.1 equiv.) were dissolved in THF (0.65 mL) and DMF (0.3 mL). Triphenylphosphine was added (0.021 g, 0.079 mmol, 1.2 equiv.), followed by a slow addition of DIAD (0.015 mL, 0.079 mmol, 1.2 equiv.). The reaction was stirred at rt under argon for 2 h. The reaction mixture was concentrated and water (~2 mL) was added to triturate the product. The precipitate was filtered and the remaining solid was washed with water. The crude residue was purified by RPHPLC (CI 8 column, MeCN/water, gradient, 40% to 60%) to give compound 2r as a white fluffy solid (0.015 g, 0.02 mmol, 31% yield). UPLCMS (2.5 min method) = 1.62 min. Mass observed (ESI+) = 732.9 (M+H)+.
Example 15.
Figure imgf000181_0001
Compound 2p (0.03g, 0.066 mmol, 1.0 equiv.) and reduced IGN monomer A
(0.02g, 0.072 mmol, 1.1 equiv.) were dissolved in THF (0.66 mL) and DMF (0.1 mL). Triphenylphosphine (0.021 g, 0.079 mmol, 1.2 equiv.) was added, followed by a slow addition of DIAD (0.015 mL, 0.079 mmol, 1.2 equiv.). The reaction mixture was stirred at rt under argon for 2 h. The reaction mixture was diluted with DCM and was washed with water (2x). The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by RPHPLC (CI 8 column, MeCN/water, gradient, 40% to 65%) to yield 2s as a white fluffy solid (0.017 g, 0.02 mmol, 35% yield). UPLCMS (2.5 min method) = 1.71 min. Mass observed (ESI+) = 735.4 (M+H)+. Example 16.
Figure imgf000181_0002
Compound 3d (0.03 g, 0.149 mmol, 1.0 equiv.) and IGN monomer A (0.046 g, 0.156 mmol, 1.05 equiv.) were dissolved in THF (1.5 mL) and DMF (0.3 mL). Triphenylphosphine was added (0.047 g, 0.179 mmol, 1.2 equiv.), followed by a slow addition of DIAD (0.032 mL, 0.164 mmol, 1.1 equiv.). The reaction was stirred at rt under argon for 12 h. The reaction mixture was concentrated and water (~2 mL) was added to triturate the product. The precipitate was filtered and the remaining solid was washed with water. The crude residue was purified by silica gel chromatography (hexane/EtOAc) to give compound 3f as a white yellow solid (0.013 g, 0.027 mmol, 18% yield). UPLCMS (2.5 min method) = 1.80 min. Mass observed (ESI+) = 478.4 (M+H)+.
Example 17.
Figure imgf000182_0001
Compound 3d (0.03 g, 0.149 mmol, 1.0 equiv.) and reduced IGN monomer A (0.046 g, 0.156 mmol, 1.05 equiv.) were dissolved in THF (1.5 mL). Triphenylphosphine was added (0.047 g, 0.179 mmol, 1.2 equiv.), followed by a slow addition of DIAD (0.032 mL, 0.164 mmol, 1.1 equiv.). The reaction was stirred at rt under argon for 2 h. The reaction mixture was concentrated and coevaporated with toluene (2 x). The crude residue was purified by silica gel chromatography (hexane/EtOAc) to give compound 3h as a orange yellow solid (0.055 g, 0.115 mmol, 77% yield). UPLCMS (2.5 min method) = 1.90 min. Mass observed (ESI+) = 480.5 (M+H)+.
Example 18.
Figure imgf000182_0002
To a solution of 2d (0.024 g, 0.078 mmol, 1.1 equiv.) in DCM (1 mL) was added
EEDQ (0.019 g, 0.078 mmol, 1.1 equiv.). The reaction was stirred for 5 min and MeOH (0.1 mL) was added, followed by a solution of 3o (0.05 g, 0.071 mmol) in DCM (1 mL). The reaction was stirred at rt for 2 h or until completion of starting material. The reaction was concentrated to form a white precipitate to which MTBE (5 mL) was added and the resulting mixture was stirred for 30 min at room temperature. The solid was filtered off to give compound 21 which was then purified by RPHPLC (CI 8 column, MeCN/water) to give 21 (0.023 g, 0.023 mmol, 33% yield). UPLCMS (2.5 min method) = 1.75 min. Mass observed (ESI+) = 993.2 (M+H)+. Example 19.
Figure imgf000183_0001
To a solution of 2p (0.05 g, 0.110 mmol, 1.0 equiv.) in DMA (1 mL), was added carbon tetrabromide (0.044 g, 0.132 mmol, 1.2 equiv.) followed by triphenylphosphine (0.043 g, 0.164 mmol, 1.5 equiv.) and the reaction was stirred at room temperature for 2 h.The solvent was removed to give a white solidwhich was triturated with MTBE and the solid was filtered off to give compound 2v. (0.03 g, 0.058 mmol, 57 % yield, 52% purity), which was carried onto the next step without further purification. UPLCMS (2.5 min method) = 1.59 min. Mass observed (ESI+) = 518.2 (M+H)+.
Figure imgf000183_0002
To a solution of 2v (0.03 g, 0.043 mmol, 1.0 equiv.) in DMA (0.5 mL) was added potassium carbonate (0.012 g, 0.087 mmol, 2.0 equiv.) followed by IGN monomer A (0.013 g, 0.046 mmol, 1.05 equiv.). The reaction mixture was stirred for 4 h at room temperature. The reaction mixture was diluted with water (5 mL) and the solid was filtered off. The solid was dissolved in DCM/MeOH (9/1, 2 mL). The organic layer was washed with water (10 mL), brine (10 mL), and dried over magnesium sulfate. After filtration and solvent removal, the crude product was purified by RPHPLC (CI 8 column, MeCN/water) to give 2r (0.011 g, 0.015 mmol, 35% yield). UPLCMS (2.5 min method) = 1.62 min. Mass observed (ESI+) = 733.2 (M+H)+.
Example 20
Figure imgf000183_0003
2v 2w
To a slurry of compound 2v (14.7 g, 0.052 mol, 1.0 equiv., prepared as described described in literature, see: Beilstein J. Org. Chem. 2014, 10, 535-543) in DCM and (100 niL) DMF (1 ml), was charged with S0C12 (12.6 g, 0.104 mol, 2.0 equiv.) in one portion. The resulting solution was stirred at 35 °C overnight resulting in a thick tan slurry. The slurry was filtered and the solid was dried to give 7.5 g as an off-white solid. NMR revealed cleavage of the Boc protecting group. The dark filtrate was charged with solid sodium carbonate (10.6 g, 0.1 mol) followed by buffering to pH -6-7 by further addition of sodium bicarbonate. To the resulting solution Boc20 (12.7 g,0.058 mol, 1.1 equiv.) was added and was stirred for 0.5 h. The filtered solid (7.5 g) was added to the reaction mixture, followed bythe addition of Boc20 (6.5 g, 0.030 mol, 1.7 equiv.) (pH- 6) and continued to stir at rt overnight. Then sat. sodium bicarbonate (10 mL) was added to reach pH 6-7. Additional Boc20 (9.3 g, 42.6 mmol), and DMAP (0.2 g, 1.63 mmol) were added and continued to stir overnight. The dark reaction was filtered to remove some precipitate. The DCM layer was washed with 1 N HCI to remove un-Boc product, which was basified and extracted with DCM and recovered 3.0 g colorless crispy solid (un-Boc product). The DCM layer was washed with brine and concentrated to a dark slush. The crude product wa purified by silica gel chromatography(EtOAc/Hexanes) to give 2w as a pale brown solid (9.5 g, 0.031 mmol, 62% yield). 1H NMR (400 MHz, CDC13): δ 7.84 (m, 2H), 7.75 (m, 1H), 6.60 (s, 1H, NH), 4.58 (s, 2H), 3.91 (s, 3H), 1.53 (s, 9H).
Figure imgf000184_0001
2w 2x
A solution of LAH/THF (0.6M, 60 mL, 1.15 equiv.) was stirred at rt for 30 min and then cooled down to -65 °C with an acetone-dry ice bath. Compound 2w (9.3 g, 0.031 mol, 1.0 equiv.) was slowly added in portions (Ti— 60°C) resulting in a yellow brown slurry which was stirred for 4 h. The reaction was quenched with water (1.3 mL), 15% NaOH (1.3 mL), and water (4 mL) and was stirred for 20 min (Ti ~5°C). The reaction was filtered and rinsed with ethyl acetate (-90 mL). The filtrate was washed with brine, and concentrated to yield 2x (8.0 g, 0.029 mol, 93% yield) as brown oil. 1H NMR (400 MHz, CDCI3) : δ 7.45 (s, 1H), 7.40 (s, 1H), 7.10 (s, 1H), 6.60 (s, 1H, NH), 4.75 (s, 2H), 4.50 (s, 2H), 1.53 (s, 9H).
Figure imgf000184_0002
HCI
2x 2y Compound 2x (8.0 g, 0.029 mol, 1.0 equiv.) was dissolved in DCM (20 mL) and cooled in ice-water bath. 4 N HCl/dioxane (15 mL, 1.5 equiv.) was added and the resulting mixture was heated at 50 °C for 1 h and then cooled down to rt. The slurry was concentrated and the solvent switched to heptane. The slurry was filtered, rinsed with hexane, and dried in oven (60 °C) to afford 2y (5.4 g, 0.026 mol, 88% yield) as light brown solid. 1H NMR (400 MHz, DMSO-J6): δ 7.45 (s, 1H), 7.25 (s, 2H), 4.76 (s, 2H), 4.52 (s, 2H).
Figure imgf000185_0001
To a solution of 2d (0.969 g, 3.20 mmol, 1.1 equiv.) in DCM (25 mL) was added EEDQ (0.79 g, 3.2 mmol, 1.1 equiv) at room temperature. After 8 min, a solution of 2y (0.5 g, 2.91 mmol, 1.0 equiv.), DIPEA (0.51 mL, 2.91 mmol, 1.0 equiv.) in MeOH (5 mL) was added dropwise over 1 minute. The reaction was stirred for 2 h. The reaction mixture was quenched with water (30 mL), the layers were separated and the aqueous layer extracted with DCM (2 x 20 mL). The combined organic layers were washed with sat. sodium bicarbonate (20 mL), brine (20 mL), dried over magnesium sulfate,filtered and concentrated to minimal amount of solvent left. The resulting white solid was diluted in MBTE and was filtered to give the desired product 2p as a white solid (0.64 g, 1.40 mmol, 48% yield). UPLCMS (2.5 min method) = 1.30 min. Mass observed (ESI+) = 456.3 (M+H)+.

Claims

A method of preparing a compound of formula (2d),
Figure imgf000186_0001
(2d) or a salt thereof, said method comprising introducing an alcohol protecting group onto one of the primary alcohols of a compound of formula (Id) by reacting the compound of formula (Id) with an alcohol protecting reagent,
Figure imgf000186_0002
(1d) wherein Pi is the alcohol protecting group; and Rioo is (Ci-C3)alkoxy.
The method of claim 1, wherein the alcohol protecting group is sterically hindered.
The method of claim 1, wherein the alcohol protecting group is pivaloyl, methoxymethyl, 2-methoxyethoxymethyl, /?-methoxybenzyl, 3,4- dimethyoxybenzyl, 2,6-dimethyoxybenzyl, diphenylmethyl, benzyloxymethyl, 2,2,2-trichloroethoxycarbonyl, tetrahydrofuranyl, tetrahydropyranyl, benzyl, benzoyl, /?ara-phenylbenzoyl, 2,4,6-trimethylbenzoyl, /¾zra-bromobenzoyl, /?ara-nitrobenzoyl, picolinoyl, nicotinoyl, 5-dibenzosuberyl,
trityl/triphenylmethyl, or tris(4-ie/ -butyrphenyl)methyl.
The method of claim 3, wherein the alcohol protecting group is methoxymethyl, tetrahydropyranyl, 2-methoxyethoxymethyl, p-methoxybenzyl,
benzyloxymethyl, or 2,2,2-trichloroethoxycarbonyl.
The method of claim 4, wherein the alcohol protecting group is 2,2,2- trichloroethoxycarbonyl. The method of claim 1, wherein the alcohol protecting group is a silyl protecting group.
The method of claim 6, wherein the silyl protecting group is
dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl, trimethylsilyl, triisopropylsilyl, tribenzylsilyl, triphenylsilyl, 2-norbornyldimethylsilyl, tert- butyldimethylsilyl, ie/t-butyldiphenylsilyl, 2-trimethyethylsilyl (TEOC), or [2- (trimethylsilyl)ethoxy]methyl.
The method of claim 7, wherein the silyl protecting group is triethylsilyl, triisopropylsilyl, or tert-butyldimethylsilyl.
The method of claim 8, wherein the silyl protecting group is tert- butyldimethylsilyl.
The method of any one of claims 6-9, wherein the silyl protecting group is introduced by reacting the compound of formula (Id) with R 3 -CI, R 3 -Br, R 3 -I or
R 3 -OSO2CF3 in the presence of a base, wherein R 3 is dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl, trimethylsilyl, triisopropylsilyl, tribenzylsilyl, triphenylsilyl, 2-norbornyldimethylsilyl, ie/ -butyldimethylsilyl, or ie/t-butyldiphenylsilyl.
The method of claim 10, wherein the base is a non-nucleophilic base.
The method of claim 11, wherein the non-nucleophilic base is imidazole, triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, 1,8- diazabicycloundec-7-ene, or tetramethylpiperidine.
The method of claim 11, wherein the non-nucleophilic base is imidazole.
The method of any one of claims 11-13, wherein the reaction is carried out in the presence of a catalyst.
The method of claim 14, wherein the catalyst is 4-dimethylaminopyridine (DMAP), 1,1,3,3-tetramethylguanidine or l,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The method of any one of claims 1- 15, wherein 0.8- 1.2, 1-5, 1-2, 1- 1.5 or 1-1.2 molar equivalents of the alcohol protecting reagent are used relative to the compound of formula (Id).
17. The method of any one of claims 11- 16, wherein more than 2 molar equivalents of the non-nucleophilic base are used relative to the compound of formula (Id).
18. A method of pre aring a compound of formula (3d),
Figure imgf000188_0001
(3d)
or a salt thereof, said method comprising reacting a halogenating reagent, a sulfonating reagent or an esterification reagent with a compound of formula (2d),
Figure imgf000188_0002
wherein Pi is an alcohol protecting group; Xi is a leaving group selected from the group consisting of: -Br, -I, -CI a sulfonate ester, and an activated ester (preferably, Xi is -Br, -I, or a sulfonate ester); and Rioo is (Ci-C3)alkoxy.
19. The method of claim 18, wherein the sulfonate ester represented by Xi is
mesylate, tosylate, brosylate, or triflate.
20. The method of claim 18, wherein the sulfonate ester represented by Xi is
mesylate.
21. The method of any one of claims 18-20, wherein the method comprising reacting the compound of formula (2d) with a sulfonating reagent in the presence of a non-nucleophilic base.
22. The method of claim 21, wherein the non-nucleophilic base is triethylamine, imidazole, diisopropylethylamine, pyridine, 2,6-lutidine, dimethylformamide, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or tetramethylpiperidine .
23. The method of claim 22, wherein the non-nucleophilic base is triethylamine or diisopropylethylamine.
24. The method of any one of claims 21-23, wherein the sulfonating reagent is methanesulfonic anhydride or methanesulfonyl chloride (MsCl). 25. The method of claim 18, wherein the method comprising reacting a halogenating reagent with the compound of formula (2d) and the halogenating reagent is bromine, hydrobromic acid, carbon tetrabromide, phosphorus tribromide, potassium bromide, hydroiodic acid, iodine, carbon tetraiodide, phosphorus triiodide, sodium iodide, or potassium iodide. 26. A method of preparing a compound of formula (4d),
Figure imgf000189_0001
(Ad)
or a salt thereof, said method comprising reacting a compound of formula (3d)
Figure imgf000189_0002
(3d)
with a monomer compound of the formula (ai),
Figure imgf000189_0003
<ai)
wherein Pi is an alcohol protecting group; Xi is a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester, and an activated ester
(preferably, X1 is -Br, -I, or a sulfonate ester); and Rioo is (Ci-C3)alkoxy.
27. The method of claim 26, wherein the compound of formula (3d) is reacted with the monomer compound of formula (ai) in the presence of a base. The method of claim 27, wherein the base is sodium carbonate, potas
carbonate, cesium carbonate, sodium hydride, or potassium hydride.
29. A method of preparing a compound of formula (5d),
Figure imgf000190_0001
(5d)
or a salt thereof, said method comprising reacting a compound of formula (4d),
Figure imgf000190_0002
with an imine reducing agent, wherein Pi is an alcohol protecting group; and Rioo is (Ci-C3)alkoxy.
30. The method of claim 29, wherein the imine reducing reagent is a hydride
reducing reagent.
31. The method of claim 29, wherein the imine reducing reagent is sodium
borohydride, sodium triacetoxy borohydride, sodium cyanoborohydride, lithium aluminum hydride, hydrogen gas, ammonium formate, borane, 9- borabicyclo[3.3.1]nonane (9-BBN), diisobutylaluminium hydride (DIBAL), lithium borohydride (LiBH4), potassium borohydride (KBH4), or sodium bis(2- methoxyethoxy)aluminumhydride (Red-Al) .
The method of claim 29, wherein the imine reducing reagent is sodium triacetoxy borohydride (NaBH(OAc)3). A method of preparing a compound of formula (6d),
Figure imgf000191_0001
(6d)
or a salt thereof, said method comprising reacting a compound of formula (5d),
Figure imgf000191_0002
(5d)
with an alcohol deprotecting reagent, wherein Pi is an alcohol protecting group; and Rioo is (Ci-C3)alkoxy.
The method of claim 33, wherein the alcohol deprotecting reagent is tetra-n- butylammonium fluoride, tris(dimethylamino)sulfonium
difluorotrimethylsilicate, hydrogen fluoride or a solvate thereof, hydrogen fluoride pyridine, silicon tetrafluoride, hexafluorosilicic acid, cesium fluoride, hydrochloric acid, acetic acid, trifluoroacetic acid, pyridinium p-toluensulfonate, p-toluenesulfonic acid (p-TsOH), formic acid, periodic acid.
The method of claim 33, wherein the alcohol deprotecting reagent is
hydrochloric acid or tetra-n-butylammonium fluoride.
A method of preparing a compound of formula (7d),
Figure imgf000191_0003
(7d)
or a salt thereof, said method comprising reacting a halogenating reagent, a sulfonating reagent or an esterification reagent with the primary alcohol compound of formula d),
Figure imgf000192_0001
(6d)
wherein X2 is a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester, and an activated ester (preferably, X2 is -Br, -I, a sulfonate ester); and Rioo is (Ci-C3)alkoxy.
37. The method of claim 36, wherein the sulfonate ester represented by X2 is
mesylate, tosylate, brosylate, or triflate.
38. The method of claim 37, wherein the sulfonate ester represented by X2 is
mesylate. 39. The method of any one of claims 36-38, wherein the method comprising reacting the compound of formula (6d) with the sulfonating reagent in the presence of a non-nucleophilic base.
40. The method of claim 39, wherein the non-nucleophilic base is triethylamine, imidazole, triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), or tetramethylpiperidine.
41. The method of claim 39, wherein the non-nucleophilic base is triethylamine or diisopropylethylamine.
42. The method of any one of claims 36-41, wherein the sulfonating reagent is
methanesulfonic anhydride or methanesulfonyl chloride (MsCl). 43. The method of claim 36, wherein the method comprising reacting the compound of formula (6d) with a halogenating reagent, wherein the halogenating reagent is bromine, hydrobromic acid, carbon tetrabromide, phosphorus tribromide, potassium bromide, hydroiodic acid, iodine, carbon tetraiodide, phosphorus triiodide, sodium iodide, or potassium iodide. A method of preparing a compound of formula (7d")
Figure imgf000193_0001
(7cT)
or a salt thereof, said method comprising reacting a compound of formula (5d')
Figure imgf000193_0002
(5d')
with an alcohol deprotecting reagent and a halogenating reagent, wherein Pi' is an acid labile alcohol protecting group; X2' is -Br or -I; and Rioo is (Ci- C3)alkoxy.
The method of claim 44, wherein the compound of formula (7d"') is represented by the following:
Figure imgf000193_0003
(7d"') ;
and the method comprising reacting the compound of formula (5d') with an alcohol deprotecting reagent and a bromination reagent.
46. The method of claim 44 or 45, wherein the acid labile alcohol protecting group is acetate, allyl, methoxymethyl, tetrahydrofuranyl, tetrahydropyranyl, 5- dibenzosuberyl, 1-ethoxyethyl, 1 -methyl- lmethoxylethyl, 2-
(phenylselenyl)ethyl, trityl/triphenylmethyl, or tris(4-ieri-butylphenyl)methyl.
47. The method of claim 46, wherein the acid labile alcohol protecting group is a silyl protecting group. The method of claim 47, wherein the silyl protecting group is dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tribenzylsilyl, triphenylsilyl, 2- norbornyldimethylsilyl, ie/t-butyldimethylsilyl, ie/ -butyldiphenylsilyl, 2- trimethyethylsilyl (TEOC), or [2-(trimethylsilyl)ethoxy]methyl.
49. The method of claim 47, wherein the silyl protecting group is triethylsilyl,
triisopropylsilyl, or tert-butyldimethylsilyl.
50. The method of claim 47, wherein the silyl protecting group is tert- butyldimethylsilyl.
51. The method of any one of claims 44-50, wherein the alcohol deprotecting reagent is tetra-n-butylammonium fluoride, tris(dimethylamino)sulfonium
difluorotrimethylsilicate, hydrogen fluoride or a solvate thereof, hydrogen fluoride pyridine, silicon tetrafluoride, hexafluorosilicic acid, cesium fluoride, hydrochloric acid, acetic acid, pyridinium p-toluensulfonate, formic acid, periodic acid, trifluoroacetic acid, or .p-toluenesulfonic acid (p-TsOH).
52. The method of claim 51, wherein the alcohol deprotecting reagent is acetic acid. 53. The method of any of one of claims 44-52, wherein the bromination reagent is
54. The method of any of one claims 44-50, wherein the compound of formula (5d') is reacted with a mixture of acetic acid and HBr.
55. A method of reparing a compound of formula (Id'),
Figure imgf000194_0001
(Id')
or a pharmaceutically acceptable salt thereof, said method comprising reacting a compound of formula (7d)
Figure imgf000195_0001
with a monomer compound of the formula (ai),
Figure imgf000195_0002
wherein Rioo is (Ci-C3)alkoxy; and, X2 is a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester and an activated ester
(preferably, X2 is -Br, -I, or a sulfonate ester).
56. The method of claim 55, wherein the compound of formula (7d) is reacted with the monomer compound of formula (ai) in the presence of a base.
57. The method of claim 56, wherein the base is sodium carbonate, potassium
carbonate, cesium carbonate, sodium hydride, or potassium hydride.
58. A method of preparing a compound of formula (Id'),
Figure imgf000195_0003
(Id') or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) introducing an alcohol protecting group onto one of the primary alcohols of a compound of formula (Id),
Figure imgf000196_0001
(1d)
to form a compound of formula (2d),
Figure imgf000196_0002
(2) reacting the compound of formula (2d) with a halogenating reagent, a sulfonating reagent or an esterification reagent to form a compound of formula (3d),
Figure imgf000196_0003
(3d)
(3) reacting the compound of fonnula (3d) with a monomer compound of the formula (ai),
Figure imgf000196_0004
(ai)
to form a compound of formula (4d),
Figure imgf000196_0005
(4d)
(4) reacting the compound of formula (4d) with an imine reducing agent to form a compound of fonnula (5d),
Figure imgf000197_0001
(5d)
(5) reacting the compound of formula (5d) with an alcohol deprotecting reagent to form a compound of formula (6d),
Figure imgf000197_0002
(6d)
(6) reacting the compound of formula (6d) with a second halogenating reagent, a second sulfonating reagent or a second esterification reagent to form a compound of formula (7d),
Figure imgf000197_0003
(7d) ; and
(7) reacting the compound of formula (7d) with a monomer compound of the formula (ai), to form the compound of formula (Id'); wherein Pi is an alcohol protecting group; Xi and X2 are each independently a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester and an activated ester (preferably, X1 and X2 are each independently -Br, -I, or a sulfonate ester); and Rioo is (Q-
C3)alkoxy. A method of formin a compound of formula (Id'),
Figure imgf000198_0001
(Id')
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) introducing an alcohol protecting group onto one of the primary alcohols of a compound of formula (Id),
Figure imgf000198_0002
(id)
to form a compound of formula (2d"),
Figure imgf000198_0003
(2d")
(2) reacting the compound of formula (2d") with a halogenating reagent, a sulfonating reagent or an esterification reagent to form a compound of formula (3d"),
Figure imgf000198_0004
(3d")
(3) reacting the compound of formula (3d") with a monomer compound of the formula (ai).
Figure imgf000198_0005
to form a compound of formula (4d"),
Figure imgf000199_0001
(4d")
(4) reacting the compound of formula (4d") with an imine reducing agent to form a compound of formula (5d"),
Figure imgf000199_0002
(5d")
(5) reacting the compound of formula (5d") with an alcohol deprotecting reagent and a halogenating reagent to form a compound of formula (7d"),
Figure imgf000199_0003
(7cT)
(6) reacting a compound of formula (7d") with a monomer compound of the formula (ai),
Figure imgf000199_0004
(ai)
to form the compound of formula (Id'), wherein Pi' is an acid labile alcohol protecting group; Xi is a leaving group selected from the group consisting of: -
Br, -I, -CI, a sulfonate ester and an activated ester (preferably, -Br, -I, a sulfonate ester); X2' is -Br or -I; and Rioo is (Ci-C3)alkoxy. A method of preparing a compound of formula (9d),
Figure imgf000200_0001
(9d)
or a salt thereof, said method comprising reacting a compound of formula (4d),
Figure imgf000200_0002
(4d)
with an alcohol deprotecting reagent; wherein Pi is an alcohol protecting group; and Rioo is (Ci-C3)alkoxy.
The method of claim 60, wherein the alcohol deprotecting reagent is tetra-n- butylammonium fluoride, tris(dimethylamino)sulfonium
difluorotrimethylsilicate, hydrogen fluoride or a solvate thereof, hydrogen fluoride pyridine, silicon tetrafluoride, hexafluorosilicic acid, cesium fluoride, hydrochloric acid, acetic acid, pyridinium p-toluensulfonate, formic acid, periodic acid, trifluoroacetic acid, or p-toluenesulfonic acid (p-TsOH).
The method of claim 60, wherein the alcohol deprotecting reagent is hydrochloric acid or tetra-n-butylammonium fluoride.
A method of preparing a compound of formula (lOd),
Figure imgf000200_0003
(10d) or a salt thereof, said method comprising reacting a halogenating reagent, a sulfonating reagent or an esterification reagent with the compound of formula (9d),
Figure imgf000201_0001
wherein X2 is a leaving group selected from the group consisting of -Br, -I, -CI, a sulfonate ester, and an activated ester (preferably, X2 is -Br, -I, or a sulfonate ester); and Rioo is (Ci-C3)alkoxy.
64. The method of claim 63, wherein the sulfonate ester represented by X2 is
mesylate, tosylate, brosylate, or triflate.
65. The method of claim 63, wherein the sulfonate ester represented by X2 is
mesylate.
66. The method of any one of claims 63-65, wherein the method comprising
reacting the compound of formula (9d) with the sulfonating reagent in the presence of a non-nucleophilic base.
67. The method of claim 66, wherein the non-nucleophilic base is triethylamine, imidazole, triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), or tetramethylpiperidine.
68. The method of claim 66, wherein the non-nucleophilic base is triethylamine or diisopropylethylamine.
69. The method of any one of claims 63-68, wherein the sulfonating reagent is
methanesulfonic anhydride or methanesulfonyl chloride.
70. The method of claim 63, wherein the method comprising reacting the compound of formula (9d) with a halogenating reagent and the halogenating reagent is bromine, hydrobromic acid, carbon tetrabromide, phosphorus tribromide, potassium bromide, hydroiodic acid, iodine, carbon tetraiodide, phosph triiodide, sodium iodide, or potassium iodide.
A method of preparing a compound of formula (18d),
Figure imgf000202_0001
(18d) or a salt thereof, said method comprising reacting a compound of formula (lOd)
Figure imgf000202_0002
(10d) with a monomer compound of the formula (di),
Figure imgf000202_0003
wherein X2 is a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester, and an activated ester (preferably, X2 is -Br, -I, or a sulfonate ester); P3 is H or P2; P2 is an amine protecting group; and Rioo is (Ci-C3)alkoxy. The method of claim 71, wherein P3 is H and the compound of (lOd) is reacted with the monomer compound of (di) to form a compound of (Id'):
Figure imgf000203_0001
The method of claim 71, wherein P3 is P2; the monomer compound is represented by formula (ci):
Figure imgf000203_0002
and the compound of formula (18d) is represented by formula (l id),
Figure imgf000203_0003
(11 d)
The method of claim 71, 72 or 73, wherein the compound of formula (lOd) is reacted with the monomer compound of formula (di) in the presence of a base.
The method of claim 74, wherein the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride.
The method of any one of claims 71-75, wherein the amine protecting group is 2 trimethylsilylethyl,(2-phenyl-2-trimethylsilyl)ethyl, triisopropylsiloxy, 2- (trimethylsilyl)ethoxymethyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2- (trimethylsilyl)ethoxycarbonyl, or 2, 2,2,2-trichloroethoxycarbonyl. A method of preparing a compound of formula (Id'),
Figure imgf000204_0001
or a pharmaceutically acceptable salt thereof, said method comprising reacting a compound of formula (l id),
Figure imgf000204_0002
with an amine deprotecting reagent; wherein P2 is an amine protecting group; and Rioo is (Ci-C3)alkoxy.
78. The method of claim 77, wherein the amine deprotecting reagent is tetra-n- butylammonium fluoride, hydrogen fluoride pyridine, cesium fluoride, piperidine, morpholine, acetic acid, or trifluroacetic acid.
79. A method of preparing a compound of formula (Id'),
Figure imgf000204_0003
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) introducing an alcohol protecting group onto one of the primary alcohols of the compound of formula (Id),
Figure imgf000205_0001
(1d) to form a compound of formula (2d),
Figure imgf000205_0002
(2d)
(2) reacting a halogenating reagent, a sulfonating reagent or an esterification reagent with the compound of formula (2d) to form a compound of formula (3d),
Figure imgf000205_0003
(3d)
(3) reacting the compound of formula (3d) with a monomer compound of the formula (ai),
Figure imgf000205_0004
to form a compound of formula (4d),
Figure imgf000205_0005
(4d) (4) reacting the compound of formula (4d) with an alcohol deprotecting reagent to form a compound of formula (9d),
Figure imgf000206_0001
(9d)
(5) reacting a second halogenating reagent, a second sulfonating reagent or a second esterification reagent with the compound of formula (9d) to form a compound of formula (lOd),
Figure imgf000206_0002
(10d)
(6) reacting the compound of formula (lOd) with a monomer compound of the formula (di)
Figure imgf000206_0003
to form a compound of formula (18d),
Figure imgf000206_0004
(7) when P3 is an amine protecting group; reacting the compound of formula (18d) with an amine deprotecting reagent to form the compound of formula (Id'), wherein Pi is an alcohol protecting group; Xi and X2 are each
independently a leaving group selected from the group consisting of: -Br, -I, -CI, a sulfonate ester, and an activated ester (preferably, -Br, -I, a sulfonate ester); P2 is an amine protecting group; and Rioo is (Ci-C3)alkoxy.
The method of claim 79, wherein P3 is H and the compound of (lOd) is reacted with the monomer compound of (di) to form a compound of (Id').
The method of claim 79, wherein P3 is P2; the monomer compound is represented by formula (ci):
Figure imgf000207_0001
and the compound of formula (18d) is represented by formula (l id),
Figure imgf000207_0002
(1 1d) wherein P2 is an amine protecting group. A method of preparing a compound of formula (12d),
Figure imgf000207_0003
(12d) or a salt thereof, said method comprising reacting a compound of formula (Id),
Figure imgf000208_0001
(1d) with a halogenating reagent, a sulfonating reagent or an esterification reagent , wherein Xi is -Br, -I, -CI, a sulfonate ester, or an activated ester (preferably, Xi is -Br, -I, or a sulfonate ester); and Rioo is (Ci-C3)alkoxy.
The method of claim 82, wherein Xi is -Br or -I.
The method of claim 82 or 83, wherein the halogenating reagent reacts with the primary alcohols of the compound of formula (Id) in the presence of an alcohol activating agent.
The method of claim 84, wherein the alcohol activating agent is thionyl chloride.
The method of any one of claims 82-85, wherein the halogenating reagent is lithium bromide, sodium bromide, potassium bromide, potassium iodide, or sodium iodide.
A method of preparing a compound of formula (10d'),
Figure imgf000208_0002
(10d') or a salt thereof, said method comprising reacting a compound of formula (12d),
Figure imgf000208_0003
(12d) with a monomer compound of the formula (ai),
Figure imgf000209_0001
wherein Xi is -Br, -I, -CI, a sulfonate ester, or an activated ester (preferably, Xi is -Br, -I, or a sulfonate ester); and Rioo is (Ci-C3)alkoxy.
88. The method of claim 87, wherein the compound of formula (12d) is reacted with the monomer compound of formula (ai) in the presence of a base.
89. The method of claim 88, wherein the base is sodium carbonate, potassium
carbonate, cesium carbonate, sodium hydride, or potassium hydride.
90. The method of any one of claims 87-89, wherein excess molar equivalent of the compound of formula (12d) relative to the monomer compound of formula (ai) is used.
91. A method of preparing a compound of formula (7d'),
Figure imgf000209_0002
(7cT) or a salt thereof, said method comprising reacting a compound of formula (10d'),
Figure imgf000209_0003
(10d') or a salt thereof, with an imine reducing agent, wherein Xi is -Br, -I, -CI, a sulfonate ester, or an activated ester (preferably, Xi is -Br, -I, a sulfonate ester); and Rioo is (Ci-C3)alkoxy.
92. The method of claim 91, wherein the imine reducing reagent is a hydride reducing reagent.
93. The method of claim 91, wherein the imine reducing reagent is sodium
borohydride, sodium triacetoxy borohydride, sodium cyanoborohydride, lithium aluminum hydride, hydrogen gas, ammonium formate, borane, 9- borabicyclo[3.3.1]nonane (9-BBN), diisobutylaluminium hydride (DIBAL), lithium borohydride (LiBH4), potassium borohydride (KBH4), or sodium bis(2- methoxyethoxy)aluminumhydride (Red-Al) .
94. The method of claim 91, wherein the imine reducing reagent is sodium triacetoxy borohydride (NaBH(OAc)3).
95. The method of any one of claims 91-94, wherein Xi is mesylate. 96. A method of preparing a compound of formula (Id'),
Figure imgf000210_0001
(Id') or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a halogenating reagent, a sulfonating reagent or an esterification reagent with a compound of formula (Id),
Figure imgf000210_0002
(1d)
to form a compound of formula (12d),
Figure imgf000211_0001
(12d)
(2) reacting the compound of formula (12d) with a monomer compound of the formula (ai),
Figure imgf000211_0002
to form a compound of a formula (10d'),
Figure imgf000211_0003
(10d')
(3) reacting the compound of formula (10d') with a monomer compound of the formula (di),
Figure imgf000211_0004
(4) when P3 is an amine protecting group, reacting the compound of formula (18d) with an amine deprotecting reagent to form the compound of formula (Id'); wherein Xi is -Br, -I, -CI, a sulfonate ester, or an activated ester (preferably, Xi is -Br, -I, or a sulfonate ester); P3 is H or an amine protecting group; and Rioo is (Ci-C3)alkoxy.
The method of claim 96, wherein P3 is H and the compound of (10d') is reacted with the monomer compound of (di) to form a compound of (Id').
The method of claim 96, wherein P3 is P2; the monomer compound is represented by formula (ci):
Figure imgf000212_0001
and the compound of formula (18d) is represented by formula (l id),
Figure imgf000212_0002
wherein P2 is an amine protecting group.
A method of preparing a compound of formula (Id'),
Figure imgf000212_0003
or a pharmaceutically acceptable salt thereof, said method comprising the steps of: (1) reacting a halogenating reagent, a sulfonating reagent or an esterification reagent with a compound of formula (Id),
Figure imgf000213_0001
(1d)
compound of formula (12d),
Figure imgf000213_0002
(12d)
(2) reacting the compound of formula (12d) with a monomer compound of the formula (ai),
Figure imgf000213_0003
to form a compound of a formula (10d'),
Figure imgf000213_0004
(3) reacting the compound (lOd') with an imine reducing reagent to form a compound (7d'),
Figure imgf000214_0001
(7d')
(4) reacting the compound of formula (7d') with a monomer compound of the formula (ai),
Figure imgf000214_0002
to form a compound of formula (Id'), or a pharmaceutically acceptable salt thereof, wherein X1 is -Br, -I, -CI, a sulfonate ester, or an activated ester (preferably, X1 is -Br, -I, or a sulfonate ester); and Rioo is (Ci-C3)alkoxy.
100. The method of claim 99, wherein Xi is mesylate.
101. A method of preparing a compound of formula (Id'),
Figure imgf000214_0003
(Id') or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a halogenating reagent, a sulfonating reagent or an esterification reagent with a compound of formula (Id),
Figure imgf000215_0001
(1d)
to form a compound of formula (12d),
Figure imgf000215_0002
(12d)
(2) reacting the compound of formula (12d) with a monomer compound of the formula (di),
Figure imgf000215_0003
to form a compound of a formula (7dl'),
Figure imgf000215_0004
(7d1 ')
(3) reacting the compound of formula (7dl ') with a monomer compound of the formula (ai),
Figure imgf000215_0005
to form a compound of formula (18d),
Figure imgf000216_0001
(4) when P3 is an amine protecting group, reacting the compound of formula (18d) with an amine deprotecting reagent to form the compound of formula (Id'); wherein Xi is -Br, -I, -Cl, a sulfonate ester, or an activated ester (preferably, Xi is -Br, -I, or a sulfonate ester); P3 is H or an amine protecting group; and Rioo is (Ci-C3)alkoxy.
102. The method of claim 101, wherein P3 is H and the compound of (10d') is reacted with the monomer compound of (di) to form a compound of (Id').
103. The method of claim 101, wherein P3 is P2; the monomer compound is
represented by formula (c
Figure imgf000216_0002
and the compound of formula (18d) is represented by formula (l id),
Figure imgf000216_0003
wherein P2 is an amine protecting group.
104. The method of any one of claims 101-103, wherein Xi is mesylate A method of preparing a compound of formula (13d),
Figure imgf000217_0001
(13d) or a salt thereof, said method comprising reacting a chlorinating reagent with a compound of formula (2d),
Figure imgf000217_0002
(2d) wherein Pi is an alcohol protecting group; X3 is -CI; and Rioo is (Ci-C3)alkoxy.
106. The method of claim 105, wherein the alcohol protecting group is a silyl
protecting group.
107. The method of claim 106, wherein the silyl protecting group is the silyl
protecting group is dimethylisopropylsilyl, diethylisopropylsilyl,
dimethylhexylsilyl, trimethylsilyl, triisopropylsilyl, tribenzylsilyl, triphenylsilyl, 2-norbornyldimethylsilyl, ie/t-butyldimethylsilyl, ie/ -butyldiphenylsilyl, 2- trimethyethylsilyl (TEOC), or [2-(trimethylsilyl)ethoxy]methyl.
108. The method of claim 107, wherein the silyl protecting group is triethylsilyl, triisopropylsilyl, or tert-butyldimethylsilyl.
109. The method of claim 108, wherein the silyl protecting group is tert- butyldimethylsilyl.
110. The method of any one of claims 105-109, wherein the chlorinating reagent is selected from the group consisting of carbon tetrachloride, methanesulfonyl chloride, sulfuryl chloride, thionyl chloride, cyanuric chloride, N- chlorosuccinimide, phosphorus(V) oxychloride, phosphorus pentachloride, and phosphorus trichloride.
111. The method of claim 110, wherein the chlorinating reagent is methanesulfonyl chloride. 112. The method of any one of claims 105-111, wherein the chlorinating reagent is reacted with a compound of formula (2d) in the presence of a non-nucleophilic base.
113. The method of claim 112, wherein the non-nucleophilic base is triethylamine, imidazole, diisopropylethylamine, pyridine, 2,6-lutidine, dimethylformamide, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or tetramethylpiperidine .
114. The method of claim 113, wherein the non-nucleophilic base is pyridine. 115. The method of any one of claims 105-114, wherein the the chlorinating reagent is reacted with a compound of formula (2d) in a polar aprotic solvent.
116. The method of claim 115, wherein the polar aprotic solvent is N,N- dimethylformamide or dimethylacetamide.
117. A method of preparing a compound of formula (14d),
Figure imgf000218_0001
(14d) or a salt thereof, said method comprising reacting a compound of formula (13d)
Figure imgf000218_0002
with an alcohol deprotecting reagent, wherein Pi is an alcohol protecting group; X3 is -CI; and Rioo is (Ci-C3)alkoxy. 118. The method of claim 117, wherein the alcohol protecting group is a silyl
protecting group.
119. The method of claim 118, the silyl protecting group is the silyl protecting group is dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl,
trimethylsilyl, triisopropylsilyl, tribenzylsilyl, triphenylsilyl, 2- norbornyldimethylsilyl, ie/t-butyldimethylsilyl, ie/ -butyldiphenylsilyl, 2- trimethyethylsilyl (TEOC), or [2-(trimethylsilyl)ethoxy]methyl.
120. The method of claim 119, wherein the silyl protecting group is triethylsilyl, triisopropylsilyl, or tert-butyldimethylsilyl.
121. The method of claim 120, wherein the silyl protecting group is tert- butyldimethylsilyl.
122. The method of any one of claims 117-121, wherein the alcohol deprotecting reagent is tetra-n-butylammonium fluoride, tris(dimethylamino)sulfonium difluorotrimethylsilicate, hydrogen fluoride or a solvate thereof, hydrogen fluoride pyridine, silicon tetrafluoride, hexafluorosilicic acid, cesium fluoride, hydrochloric acid, acetic acid, trifluoroacetic acid, pyridinium p-toluensulfonate, p-toluenesulfonic acid (p-TsOH), formic acid, periodic acid.
123. The method of claim 122, wherein the alcohol deprotecting agent is hydrogen fluoride pyridine.
124. A method of preparing a compound of formula (15d):
Figure imgf000219_0001
(15d) or a salt thereof, said method comprising reacting a sulfonating reagent or an esterification reagent with a compound of formula (14d),
Figure imgf000219_0002
(14d) wherein X3 is -CI; X4 is a sulfonate ester or an activated ester (preferably, a sulfonate ester); and Rioo is (Ci-C3)alkoxy.
125. The method of claim 124, wherein the sulfonating reagent is methansufonyl anhydride, methanesufonyl chloride, p-toluenesulfonyl chloride, 4- bromobenzenesulfonyl chloride, or trifluoromethanesulfonyl anhydride.
126. The method of claim 125, wherein the sulfonate ester represented by X4 is
mesylate, tosylate, brosylate, or triflate. 127. The method of claim 126, wherein the sulfonate ester represented by X4 is
mesylate. 128. The method of any one of claims 124-127, wherein the sulfonate ester is reacted with a compound of formula (14d) in the presence of a non-nucleophilic base 129. The method of claim 128, wherein the non-nucleophilic base is triethylamine, imidazole, diisopropylethylamine, pyridine, 2,6-lutidine, dimethylformamide, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or tetramethylpiperidine.
130. The method of claim 129, wherein the amine base is diisopropylethylamine. 131. A method of preparing a compound of formula (20d):
Figure imgf000220_0001
(20d)
or a salt thereof, said method comprising reacting a brominating or iodinating reagent with a compound of formula (14d),
Figure imgf000220_0002
(14d) wherein X3 is -CI; X5 is -Br or -I; and Rioo is (Ci-C3)alkoxy.
132. The method of claim 131, wherein the brominating or iodinating reagent is bromine, hydrobromic acid, carbon tetrabromide, phosphorus tribromide, potassium bromide, hydroiodic acid, iodine, carbon tetraiodide, phosphorus triiodide, sodium iodide, or potassium iodide. 133. A method of preparing a compound of formula (16d):
Figure imgf000221_0001
(16d) or a salt thereof, said method comprising reacting a compound of formula (15d)
Figure imgf000221_0002
(15d) with a monomer compound of formula (ai),
Figure imgf000221_0003
wherein X3 is -CI; X4 is a sulfonate ester or an activated ester (preferably, a sulfonate ester); and Rioo is (Ci-C3)alkoxy.
134. The method of claim 133, wherein the compound of formula (15d) is reacted with a monomer compound of formula (ai) in the presence of a base. 135. The method of claim 133, wherein the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride.
136. The method of claim 135, wherein the base is potassium carbonate.
137. The method of any one of claims 133-136, wherein the compound of formula (15d) is reacted with a monomer compound of formula (ai) in the presence of a polar aprotic solvent.
138. The method of claim 137, wherein the polar aprotic solvent is
dimethylacetamide.
139. A method of preparing a compound of formula (16d):
Figure imgf000222_0001
(16d) or a salt thereof, said method comprising reacting a compound of formula (20d)
Figure imgf000222_0002
(20d) with a monomer compound of formula (ai),
Figure imgf000222_0003
wherein X3 is -CI; X5 is -Br or -I; and R100 is (Ci-C3)alkoxy.
140. The method of claim 139, wherein the compound of formula (20d) is reacted with the monomer compound of formula (ai) in the presence of a base. 141. The method of claim 139, wherein the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride.
142. The method of claim 141, wherein the base is potassium carbonate.
143. The method of any one of claims 139-142, wherein the compound of formula (20d) is reacted with a monomer compound of formula (ai) in the presence of a polar aprotic solvent.
144. The method of claim 143, wherein the polar aprotic solvent is
dimethylacetamide.
145. A method of preparing a compound of formula (16d):
Figure imgf000223_0001
(16d) or a salt thereof, said method comprising reacting a compound of formula (14d)
Figure imgf000223_0002
with a monomer compound of formula (ai),
Figure imgf000223_0003
wherein X3 is -CI; and Rioo is (Ci-C3)alkoxy.
146. The method of claim 145, wherein the compound of formula (14d) is reacted with a monomer of formula (ai) in the presence of an alcohol activating agent. 147. The method of claim 146, wherein the alcohol activating agent is
triphenylpho sphine .
148. The method of any one of claims 145-147, wherein the compound of formula (14d) is reacted with a monomer of formula (ai) in the presence of an azodicarboxylate.
149. The method of claim 148, wherein the azodicarboxylate is selected from the group consisting of: diethyl azodicarboxylate (DEAD), diisopropyl
azodicarboxylate (DIAD), l,l'-(azodicarbonyl)dipiperidine (ADDP), and ditertbutyl azodicarboxylate (DTAD).
150. A method of preparing a compound of formula (18d):
Figure imgf000224_0001
or a pharmaceutically acceptable salt thereof, said method comprising reacting a compound of formula of (16d):
Figure imgf000224_0002
(16d) with a reduced monomer of formula (di):
Figure imgf000224_0003
wherein X3 is -CI; P3 is H or an amine protecting group; and Rioo is (Q- C3)alkoxy.
151. The method of claim 150, wherein the compound of formula (16d) is reacted with a monomer compound of formula (di) in the presence of a base.
152. The method of claim 151, wherein the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride.
153. The method of claim 152, wherein the base is potassium carbonate. 154. The method of any one of claims 150-153, wherein the compound of formula (16d) is reacted with a monomer compound of formula (di) in the presence of a polar aprotic solvent.
155. The method of claim 154, wherein the polar aprotic solvent is
dimethylformamide or dimethylacetamide. 156. The method of any one of claims 150-155, wherein the compound of formula (16d) is reacted with reduced monomer of formula (di), wherien P3 is H, to form a compound of formula (Id'):
Figure imgf000225_0001
157. The method of any one of claims 150-155, wherein P3 is an amine protecting
158. The method of claim 157, wherein the amine protecting group is selected from the group consisting of 2-trimethylsilylethyl,(2-phenyl-2-trimethylsilyl)ethyl, triisopropylsiloxy, 2-(trimethylsilyl)ethoxymethyl, allyloxycarbonyl, 9- fluorenylmethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, and 2, 2,2,2- trichloroethoxycarbonyl.
159. The method of claim 157 or 158, wherein the compound of formula (18d) is further reacted with an amine deprotecting reagent to form a compound of formula (Id'):
Figure imgf000226_0001
160. The method of claim 159, wherein the amine deprotecting reagent is selected from the group consisting of tetra-n-butylammonium fluoride, acetic acid, hydrogen fluoride pyridine, cesium fluoride, piperidine, morpholine, or trifluroacetic acid.
161. A method of preparing a compound of formula (17d):
Figure imgf000226_0002
(17d) or a salt thereof, said method comprising reacting a compound of formula (15d)
Figure imgf000226_0003
(15d) with a monomer compound of formula (di),
Figure imgf000226_0004
wherein X3 is -CI; X4 is a sulfonate ester or an activated ester (preferably, a sulfonate ester); P3 is H or an amine protecting group; and Rioo is (Ci-C3)alkoxy.
162. The method of claim 161, wherein the compound of formula (15d) is reacted with a monomer compound of formula (di) in the presence of a base.
163. The method of claim 162, wherein the base is sodium carbonate, potassium
carbonate, cesium carbonate, sodium hydride, or potassium hydride.
164. The method of claim 163, wherein the base is potassium carbonate. 165. The method of any one of claims 161-164, wherein the compound of formula (15d) is reacted with a monomer compound of formula (di) in the presence of a polar aprotic solvent.
166. The method of claim 165, wherein the polar aprotic solvent is
dimethylacetamide. 167. The method of any one of claims 161-166, wherein the compound of formula (15d) is reacted with the monomer compound of formula (di), wherein P3 is H, to form a compound of formula (17d'):
Figure imgf000227_0001
168 The method of any one of claims 161-166, wherein P3 is an amine protecting
169 The method of claim 168, further comprising the step of reacting the compound of formula (17d) with an amine deprotecting reagent to form a compound of formula (17d'):
Figure imgf000228_0001
(17d')
170. The method of claim 169, wherein the amine deprotecting reagent is selected from the group consisting of tetra-n-butylammonium fluoride, hydrogen fluoride pyridine, cesium fluoride, piperidine, morpholine, acetic acid, or trifluroacetic acid.
171. A method of preparing a compound of formula (17d):
Figure imgf000228_0002
(17d) or a salt thereof, said method comprising reacting a compound of formula (14d)
Figure imgf000228_0003
(14d) with a monomer compound of formula (di),
Figure imgf000228_0004
wherein X3 is -CI; P3 is H or an amine protecting group; and Rioo is (Q- C3)alkoxy.
172. The method of claim 171, wherein the compound of formula (14d) is reacted with a monomer of formula (di) in the presence of an alcohol activating agent.
173. The method of claim 172, wherein the alcohol activating agent is
triphenylpho sphine .
174. The method of any one of claims 171-173, wherein the compound of formula (14d) is reacted with a monomer of formula (di) in the presence of an azodicarboxylate.
175. The method of claim 174, wherein the azodicarboxylate is selected from the group consisting of: diethyl azodicarboxylate (DEAD), diisopropyl
azodicarboxylate (DIAD), l,l'-(azodicarbonyl)dipiperidine (ADDP), and ditertbutyl azodicarboxylate (DTAD).
176. The method of any one of claims 171-175, wherein the compound of formula (15d) is reacted with the monomer compound of formula (di), wherein P3 is H, to form a compound of formula (17d'):
Figure imgf000229_0001
177 The method of any one of claims 171-175, wherein P3 is an amine protecting
178 The method of claim 177, further comprising the step of reacting the compound of formula (17d) with an amine deprotecting reagent to form a compound of formula (17d'):
Figure imgf000230_0001
(17d')
179. The method of claim 178, wherein the amine deprotecting reagent is selected from the group consisting of tetra-n-butylammonium fluoride, hydrogen fluoride pyridine, cesium fluoride, piperidine, morpholine, acetic acid, or trifluroacetic acid.
180. A method of preparing a compound of formula (17d):
Figure imgf000230_0002
(17d) or a salt thereof, said method comprising reacting a compound of formula (20d)
Figure imgf000230_0003
(20d)
with a monomer compound of formula (di),
Figure imgf000230_0004
wherein X3 is -CI; X5 is -Br or -I; P3 is H or an amine protecting group; and R100 is (Ci-C3)alkoxy.
181. The method of claim 180, wherein the compound of formula (20d) is reacted with a monomer compound of formula (di) in the presence of a base.
182. The method of claim 181, wherein the base is sodium carbonate, potassium
carbonate, cesium carbonate, sodium hydride, or potassium hydride.
183. The method of claim 182, wherein the base is potassium carbonate. 184. The method of any one of claims 180-183, wherein the compound of formula (20d) is reacted with a monomer compound of formula (di) in the presence of a polar aprotic solvent.
185. The method of claim 184, wherein the polar aprotic solvent is
dimethylacetamide. 186. The method of any one of claims 180-183, wherein the compound of formula (20d) is reacted with the monomer compound of formula (di), wherein P3 is H, to form a compound of formula (17d'):
Figure imgf000231_0001
187 The method of any one of claims 180-183, wherein P3 is an amine protecting
188 The method of claim 187, further comprising the step of reacting the compound of formula (17d) with an amine deprotecting reagent to form a compound of formula (17d'):
Figure imgf000232_0001
(17d')
189. The method of claim 188, wherein the amine deprotecting reagent is selected from the group consisting of tetra-n-butylammonium fluoride, hydrogen fluoride pyridine, cesium fluoride, piperidine, morpholine, acetic acid, or trifluroacetic acid.
190. A method of preparing a compound of formula (17d'):
Figure imgf000232_0002
or a salt thereof, said method comprising reacting a compound of formula (16d)
Figure imgf000232_0003
with an imine reducing agent, wherein X3 is -CI; and Rioo is (Ci-C3)alkoxy.
191. The method of claim 190, wherein the imine reducing reagent is a hydride reducing reagent. 192. The method of claim 191, wherein the imine reducing reagent is sodium
borohydride, sodium triacetoxy borohydride, sodium cyanoborohydride, lithium aluminum hydride, hydrogen gas, ammonium formate, borane, 9- borabicyclo[3.3.1]nonane (9-BBN), diisobutylaluminium hydride (DIBAL), lithium borohydride (LiBH4), potassium borohydride (KBH4), or sodium bis(2- methoxyethoxy)aluminumhydride (Red-Al) .
193. The method of claim 192, wherein the imine reducing reagent is sodium
triacetoxy borohydride (NaBH(OAc)3).
194. A method of preparing a compound of formula (18d),
Figure imgf000233_0001
or a pharmaceutically acceptable salt thereof, said method comprising reacting a compound of formula of (17d):
Figure imgf000233_0002
with a monomer of formula (ai):
Figure imgf000233_0003
wherein X3 is -CI; P3 is H or an amine protecting group; and Rioo is (Q- C3)alkoxy. 195. The method of claim 194, wherein the compound of formula (17d) is reacted with a monomer compound of formula (di) in the presence of a base.
196. The method of claim 195, wherein the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride.
197. The method of claim 196, wherein the base is potassium carbonate. 198. The method of any one of claims 194-197, wherein the compound of formula (17d) is reacted with a monomer compound of formula (ai) in the presence of a polar aprotic solvent. 199. The method of claim 198, wherein the polar aprotic solvent is
dimethylformamide or dimethylacetamide. 200. The method of any one of claims 194-199, wherein the compound of formula (17d) is reacted with reduced monomer of formula (di), wherien P3 is H, to form a compound of formula (Id'):
Figure imgf000234_0001
201. The method of any one of claims 194-199, wherein P3 is an amine protecting
202. The method of claim 201, wherein the amine protecting group is selected from the group consisting of 2-trimethylsilylethyl,(2-phenyl-2-trimethylsilyl)ethyl, triisopropylsiloxy, 2-(trimethylsilyl)ethoxymethyl, allyloxycarbonyl, 9- fluorenylmethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, and 2, 2,2,2- trichloroethoxycarbonyl.
203. The method of claim 201 or 202, wherein the compound of formula (18d) is further reacted with an amine deprotecting reagent to form a compound of formula (Id'):
Figure imgf000235_0001
204. The method of claim 203, wherein the amine deprotecting reagent is selected from the group consisting of tetra-n-butylammonium fluoride, acetic acid, hydrogen fluoride pyridine, cesium fluoride, piperidine, morpholine, or trifluroacetic acid.
205. A method of preparing a compound of formula (18d),
Figure imgf000235_0002
(18d) or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a sulfonating reagent or an esterification reagent with the compound of formula (14d):
Figure imgf000235_0003
(14d) or a salt thereof, to form a compound of formula (15d):
Figure imgf000236_0001
(15d) or a salt thereof;
(2) reacting the compound of formula (15d) with a monomer compound of formula (ai),
Figure imgf000236_0002
to form a compound of formula (16d):
Figure imgf000236_0003
(16d) or a salt thereof; and
(3) reacting the compound of formula of (16d) with a reduced monomer of formula (di):
Figure imgf000236_0004
to form a compound of formula (18d), or a pharmaceutically acceptable salt thereof, wherein X3 is -CI; X4 is a sulfonate ester or an activated ester (preferably, a sulfonate ester); Pi is an alcohol protecting group; P3 is H or an amine protecting group; and Rioo is (Ci-C3)alkoxy. A method of preparing a compound of formula (18d),
Figure imgf000237_0001
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting the compound of formula (14d):
Figure imgf000237_0002
(14d) or a salt thereof, with a monomer compound of formula (ai),
Figure imgf000237_0003
to form a compound of formula (16d):
Figure imgf000237_0004
(16d) or a salt thereof; and
(2) reacting the compound of formula of (16d) with a reduced monomer of formula (di):
Figure imgf000238_0001
to form a compound of formula (18d), or a pharmaceutically acceptable salt thereof, wherein X3 is -CI; Pi is an alcohol protecting group; P3 is H or an amine protecting group; and Rioo is (Ci-C3)alkoxy. 207. A method of preparing a compound of formula (18d),
Figure imgf000238_0002
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a halogenating reagent with the compound of formula (14d):
Figure imgf000238_0003
(14d) or a salt thereof, to form a compound of formula (20d):
Figure imgf000238_0004
(20d) or a salt thereof; (2) reacting a compound of formula (20d) or a salt thereof with a monomer compound of formula (ai),
Figure imgf000239_0001
(ai) to form a compound of formula (16d):
Figure imgf000239_0002
(16d) or a salt thereof; and
(3) reacting the compound of formula of (16d) with a reduced monomer of formula (di):
Figure imgf000239_0003
to form a compound of formula (18d), or a pharmaceutically acceptable salt thereof, wherein X3 is -CI; X5 is -Br or -I; P3 is H or an amine protecting group; and R100 is (Ci-C3)alkoxy.
208. The method of claim 205, 206, or 207, wherein the compound of formula (16d) is reacted with reduced monomer of formula (di), wherien P3 is H, to form a compound of formula (Id'):
Figure imgf000240_0001
209. The method of claim 205, 206, or 207, wherein P3 is an amine protecting group.
210. The method of claim 209, wherein the compound of formula (18d) is further reacted with an amine deprotecting reagent to form a compound of formula (Id'):
Figure imgf000240_0002
211. A method of preparing a compound of formula (18d),
Figure imgf000240_0003
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a sulfonating reagent or an esterification reagent with the compound of formula (14d):
Figure imgf000240_0004
(14d)
or a salt thereof, to form a compound of formula (15d):
Figure imgf000241_0001
(15d)
or a salt thereof;
(2) reacting the compound of formula (15d) with a reduced monomer compound of formula (di),
Figure imgf000241_0002
to form a compound of formula (17d):
Figure imgf000241_0003
(17d)
or a salt thereof; and
(3) reacting the compound of formula of (17d) with a monomer of formula (ai):
Figure imgf000241_0004
to form a compound of formula (18d), or a pharmaceutically acceptable salt thereof,
wherein X3 is -CI; X4 is a sulfonate ester or an activated ester (preferably, a sulfonate ester); Pi is an alcohol protecting group; P3 is H or an amine protecting group; and Rioo is (Ci-C3)alkoxy. A method of preparing a compound of formula (18d),
Figure imgf000242_0001
(18d) or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting the compound of formula (14d):
Figure imgf000242_0002
(14d)
or a salt thereof, with a reduced monomer compound of formula (di),
Figure imgf000242_0003
to form a compound of formula (17d):
Figure imgf000242_0004
(17d)
or a salt thereof; and
(2) reacting the compound of formula of (17d) with a monomer of formula (ai):
Figure imgf000242_0005
to form a compound of formula (18d), or a pharmaceutically acceptable salt thereof, wherein X3 is -CI; Pi is an alcohol protecting group; P3 is H or an amine protecting group; and Rioo is (Ci-C3)alkoxy. A method of preparing a compound of formula (18d),
Figure imgf000243_0001
(18d)
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a brominating or iodinating reagent with the compound of formula (14d):
Figure imgf000243_0002
(14d)
or a salt thereof, to form a compound of formula (20d):
Figure imgf000243_0003
(20d)
or a salt thereof;
(2) reacting the compound of formula (20d) with a reduced monomer compound of formula (di),
Figure imgf000243_0004
to form a compound of formula (17d):
Figure imgf000244_0001
(17d)
or a salt thereof; and
(3) reacting the compound of formula of (17d) with a monomer of formula (ai):
Figure imgf000244_0002
to form a compound of formula (18d), or a pharmaceutically acceptable salt thereof, wherein X3 is -CI; X5 is -Br or -I; Pi is an alcohol protecting group; P3 is H or an amine protecting group; and R100 is (Ci-C3)alkoxy.
The method of claim 211, 212, or 213, wherein the compound of formula (16) is reacted with reduced monomer of formula (di), wherien P3 is H, to form a compound of formula (Id'):
Figure imgf000244_0003
The method of any one of claims 211-214, wherein P3 is an amine protecting
The method of claim 215, wherein the compound of formula (18a) is further reacted with an amine deprotecting reagent to form a compound of formula (Id'):
Figure imgf000245_0001
A method of preparing a compound of formula (Id'),
Figure imgf000245_0002
(Id')
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a sulfonating reagent or an esterification reagent with the compound of formula (14d):
Figure imgf000245_0003
(14d)
or a salt thereof, to form a compound of formula (15d):
Figure imgf000245_0004
(15d)
or a salt thereof;
(2) reacting the compound of formula (15d) with a monomer compound of formula (ai),
Figure imgf000245_0005
to form a compound of formula (16d):
Figure imgf000246_0001
(16d)
or a salt thereof;
(3) reacting the compound of formula (16d) with an imine reducing agent to form a compound of formula (17d'):
Figure imgf000246_0002
(17d')
or a salt thereof; and
(4) reacting the compound of formula (17d') with a monomer of formula (ai):
Figure imgf000246_0003
to form the compound of formula (Id'); wherein X3 is -CI; X4 is a sulfonate ester or an activated ester (preferably, a sulfonate ester); Pi is an alcohol protecting group; P2 is an amine protecting group; and Rioo is (Ci-C3)alkoxy.
218. A method of preparing a compound of formula (Id'),
Figure imgf000246_0004
(Id')
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting the compound of formula (14d):
Figure imgf000247_0001
(14d)
or a salt thereof, with a monomer compound of formula (ai),
Figure imgf000247_0002
(ai)
to form a compound of formula (16d):
Figure imgf000247_0003
(16d)
or a salt thereof;
(2) reacting the compound of formula (16d) with an imine reducing agent to form a compound of formula (17d'):
Figure imgf000247_0004
(17d')
or a salt thereof; and
(3) reacting the compound of formula (17d') with a monomer of formula (ai):
Figure imgf000247_0005
(ai)
to form the compound of formula (Id'); wherein X3 is -CI; Pi is an alcohol protecting group; and Rioo is (Ci-C3)alkoxy. A method of preparing a compound of formula (Id'),
Figure imgf000248_0001
(Id')
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a halogenating reagent with the compound of formula (14d):
Figure imgf000248_0002
(14d)
or a salt thereof, to form a compound of formula (20d):
Figure imgf000248_0003
(20d)
or a salt thereof;
(2) reacting a compound of formula (20d) or a salt thereof with a monomer compound of formula (ai)
Figure imgf000248_0004
to form a compound of formula (16d):
Figure imgf000248_0005
(16d) (3) reacting the compound of formula (16d) with an imine reducing agent to form a compound of formula (17d'):
Figure imgf000249_0001
or a salt thereof; and
(4) reacting the compound of formula (17d') with a monomer of formula (ai):
Figure imgf000249_0002
to form the compound of formula (Id'); wherein X3 is -CI; Pi is an alcohol protecting group; and Rioo is (Ci-C3)alkoxy.
The method of any one of claims 205-219, wherein the compound of formula (14d) or a salt thereof is prepared a method comprising the following steps: (1) reacting a chlorinating reagent with a compound of formula (2d),
Figure imgf000249_0003
(2d) a compound a compound of formula (13d),
Figure imgf000249_0004
(13d) or a salt thereof; (2) reacting the compound of formula (13d) with an alcohol deprotecting reagent to form the compound of formula (14d) or a salt thereof. The method of claim 220, wherein the compound of formula (2d) is prepared by reacting a compound of formula (Id) with an alcohol protecting reagent
Figure imgf000250_0001
A method of preparing a compound of formula (Id'),
Figure imgf000250_0002
or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
Figure imgf000250_0003
(2) reacting the compound of formula (IB) with a compound of formula (LI):
Figure imgf000251_0001
to form the compound of formula (Id), wherein E is -OH, halide or -C(=0)E is an activated ester; and Rioo is (Ci-C3)alkoxy.
223. The method of claim 222, wherein E is -OH and the reaction of the compound of formula (IB) and the compound of formula (LI) is carried out in the presence of activating agent. 224. The method of claim 223, wherein the activating agent is a carbodiimide, a
uronium, an active ester, a phosphonium, 2-alkyl-l-alkylcarbonyl-l,2- dihydroquinoline, 2-alkoxy-l-alkoxycarbonyl-l,2-dihydroquinoline, or alkylchlorof ormate .
225. The method of claim 223, wherein the activating agent is a carbodiimide. 226. The method of claim 225, wherein the carbodiimide is dicyclohexylcarbodiimide (DCC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), or
diisopropylcarbodiimide (DIC).
227. The method of claim 223, wherein the activating agent is N-ethoxycarbonyl-2- ethoxy- 1 ,2-dihydroquinoline (EEDQ) . 228. The method of any one of claims 222-227, wherein the reducing agent is selected from the group consisting of: hydrogen gas, sodium hydrosulfite, sodium sulfide, stanneous chloride, titanium (II) chloride, zinc, iron and samarium iodide.
229. The method of claim 228, wherein the reducing agent is Fe/NH4C1 or Zn/NH4C1. 230. The method of any one of claims 1-229, wherein Rioo is methoxy.
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018075692A2 (en) 2016-10-19 2018-04-26 Invenra Inc. Antibody constructs
WO2018140435A1 (en) * 2017-01-25 2018-08-02 Immunogen, Inc. Methods of preparing cytotoxic benzodiazepine derivatives
WO2019234136A1 (en) 2018-06-05 2019-12-12 King's College London Btnl3/8 targeting constructs for delivery of payloads to the gastrointestinal system
WO2020102051A1 (en) * 2018-11-12 2020-05-22 Immunogen, Inc. Methods of preparing cytotoxic benzodiazepine derivatives
WO2020205564A1 (en) * 2019-03-29 2020-10-08 Immunogen, Inc. Cytotoxic bis-benzodiazepine derivatives and conjugates thereof with cell-binding agents for inhibiting abnormal cell growth or for treating proliferative diseases
US11174318B2 (en) 2016-12-22 2021-11-16 Università Degli Studi Magna Graecia Catanzaro Monoclonal antibody targeting a unique sialoglycosylated cancer-associated epitope of CD43
RU2807546C2 (en) * 2018-11-12 2023-11-16 Иммуноджен, Инк. Methods for obtaining cytotoxic benzodiazepine derivatives
WO2024005123A1 (en) 2022-06-30 2024-01-04 東レ株式会社 Pharmaceutical composition for treating and/or preventing cancer

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3325482B1 (en) * 2015-07-21 2020-06-24 ImmunoGen, Inc. Methods of preparing cytotoxic benzodiazepine derivatives
KR102864278B1 (en) 2016-03-22 2025-09-30 에베 그룹 에. 탈너 게엠베하 Device and method for bonding substrates
CN113166053A (en) * 2018-11-12 2021-07-23 伊缪诺金公司 Method for preparing cytotoxic benzodiazepine derivatives

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012128868A1 (en) * 2011-02-15 2012-09-27 Immunogen, Inc. Cytotoxic benzodiazepine derivatives
WO2016036794A1 (en) * 2014-09-03 2016-03-10 Immunogen, Inc. Conjugates comprising cell-binding agents and cytotoxic agents
WO2016036801A1 (en) * 2014-09-03 2016-03-10 Immunogen, Inc. Cytotoxic benzodiazepine derivatives

Family Cites Families (60)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3763183A (en) 1972-07-10 1973-10-02 Sterling Drug Inc 1,2,3,10,11,11a-hexahydro-5h-pyrrolo (2,1-c)(1,4)benzodiazepines
US3860600A (en) 1972-07-10 1975-01-14 Sterling Drug Inc Octahydropyrrido{8 2,1-c{9 {8 1,4{9 benzodiazepines
US4678784A (en) 1984-04-11 1987-07-07 Mcneilab, Inc. Method for the treatment of LHRH diseases and conditions
US5208020A (en) 1989-10-25 1993-05-04 Immunogen Inc. Cytotoxic agents comprising maytansinoids and their therapeutic use
GB9205051D0 (en) 1992-03-09 1992-04-22 Cancer Res Campaign Tech Pyrrolobenzodiazepine derivatives,their preparation,and compositions containing them
EP0563475B1 (en) 1992-03-25 2000-05-31 Immunogen Inc Cell binding agent conjugates of derivatives of CC-1065
DE69925133T2 (en) 1998-08-27 2006-01-19 Spirogen Ltd., Ryde PYRROLOBENZODIAZEPINE
GB9818731D0 (en) 1998-08-27 1998-10-21 Univ Portsmouth Compounds
CA2388063C (en) 1999-11-24 2010-06-08 Immunogen, Inc. Cytotoxic agents comprising taxanes and their therapeutic use
US6548042B2 (en) * 2000-08-07 2003-04-15 Arstad Erik Bis-phosphonate compounds
UA75093C2 (en) * 2000-10-06 2006-03-15 Dimensional Pharm Inc Aminopyridinyl-,aminoguanidinyl-, and alkoxyguanidinesubstituted phenylsubstituted phenylacetamides as protease inhibitors
US6441163B1 (en) 2001-05-31 2002-08-27 Immunogen, Inc. Methods for preparation of cytotoxic conjugates of maytansinoids and cell binding agents
US6716821B2 (en) 2001-12-21 2004-04-06 Immunogen Inc. Cytotoxic agents bearing a reactive polyethylene glycol moiety, cytotoxic conjugates comprising polyethylene glycol linking groups, and methods of making and using the same
US6756397B2 (en) 2002-04-05 2004-06-29 Immunogen, Inc. Prodrugs of CC-1065 analogs
BR0313197A (en) 2002-08-02 2005-08-09 Immunogen Inc Cytotoxic agents containing potent taxanes and their therapeutic use
DE60336149D1 (en) 2002-08-16 2011-04-07 Immunogen Inc Highly reactive and soluble crosslinkers and their use in the preparation of conjugates for the targeted delivery of small-molecule drugs
CA2520897C (en) 2003-03-31 2010-08-24 Council Of Scientific And Industrial Research Pyrrolo (2,1-c)(1,4) benzodiazepine dimers as antitumour agents and process thereof
ATE421967T1 (en) 2003-03-31 2009-02-15 Council Scient Ind Res NON-CROSS-LINKING PYRROLOÄ2,1-CÜÄ1, 4ÜBENZODIAZEPINES AS POTENTIAL ANTITUMOR AGENTS AND THEIR PRODUCTION
RU2338747C2 (en) 2003-03-31 2008-11-20 Каунсил Оф Сайентифик Энд Индастриал Рисерч DIMERS OF PYRROL[2,1-c][1,4]BENZODIAZEPINE AS ANTITUMORAL AGENTS AND METHOD OF THEIR OBTAINING
RU2314309C2 (en) 2003-03-31 2008-01-10 Каунсил Оф Сайентифик Энд Индастриал Рисерч Pyrrolo[2.1-c][1.4]benzodiazepines, method for their preparing and pharmaceutical composition based on thereof
US8088387B2 (en) 2003-10-10 2012-01-03 Immunogen Inc. Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates, and methods of making said conjugates
US7276497B2 (en) 2003-05-20 2007-10-02 Immunogen Inc. Cytotoxic agents comprising new maytansinoids
WO2005040170A2 (en) 2003-10-22 2005-05-06 Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Pyrrolobenzodiazepine derivatives, compositions comprising the same and methods related thereto
AU2003300718A1 (en) 2003-12-31 2005-07-21 Council Of Scientific And Industrial Research Process for preparing pyrrolo(2, 1-c) (1, 4) benzodiazepine hybrids
WO2005085251A1 (en) * 2004-03-01 2005-09-15 Spirogen Limited 11-hydroxy-5h-pyrrolo[2,1-c][1,4]benzodiazepin-5-one derivatives as key intermediates for the preparation of c2 substituted pyrrolobenzodiazepines
GB0404578D0 (en) 2004-03-01 2004-04-07 Spirogen Ltd Pyrrolobenzodiazepines
GB0410725D0 (en) 2004-05-13 2004-06-16 Spirogen Ltd Pyrrolobenzodiazepine therapeutic agents
GB0412492D0 (en) * 2004-06-04 2004-07-07 Sterix Ltd Compound
US7612062B2 (en) 2005-04-21 2009-11-03 Spirogen Limited Pyrrolobenzodiazepines
GB0508084D0 (en) * 2005-04-21 2005-06-01 Spirogen Ltd Pyrrolobenzodiazepines
US8637664B2 (en) 2005-10-05 2014-01-28 Spirogen Sarl Alkyl 4- [4- (5-oxo-2,3,5, 11a-tetrahydo-5H-pyrrolo [2, 1-c] [1,4] benzodiazepine-8-yloxy)-butyrylamino]-1H-pyrrole-2-carboxylate derivatives and related compounds for the treatment of a proliferative disease
EP1979349B1 (en) * 2005-12-21 2010-07-28 Abbott Laboratories Anti-viral compounds
RS52060B (en) 2006-01-25 2012-04-30 Sanofi CYTOTOXIC AGENTS CONTAINING NEW TOMAIMYCIN DERIVATIVES
WO2007093873A1 (en) 2006-02-13 2007-08-23 Council Of Scientific And Industrial Research Bis-pyrr0l0[2,l-c] [1, 4] benzodiazepine- anthraquinone conjugates as antitumour agents and a process for the preparation thereof
EP2032606B1 (en) 2006-05-30 2013-11-27 Genentech, Inc. Antibodies and immunoconjugates and uses therefor
SI2019104T1 (en) 2007-07-19 2013-12-31 Sanofi Cytotoxic agents comprising new tomaymycin derivatives and their therapeutic use
JP5404624B2 (en) 2007-08-01 2014-02-05 カウンスィル オブ サイエンティフィック アンド インダストリアル リサーチ Pyrrolo [2,1-c] [1,4] benzodiazepine-glycoside prodrugs useful as selective antitumor agents
NZ610239A (en) 2008-04-30 2014-11-28 Immunogen Inc Cross-linkers and their uses
SG189817A1 (en) 2008-04-30 2013-05-31 Immunogen Inc Potent conjugates and hydrophilic linkers
GB0819095D0 (en) 2008-10-17 2008-11-26 Spirogen Ltd Pyrrolobenzodiazepines
GB0822260D0 (en) * 2008-12-05 2009-01-14 Merten Christoph Assay
KR101172638B1 (en) * 2008-12-30 2012-08-08 조선대학교산학협력단 Thiazolidinedione Derivative and Use Thereof
RU2683325C2 (en) * 2009-02-05 2019-03-28 Иммьюноджен, Инк. New benzodiazepine derivatives
CN102596922A (en) 2009-10-06 2012-07-18 免疫基因公司 Potent conjugates and hydrophilic linkers
US8314250B2 (en) * 2009-11-24 2012-11-20 Hoffmann-La Roche Inc. Sultam derivatives
EP2511260B1 (en) * 2009-12-08 2015-07-29 Gifu University Aromatic compound, modification carrier that uses same and is used for synthesizing an oligonucleotide derivative, oligonucleotide derivative, and oligonucleotide construct
US8962279B2 (en) * 2009-12-30 2015-02-24 Intel Corporation Solid-phase chelators and electronic biosensors
PL3202460T3 (en) * 2010-02-11 2019-12-31 Celgene Corporation Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the same
TWI622402B (en) 2010-02-24 2018-05-01 免疫遺傳股份有限公司 Folate receptor 1 antibodies and immunoconjugates and their use
JP5875083B2 (en) 2010-04-15 2016-03-02 メディミューン リミテッド Pyrrolobenzodiazepine for the treatment of proliferative diseases
SI2528625T1 (en) 2010-04-15 2013-11-29 Spirogen Sarl Pyrrolobenzodiazepines and conjugates thereof
CA2795349C (en) * 2010-04-15 2016-11-29 Seattle Genetics, Inc. Targeted pyrrolobenzodiazepine conjugates
CN102234253B (en) * 2011-06-02 2013-07-03 重庆莱美药业股份有限公司 Method for preparing febuxostat intermediate
HK1211208A1 (en) 2012-08-22 2016-05-20 Immunogen, Inc. Cytotoxic benzodiazepine derivative
EP3052464B1 (en) * 2013-10-04 2020-04-15 Novartis AG 3'end caps for rna-interferring agents for use in rna interference
CN104628772A (en) 2013-11-07 2015-05-20 四川恒康发展有限责任公司 Antitumor prodrug, activator, composition, and application thereof
CN103664896B (en) * 2013-11-25 2016-03-02 济南精合医药科技有限公司 A kind of synthetic process of crizotinib serving as antitumor molecular targeting medicament
WO2016036804A1 (en) 2014-09-03 2016-03-10 Immunogen, Inc. Cytotoxic benzodiazepine derivatives
EP3325482B1 (en) * 2015-07-21 2020-06-24 ImmunoGen, Inc. Methods of preparing cytotoxic benzodiazepine derivatives
US20170189548A1 (en) * 2015-11-25 2017-07-06 Immunogen, Inc. Pharmaceutical formulations and methods of use thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012128868A1 (en) * 2011-02-15 2012-09-27 Immunogen, Inc. Cytotoxic benzodiazepine derivatives
WO2016036794A1 (en) * 2014-09-03 2016-03-10 Immunogen, Inc. Conjugates comprising cell-binding agents and cytotoxic agents
WO2016036801A1 (en) * 2014-09-03 2016-03-10 Immunogen, Inc. Cytotoxic benzodiazepine derivatives

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4729535A2 (en) 2016-10-19 2026-04-22 Invenra Inc. Antibody constructs
WO2018075692A2 (en) 2016-10-19 2018-04-26 Invenra Inc. Antibody constructs
US11965033B2 (en) 2016-12-22 2024-04-23 Università Degli Studi Magna Graecia Catanzaro Monoclonal antibody targeting a unique sialoglycosylated cancer-associated epitope of CD43
US11174318B2 (en) 2016-12-22 2021-11-16 Università Degli Studi Magna Graecia Catanzaro Monoclonal antibody targeting a unique sialoglycosylated cancer-associated epitope of CD43
KR102480594B1 (en) 2017-01-25 2022-12-26 이뮤노젠 아이엔씨 Methods for preparing cytotoxic benzodiazepine derivatives
WO2018140435A1 (en) * 2017-01-25 2018-08-02 Immunogen, Inc. Methods of preparing cytotoxic benzodiazepine derivatives
US10385071B2 (en) 2017-01-25 2019-08-20 Immunogen, Inc. Methods of preparing cytotoxic benzodiazepine derivatives
KR20190116331A (en) * 2017-01-25 2019-10-14 이뮤노젠 아이엔씨 Method for preparing cytotoxic benzodiazepines derivatives
US11981687B2 (en) 2017-01-25 2024-05-14 Immunogen, Inc. Methods of preparing cytotoxic benzodiazepine derivatives
US10844078B2 (en) 2017-01-25 2020-11-24 Immunogen, Inc. Methods of preparing cytotoxic benzodiazepine derivatives
US11390633B2 (en) 2017-01-25 2022-07-19 Immunogen, Inc. Methods of preparing cytotoxic benzodiazepine derivatives
WO2019234136A1 (en) 2018-06-05 2019-12-12 King's College London Btnl3/8 targeting constructs for delivery of payloads to the gastrointestinal system
JP2022512935A (en) * 2018-11-12 2022-02-07 イミュノジェン・インコーポレーテッド Method for preparing cytotoxic benzodiazepine derivative
US11396519B2 (en) 2018-11-12 2022-07-26 Immunogen, Inc. Methods of preparing cytotoxic benzodiazepine derivatives
RU2807546C2 (en) * 2018-11-12 2023-11-16 Иммуноджен, Инк. Methods for obtaining cytotoxic benzodiazepine derivatives
RU2813137C2 (en) * 2018-11-12 2024-02-06 Иммуноджен, Инк. Methods of obtaining cytotoxic benzodiazepine derivatives
JP7437395B2 (en) 2018-11-12 2024-02-22 イミュノジェン・インコーポレーテッド Method for preparing cytotoxic benzodiazepine derivatives
US10851117B2 (en) 2018-11-12 2020-12-01 Immunogen, Inc. Methods of preparing cytotoxic benzodiazepine derivatives
US11981688B2 (en) 2018-11-12 2024-05-14 Immunogen, Inc. Methods of preparing cytotoxic benzodiazepine derivatives
EP4361128A3 (en) * 2018-11-12 2024-07-17 ImmunoGen, Inc. Methods of preparing cytotoxic benzodiazepine derivatives
WO2020102051A1 (en) * 2018-11-12 2020-05-22 Immunogen, Inc. Methods of preparing cytotoxic benzodiazepine derivatives
WO2020205564A1 (en) * 2019-03-29 2020-10-08 Immunogen, Inc. Cytotoxic bis-benzodiazepine derivatives and conjugates thereof with cell-binding agents for inhibiting abnormal cell growth or for treating proliferative diseases
WO2024005123A1 (en) 2022-06-30 2024-01-04 東レ株式会社 Pharmaceutical composition for treating and/or preventing cancer

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