Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
  • C07D471/14—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
  • C07D498/14—Ortho-condensed systems
• • 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
  • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
  • C07D471/18—Bridged systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
  • C07D498/18—Bridged systems

Definitions

• the present invention relates to macrocyclic compounds, in particular macrocyclic pyridotriazine derivatives and the prodrugs thereof, to methods to prevent or treat influenza viral infections by using said compounds and to said compounds for use as a medicine, more preferably for use as a medicine to treat or prevent influenza viral infections.
• the present invention also relates to pharmaceutical compositions or combination preparations of the compounds, to the compositions or preparations for use as a medicine, more preferably for the prevention or treatment of influenza viral infections.
• Influenza is a serious public health problem with high incidence in the human population resulting in regular large-scale morbidity and mortality.
• WHO the average global burden of annual epidemics may be on the order of 1 billion cases, 3-5 million cases of severe illness and 300,000-500,000 deaths annually.
• annual influenza epidemics lead to approximately 30 million outpatient visits, resulting in medical costs of $10 billion annually.
• Lost earnings due to illness and loss of life represent a cost of over $15 billion annually and the total US economic burden of annual influenza epidemics amounts to over $85 billion.
• Influenza A viruses are the most common form, which can spread in mammals and birds.
• the subtypes of influenza A are named by the types of surface proteins hemagglutinin (H) and neuraminidase (N). There are 18 different hemagglutinin and 11 known neuraminidases.
• Current seasonal influenza viruses found in human are mainly H1N1 and H3N2 subtypes.
• Influenza B viruses are usually found only in humans. They are not divided into subtypes, but can be further broken down into different strains. Circulating influenza viruses are highly variable each year, and both influenza A and B cause seasonal epidemics all over the world. Influenza C viruses give much milder symptoms, which do not cause epidemics.
• the genome comprises 8 segments, encoding 9-11 proteins, depending on the type.
• Influenza A encodes 11 proteins, which includes the surface proteins (hemagglutinin (HA) and Neuraminidase (NA), the polymerase complex, nucleoprotein (NP), membrane proteins (Ml and M2), and other proteins (NS1, NS2, NEP).
• the polymerase complex is a heterotrimer composed of three subunits: polymerase acid (PA), polymerase basic 1 (PB1) and polymerase basic 2 (PB2). This polymerase is responsible for replication and transcription of the viral RNA in the nuclei of infected cells.
• the PA subunit contains the endonuclease active site. The endonuclease activity of the PA cleaves the cellular mRNA. which is then used by the PB1 subunit as a primer for the viral mRNA synthesis.
• influenza vaccine may be less effective in preventing illness among the elderly, and may only reduce severity of disease and incidence of complications and deaths.
• influenza vaccination is most effective when circulating viruses are well-matched with vaccine viruses, and the success of vaccination is largely dependent on the good prediction of the most prevalent virus type of the season. Rapid and continual evolution of influenza viral strains through antigenic drift, coupled with the short-lived nature of vaccine-induced immune responses to current influenza vaccines, means that vaccination with seasonally appropriate strains is required every year for prevention.
• influenza antiviral drugs There are two classes of influenza antiviral drugs available on the market: neuraminidase inhibitors and M2 channel inhibitors. Neuraminidase inhibitors oseltamivir or zanamivir are the primary antiviral agents recommended for the prevention and treatment of influenza. These are effective against both influenza type A and B viruses. Development of resistance to these antiviral drugs has been identified during treatment of seasonal influenza and in sporadic oseltamivir- resistant 2009 H1N1 virus, but the public health impact has been limited to date.
• M2 channel inhibitors such as amantadine and rimantadine (adamantanes) are active against influenza A strains, but not influenza B strains.
• Amantadine and rimantadine are active against influenza A strains, but not influenza B strains.
• Adamantane resistance among circulating influenza A viruses increased rapidly worldwide beginning during 2003-2004. Therefore, amantadine and rimantadine are not recommended for antiviral treatment or chemoprophylaxis of currently circulating influenza A virus strains.
• the novel swine H1N1 strain caused an unexpected influenza pandemic as a result of reassortment of genes from human, pig, and bird’s H1N1 viruses.
• This past pandemic together with the ongoing circulation of highly pathogenic avian H5N1 strains and the recent emergence of the H7N9 virus, a new reassortant of avian origin isolated in China, and associated with severe respiratory disease with 40% of mortality, which could potentially adapt for human-to-human transmission, highlighted the vulnerability of the world population to novel influenza strains.
• the present invention provides macrocyclic pyridotriazine derivatives and the prodrugs thereof, the pharmaceutically acceptable salts and solvates thereof, having activity against influenza virus, in particular influenza A and B strains.
• the present invention provides compounds of Formula (I)
• Ri is C, -CH2-CH2-O-, C3-6cycloalkyl, oxetanyl, C 1-3 alkyl-cyclopropyl or Ci-3alkyl- cyclobutyl, optionally substituted by one or more substituents independently selected from, halo, oxo, Chk-methoxy, Ci- 4 alkyl, Ci -6 cycloalkyl and tetrahydrofuran;
• R2 is Ci- 6 alkyl, Ci- 6 alkyl-0-, Ci- 6 alkyl-N-, C2-6alkenyl, C 2-6 alkenyl-0- or C2-6alkenyl-N- optionally substituted by one or more substituents independently selected from halo, oxo or Ci- 4 alkyl;
• R3 is C or O optionally substituted by one or more substituents independently selected from halo, oxo and methyl;
• R2 and R3 together form Cb-xalkenyl optionally substituted by one or more substituents independently selected from halo, oxo and methyl;
• Xi to X9 are each N or C and wherein any of Xi to X9 is C, said C is optionally substituted by one or more substituents independently selected from Ci- 4 alkyl, C 3-6 cycloalkyl, CHF 2 , CH 2 F, CF 3 , OCF 3 , SCF 3 , OCH 3 , SCH 3 , S-(0) 2 -CH 3 or halogen;
• the dotted lines are each an optional bond
• R 4 is absent, -CH 2 -CH 2 -, -0-CH 2 -, -S-CH 2 -, S-(0) 2 -CH 2 or cyclopropyl optionally substituted by one or more substituents independently selected from halo, oxo and methyl;
• Y is Ci- 6 alkyl, C 3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, Ci -4 alkyl-(0-R 7 ), Ci -4 alkyl- N-(R 7 )(R 8 ), R 7 -0-R 8 -0-CH 2 ;
• R 7 and R 8 are independently hydrogen or Ci -4 alkyl
• 3 ⁇ 4 is H, methyl or CH 2 -0-CH 3 ;
• the invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising a therapeutically effective amount, in particular an anti-virally effective amount, of the compound of Formula (I) or a stereoisomeric forms thereof or a prodrug thereof, a pharmaceutically acceptable salt, solvate or polymorph thereof, and one or more pharmaceutically acceptable excipients, diluents or carriers.
• the invention further relates to a compound of Formula (I) or a stereoisomeric forms thereof or a prodrug thereof or a pharmaceutically acceptable salt, solvate or polymorph thereof, for use as a medicament, in particular for use in the treatment or in the prevention of influenza virus infections, particularly influenza A and/or influenza B virus infections.
• the invention relates to the use of a compound of Formula (I) or a stereoisomeric forms thereof or a prodrug thereof or a pharmaceutically acceptable salt, solvate or polymorph thereof, in combination with an additional antiviral for use in the treatment or prevention of influenza virus infections, particularly influenza A and/or influenza B virus infections.
• the invention also relates to a product comprising a compound of Formula (I) or a stereoisomeric forms thereof or a prodrug thereof or a pharmaceutically acceptable salt, solvate or polymorph thereof, and an additional pharmaceutical agent, in particular an additional antiviral, as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of influenza virus infections, influenza A and/or influenza B virus infections.
• a product comprising a compound of Formula (I) or a stereoisomeric forms thereof or a prodrug thereof or a pharmaceutically acceptable salt, solvate or polymorph thereof, and an additional pharmaceutical agent, in particular an additional antiviral, as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of influenza virus infections, influenza A and/or influenza B virus infections.
• the term“about” has the meaning known to the person skilled in the art. In certain embodiments, the term“about” may be left out and the exact amount is meant. In other embodiments the term“about” means that the numerical following the term“about” is in the range of ⁇ 15%, or of ⁇ 10%, or of ⁇ 5%, or of ⁇ 1%, of said numerical value.
• C x-y refers to the number of carbon atoms in a given group.
• a C l-6 alkyl group contains from 1 to 6 carbon atoms
• a Ci- 4 alkyl group contains from 1 to 4 carbon atoms
• a C 1-3 alkyl group contains from 1 to 3 carbon atoms
• a C 3-6 cycloalkyl group contains from 3 to 6 carbon atoms, and so on.
• alkyl refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon containing the specified number of carbon atoms.
• cycloalkyl refers to a carbocyclic ring containing the specified number of carbon atoms including organic, inorganic and heterocycles.
• C 2 -C 6 alkenyl and“Cb-Cxalkenyl” used herein as a group or part of a group are meant to comprise straight or branched chain unsaturated hydrocarbon radicals having at least one double bond, and preferably having one double bond, and respectively from 2 to 6 and 2 to 8 carbon atoms such as ethenyl, propenyl, buten-l-yl, buten-2-yl, penten-l-yl, penten-2-yl, hexen-l-yl, hexen-2-yl, hexen-3-yl, 2-methylbuten-l-yl, hepten-l-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, 2-methylhexen-l-yl, octen-l-yl, octen-2-yl, octen-3-yl, octen-4-yl, 2-methylhexen-
• halo or“halogen” is generic to fluoro, chloro, bromo and iodo.
• radical positions on any molecular moiety used in the definitions may be anywhere on such moiety as long as it is chemically stable. Radicals used in the definitions of the variables include all possible isomers unless otherwise indicated.
• each definition is independent.
• prodrug of a compound of the invention includes any compound that when administered to a biological system, generates the biologically active agent having the desired pharmacological effect, i.e. the antiviral activity, as a result of a biotransformation or chemical transformation (e.g. spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), and/or metabolic chemical reaction(s)). Ideally the prodrug is pharmacologically inactive.
• General information on prodrugs may be found e.g. in Bundegaard, H.“Design of Prodrugs” p. 1-92, Elsevier, New York-Oxford (1985).
• prodrug forming strategies are available in the field of antivirals and known to the skilled person. Such prodrug strategies have been reviewed, for instance, in Jones RJ and Bischofberger N, Antiviral Research 1995, 27, 1-17; Sofia, MJ, Antivir Chem Chemother 2011, 22, 23-49; Bobeck DR et al. Antiviral Therapy 2010, 15, 935-950; Sofia MJ, Adv Pharmacol 2013, 67, 39-73; Schultz C, Bioorg Med Chem 2003, 11, 885- 898; Pertusati F et al. Antivir Chem Chemother 2012, 22, 181-203; Sofia MJ et al. J Med Chem 2012, 55(6), 2481-2531; Coats SJ et al. Antiviral Res 2014, 102, 119-147; Meier C and Balzarini J, Antiviral Res 2006, 71 (2-3), 282-292, incorporated by reference herein in their entirety.
• Prodrugs may be prepared by modifying functional groups present on the compound in such a way that the modified functional groups are cleaved, in vivo when such prodrug is administered to a subject. The modifications typically are achieved by synthesising the parent compound with a prodrug substituent.
• prodrugs include compounds of the invention wherein a hydroxyl, amino or phosphate group is modified.
• polymorph refers to the ability of the compound of the invention to exist in more than one form or crystal structure.
• subject refers to a warm-blooded animal, preferably a mammal (e.g. cat, dog, primate or human), more preferably a human, who is or has been the object of treatment, observation or experiment.
• a mammal e.g. cat, dog, primate or human
• pharmaceutically acceptable salt refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
• the salt is an acid addition salt of the compound.
• Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid.
• Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic. p- toluenesulfonic. salicylic or naphthalenesulfonic acid.
• an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic.
• p- toluenesulfonic salicylic or naphthalenesulfonic acid.
• Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, Ci -7 alkylamine, Cyclohexylamine, Triethanolamine, ethyienediamine, and salts with amino acids such as arginine and lysine.
• a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, Ci -7 alkylamine, Cyclohexylamine, Triethanol
• solvates covers any pharmaceutically acceptable solvates that the compounds of Formula (I), as well as the prodrugs and the salts thereof, are able to form.
• Such solvates are for example hydrates, alcoholates, e.g. ethanolates, propanolates, and the like.
• terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medicinal doctor or other clinician, which includes alleviation or reversal of the symptoms of the disease or disorder being treated.
• composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
• treatment is intended to refer to all processes wherein there may be a slowing, interrupting, arresting or stopping of the progression of a disease, but does not necessarily indicate a total elimination of all symptoms.
• stereochemical configuration for centres in some compounds may be designated“i?” or“A’ when the mixture(s) was separated; for some compounds, the stereochemical configuration at indicated centres has been designated as“R*”,“S*”,“*R” or“*S” when the absolute stereochemistry is undetermined although the compound itself has been isolated as a single stereoisomer and is enantiomerically/diastereomerically pure.
• E*”,“Z*”,“*E” or“*E” when shown in a compound containing a double bond refer to a double bond for which the configuration is undetermined although the compound itself has been isolated as a single stereoisomer.
• stereoisomerically pure concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e.
• Pure stereoisomeric forms of the compounds and intermediates of this invention may be obtained by the application of art-known procedures.
• enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids or bases. Examples thereof are tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid.
• enantiomers may be separated by chromatographic techniques using chiral stationary layers.
• Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
• said compound is synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
• the diastereomeric racemates of the compounds of Formula (I) can be obtained separately by conventional methods.
• Appropriate physical separation methods that may advantageously be employed are, for example, selective crystallization and chromatography, e.g. column chromatography.
• Ri is C, -CH 2 -CH 2 -O-, C 3-6 cycloalkyl, oxetanyl, C 1-3 alkyl-cyclopropyl or Ci- 3 alkyl- cyclobutyl, optionally substituted by one or more substituents independently selected from, halo, oxo, CFk-methoxy, Ci- 4 alkyl, Ci -6 cycloalkyl and tetrahydrofuran;
• R 2 is Ci- 6 alkyl, Ci- 6 alkyl-0-, Ci- 6 alkyl-N-, C 2-6 alkenyl, C 2-6 alkenyl-0- or C 2-6 alkenyl-N- optionally substituted by one or more substituents independently selected from halo, oxo or Ci- 4 alkyl;
• R3 is C or O optionally substituted by one or more substituents independently selected from halo, oxo and methyl;
• R2 and R3 together form CYxalkenyl optionally substituted by one or more substituents independently selected from halo, oxo and methyl;
• Xi to X9 are each N or C and wherein any of Xi to X9 is C, said C is optionally substituted by one or more substituents independently selected from Ci -4 alkyl, C3-6cycloalkyl, CHF2, CH 2 F, CF3, 0CF3, SCF 3 , 0CH3, SCH 3 , S-(0) 2 -CH 3 or halogen;
• the dotted lines are each an optional bond
• R 4 is absent, -CH2-CH2-, -O-CH2-, -S-CH2-, S-(0) 2 -CH 2 or cyclopropyl optionally substituted by one or more substituents independently selected from halo, oxo and methyl;
• Y is Ci- 6 alkyl, C 3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, Ci -4 alkyl-(0-R 7 ), Ci -4 alkyl- N-(RV)(R 8 ), R7-O-R8-O-CH2;
• R 7 and Rx are independently hydrogen or Ci -4 alkyl
• R 6 is H, methyl or CH 2 -O-CH 3 ;
• Ri is C, -CH 2 -CH 2 -O-, C 3-6 cycloalkyl, Ci- 3 alkyl-cyclopropyl or Ci- 3 alkyl-cyclobutyl, optionally substituted by one or more substituents independently selected from, halo, oxo, CFk-methoxy, Ci -4 alkyl, and Ci -6 cycloalkyl;
• R 2 is Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkenyl-0- or C 2-6 alkenyl-N- optionally substituted by one or more substituents independently selected from halo, oxo or Ci -4 alkyl;
• R3 is C or O optionally substituted by one or more substituents independently selected from halo, oxo and methyl;
• R2 and R3 together form CYxalkenyl optionally substituted by one or more substituents independently selected from halo, oxo and methyl;
• Xi to X9 are each N or C and wherein any of Xi to X9 is C, said C is optionally substituted by one or more substituents independently selected from Ci- 4 alkyl, C 3-6 cycloalkyl, CHF 2 , CH 2 F, CF 3 , OCF 3 , SCF 3 , OCH 3 , SCH 3 , S-(0) 2 -CH 3 or halogen;
• R 4 is absent, -CH 2 -CH 2 - or -S-CH 2 - optionally substituted by one or more substituents independently selected from halo, oxo and methyl;
• Y is Ci- 6 alkyl, C 3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, Ci -4 alkyl-(0-R 7 ), Ci -4 alkyl- N-(R 7 )(R 8 ), R 7 -0-R 8 -0-CH 2 ;
• R 7 and R 8 are independently hydrogen or Ci -4 alkyl
• 3 ⁇ 4 is H or methyl.
• Ri is C, C 3-6 cycloalkyl, Ci -3 alkyl-cyclopropyl or Ci -3 alkyl-cyclobutyl, optionally substituted by one or more substituents independently selected from, halo, Ci -4 alkyl, and Ci - 6 cycloalkyl;
• R 2 is Ci- 6 alkyl or C 2-6 alkenyl optionally substituted by one or more substituents independently selected from halo or Ci -4 alkyl;
• R 3 is C or O optionally substituted by one or more substituents independently selected from halo and methyl;
• R 2 and R 3 together form C 2-8 alkenyl optionally substituted by one or more substituents independently selected from halo, oxo and methyl;
• Xi to X9 are each N or C and wherein any of Xi to X9 is C, said C is optionally substituted by one or more substituents independently selected from Ci- 4 alkyl, C 3-6 cycloalkyl, CHF 2 , CH 2 F, CF 3 , OCF 3 , SCF 3 , OCH 3 , SCH 3 , S-(0) 2 -CH 3 or halogen;
• R 4 is absent or -S-CH 2 - optionally substituted by one or more substituents independently selected from halo and methyl;
• 3 ⁇ 4 is H or methyl.
• Ri is C, C 3-6 cycloalkyl or Ci -3 alkyl-cyclopropyl, optionally substituted by one or more substituents independently selected from, halo and Ci -4 alkyl;
• R 2 is Ci- 6 alkyl or C 2-6 alkenyl optionally substituted by one or more substituents independently selected from halo or Ci -4 alkyl;
• R 3 is C or O optionally substituted by one or more substituents independently selected from halo and methyl;
• Xi to X9 are each N or C and wherein any of Xi to X9 is C, said C is optionally substituted by one or more substituents independently selected from Ci- 4 alkyl, C 3-6 cycloalkyl, CHF 2 , CH 2 F, CF 3 , OCF 3 , SCF 3 , OCH 3 , SCH 3 , S-(0) 2 -CH 3 or halogen;
• R 4 is absent or -S-CH 2 - optionally substituted by one or more substituents independently selected from halo and methyl;
• R5 is H
• 3 ⁇ 4 is H or methyl.
• Ri is C, C 3-6 cycloalkyl or Ci -3 alkyl-cyclopropyl, optionally substituted by one or more substituents independently selected from, halo and Ci -4 alkyl;
• R 2 is Ci- 6 alkyl or C 2-6 alkenyl optionally substituted by one or more substituents independently selected from halo or Ci -4 alkyl;
• R 3 is C or O optionally substituted by one or more substituents independently selected from halo and methyl;
• Xi to X9 are each C which is optionally substituted by one or more substituents independently selected from Ci -4 alkyl, C 3-6 cycloalkyl or halogen;
• R 4 is absent or -S-CH 2 - optionally substituted by one or more substituents independently selected from halo and methyl;
• R5 is H
• 3 ⁇ 4 is H or methyl.
• the present invention relates to those compounds of Formula (I) or any subgroup thereof as mentioned in any of the other embodiments, wherein Ri is C, -C 3-6 cycloalkyl, Ci -3 alkyl-cyclopropyl or Ci -3 alkyl-cyclobutyl, optionally substituted by one or more substituents independently selected from, halo and Ci -4 alkyl.
• the present invention relates to those compounds of Formula (I) or any subgroup thereof as mentioned in any of the other embodiments, wherein R 2 is Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkenyl-0- or C 2-6 alkenyl-N- optionally substituted by one or more substituents independently selected from halo or Ci -4 alkyl.
• the present invention relates to those compounds of Formula (I) or any subgroup thereof as mentioned in any of the other embodiments, wherein R 3 is C optionally substituted by one or more substituents independently selected from halo and methyl. In an embodiment, the present invention relates to those compounds of Formula (I) or any subgroup thereof as mentioned in any of the other embodiments, wherein R 3 is O.
• the present invention relates to those compounds of Formula (I) or any subgroup thereof as mentioned in any of the other embodiments, wherein R 2 and R 3 together form Cb-xalkenyl optionally substituted by one or more substituents independently selected from halo and methyl.
• the present invention relates to those compounds of Formula (I) or any subgroup thereof as mentioned in any of the other embodiments, wherein Xi to X 9 are each N.
• the present invention relates to those compounds of Formula (I) or any subgroup thereof as mentioned in any of the other embodiments, wherein Xi to X 9 are each C, said C is optionally substituted by one or more substituents independently selected from Ci- 4 alkyl, C 3- 6cycloalkyl or halogen.
• the present invention relates to those compounds of Formula (I) or any subgroup thereof as mentioned in any of the other embodiments, wherein R 4 is absent.
• the present invention relates to those compounds of Formula (I) or any subgroup thereof as mentioned in any of the other embodiments, wherein R 4 is -CH 2 - CFF 2 - optionally substituted by one or more substituents independently selected from halo and methyl;
• the present invention relates to those compounds of Formula (I) or any subgroup thereof as mentioned in any of the other embodiments, wherein R 4 is -S- CFF 2 - optionally substituted by one or more substituents independently selected from halo and methyl.
• the present invention relates to those compounds of Formula (I) or any subgroup thereof as mentioned in any of the other embodiments, wherein R 5 is H.
• the present invention relates to those compounds of Formula (I) or any subgroup thereof as mentioned in any of the other embodiments, wherein Re is H.
• Ri is C optionally substituted by one or more substituents independently selected from, halo and Ci- 4 alkyl;
• R- 2 is C 2-6 alkenyl
• R-3 is O
• Xi to X 9 are each C which is optionally substituted by one or more substituents independently selected from Ci -4 alkyl or halogen;
• R 4 is absent
• R 5 and 5 are each H.
• Ri is C 3 -6cycloalkyl
• R 2 is C 2-6 alkenyl
• R 3 is O
• Xi to X 9 are each C which is optionally substituted by one or more substituents independently selected from Ci -4 alkyl or halogen;
• R 4 is absent
• R 5 and 5 are each H.
• Ri is C, optionally substituted by one or more substituents independently selected from, halo and Ci -4 alkyl;
• R 2 is C 2-6 alkenyl optionally substituted by one or more substituents independently selected from halo or Ci -4 alkyl;
• R3 is O
• Xi to X 9 are each C which is optionally substituted by one or more substituents independently selected from Ci -4 alkyl, C 3-6 cycloalkyl or halogen;
• R 4 is -S-CH 2 - optionally substituted by one or more substituents independently selected from halo and methyl;
• R 5 and 5 are each H.
• Ri is C 3-6 cycloalkyl
• R 2 is Ci- 6 alkyl optionally substituted by one or more substituents independently selected from halo or Ci -4 alkyl;
• R3 is O
• Xi to X 9 are each C which is optionally substituted by one or more substituents independently selected from Ci -4 alkyl, C 3-6 cycloalkyl or halogen;
• R 4 is -S-CH2- optionally substituted by one or more substituents independently selected from halo and methyl;
• R 5 and 5 are each H.
• compounds of Formula (I) are provided wherein
• Ri is Ci -3 alkyl-cyclopropyl optionally substituted by one or more substituents independently selected from halo and Ci -4 alkyl;
• R2 is C2-6alkenyl optionally substituted by one or more substituents independently selected from halo or Ci -4 alkyl;
• R 3 is O
• Xi to X9 are each C which is optionally substituted by one or more substituents independently selected from Ci -4 alkyl, C 3-6 cycloalkyl or halogen;
• R 4 is -S-CH2- optionally substituted by one or more substituents independently selected from halo and methyl;
• R 5 and 5 are each H.
• the present invention relates to those compounds of Formula (I) and the prodrugs thereof, the pharmaceutically acceptable salts, and the solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments wherein at least 1, 2, 3, 4 or 5 of Xi to X 9 is N.
• the compound of Formula (I) may be prepared by the methods described below, using synthetic methods known in the art of organic chemistry, or modifications and derivatisations that are familiar to those of skilled in the art.
• the starting materials used herein are commercially available or may be prepared by routine methods known in the art such as those methods disclosed in standard reference books. Preferred methods include, but are not limited to, those described below.
• HPLC High Performance Liquid Chromatography
• MS Mass Spectrometer
• SQL Single Quadrupole Detector
• MSD Mass Selective Detector
• RT room temperature
• BEH bridged ethylsiloxane/silica hybrid
• DAD Diode Array Detector
• HSS High Strength silica
• the HPLC measurement was performed using Analytical system from Waters comprises a modules pump-autosampler alliance 2695 and a diode array detector996. Data acquisition and reprocess was performed with a Waters-Micromass MassLynx data system.
• the SFC measurement was performed using an Analytical Supercritical fluid chromatography (SFC) system composed by a binary pump for delivering carbon dioxide (CO2) and modifier, an autosampler, a column oven, a diode array detector equipped with a high-pressure flow cell standing up to 400 bars. If configured with a Mass Spectrometer (MS) the flow from the column was brought to the (MS). It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time%) in order to obtain ions allowing the identification of the compound’s nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software. Analytical SFC-MS Methods (Flow expressed in mL/min; column temperature (T) in °C; Run time in minutes, Backpressure (BPR) in bars.
• SFC Analytical Supercritical fluid chromatography
• Values are either peak values or melt ranges, and are obtained with experimental uncertainties that are commonly associated with this analytical method.
• DSC823e (indicated as DSC)
• [a] l T (100a) / (l c): where / is the path length in dm and c is the concentration in g/lOO ml for a sample at a temperature T (°C) and a wavelength l (in nm). If the wavelength of light used is 589 nm (the sodium D line), then the symbol D might be used instead.
• the sign of the rotation (+ or -) should always be given. When using this equation, the concentration and solvent are always provided in parentheses after the rotation. The rotation is reported using degrees and no units of concentration are given (it is assumed to be g/lOO ml).
• Example 1 synthesis of 4-hydroxy-l6-phenyl-7,8,l l,l6-tetrahydro-6,l7- methanobenzo[&]pyrido[l,2-Z>][l,2,5]triazacyclotridecine-3,5-dione (Compound 1).
• Example 2 synthesis of l5-hydroxy-2-phenyl-l2,l3,l4,l6-tetrahydro-H7/-l(l,3)- pyrido[2,l-/][l,2,4]triazina-3(l,2)-benzenacyclononaphane-l4,l6-dione (Compound 2).
• methanesulfonyl chloride (974 pL, 12.59 mmol) was added dropwise to a solution of (2-(but-3-en-l-yl)phenyl)(phenyl)methanol (intermediate 2b, 1.5 g, 6.29 mmol) and NEt 3 (2.62 mL, l8.8 mmol) in CH2CI2 (30 mL). The mixture was stirred at 0°C for 2 h. Water was added and the mixture was extracted with CH2CI2.
• Example 4 synthesis of 4-hydroxy-l6-phenyl-7,8,9,l0,l l, l6-hexahydro-6, l7- methanobenzo[U]pyrido[l,2-/>][l,2,5]triazacyclotridecine-3,5-dione (Compound 4).
• Each enantiomer was further purified via achiral SFC (Stationary phase: NFL 5 pm 150 x 30 mm, Mobile phase: 80% CO2, 20% EtOH) to give 137 mg of enantiomer 5fA and 146 mg of enantiomer 5fB.
• Example 6 synthesis of (*//)- 15-hydroxy-2-phenyl- l 2, 13, 14, 16-tetrahydro- 1 1 H-4-oxa- l(l,3)-pyrido[2, l-f][l,2,4]triazina-3(l,3)-benzenacyclononaphan-7-ene-l4, l6-dione (compound 6)
• Example 8 synthesis of 12-hydroxy- 18-phenyl-6,7,8,9-tetrahydro- 18//- 10, 17- methanobenzo[Z>]pyrido[ 1 ,2 -f ⁇ [ 1 ]oxa[5,6,9]triazacyclotridecine- 11, 13 -dione
• the celite ® was washed with EtOAc, and then with CFbCb/MeOH The filtrate was concentrated under reduced pressure. Purification was carried out by flash chromatography over silica gel (regular 30 pm, 4 g, CH 2 CI 2 /CH 3 OH from 99/1 to 97/3). The pure fractions were collected and concentrated under reduced pressure.
• Example 9 synthesis of l5-hydroxy-2-phenyl-l2,l3,l4, l6-tetrahydro-l l77-4-oxa- 1 ( 1 ,3)-pyrido[2, 1 -f ⁇ [ 1 ,2,4]triazina-3 (1 ,2)-benzenacyclononaphane- 14, 16-dione
• Example 10 synthesis of (25' v E)-l5-hydroxy-2-phenyl-l2,l3, l4, l6-tetrahydro-l l/7-4- oxa- 1 ( 1 ,3)-pyrido[2, 1 -f ⁇ [ 1 ,2,4]triazina-3 (1 ,2)-benzenacyclononaphan-6-ene- 14, 16- dione (enantiomer 10A) and (27? ⁇ E)- l5-hydroxy-2-phenyl- 12, 13, 14, 16-tetrahydro- 1177- 4-oxa- 1 (1 ,3)-pyrido[2, 1 -f] [ 1 ,2,4]triazina-3 (1 ,2)-benzenacyclononaphan-6-ene- 14, 16- dione (enantiomer 10A) and (27? ⁇ E)- l5-hydroxy-2-phenyl- 12, 13, 14, 16-tetrahydro- 1177- 4-oxa- 1 (1 ,3)-
• Example 11 synthesis of l5-hydroxy-2-(pyridin-2-yl)-l2,l3,l4,l6-tetrahydro-l ⁇ H- 1 ( 1 ,3)-pyrido[2, 1 -f ⁇ [ 1 ,2,4]triazina-3 (1 ,2)-benzenacyclononaphane- 14,16-dione
• Example 12 synthesis of 4-hydroxy-l6-(pyridin-2-yl)-7,8,9,l0,l l, l6-hexahydro-6, l7- methanobenzo[k]pyrido[l,2-b][l,2,5]triazacyclotridecine-3,5-dione (Compound 12).
• Example 13 synthesis of 4-hydroxy-7-methyl- 15-phenyl-8,9, 10, 15-tetrahydro-7//-6, 16- methanobenzo[/]pyrido[l,2-Z>][l,2,5]triazacyclododecine-3,5-dione (Compound 13).
• Examples 15 and 16 synthesis of (Z)-l5-hydroxy-2-(pyridin-2-yl)-l2,l3,l4,l6- tetrahydro- 1 ⁇ H- 1 (1 ,3)-pyrido[2, 1 -f ⁇ [ 1 ,2,4]triazina-3 ( 1 ,2)-benzenacyclononaphan-5- ene- 14,16-dione (Compound 15) and (£)-l5-hydroxy-2-(pyridin-2-yl)-l2,l3,l4,l6- tetrahydro- 1 ⁇ H- 1 (1 ,3)-pyrido[2, 1 -f ⁇ [ 1 ,2,4]triazina-3 ( 1 ,2)-benzenacyclononaphan-5- ene- 14,16-dione (Compound 16).
• Example 18 synthesis of l2-hydroxy-l8-phenyl-5,8,9,l8-tetrahydro-l0,l7- methanobenzo[k]pyrido[ 1 ,2-Z>] [ 1 ,2,5,9]tetraazacyclotridecine-7, 11,13 (6//)-trione
• Example 19 synthesis of (*Z)-l5-hydroxy-2-phenyl-l2,l3, l4, l6-tetrahydro-l 177-4- oxa- 1 ( 1 ,3)-pyrido[2, 1 -f ⁇ [ 1 ,2,4]triazina-3 (1 ,2)-benzenacyclononaphan-7-ene- 14, 16- dione (compound 19)
• the two enantiomers were separated via chiral SFC (Stationary phase: Whelk 01 (S,S) 5 pm 250 x 21.1 mm, Mobile phase: 60% C0 2 , 40% MeOH) to give the first eluted enantiomer 19eA (531 mg) and the second eluted enantiomer 19eB (536 mg).
• Enantiomer 19eB (270 mg, 0.52 mmol) was treated under the same conditions and gave the same compound 19 (1 10 mg, racemate (full racemization occurred during this step).
• Hoveyda-Grubbs catalyst 2 nd generation [CAS 301224-40-8] (120 mg, 0.19 mmol) was added and the mixture was stirred at 80°C for 2 h.
• SiliaMetS ® DMT (1.2 g, 0.75 mmol) was added and the mixture was stirred at rt for 18 h.
• the reaction mixture was filtered through celite ® .
• Celite ® was washed with CH2CI2 and the filtrate was concentrated under reduced pressure. Purification was carried out by flash chromatography over silica gel (30 pm, 12 g, CH2CI2/CH3OH from 100/0 to 97/3).
• the two enantiomers were separated via chiral SFC (Stationary phase: Chiralcel ® OD-H 5 pm 250 x 20 mm, Mobile phase: 70% CO2, 30% MeOH) to give the first eluted enantiomer 20dA (17 mg) and the second eluted enantiomer 20dB (22 mg).
• Example 21 synthesis of (l7*f?,*Z)-4-hydroxy-l6-phenyl-7, l0, l l, l6-tetrahydro-6, l7- methanobenzo[&]pyrido[l,2-Z>][l,2,5]triazacyclotridecine-3,5-dione (Compound 21A) and (l7*ri',*Z)-4-hydroxy-l6-phenyl-7, 10, H, l6-tetrahydro-6, l7- methanobenzo[&]pyrido[l,2-Z>][l,2,5]triazacyclotridecine-3,5-dione (compound 21B)
• phenylmagnesium bromide [CAS 100-58-3] (35 mL, 34.89 mmol) was added dropwise to a solution of 2-(but-3-en-l-yl)benzaldehyde [CAS 70576-29-3] (4.3 g, 26.84 mmol) in THF (30 mL). The mixture was stirred under N 2 at rt for 1 h. The reaction was quenched at 0°C with a saturated aqueous solution of NELCl and the mixture was extracted with EtOAc.
• the two enantiomers were separated via chiral SFC (Stationary phase: Chiralcel ® OJ-H 5 pm 250 x 20mm, Mobile phase: 65% C0 2 , 35% MeOH) to give the first eluted enantiomer 22eA (326 mg) and the second eluted enantiomer 22eB (340 mg).
• Example 23 synthesis of (l8*f?)-l2-hydroxy-l8-phenyl-5,6,7,8,9, l8-hexahydro-l0, l7- methanodipyrido[l,2-b:2',3'-&][l,2,5]triazacyclotridecine-l l, l3-dione (Compound 23A) and (18 *S)- 12-hydroxy- 18-phenyl-5 ,6, 7, 8, 9, 18-hexahydro- 10, 17-methanodipyrido[ 1 ,2- b:2',3'-&][l,2,5]triazacyclotridecine-l l,l3-dione (Compound 23B)
• the two enantiomers were separated via chiral SFC (Stationary phase: Whelk ® 01 (S,S) 5 pm 250 x 21.1 mm, Mobile phase: 60% C0 2 , 40% MeOH) to give the first eluted enantiomer 23dA (190 mg) and the second eluted enantiomer 23dB (200 mg).
• Example 24 synthesis of (l8*f?,*Z)-l2-hydroxy-l8-phenyl-5,6,9, l8-tetrahydro-l0, l7- methanodipyrido[l,2-A2',3'-&][l,2,5]triazacyclotridecine-l l, l3-dione (Compound 24A) and ( 18 * , *Z )- 12-hydroxy- 18-phenyl-5 ,6,9, 18-tetrahydro- 10, 17-methanodipyrido[ 1 ,2- A2',3'-&][l,2,5]triazacyclotridecine-l l,l3-dione (Compound 24B)
• Example 25 synthesis of (l8*7?,Z)-2-fluoro-l8-(3-fluorophenyl)-l2-hydroxy-6,9- dihydro- 1877- 10, 17-methanobenzo[b]pyrido[ 1 ,2-f] [ 1 ]oxa[5,6,9]triazacyclotridecine- l l, l3-dione (Compound 25A) and (l8* ,Z)-2-fhioro-l8-(3-fhiorophenyl)-l2-hydroxy- 6, 9-dihydro- 1877- 10,17-methanobenzo[b]pyrido[ 1 ,2- _/][l]oxa[5,6,9]triazacyclotridecine-l l,l3-dione (compound 25B)
• the two enantiomers were separated via chiral SFC (Stationary phase: Whelk ® 01 (S,S) 5 pm 250 x 21.1 mm, Mobile phase: 40% C0 2 , 60% EtOH) to give the first eluted enantiomer 26dA (93 mg) and the second eluted enantiomer 26dB (99 mg).
• Example 27 synthesis of (l8*i?,*Z)-l2-hydroxy-l8-phenyl-6,9-dihydro-l8/7-l0, l7- methanodipyrido[3 ,2-6 : 1 2'-f ⁇ [ 1 ]oxa[5,6,9]triazacyclotridecine- 11, 13 -dione
• the two enantiomers were separated via chiral SFC (Stationary phase: Chiralcel ® OD-H 5 pm 250 x 30 mm, Mobile phase: 70% C0 2 , 30% EtOH) to give the first eluted enantiomer 27dA (65 mg) and the second eluted enantiomer 27dB (61 mg).
• the first eluted enantiomer was further purified via chiral SFC (Stationary phase: Chiralcel ® OD-H 5 pm 250 x 30 mm, Mobile phase: 60% CO2, 40% MeOH) to give enantiomer 28eA (139 mg, pure *Z isomer).
• the second eluted enantiomer was further purified via chiral SFC (Stationary phase: Chiralpak ® AD-H 5 pm 250 x 30 mm, Mobile phase: 60% CO2, 40% MeOH) to give enantiomer 28eB (129 mg, pure *Z isomer).
• Example 29 synthesis of (9 *7?, 18*7?, 77)-l2-hydroxy-9-methyl-l8-phenyl-6,9-dihydro- 1877- 10, 17-methanobenzo[b]pyrido[ 1 ,2 -f] [ 1 ]oxa[5,6,9]triazacyclotridecine- 11, 13 -dione (Compound 29AA), (9*7?, 18*/?, 12-hydroxy-9-methyl- l 8-phenyl-6,9-dihydro- l 877- 10, 17-methanobenzo[b]pyrido[ 1 ,2 -f] [ 1 ]oxa[5,6,9]triazacyclotridecine- 11, 13 -dione
• intermediate 29e 174 mg, 1 diasteroisomer
• intermediate 29e 174 mg, 1 diasteroisomer
• the two enantiomers were separated via chiral SFC (Stationary phase: Chiralpak ® AS-H 5 pm 250 x 20 mm, Mobile phase: 60% C0 2 , 40% EtOH) to give the first eluted enantiomer 29eA (74 mg) and the second eluted enantiomer 29eB (75 mg).
• Example 31 synthesis of ( ⁇ 9bR, Z)-4-hydroxy-8, 9, 15, l9Z>-tetrahydro-7i7, 1477-13, 12- (epiprop[ 1 ]en[ 1 ]yl [3 ]ylidene)-6,20-methanobenzo[3 ,4]cyclohepta[ 1 ,2-l]pyrido[ 1 ,2- 6][l,2,5]triazacyclotridecine-3,5-dione (Compound 31B)
• Example 33 synthesis of ( ⁇ 9b*R,Z)A- y droxy-7, l 0, 15, 19b-tetrahydro- 14/7-13,12- (epiprop[ 1 ]en[ 1 ]yl [3 ]ylidene)-6,20-methanobenzo[3 ,4]cyclohepta[ 1 ,2-c]pyrido[ 1 ,2- _/][l]oxa[5,6,9]triazacyclotridecine-3,5-dione (Compound 33A) and (19b*S,Z)-4- hydroxy-7, 10,15,19b-tetrahydro- ⁇ 4H- 13,12-(epiprop[ 1 ]en[ 1 ]yl[3 ]ylidene)-6,20- methanobenzo[3 ,4]cyclohepta[ 1 ,2-c]pyrido[ 1 ,2 -f ⁇ [ 1 ]oxa[5,6,9]triaza
• the two enantiomers were separated via chiral SFC (Stationary phase: Whelk-01 (S,S) 5 pm 250 x 21.2mm, Mobile phase: 45% CO2, 55% MeOH) to give the first eluted enantiomer 33b A (42 mg) and the second eluted enantiomer 33bB (49 mg).
• Example 34 synthesis of (l8*f?)-l2-hydroxy-l8-phenyl-5,6,7,8,9, l8-hexahydro-l0, l7- methanodipyrido[l,2-Z>:4',3'-&][l,2,5]triazacyclotridecine-l l, l3-dione (Compound 34A) and (18 *5)- 12-hydroxy- 18-phenyl-5 ,6, 7, 8, 9, 18-hexahydro- 10, 17-methanodipyrido[ 1 ,2- 6:4',3'-&][l,2,5]triazacyclotridecine-l l,l3-dione (Compound 34B)
• the two enantiomers were separated via chiral SFC (Stationary phase: Chiralpak ® AD IT 5 pm 250 x 30 mm, Mobile phase: 70% C0 2 , 30% MeOH) to give the first eluted enantiomer 34dA (142 mg) and the second eluted enantiomer 34dB (145 mg).
• Example 35 synthesis of (l8*f?,*Z)-l2-hydroxy-l8-phenyl-5,6,9, l8-tetrahydro-l0, l7- methanodipyrido[l,2-Z>:4',3'-&][l,2,5]triazacyclotridecine-l l, l3-dione (Compound 35A) and ( 18 * , *Z)- 12-hydroxy- 18-phenyl-5 ,6,9, 18-tetrahydro- 10, 17-methanodipyrido[ 1 ,2- 6:4',3'-&][l,2,5]triazacyclotridecine-l l,l3-dione (Compound 35B)
• Example 36 synthesis of ( 18*//,Z)- l 8-(2-fluorophenyl)- l 2-hydroxy-6,9-dihydro- l 8//- 10, 17-methanobenzo[b]pyrido[ 1 ,2 -f] [ 1 ]oxa[5,6,9]triazacyclotridecine- 11,13 -dione (Compound 36A) and ( 18L5',Z)- 18-(2-fluorophenyl)- l 2-hydroxy-6,9-dihydro- l 8//- 10, 17-methanobenzo[b]pyrido[ 1 ,2 -f] [ 1 ]oxa[5,6,9]triazacyclotridecine- 11,13 -dione (Compound 36B)
• intermediate 36d (intermediate 36d, 460 mg) was obtained using the procedures described in example 5 starting from intermediates 36b (synthesized as 5a) and 5d.
• the two enantiomers were separated via chiral SFC (Stationary phase: Chiralcel ® OD-H 5 pm 250 x 30 mm, Mobile phase: 60% C0 2 , 40% EtOH) to give the first eluted enantiomer 36dA (195 mg) and the second eluted enantiomer 36dB (195 mg).
• Example 37 synthesis of (l*R,l3Z)-7-hydroxy-l6-oxa-23-thia-2,3,l0- triazahexacyclo[l5.l2. l.l2,l0.03,8.02l,30.024,29]hentriaconta-
• the two enantiomers of intermediate 37e were separated via chiral SFC (Stationary phase: Whelk-Ol (S,S) 5 pm 250 x 21.2 mm, Mobile phase: 45% CO2, 55% EtOH+lO% CH2CI2) to give the first eluted enantiomer 37eA (530 mg) and the second eluted enantiomer 37eB (520 mg).
• the two enantiomers of intermediate 37f were separated via chiral SFC (Stationary phase: Whelk-Ol (S,S) 5 pm 250 x 21.2 mm, Mobile phase: 45% CO2, 55% EtOH+lO% CH2CI2) to give the first eluted enantiomer 37fA (134 mg) and the second eluted enantiomer 37fB (133 mg).
• Example 38 synthesis of ( 18*//,Z)- l 2-hydroxy-8-methyl- 18-phenyl-6, 9-dihydro- 18//- 10, 17-methanobenzo[b]pyrido[ 1 ,2- ] [ 1 ]oxa[5,6,9]triazacyclotridecine- 11,13 -dione (Compound 38A) and ( 18*L',Z)- 12-hydroxy-8-methyl- 18-phenyl-6, 9-dihydro- 18//- 10, 17-methanobenzo[b]pyrido[ 1 ,2- ] [ 1 ]oxa[5,6,9]triazacyclotridecine- 11,13 -dione (Compound 38B)
• the two enantiomers were separated via chiral SFC (Stationary phase: Chiralpak ® AS- H 5 pm 250 x 20 mm, Mobile phase: 45% C0 2 , 55% EtOH) to give the first eluted enantiomer 38eA (134 mg) and the second eluted enantiomer 38eB (145 mg).
• reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography over silica gel (120 g, CTECh/MeOH from 100:0 to 98:2).
• the compound was purified again by flash chromatography over silica gel (petroleum ether/EtOAc from 100:0 to 0: 100) and by reverse phase chromatography (Cl 8: 40 pm, 45 g, TEO/MeOH from 70:30 to 0: 100) to give (£)-l2-(benzyloxy)-9-ethyl-l8-phenyl- 6, 9-dihydro- 18 H- 10,17-methanobenzo[A]pyrido[ 1 ,2- _/][l]oxa[5,6,9]triazacyclotridecine-l l,l3-dione (intermediate 39g, 580 mg).
• the 4 isomers (780 mg batch) were separated.
• a first separation via achiral SFC (Stationary phase: diethylaminopropyl 5 pm 150 x 30 mm, Mobile phase: 90% C0 2 , 10% MeOH) delivered fraction 1 (460 mg) and fraction 2 (196 mg).
• Isomers of fraction 1 were separated via chiral SFC (Stationary phase: Chiralpak ® IC 5 pm 250 x 30mm, Mobile phase: 40% CO2, 60% MeOH) to give isomer 39gAA (203 mg) and isomer 39gBB (217 mg).

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