WO2024121395A1 - Inhibiteurs d'iap, leurs procédés de fabrication et leurs utilisations - Google Patents

Inhibiteurs d'iap, leurs procédés de fabrication et leurs utilisations Download PDF

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WO2024121395A1
WO2024121395A1 PCT/EP2023/084910 EP2023084910W WO2024121395A1 WO 2024121395 A1 WO2024121395 A1 WO 2024121395A1 EP 2023084910 W EP2023084910 W EP 2023084910W WO 2024121395 A1 WO2024121395 A1 WO 2024121395A1
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compound
mmol
compounds
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methyl
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Leo MARX
Aurelien ADAM
Norbert WIEDEMANN
Juan Bravo
Mathilde Muzerelle
Thomas Fuchss
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Debiopharm International Sa
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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

Definitions

  • Inhibitors of apoptosis proteins are a class of key regulators of apoptosis characterized by the presence of one to three protein domains known as BIR.
  • clAPl and clAP2 play a critical role in the regulation of death receptor-mediated apoptosis and NF-KB signaling pathways, which drive the expression of genes relevant for inflammation and immunity;
  • XIAP is a central regulator of both death receptor-mediated and mitochondria-mediated apoptosis pathways.
  • XIAP and clAPl/2 are promising drug targets.
  • a known IAP inhibitor at a particularly advanced stage of development is xevinapant, also known as Debio 1143 or SM406 or AT406.
  • Xevinapant has the following chemical structure:
  • IAP inhibitors may be suitable for HIV latency reversal (e.g. Rasmussen et al., Curr Opin HIV AIDS, 2017 January; 12(1): 96– 104.doi:10.1097/COH.0000000000000328, Pache et al., Cell Host & Microbe 18, 345–353, 2015 (http://dx.doi.org/10.1016/j.chom.2015.08.009)).
  • Such re-activation of replication of viral reservoirs needs to be accompanied by suitable agents to effectively eradicate the reactivated viruses and/or their host cells.
  • Figure 5 shows the individual HIV-1 DNA organ titers measured at 17 weeks in the Compound 18-PRO + Anti-PD-1 group as per Biological Example 3.
  • Figure 6 shows the cellular permeability of compound 18 and xevinapant in MDA-MB-231 cells as per Biological Example 6. 2.
  • Definitions The following definitions are provided to assist the reader. Unless otherwise defined, all terms of art, notations, and other scientific or medical terms or terminology used herein are intended to have the meanings commonly understood by those of skill in the chemical and medical arts. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not be construed as representing a substantial difference over the definition of the term as generally understood in the art.
  • alkyl refers to a saturated straight, branched or cyclic hydrocarbon, such as a straight, branched or cyclic group of 1-8 or 1-6 carbon atoms referred to herein as C1-C8 alkyl, or C1-C6 alkyl, respectively.
  • lower alkyl as used herein specifically refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-4 or 1-3 carbon atoms, referred to herein as C1-C4 alkyl, and C1- C3 alkyl, respectively.
  • carbocycle refers to an aromatic or non-aromatic fully or partially saturated ring in which each atom of the ring is carbon.
  • the carbocycle may have 4- 8 ring members such as 5, 6 or 7 ring members.
  • the carbocycle may also carry one or more substitutents as specified above for the aryl group.
  • the terms “comprising” or “containing” indicate that further unmentioned items may be present in addition to the specified items. In one embodiment, these terms have the meaning of “consisting of”, thereby excluding unmentioned items.
  • cycloalkyl refers to a monocyclic saturated ring of for example 3- 6, or 4-6 carbons, referred to herein, e.g., as " C3-6 cycloalkyl” or “C4-6 cycloalkyl,” and derived from a cycloalkane.
  • exemplary cycloalkyl groups include, but are not limited to, cyclohexane, cyclohexene, cyclopentane, cyclobutane, and cyclopropane.
  • Hal or “halogen” represents an atom selected from I, Br, Cl and F, preferably selected from Cl and F and most preferably F.
  • amino refers to any group of the general structure NRaRb, wherein, unless specified otherwise, Ra and Rb are independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic groups. Alternatively, Ra and Rb may represent hydrocarbon groups that are linked to form a heterocycle together with the nitrogen atom to which they are attached.
  • heteroaryl refers to a monocyclic aromatic 4-6 membered ring system containing one or more heteroatoms, for example one to three heteroatoms, which may be the same or different, such as nitrogen, oxygen, and sulfur.
  • the heterocycle typically has 4 to 8 ring members and preferably 5 or 6 ring members. Unless specified otherwise, a heterocycle may be aromatic, partially or fully saturated. Unless specified otherwise, it may or may not contain permissible substituents as specified herein.
  • Terms “hydroxy” and “hydroxyl” as used herein refer to the radical -OH.
  • the term “nitro” refers to -NO2; the term “sulfhydryl” refers to -SH; and the term “sulfonyl” refers to -SO2-.
  • the definition of each expression, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
  • triflyl refers to trifluoromethanesulfonyl, p- toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively.
  • triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate, p-toluenesulfonate, methanesulfonate, and nonafluorobutanesulfonate functional groups and molecules that contain said groups, respectively.
  • Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively.
  • a more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • substitution is also contemplated to include all permissible substituents of organic compounds unless a more specific indication is provided.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, heteroaryl, aromatic and nonaromatic substituents of organic compounds such as the specific substituents listed above in relation to the aryl group.
  • the permissible substituents may be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • permissible substituents means any substituent that can be bonded to the core molecule without contravening general principles of chemical bond formation such as the maximum number of valence electrons for an atom of interest, and without making the compound so toxic for the patient that inacceptable toxicity is found even at the minimum dosage required for achieving a therapeutic effect.
  • substitution or presence of other functional groups with certain size there is an implicit restriction of carbon atom ranges to those members of the range that are capable of forming the resulting moiety.
  • references to a C1-6 alkyl, which is substituted by an oxygen atom bonded to 2 different carbon atoms to form an oxygen-containing heterocycle having 4-7 ring members are intended to characterize a C3-6 alkyl group to which an oxygen atom is bonded to 2 different carbon atoms to form an oxygen-containing heterocycle having 4-7 ring members.
  • the number of 4-7 ring members imposes a boundary condition that requires a minimum of 3 carbon atoms and thus excludes the option of an alkyl having only 1 or 2 carbon atoms.
  • hydrocarbon is contemplated to include all permissible compounds having at least one hydrogen and one carbon atom.
  • permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, heteroaryl, aromatic and nonaromatic organic compounds that may be substituted or unsubstituted.
  • solvent is used herein to mean a liquid chemical substance that is capable of dissolving a significant quantity of another substance of interest, the “solute”, to thereby generate a clear homogeneous solution.
  • significant quantity is determined by the intended use of the solution in such a manner that the intended use must be possible by the dissolved quantity of the solute. For instance, if it is intended to administer a compound of the present invention in the form of a solution by injection, the solvent must be capable of dissolving the compound in such amounts, to make administration of a therapeutic dose possible.
  • all reactions described herein are carried out at reaction temperatures that yield the desired target compound and that provide a reasonable compromise between reaction rate and selectivity.
  • variable groups are to be understood such that the more specific meanings and combinations of meanings, as embodied for instance by the formulae Ia to Irm, are also possible and even preferred.
  • said variable group may have any meaning described herein for the corresponding variable group in other embodiments.
  • the variable group has the same meaning as provided herein for the same variable group in connection with the more general embodiment that encompasses the specific embodiment of interest.
  • variable group in an independent claim applies also to the corresponding variable group in a claim dependent thereon unless a more specific meaning is indicated in the dependent claim.
  • the presence of a solid line pointing into the middle of a cyclic group or into the middle of a covalent bond forming part of a cyclic group indicates a covalent bond, but wherein the position of attachment is not restricted to a single ring atom.
  • the covalent bond may be formed to any ring atom capable of providing a free valence by removal of a hydrogen atom attached to this atom. This understanding is applicable irrespective whether the solid line is shown to be above or below the bonds of the ring.
  • the position of attachment is only at the ring to which the solid line points but not at the condensed second ring.
  • the term “protective group” is used herein to characterize a group that is bonded to a functional group to prevent this functional group from participating in a contemplated chemical reaction.
  • the protective group must be inert under the conditions of the contemplated chemical reaction, but it must be possible to remove the protective group from the compound such that no further transformations take place in other parts of the molecule. Suitable protective groups are described for each functional group in “Greene’s Protective Groups in Organic Synthesis”, Peter G. M. Wuts, Theodora W.
  • the R1 group is a heteroaryl group with two fused rings.
  • the heteroatom X may be oxygen or sulfur.
  • the respective groups are a chromane group if X is oxygen and the heterocycle has six ring members and a dihydrobenzofurane group is X is oxygen and the heterocycle is a 5-membered ring. If X is sulfur, the corresponding groups are benzothiane and benzothiolane, respectively.
  • Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.
  • the arrangement of substituents around a carbocyclic ring can also be designated as “cis” or “trans.”
  • the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring.
  • stereoisomers when used herein refers to any geometric isomers, enantiomers or diastereomers.
  • the present invention encompasses various stereoisomers of the compounds of the invention and mixtures thereof. Conformational isomers and rotamers of disclosed compounds are also contemplated.
  • the compounds of the invention may be defined in such a way that they also encompass pharmaceutically acceptable derivatives including salts, tautomers, polymorphs, hydrates, solvates, esters and any solid forms thereof.
  • Solvates of compounds may be taken to mean adductions of inert solvent molecules onto the compounds, which form owing to their mutual attractive force. Solvates can, for example, be hydrates. It may be understood that the compounds and salts according to the present invention may exist in any form, including solid form, and that the present invention encompasses any crystalline or amorphous form, and mixtures thereof. If the compound or salt according to the present invention is in crystalline form, it may exist in a number of different polymorphic forms.
  • references to the compounds of the invention may be understood also as references to pharmaceutically acceptable derivatives such as salts, tautomers, polymorphs, solvates (including hydrates), esters, and solid forms (including amorphous and crystalline, e.g. polymorphic, forms) as well as any combinations thereof.
  • pharmaceutically acceptable derivatives such as salts, tautomers, polymorphs, solvates (including hydrates), esters, and solid forms (including amorphous and crystalline, e.g. polymorphic, forms) as well as any combinations thereof.
  • the present disclosure of the compounds of the invention may be interpreted as explained above, irrespective of whether some forms of derivatives are mentioned while others are not mentioned, and even when no derivatives at all are mentioned.
  • the metabolites and prodrugs of the invention may be defined in such a way that they also encompass pharmaceutically acceptable derivatives including salts, tautomers, polymorphs, hydrates, solvates, esters and any solid forms thereof.
  • solvates of compounds may be taken to mean adductions of inert solvent molecules onto the compounds, which form owing to their mutual attractive force, so that solvates can, for example, be hydrates.
  • the metabolites or prodrugs of the present invention may exist in any form, including solid form, and that the present invention encompasses any crystalline or amorphous form, and mixtures thereof.
  • the metabolite or prodrug according to the present invention is in crystalline form, it may exist in a number of different polymorphic forms.
  • all references to the metabolites and prodrugs of the invention may be understood also as references to pharmaceutically acceptable derivatives such as salts, tautomers, polymorphs, solvates (including hydrates), esters, and solid forms (including amorphous and crystalline, e.g. polymorphic, forms) as well as any combinations thereof.
  • the present disclosure of the metabolites and prodrugs of the invention may be interpreted as explained above, irrespective of whether some forms of derivatives are mentioned while others are not mentioned, and also when no derivatives at all are mentioned.
  • administering refers to direct administration, which may be administration to a patient by a medical professional or may be self-administration, and/or indirect administration, which may be the act of prescribing a drug.
  • direct administration which may be administration to a patient by a medical professional or may be self-administration
  • indirect administration which may be the act of prescribing a drug.
  • a physician who instructs a patient to self- administer a drug or provides a patient with a prescription for a drug is administering the drug to the patient.
  • Antibody is an immunoglobulin molecule capable of specific binding to a target, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site, located in the variable region of the immunoglobulin molecule.
  • antibody encompasses not only intact polyclonal or monoclonal antibodies, but also, unless otherwise specified, any antigen-binding fragment or antibody fragment thereof that competes with the intact antibody for specific binding, fusion proteins comprising an antigen-binding portion (e.g., antibody-drug conjugates), any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site, antibody compositions with poly-epitopic specificity, and multi-specific antibodies (e.g., bispecific antibodies).
  • intact, i.e. non-fragmented, monoclonal antibodies are preferred.
  • the term “combination product” can refer to (i) a product comprised of two or more regulated components that are physically, chemically, or otherwise combined or mixed and produced as a single entity; (ii) two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products; (iii) a drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose; or (iv) any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect.
  • Combination therapy “combination treatment”, “in combination with”, “together with” or “in conjunction with” as used herein denotes any form of concurrent, parallel, simultaneous, sequential or intermittent treatment with at least two distinct treatment modalities (i.e., compounds, components, targeted agents or therapeutic agents).
  • the terms refer to administration of one treatment modality before, during, or after administration of the other treatment modality to the subject.
  • the modalities in combination can be administered in any order.
  • the therapeutically active modalities are administered together (e.g., simultaneously in the same or separate compositions, formulations or unit dosage forms) or separately (e.g., on the same day or on different days and in any order as according to an appropriate dosing protocol for the separate compositions, formulations or unit dosage forms) in a manner and dosing regimen prescribed by a medical care taker or according to a regulatory agency.
  • each treatment modality will be administered at a dose and/or on a time schedule determined for that treatment modality.
  • three or more modalities may be used in a combination therapy.
  • combination therapies may be used in conjunction with other types of treatment. The disclosure below sometimes relies on expressions such as “combination therapy” or the like.
  • Dose and “dosage” refer to a specific amount of active or therapeutic agents for administration. Such amounts are included in a “dosage form,” which refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active agent calculated to produce the desired onset, tolerability, and therapeutic effects, in association with one or more suitable pharmaceutical excipients such as carriers.
  • HIV is an acronym for human immunodeficiency virus.
  • the present text uses the acronym HIV in the sense of its established meaning as described for instance in the Wikipedia entry “HIV”, version of November 1, 2018, or by S. Lucas and A.M. Nelson in J Pathol. 2015 Jan;235(2):229-41. doi: 10.1002/path.4449.
  • references to HIV should be understood as references to HIV-1, as discussed for instance by J. Hemelaar in Trends Mol Med. 2012 Mar;18(3):182-92. doi: 10.1016/j.molmed.2011.12.001. Epub 2012 Jan 11 and also by A. Engelman and P. Cherepanov in Nat Rev Microbiol.2012 Mar 16;10(4):279-90.
  • HIV latency characterizes the phenomenon that in patients treated with antiretroviral therapy (ART), viral reservoirs persist despite treatment and lead to rapid viral rebound when ART is interrupted. HIV latency is due to the integration of a DNA copy of the HIV RNA genome into the host cell DNA genome. At this stage, the cells are normally not susceptible to ART. HIV Latency is discussed for instance by M.S. Dahabieh et al. in Annu Rev Med. 2015;66:407-21 doi: 10.1146/annurev-med-092112-152941 and references cited therein.
  • Human antibody is an antibody that possesses an amino-acid sequence corresponding to that of an antibody produced by a human and/or has been made using any of the techniques for making human antibodies as disclosed herein. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues.
  • Human antibodies can be produced using various techniques known in the art, including phage-display libraries (see e.g., Hoogenboom & Winter, 1991. JMB.227: 381; Marks et al., 1991. JMB. 222: 581). Also available for the preparation of human monoclonal antibodies are methods described in Cole et al., 1985. Monoclonal Antibodies and Cancer Therapy, Alan R.
  • Human antibodies can be prepared by administering the antigen to a transgenic animal that has been modified to produce such antibodies in response to antigenic challenge but whose endogenous loci have been disabled, e.g., immunized xenomice (see e.g., U.S. Pat. Nos. 6,075,181; and 6,150,584 regarding XENOMOUSE technology). See also, for example, Li et al., 2006. PNAS USA.
  • IAP inhibitors in the sense of the present invention are substances capable of inhibiting at least one of these IAP proteins, preferably two or more IAP proteins and most preferably cIAP1 and/or cIAP2 and/or XIAP, as further defined below with reference to Biological Example 1.
  • the Smac (Diablo) protein is an endogenous antagonist of IAP proteins. IAP inhibitors are therefore in some instances referred to as Smac mimetics. Such Smac mimetics are meant to be encompassed by the term “IAP inhibitor”.
  • IAP inhibitors There is an interaction between IAP inhibitors and the BIR3 domain of IAP proteins.
  • an IAP inhibitor may be identified as a compound having an IC50 of ⁇ 1 ⁇ M against XIAP BIR3 and/or cIAP1 BIR3 and/or cIAP2 BIR3, when carrying out the experiment described in Biological Example 1.
  • the terms “individual”, “patient” or “subject” are used interchangeably in the present application and are not meant to be limiting in any way.
  • the “individual”, “patient” or “subject” can be of any age, sex and physical condition.
  • the compounds, compositions and methods of treatment of the present invention are for use in a human patient. In other words, the individual, patient or subject is preferably human.
  • a “patient in need thereof” in the context of the present invention is a patient afflicted with HIV infection or cancer. In some embodiments, it is a patient infected with HIV and preferably HIV-1, characterized by HIV infected CD4+ T cells exhibiting an increased level of either PD-1, PD-L1, CTLA-4, TIGIT, LAG-3, Tim-3, or any combination thereof (as discussed by T.A. Rasmussen in Curr Opin HIV AIDS. 2017 January; 12(1): 96–104. doi:10.1097/COH.0000000000000328, R.
  • the patient may be characterized by an increased level at the surfaces of the patient’s CD8+ T cells of either PD- 1, PD-L1, CTLA-4, TIGIT, LAG-3, Tim-3, or any combination thereof (as described by R.B. Jones et al. in J. Exp. Med. Vol. 205 No.
  • Non-limiting examples of pharmaceutically acceptable adjuvants are: Alum, Freund’s Incomplete Adjuvant, MF59, synthetic analogs of dsRNA such as poly(I:C), bacterial LPS, bacterial flagellin, imidazolquinolines, oligodeoxynucleotides containing specific CpG motifs, fragments of bacterial cell walls such as muramyl dipeptide.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable diluent” means any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art.
  • Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed and, without limiting the scope of the present invention, include: additional buffering agents; preservatives; co-solvents; antioxidants such as methionine; chelating agents such as EDTA; metal complexes (e.g., Zn-protein complexes); biodegradable polymers, such as polyesters; salt-forming counterions, such as sodium, polyhydric sugar alcohols; amino acids, such as alanine, glycine, glutamine, asparagine, histidine, arginine, lysine, ornithine, leucine, 2-phenylalanine, glutamic acid, and threonine; organic sugars or sugar alcohols, such as lactitol, stachyose, mannose, sorbose, xylose, ribose, ribitol, myoinisitose, myoinisitol, gal
  • compositions described herein may also be included in a pharmaceutical composition described herein, provided that they do not adversely affect the desired characteristics of the pharmaceutical composition.
  • pharmaceutically acceptable salts refers to the relatively non-toxic, inorganic and organic acid addition salts, or inorganic or organic base addition salts of compounds, including, for example, those contained in compositions of the present invention, such as TFA salts (acid addition salts of trifluoroacetic acid), HCl salts (acid addition salts of hydrochloric acid) and formate salts (acid addition salts of formic acid), and including those present in other approved drugs (wherein approval may be by any competent authority in the EU, USA, CA, JP, CN or KR).
  • Pharmaceutically acceptable salts are meant to be encompassed by the present invention.
  • references to compounds of the invention are to be understood as references not only to the compounds as such, but also to pharmaceutically acceptable salts of the respective compounds.
  • the pharmaceutically acceptable salts may be selected from the salts acknowledged as pharmaceutically acceptable in the literature at the filing date, and in particular as described in G.S. Paulekuhn et al. in J. Med. Chem.2007, 50, 6665-6672 and references cited therein.
  • pharmaceutically acceptable salts is intended to include salts of the active compounds which are prepared with acids or bases, depending on the particular substituents found on the compounds described herein.
  • composition refers to any composition comprising at least one active agent, which is suitable for use in therapy, possibly after reconstitution. This includes unit dosage forms such as tablets or capsules but also infusion liquids, compositions for inhalation or any other administration form. Such pharmaceutical compositions may comprise one or more pharmaceutically acceptable carriers or excipients as described herein.
  • therapeutically effective amount refers to an amount of active agent (e.g.
  • the therapeutically effective amount of the drug or drug combination leads to reversal of HIV latency and/or killing of HIV infected cells and preferably both of these therapeutic effects.
  • the therapeutically effective amount of the drug or drug combination leads to remission, halt or at least slowing of tumour growth in a cancer patient.
  • the therapeutic effect is required for the respective drug combination.
  • the therapeutically effective amount of a drug forming part of the combination therapy may be lower than the therapeutically effective amount of the same drug when used in monotherapy.
  • treatment and “therapy”, as used in the present application, refer to a set of hygienic, pharmacological, surgical and/or physical means used with the intent to cure and/or alleviate a disease and/or symptoms with the goal of remediating the health problem.
  • treatment and “therapy” include preventive and curative methods, since both are directed to the maintenance and/or reestablishment of the health of an individual or animal. Regardless of the origin of the symptoms, disease and disability, the administration of a suitable medicament to alleviate and/or cure a health problem should be interpreted as a form of treatment or therapy within the context of this application.
  • "Unit dosage form” as used herein refers to a physically discrete unit of therapeutic formulation appropriate for the subject to be treated.
  • compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular subject or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of specific active agent employed; specific composition employed; age, body weight, general health, sex and diet of the subject; time of administration, and rate of excretion of the specific active agent employed; duration of the treatment; drugs and/or additional therapies (if any) used in combination or coincidental with specific compound(s) employed, and like factors well known in the medical arts. 3. Overview The compounds of the present invention show high IAP inhibitory activity. These compounds are suitable as HIV latency reversal agents and/or as agents suitable for the treatment of cancer.
  • IAP inhibitor compounds (and specific metabolites thereof) of the present invention pose a comparatively low risk of interference with liver enzymes like CYP3A4, as for instance shown in Biological Example 4.
  • the present invention provides compounds that show sufficiently high oral bioavailability for instance to allow their use in therapy via oral administration.
  • the present invention provides compounds with high cell permeability.
  • the present invention provides compounds that show a particularly favorable safety profile. 4.
  • IAP Inhibitors 4.1 General Formula The compounds of the present invention are characterized by the following formula I as the general embodiment: In some embodiments, the compounds of the present invention are characterized by the above formula I, wherein R1 represents a group selected from
  • R2 represents a group selected from H, CH3, Et, Pr, iPr, iBu, Cpr and CH2-Cpr;
  • R2a represents a group selected from CH3, Et and CH2CH2OH;
  • R3 represents a group selected from H, R4 and R4’ each represents a group independently selected from H, OCH3 and Hal;
  • R5 represents a group selected from H and CH3;
  • R6 represents a group selected from C1-3 alkylene-sulfonyl-R7, linear, branched or cyclic C1-6 alkyl, which is optionally substituted by 1, 2 or 3 substituents independently selected from Hal, OH, methoxy and an oxygen atom bonded to 2 different carbon atoms to form an oxygen-containing heterocycle having 4-7 ring members;
  • R7 represents a C1-3 alkyl;
  • R8 represents a group selected from H and CH3;
  • R9 represents a group selected from H and linear, branched or cyclic C1-6 alkyl
  • the compound or pharmaceutically acceptable salt, polymorph, hydrate, solvate, ester, tautomer, prodrug or metabolite thereof can be in deuterated form.
  • the compound or pharmaceutically acceptable salt, polymorph, hydrate, solvate, ester, tautomer, prodrug or metabolite thereof may have at least one hydrogen atom in formula I replaced by a deuterium atom.
  • the substituents R4 and R4‘ (if present) represent a hydrogen atom.
  • R1 is selected from
  • R2 and R2a are a methyl group.
  • the corresponding compounds have the following structures of formulae I-1, I-2 and I-3 shown below: and
  • the compound has a structure in accordance with any of the above formulae I, I-1, I-2 and I-3, wherein R1 is wherein R4 and R5 are as defined above with respect to formula I.
  • the compound has a structure in accordance with any of the above formulae I, I-1, I-2 and I-3, wherein R1 is wherein R5 is as defined above with respect to formula I.
  • the compound has a structure in accordance with any of the above formulae I, I-1, I-2 and I-3, wherein R1 is wherein R5 is as defined above.
  • the compound has a structure in accordance with formula I, but wherein R1 represents a group selected from R2 represents a group selected from H, CH3, Et, Pr, iPr, iBu, Cpr and CH2-Cpr; R2a represents a group selected from CH3, Et and CH2CH2OH; R3 represents a group selected from H, R4 represents a group selected from H, OCH3 and Hal; R5 represents a group selected from H and CH3; R6 represents a group selected from C1-3 alkylene-sulfonyl-R7, linear, branched or cyclic C1-6 alkyl, which is optionally substituted by 1, 2 or 3 substituents independently selected from Hal, OH, methoxy and an oxygen atom bonded to 2 different carbon atoms to form an oxygen-containing heterocycle having 4-7 ring members; R7 represents a group selected from C1-3 alkyl; R8 represents a group selected from H and CH3; R9 represents a group selected from H and linear,
  • the compound is according to one of formulae I-1, I-2 or I-3 and the meanings of R2 and/or R2a are restricted accordingly. More specific embodiments relate to compounds as specified above in connection with any of formulae I, I-1, I-2 and I-3 and any of the further definitions of variable groups provided above, but wherein the R3 is group selected from wherein the variable groups R8 to R11 have the same meanings as specified above in connection with formula I. Preferably, these compounds are characterized by a group R3 selected from and most preferably a group. More specific embodiments of the compounds of the present invention are described in the following sections. Unless specified otherwise, the compounds of the specific embodiments described below are in accordance with the above description of compounds of formula I and the associated definitions of variable groups.
  • the R1 group is The corresponding structure with this R1 group is shown in formula Ia below:
  • the carbon atom carrying the R5 group is chiral if R5 is a substituent other than hydrogen. This chiral center is preferably in the R-configuration as shown by formula Ib below:
  • the position of the R4 substituent is not particularly limited. Substitution of the phenyl ring with R4 in the meta- and para-position is preferred and substitution in the para-position is most preferred.
  • the R2a group is a methyl group.
  • the structures corresponding to formulae Ia to If but having a methyl group in the R2a position are shown in the following as formulae Iam to Ifm: Iam
  • the R2 groups can be selected from the same groups as described above with respect to formula I, i.e. it is selected from the group consisting of H, CH3, Et, iPr, iBu, Cpr and CH2-Cpr.
  • group R2a represents a group selected from CH3, Et, and CH2CH2OH.
  • the R4 groups can be selected from the same groups as described above with respect to formula I, i.e.
  • R4 is F or Cl and preferably F.
  • the compounds are represented by any of the above formulae Ia to If and formulae Iam to Ifm and formulae Iem1 to Iem3 and are further characterized by a group R3 selected from wherein the variable groups R8 to R11 have the same meanings as specified above in connection with formula I.
  • these compounds are characterized by a group R3 selected from group.
  • Embodiment Aa In some embodiments, the compounds are represented by any of the above formulae Ia to If and formulae Iam to Ifm and formulae Iem1 to Iem3 and they carry a group R3 that is represented by represents a group selected from C2-6 alkyl, which is optionally substituted by 1, 2 or 3 substituents independently selected from F and Cl. Preferably, the 1, 2 or 3 substituents are independently selected either from F that may be present in any position or are selected from Cl that is present in any position other than the position adjacent to the carbonyl group.
  • the R5 group represents a group selected from H and CH3 for most the formulae shown hereinabove, but it is H for formula Iem3.
  • these compounds are represented by formula Icm.
  • these compounds are represented by formula Idm.
  • these compounds are represented by formula Iem.
  • these compounds are represented by formula Ifm.
  • these compounds are represented by formula Iem1.
  • such compounds are represented by formula Iem2.
  • Such compounds may even be represented by formula Iem3.
  • Embodiment Ab the compounds represented by any of the above formulae Ia to If and formulae Iam to Ifm and formulae Iem1 to Iem3 carry a group R3 is represented by wherein R8 is H and R9 represents a group selected from C2-4 alkyl. Group R5 is H.
  • these compounds are represented by formula Icm.
  • these compounds are represented by formula Idm.
  • these compounds are represented by formula Iem.
  • these compounds are represented by formula Ifm.
  • such compounds also fall within the scope of formula Iem2. Such compounds may even be represented by formula Iem3.
  • Embodiment Ac the compounds represented by any of the above formulae Ia to If and formulae Iam to Ifm and formulae Iem1 to Iem3 carry a group R3 is represented by wherein R10 represents a group selected from C2-4 alkyl and the R5 group represents a group selected from H and CH3.
  • these compounds are represented by formula Icm.
  • these compounds are represented by formula Idm.
  • these compounds are represented by formula Iem.
  • these compounds are represented by formula Ifm.
  • such compounds are represented by formula Iem2.
  • Such compounds may even be represented by the formula Iem3.
  • Embodiment Ad the compounds represented by any of the above formulae Ia to If and formulae Iam to Ifm and formulae Iem1 to Iem3 carry a group R3 is represented by wherein R11 represents a group selected from H and C1-6 alkyl, preferably C3-6 alkyl, which is optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl and an oxygen atom bonded to 2 different carbon atoms to form an oxygen-containing heterocycle having 4-7 ring members.
  • R11 represents a group selected from H and C1-6 alkyl, preferably C3-6 alkyl, which is optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl and an oxygen atom bonded to 2 different carbon atoms to form an oxygen-containing heterocycle having 4-7 ring members.
  • R11 represents a group selected from H and C1-6 alkyl, preferably C3-6 alkyl, which is optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl and an oxygen atom bonded to 2 different
  • these compounds are represented by formula Ifm. In even more specific embodiments, such compounds are represented by formula Iem2. Such compounds may even be represented by the formula Iem3. 4.3 Chromaneamide embodiment In another embodiment, R1 is represented by the group The corresponding compounds are characterized by the following formula Ig:
  • the carbon atom of the six-membered heterocycle forming a bond to the amide group is chiral. It is preferably in the R-configuration.
  • the corresponding compounds are characterized by the following general formula Ih:
  • Variable group X is preferably an oxygen atom.
  • the above general formulae Ig and Ih can be expressed by the following formulae Ig1 and Ih1, respectively. If R2a has the preferred meaning of a methyl group, the formulae can be drawn as formulae Ig1m and Ih1m, respectively: Ig1
  • the position of the R4 group is not particularly restricted.
  • the R4 group is attached to one of the carbon atoms of the phenyl ring that are closest to the X atom, i.e. the 7- and 8-positions of the chromane group.
  • the R4 group is attached to the 7-position.
  • the corresponding structures for the 7- and 8-positions are shown in the following for the racemic chromane group as formulae Ii and Ij, respectively, and for the preferred enantiomer of the chromane group as formulae Ik and Il, respectively:
  • the R2a group is a methyl group.
  • the structures corresponding to formulae Ig to Il but having a methyl group in the R2a position are shown in the following as formulae Igm to Ilm:
  • X is O or S and preferably O
  • R4 is as specified above with respect to formula I, i.e. it is selected from H, OCH3 and Hal.
  • Hal is F or Cl and preferably F.
  • the remaining variable groups may have the meanings described above with respect to formula I or below in connection with anyone of the specific embodiments Ba to Bh.
  • R4 is a hydrogen atom.
  • formula Igm1 can be drawn as formula Igm2, which is shown in the following: Igm2
  • X has the preferred meaning oxygen.
  • the compounds of these special embodiments can be represented by the following formulae Ii1 to ik1: Ii1
  • group R2a represents a methyl group, which gives rise to the following formulae Ii1m to Il1m, which are depicted below:
  • R4 is a hydrogen.
  • the above formulae Ii to Il give rise to the following formulae Ii2 and Ik2:
  • the compounds of formulae Ii2 and ik2 carry an oxygen atom in the position of X.
  • the compounds of these specific embodiments are represented by the following formulae Ii3 and Ik3: Ii3
  • the compounds are represented by any of the above formulae Ig to Il, Ig1, Ig1m, Ih1, Ih1m, Igm to Ilm, Igm1, Igm2, Ii1 to Il1, Ii1m to Il1m, Ii2, Ik2, Ii3, Ik3 and Ihm1 to Ihm3 and are further characterized by a group R3 selected from and wherein the variable groups R8 to R11 have the same meanings as specified above in connection with formula I in section 4.1.
  • R11 represents a group selected from H and linear, branched or cyclic C1-6 alkyl, which is optionally substituted by 1, 2 or 3 substituents independently selected from Hal, cyano and an oxygen atom bonded to 2 different carbon atoms to form an oxygen-containing heterocycle having 4-7 ring members.
  • these compounds are characterized by a group R3 selected from group.
  • R3 selected from group.
  • Embodiment Ba In some of the embodiments described above by means of formulae I, Ig to Il, Ig1, Ig1m, Ih1, Ih1m, Igm to Ilm, Igm1, Igm2, Ii1 to Il1, Ii1m to Il1m, Ii2, Ik2, Ii3, Ik3 and Ihm1 to Ihm3, R3 is R6 represents a C1-6 alkyl, which is optionally substituted by 1, 2 or 3 Cl and/or F atoms, or R6 represents a 4 to 6-membered heterocycle containing 1 oxygen atom; and R2 represents a group selected from H, CH3, Et, iPr, iBu, Cpr and CH2-Cpr.
  • these compounds are represented by formula Iim. In further specific embodiments, these compounds are represented by formula Ijm. In further specific embodiments, these compounds are represented by formula Ikm. In even further specific embodiments, these compounds are represented by formula Ilm. In very specific embodiments, the compounds are furthermore represented by formula Ihm1. In even more specific embodiments, the compounds are also represented by formula Ihm2. The compounds of the embodiment specified herein even more specifically are represented by formula Ihm3.
  • Embodiment Bb In further embodiments characterized by the formulae I, Ig to Il, Ig1, Ig1m, Ih1, Ih1m, Igm to Ilm, Igm1, Igm2, Ii1 to Il1, Ii1m to Il1m, Ii2, Ik2, Ii3, Ik3 and Ihm1 to Ihm3, R3 is selected from the group consisting of the following formulae IIa, IIb and IIc: IIa IIb IIc wherein R12 is selected from CH3, CF3, OH, O-CH3, H and F; and R2 represents a group selected from H, CH3, Et, iPr, iBu, Cpr and CH2-Cpr. In specific embodiments, these compounds are represented by formula Iim.
  • these compounds are represented by formula Ijm. In further specific embodiments, these compounds are represented by formula Ikm. In even further specific embodiments, these compounds are represented by formula Ilm. In very specific embodiments, the compounds are furthermore represented by formula Ihm1. In even more specific embodiments, the compounds are also represented by formula Ihm2. The compounds of the embodiment specified herein even more specifically are represented by formula Ihm3.
  • Embodiment Bc Yet further embodiments of formulae I, Ig to Il, Ig1, Ig1m, Ih1, Ih1m, Igm to Ilm, Igm1, Igm2, Ii1 to Il1, Ii1m to Il1m, Ii2, Ik2, Ii3, Ik3 and Ihm1 to Ihm3 are characterized by O a group R3 which is wherein R6 is a group selected from C1-3 alkylene-sulfonyl-R7, linear, branched or cyclic C1-6 alkyl, which is optionally substituted by 1, 2 or 3 substituents independently selected from Hal, OH, methoxy and an oxygen atom bonded to 2 different carbon atoms to form an oxygen-containing heterocycle having 4-7 ring members, and R6 is preferably CH3 or CH2F; R7 represents a group selected from C1-3 alkyl and R2 is selected from iPr, iBu, Cpr and CH2-Cpr.
  • these compounds are represented by formula Iim. In further specific embodiments, these compounds are represented by formula Ijm. In further specific embodiments, these compounds are represented by formula Ikm. In even further specific embodiments, these compounds are represented by formula Ilm. In very specific embodiments, the compounds are furthermore represented by formula Ihm1. In even more specific embodiments, the compounds are also represented by formula Ihm2. The compounds of the embodiment specified herein even more specifically are represented by formula Ihm3.
  • Embodiment Bd Other embodiments in relation to formulae I, Ig to Il, Ig1, Ig1m, Ih1, Ih1m, Igm to Ilm, Igm1, Igm2, Ii1 to Il1, Ii1m to Il1m, Ii2, Ik2, Ii3, Ik3 and Ihm1 to Ihm3 are characterized by R3 being R6 , wherein R6 is CH3, CH2F, CHF2, CH2CH(CH3)2 or CHFCH(CH3)2; and R2 is CH3.
  • R6 is CH3, CH2F, CHF2, CH2CH(CH3)2 or CHFCH(CH3)2; and R2 is CH3.
  • these compounds are represented by formula Iim.
  • these compounds are represented by formula Ijm.
  • these compounds are represented by formula Ikm.
  • these compounds are represented by formula Ilm.
  • the compounds are represented by formula Ihm2.
  • the compounds of the embodiment specified herein are even more specifically represented by formula Ihm3.
  • Embodiment Be Some embodiments of the compounds of the invention characterized by formulae I, Ig to Il, Ig1, Ig1m, Ih1, Ih1m, Igm to Ilm, Igm1, Igm2, Ii1 to Il1, Ii1m to Il1m, Ii2, Ik2, Ii3, Ik3 and Ihm1 to Ihm3 have a R3 group, which is , wherein R8 is H and R9 is a group selected from H and linear, branched or cyclic C1-6 alkyl, which is optionally substituted by 1 or 2 substituents independently selected from F, Cl, methoxy and an oxygen atom bonded to 2 different carbon atoms to form an oxygen-containing heterocycle having 4-7 ring members and R9 preferably represents a group selected from linear or branched or cyclic C1-6
  • R2 is CH3, R8 is H and R9 represents a group selected from linear, branched or cyclic C1-4 alkyl, which is optionally substituted by 1 or 2 substituents independently selected from F and O-CH3. More preferably, R2 is CH3, R8 is H and R9 represents a linear C1-4 alkyl, which is substituted by 1 F substituent. According to other more specific embodiments, R2 is CH3, R8 is H and R9 represents an unsubstituted cyclic C3-5 alkyl.
  • R2 is CH3, R8 is H and R9 represents a linear C1-3 alkyl, which is substituted by 1 F substituent, or R2 is CH3, R8 is H and R9 represents an unsubstituted cyclic C3-4 alkyl.
  • these compounds are represented by formula Iim.
  • these compounds are represented by formula Ijm.
  • these compounds are represented by formula Ikm.
  • these compounds are represented by formula Ilm.
  • the compounds are represented by formula Ihm1.
  • the compounds are represented by formula Ihm2.
  • the compounds of the embodiment specified herein even more specifically are represented by formula Ihm3.
  • Embodiment Bf Further embodiments concern compounds of formulae I, Ig to Il, Ig1, Ig1m, Ih1, Ih1m, Igm to Ilm, Igm1, Igm2, Ii1 to Il1, Ii1m to Il1m, Ii2, Ik2, Ii3, Ik3 and Ihm1 to Ihm3 wherein R3 is , R10 is represents a group selected from linear, branched or cyclic C1-6 alkyl, which is optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl, methoxy, an oxygen atom bonded to 2 different carbon atoms to form an oxygen- containing heterocycle having 4-7 ring members, and phenyl, which is optionally substituted by Hal, and R10
  • these compounds are represented by formula Iim. In further specific embodiments, these compounds are represented by formula Ijm. In further specific embodiments, these compounds are represented by formula Ikm. In even further specific embodiments, these compounds are represented by formula Ilm. In very specific embodiments, the compounds are represented by formula Ihm1. In even more specific embodiments, the compounds are represented by formula Ihm2. The compounds of the embodiment specified herein even more specifically are represented by formula Ihm3.
  • Embodiment Bg the compounds of formulae I, Ig to Il, Ig1, Ig1m, Ih1, Ih1m, Igm to Ilm, Igm1, Igm2, Ii1 to Il1, Ii1m to Il1m, Ii2, Ik2, Ii3, Ik3 and Ihm1 to Ihm3 have an R3 group, which is wherein R11 is a group selected from H and linear, branched or cyclic C1-6 alkyl, which is optionally substituted by 1, 2 or 3 substituents independently selected from Hal, cyano and an oxygen atom bonded to 2 different carbon atoms to form an oxygen-containing heterocycle having 4-7 ring members, and R11 preferably represents a group selected from H and linear or branched C1-5 alkyl, which is optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl and cyano; and R2 represents a group selected from H, CH3, Et, iPr, iBu, Cpr
  • R11 represents a 4 to 6-membered heterocycle containing 1 oxygen atom; and R2 represents a group selected from H, CH3, Et, iPr, iBu, Cpr and CH2-Cpr.
  • R2 is CH3, and R11 represents a linear, branched or cyclic C1-6 alkyl, which is optionally substituted by 1, 2 or 3 F substituents, such as CH2CF3.
  • R2 is CH3, and R11 represents a linear, branched or cyclic C1-4 alkyl, which is optionally substituted by 1, 2 or 3 F substituents, such as CH2CF3.
  • R2 is CH3, and R11 represents a linear or branched C1-4 alkyl, which is optionally substituted by 2 or 3 F substituents, such as CH2CF3.
  • R2 is CH3, and R11 represents a linear C1-3 alkyl group, which is substituted by 2 or 3 F substituents, such as especially CH2CF3, CHF2 or CF3.
  • these compounds are represented by formula Iim.
  • these compounds are represented by formula Ijm.
  • these compounds are represented by formula Ikm.
  • these compounds are represented by formula Ilm.
  • the compounds are represented by formula Ihm1.
  • the compounds are represented by formula Ihm2.
  • the compounds of the embodiment specified herein even more specifically are represented by formula Ihm3. Particularly advantageous are those compounds, wherein the above-mentioned more preferred and most preferred meanings are combined with one of formulae Ihm1 to Ihm3, especially Ihm3-3. This applies especially to the more preferred and most preferred variable group meanings indicated above.
  • the R1 group is represented by the following formula: The compound of formula I containing this moiety is shown below as formula Im: Im
  • the carbon atom of the dihydrofuran group forming the covalent bond to the amide group is chiral. Compounds having this carbon atom in the S-configuration are preferred.
  • the corresponding structure is shown as formula In below:
  • the R4 group can be attached to any free valency of the phenyl group.
  • Preferred are compounds having the R4 group bonded to one of the positions of the phenyl group adjacent to the X atom, i.e. the 6- or 7-position, more preferably the 6-position.
  • the structures of these compounds are shown below as formulae Io (6-position, racemic group), Ip (7- position, racemic group), Iq (6-position, S-configuration) and Ir (7-position, S-configuration):
  • the R2a group is a methyl group.
  • the structures corresponding to formulae Im to Ir but having a methyl group in the R2a position are shown in the following as formulae Imm to Irm:
  • X is O or S and preferably O
  • R4 is as specified above with respect to formula I, i.e. it is selected from H, OCH3 and Hal.
  • Hal is F or Cl and preferably F.
  • the compounds are represented by any of the above formulae Im to Ir and formulae Imm to Irm and formulae Inm1 to Inm3 and are further characterized by a group R3 selected from and wherein the variable groups R8 to R11 have the same meanings as specified above in connection with formula I.
  • these compounds are characterized by a group R3 selected from and and most preferably a group.
  • Embodiment Ca In some of these embodiments, R3 is R6 represents a C1-6 alkyl, which is optionally substituted by 1, 2 or 3 Cl and/or F atoms, or R6 represents a 4 to 6- membered heterocycle containing 1 oxygen atom; and R2 represents a group selected from H, CH3, Et, iPr, iBu, Cpr and CH2-Cpr. In specific embodiments, these compounds are represented by formula Iom. In further specific embodiments, these compounds are represented by formula Ipm. In further specific embodiments, these compounds are represented by formula Iqm.
  • these compounds are represented by formula Irm.
  • the compounds furthermore are represented by formula Inm1.
  • the compounds are represented by formula Inm2.
  • the compounds of the embodiment specified herein even more specifically are represented by formula Inm3.
  • Embodiment Cb In further embodiments characterized by the formulae Im to Ir and Imm to Irm, R3 is selected from the group consisting of the following formulae IIa, IIb and IIc: wherein R12 is selected from CH3, CF3, OH, O-CH3, H and F; and R2 represents a group selected from H, CH3, Et, iPr, iBu, Cpr and CH2-Cpr. In specific embodiments, these compounds are represented by formula Iom.
  • these compounds are represented by formula Ipm. In further specific embodiments, these compounds are represented by formula Iqm. In even further specific embodiments, these compounds are represented by formula Irm. In very specific embodiments, the compounds are represented by formula Inm1. In even more specific embodiments, the compounds are represented by formula Inm2. The compounds of the embodiment specified herein even more specifically are represented by formula Inm3.
  • Embodiment Cc Yet further embodiments of formulae Im to Ir and Imm to Irm are characterized by a group R3 which is wherein R6 is a group selected from C1-3 alkylene-sulfonyl-R7, linear, branched or cyclic C1-6 alkyl, which is optionally substituted by 1, 2 or 3 substituents independently selected from Hal, OH, methoxy and an oxygen atom bonded to 2 different carbon atoms to form an oxygen-containing heterocycle having 4-7 ring members, and R6 is preferably CH3 or CH2F; R7 represents a group selected from C1-3 alkyl and R2 is selected from iPr, iBu, Cpr and CH2-Cpr.
  • R6 is a group selected from C1-3 alkylene-sulfonyl-R7, linear, branched or cyclic C1-6 alkyl, which is optionally substituted by 1, 2 or 3 substituents independently selected from Hal, OH, methoxy and an oxygen atom bonded
  • these compounds are represented by formula Iom. In further specific embodiments, these compounds are represented by formula Ipm. In further specific embodiments, these compounds are represented by formula Iqm. In even further specific embodiments, these compounds are represented by formula Irm. In very specific embodiments, the compounds are represented by formula Inm1. In even more specific embodiments, the compounds are represented by formula Inm2. The compounds of the embodiment specified herein even more specifically are represented by formula Inm3.
  • Embodiment Cd Other embodiments in relation to formulae Im to Ir and Imm to Irm are characterized by R3 being wherein R6 is CH3, CH2F, CHF2, CH2CH(CH3)2 or CHFCH(CH3)2; and R2 is CH3.
  • these compounds are represented by formula Iom. In further specific embodiments, these compounds are represented by formula Ipm. In further specific embodiments, these compounds are represented by formula Iqm. In even further specific embodiments, these compounds are represented by formula Irm. In very specific embodiments, the compounds are represented by formula Inm2. The compounds of the embodiment specified herein even more specifically are represented by formula Inm3.
  • Embodiment Ce Some embodiments of the compounds of the invention characterized by formulae Ig to Il and Igm to Ilm have a R3 group, which is wherein R8 is H and R9 is a group selected from H and linear, branched or cyclic C1-6 alkyl, which is optionally substituted by 1 or 2 substituents independently selected from F, Cl, methoxy and an oxygen atom bonded to 2 different carbon atoms to form an oxygen-containing heterocycle having 4-7 ring members and R9 preferably represents a group selected from linear or branched C1-4 alkyl, optionally substituted with 1 or 2 substituents independently selected from F, Cl and O-CH3, C3-6 cycloalkyl and saturated 6-membered heterocycle containing 1 oxygen atom; and R2 represents a group selected from H, CH3, Et, iPr, iBu, Cpr and CH2-Cpr.
  • these compounds are represented by formula Iom. In further specific embodiments, these compounds are represented by formula Ipm. In further specific embodiments, these compounds are represented by formula Iqm. In even further specific embodiments, these compounds are represented by formula Irm. In very specific embodiments, the compounds furthermore are represented by formula Inm1. In even more specific embodiments, the compounds are represented by formula Inm2. The compounds of the embodiment specified herein even more specifically are represented by formula Inm3.
  • Embodiment Cf Further embodiments concern compounds of formulae Im to Ir and Imm to Irm wherein R3 is R10 is represents a group selected from linear, branched or cyclic C1-6 alkyl, which is optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl, methoxy, an oxygen atom bonded to 2 different carbon atoms to form an oxygen- containing heterocycle having 4-7 ring members, and phenyl, which is optionally substituted by Hal, and R10 preferably represents a group selected from C1-4 alkyl, which is optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl and phenyl, which is optionally substituted by an F or Cl atom; and R2 represents a group selected from H, CH3, Et, iPr, iBu, Cpr and CH2-Cpr.
  • these compounds are represented by formula Iom. In further specific embodiments, these compounds are represented by formula Ipm. In further specific embodiments, these compounds are represented by formula Iqm. In even further specific embodiments, these compounds are represented by formula Irm. In very specific embodiments, the compounds are represented by formula Inm1. In even more specific embodiments, the compounds are represented by formula Inm2. The compounds of the embodiment specified herein even more specifically are represented by formula Inm3.
  • Embodiment Cg In other embodiments the compounds of compounds of formulae Im to Ir and Imm to Irm have an R3 group, which is wherein R11 is a group selected from H and linear, branched or cyclic C1-6 alkyl, which is optionally substituted by 1, 2 or 3 substituents independently selected from Hal, cyano and an oxygen atom bonded to 2 different carbon atoms to form an oxygen-containing heterocycle having 4-7 ring members and R11 preferably represents a group selected from H and linear or branched C1-5 alkyl, which is optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl and cyano, or R11 preferably represents a 4 to 6-membered heterocycle containing 1 oxygen atom; and R2 represents a group selected from H, CH3, Et, iPr, iBu, Cpr and CH2-Cpr.
  • R11 is a group selected from H and linear, branched or cyclic C1-6 alkyl, which is optionally substituted by
  • these compounds are represented by formula Iom. In further specific embodiments, these compounds are represented by formula Ipm. In further specific embodiments, these compounds are represented by formula Iqm. In even further specific embodiments, these compounds are represented by formula Irm. In very specific embodiments, the compounds are represented by formula Inm1. In even more specific embodiments, the compounds are represented by formula Inm2. The compounds of the embodiment specified herein even more specifically are represented by formula Inm3. Specific compounds Specific compounds of the present invention are characterized by the following structures: Compound 12, Compound 15,
  • Deuterated compounds The present invention also relates to deuterated forms of any of the compounds or pharmaceutically acceptable salts, polymorphs, hydrates, solvates, esters, tautomers, prodrugs or metabolites thereof of the invention described above and below herein, e.g. to compounds of the invention that are deuterated, for instance to delay metabolization of the compound.
  • This objective can be accomplished e.g. if one or more of the hydrogen atoms bonded to the carbon atoms in the side chain carrying R2 are replaced by deuterium atoms.
  • the number and position of the replacements is not particularly limited. To illustrate this flexibility, possible replacement patterns are shown below for a typical side chain with R2 and R2a being methyl: .
  • deuterated compounds of the present invention include compounds of formula I, wherein the R1 is represented by the group wherein at least one position of the group is deuterated. In a particular embodiment, one to four positions on the aromatic cycle are deuterated. If 3 positions on the aromatic cycle are deuterated, R4 or R4’ in the above group is a deuterium atom and the respective other of R4 and R4’ is as defined further above.
  • R4 and R4’ in the above group are deuterium atoms.
  • one or more positions on the non-aromatic cycle are deuterated once or twice.
  • the four positions on the aromatic cycle are deuterated and at least one position on the non-aromatic cycle is deuterated twice.
  • deuterated compounds of the present invention include compounds of formula I, wherein the R1 is represented by the group , wherein at least one position of the chromaneamide group is deuterated.
  • the one to four positions on the aromatic cycle are deuterated. If 4 positions on the aromatic cycle are deuterated, R4 in the above group is a deuterium atom.
  • the 3-position on the non-aromatic cycle is deuterated once or twice (as shown for deuterated compound 18 below).
  • the four positions on the aromatic cycle are deuterated and the 3-position on the non-aromatic cycle is deuterated twice.
  • deuterated compounds of the present invention include compounds of formula I, wherein the R1 is represented by the group wherein at least one position of the dihydrobenzofuranamide group is deuterated.
  • the one to four positions on the aromatic cycle are deuterated. If 4 positions on the aromatic cycle are deuterated, R4 in the above group is a deuterium atom.
  • the 2-position on the non- aromatic cycle is deuterated once or twice.
  • the four positions on the aromatic cycle are deuterated and the 2-position on the non-aromatic cycle is deuterated twice.
  • deuterated forms of the compounds, metabolites or prodrugs of the invention are deuterated at the same positions as in the following structures of deuterated forms of compound 18 and its metabolite (compound 18-MET), respectively: and .
  • deuterated forms of compound 18 and compound 18-MET depicted above are also provided by the present invention.
  • the deuterated forms of any of the compounds or pharmaceutically acceptable salts, polymorphs, hydrates, solvates, esters, tautomers, prodrugs or metabolites thereof, of the invention can be prepared by methods known to the skilled person, taking into account also the methods described further below herein, for instance by employing appropriate deuterium-containing reagents.
  • Prodrugs also relates to prodrugs of the compounds of the present invention and specifically to a prodrug of the compound of formula I, which is characterized by the following formula III: III wherein R1, R2, R2a and R3 represent groups as specified above in connection with formula I in section 4.1 or any of the more specific embodiments described above but falling within the scope of formula III due to the prodrug modification at the nitrogen carrying R2.
  • Specific prodrug structures of the present invention are characterized by the following structures: Compound 12-PRO Compound 15-PRO Compound 14-PRO Compound 13-PRO Compound 43-PRO Compound 42-PRO Compound 11-PRO Compound 9-PRO Compound 10-PRO Compound 28-PRO Compound 40-PRO Compound 6-PRO Compound 41-PRO Compound 29-PRO Compound 36-PRO Compound 44-PRO Compound 45-PRO Compound 23-PRO Compound 49-PRO Compound 35-PRO Compound 17-PRO Compound 39-PRO Compound 46-PRO Compound 16-PRO Compound 20-PRO Compound 25-PRO Compound 19-PRO Compound 37-PRO Compound 47-PRO Compound 30-PRO Compound 34-PRO Compound 33-PRO Compound 38-PRO Compound 31-PRO Compound 32-PRO Compound 26-PRO Compound 18-PRO Compound 27-PRO Compound 48-PRO Compound 22-PRO Compound 21-PRO Compound 7-PRO Compound 4-PRO Compound 24-PRO Compound 5-PRO Metabolite
  • the present invention also relates to specific metabolites of the I
  • Said specific metabolites are characterized by the following general formula IV: wherein the meanings of the variable groups R1 and R3 are the same as specified above for general formula I in section 4.1.
  • Specific metabolite structures of the present invention are characterized by the following structures: Compound 12-MET Compound 15-MET Compound 14-MET Compound 13-MET Compound 43-MET Compound 42-MET Compound 11-MET Compound 9-MET Compound 10-MET Compound 28-MET Compound 40-MET Compound 6-MET Compound 41-MET Compound 29-MET Compound 36-MET Compound 44-MET Compound 45-MET Compound 23-MET Compound 49-MET Compound 35-MET Compound 17-MET Compound 39-MET Compound 46-MET Compound 16-MET Compound 20-MET Compound 25-MET Compound 19-MET Compound 37-MET Compound 47-MET Compound 30-MET Compound 34-MET Compound 33-MET Compound 38-MET Compound 31-MET Compound 32-MET Compound 26-MET Compound 18-MET Compound 27-MET Compound 48
  • Xevinapant-MET. 5 The following synthetic routes provide access to the compounds of the present invention. These general synthetic approaches may be applied to the specific reaction of interest by suitably modifying and/or adapting the described reactions and starting materials, selecting suitable reaction conditions, and the like, relying on common general knowledge of the synthetic organic chemist as reflected for instance by the textbooks on “Advanced Organic Chemistry” by F.A. Carey and R.J. Sundberg, Springer, 2013, “March’s Advanced Organic Chemistry” by M.B. Smith, Wiley, 2020, and “Advanced Organic Chemistry” by D.E. Lewis, Oxford University Press, 2016.
  • R3 is not acid sensitive, standard conditions can be applied such as use of HCl/Dioxan or TFA/DCM. If R3 is acid sensitive (e.g. including an oxetane group), pTSA/MeCN or FA at room temperature is preferred. Amide formation Standard coupling conditions using HATU and DIEA in DMF or DCM are suitable. Many other types of amide coupling conditions can be used. Saponification conditions Standard conditions (THF / 1M aqueous LiOH) can be employed. Route 1 is not compatible if R3 is base sensitive (case of many sulfonamides). R3 introduction depends on the type of group to be introduced: ⁇ Amide formation as described above.
  • N-alkylation with R3-X (halogen), R3-OTs or reductive amination with an aldehyde or a ketone ⁇ Urea formation from isocyanate derived from R3. Or urea formation from amine derived from an activating agents such as phosgene, triphosgene, N,N ⁇ -disuccinimidyl carbonate, bis(4-nitrophenyl) carbonate, carbonyldiimidazole, bis(pentafluorophenyl) carbonate, pentafluorophenyl chloroformate, 4-nitrophenyl chloroformate.
  • activating agents such as phosgene, triphosgene, N,N ⁇ -disuccinimidyl carbonate, bis(4-nitrophenyl) carbonate, carbonyldiimidazole, bis(pentafluorophenyl) carbonate, pentafluorophenyl chloroformate, 4-nitrophenyl chloroformate.
  • the present invention provides a process for manufacturing compounds of the present invention, as specified by means of formula I above (or any of the more specific embodiments based on any of formulae Ia to Inm3 above), which comprises the step of reacting the intermediate of formula 1-1 1-1 with intermediate of formula 1-2 1-2, followed by Boc-deprotection of the resulting intermediate of formula 1-3 1-3.
  • Embodiment P2 In some embodiments, this method is carried out using HCl/dioxan or TFA/DCM or pTSA/MeCN or FA if R3 is not acid sensitive, and using pTSA/MeCN or FA if R3 is acid sensitive.
  • Embodiment P3 In this embodiment, a method according to embodiment P1 or P2 is provided, comprising a step wherein the intermediate of formula 1-1 is obtained by saponification of an intermediate with formula 1-4 followed by amidation with a primary amine derived from R1 (R1’-NH2) wherein R1’ is the same as R1 but without the amino group, to yield intermediate of formula 1-5 Said method comprises the further step, wherein the intermediate of formula 1-5 is then BOC-deprotected to yield the intermediate of formula 1-1.
  • Embodiment P4 In embodiments pursuant to embodiment P3, saponification is carried out using THF with aqueous LiOH typically having a concentration of 1M.
  • R3’, R3’’ and R3’’ are derived from R3 and contain the same atomic group except for the functional group that is shown above in combination with R3’, R3’’ and R3’’’.
  • PG protection The protection of the secondary amine can be achieved using benzoyl or allyl chloroformate with DIEA in DCM.
  • PG deprotection Standard conditions can be applied. For instance, alloxycarbonyl can be removed using catalytic amount tetrakistriphenyl phosphine palladium (0) in degassed solvent (mixture of EtOAc and DCM). Benzyloxycarbonyl can be removed using catalytic amount of Pd/C in Ethanol or IMS under hydrogen atmosphere at room temperature.
  • Embodiment P6 Hence, according to route 2, an alternative method for preparing the compounds of the present invention is provided.
  • This alternative method comprises the same step of reacting intermediate 1-1 with intermediate 1-2 to give rise to the intermediate 1-3 and ultimately the compounds of the present invention. These steps are as described above as embodiments P1 and P2 of route 1.
  • the method of this embodiment further comprises a step, wherein intermediate 1-1 is obtained by deprotection of intermediate 1-5, as described above as part of embodiment P-3.
  • Embodiment P7 In embodiments pursuant to embodiment P6, said method comprises further steps wherein intermediate 2-1 is obtained from the compound of formula 1-6 as shown above, which is protected with a protecting group PG to yield intermediate of formula 2-2 wherein PG has the same meaning as specified above, and wherein said intermediate 2-2 is then saponified followed by introduction of the R1 group by amide formation reaction to yield intermediate 2-1 as shown above.
  • Route 3 Reductive amination
  • the reductive amination can be carried under standard conditions using sodium triacetoxyborohydride in DCM in the optional presence of acetic acid.
  • the carbonyl derivative containing R2 can be a ketone or an aldehyde. Reaction may require heating for ketones.
  • Embodiment P9 In methods according to embodiment P8, reductive amination may be carried out using sodium triacetoxyborohydride in DCM in the optional presence of acetic acid.
  • Embodiment P10 According to this embodiment, in the method of embodiment P8 or P9, the method further comprises a step wherein the intermediate 3-1 is obtained by reacting intermediate 1-1, as shown in embodiment P1 above, with intermediate 3-2 Route 4 (prodrug access 1): N-alkylation Standard procedures reported in the literature show moderate yield for the reaction (K2CO3 and DMF). The use of K3PO4 and KI in THF at room temperature are more efficient in some cases.
  • Embodiment P11 According to this embodiment, a prodrug of formula III, as described hereinabove, is prepared by means of a method, wherein a compound of the present invention, as specified by means of formula I above (or any of the more specific embodiments based on any of formulae Ia to Inm3 above), is reacted with the intermediate of formula 4-1 to cause N-alkylation and thus yield the prodrug of formula III.
  • Embodiment P12 The method according to embodiment P11, which is carried out in the presence of K3PO4 and KI in THF.
  • Embodiment P13 This embodiment provides a method for preparing the prodrug of formula III, which comprises a step of reacting intermediate 1-1, as specified above, with the intermediate of formula 5-1
  • Embodiment P14 This embodiment specifies a method according to embodiment P13, wherein the intermediate 5-1 is obtained by reacting intermediate 4-1, as specified above, with intermediate 5-2 This route is most suitable for the introduction of urea-containing R3 groups.
  • Embodiment P16 This embodiment provides a method according to embodiment P15, which further comprises a step of preparing intermediate 6-1 by reacting intermediate 6-2 with intermediate 5-1, as specified above.
  • Embodiment P17 This embodiment provides a method according to embodiment P16, which further comprises a step of subjecting intermediate 2-1, as specified above but wherein PG is alloc, to Boc-deprotection.
  • Embodiment P18 According to this embodiment, amide formation reaction in any of the above embodiments is carried out using HATU and DIEA in DMF or DCM.
  • Embodiment P19 the compound or deprotected compound of any of the embodiments described above is further subjected to a) solvate formation, preferably methyl tert-butyl ether solvate formation, and b) at least one of melting, evaporation and homogenization. 6.
  • Therapeutic Use The present invention also provides therapeutic uses of the compounds of the present invention. Such uses include the use of a compound of the present invention in the treatment of HIV or cancer. For example, for the treatment of HIV, the compounds of the present invention may be used in combination with ART, and/or in combination therapy together with one or more additional active agents. By consequence, the present invention also provides methods for treating HIV, i.e. compounds for use in the treatment of HIV.
  • the compound may be used together with one or more further active agents.
  • Such methods for treating HIV may include the “shock and kill” approach described above.
  • the choice of suitable co-agents to be used in the combination therapy of the present invention is determined by the objective to be accomplished by the co-agent. That is, for latency reversal, i.e. the “shock” aspect of the above strategy, it may be appropriate to rely on an active agent that is different from active agents that can be used for the “kill” aspect, and vice versa.
  • the present invention provides methods for treating cancer, i.e. compounds for use in the treatment of cancer such as breast cancer.
  • the compound may be used for treating cancer as part of a combination therapy together with any one or more other anti-cancer agents and/or treatments, such as radiation treatment.
  • the compounds of the present invention may be administered alone or combined with other latency reversing agents.
  • the compounds of the present invention may be combined with histone deacetylase inhibitors such as vorinostat, valproic acid, belinostat, panobinostat, givinostat, entinostat, or romidepsin, as described in L. Pache et al. in Cell Host & Microbe 18, 345–353, 2015 and WO 2015/187998 A.
  • an immune checkpoint inhibitor for this purpose is selected from the group consisting of CTLA-4 inhibitors, PD-1 inhibitors, LAG-3 inhibitors, TIGIT inhibitors, Tim-3 inhibitors and PDL-1 inhibitors, and more preferably selected from inhibitors of PD-1 or PD- L1.
  • the “kill” aspect in the “shock and kill” approach to treating HIV infection may be accomplished by the compounds of the present invention via their IAP inhibitory activity.
  • the compounds of the present invention are combined with one, two or more further drugs to accomplish more effective virus eradication.
  • NRTIs Nucleoside reverse transcriptase inhibitors
  • ZDT Zidovudine
  • Didanosine Videx, Videx EC, ddI
  • Stavudine Zerit, d4T
  • Lamivudine Epivir, 3TC
  • Abacavir Zaiagen, ABC
  • Tenofovir especially in its prodrug forms (i.e.
  • NRTIs Non-nucleoside reverse transcriptase inhibitors
  • Nevirapine Viramune, NVP
  • Delavirdine Rescriptor, DLV
  • Efavirenz Sustiva or Stocrin, EFV, also part of Atripla
  • Etravirine Intelence, ETR
  • Rilpivirine Edurant, RPV, also part of Complera or Epivlera
  • PIs Protease inhibitors
  • the therapeutically effective amount of the compound of the present invention is typically about 50 to about 1000 mg per day.
  • the skilled person knows how to determine the therapeutically effective amount of such a compound for the treatment of a disease such as HIV infection or cancer.
  • the overall duration of the treatment is not particularly restricted.
  • Therapeutic use of IAP inhibitors in the treatment of cancer patients is being investigated in clinical trials, as mentioned for xevinapant (Sun et al., The Lancet Oncology, Vol.21, Issue 9, p.1173-1187, September 1, 2020; Bourhis et.
  • the compounds of the present invention are IAP inhibitors and are suitable for the treatment of cancer in patients in need thereof.
  • the cancer may for instance be breast cancer.
  • the compounds, compositions, treatment methods, as well as compounds for use in the treatment methods of the present invention are suitable for use in any patient suffering from cancer or infected with HIV.
  • the patient can be either na ⁇ ve or in virological failure after ART (for instance incomplete suppression: HIV-Viral Load > 200 copies/mL at 6 months after starting therapy in persons not previously on ART or rebound: e.g.
  • the patient can also be on ART with stable low HIV-Viral-Loads.
  • the patient is a patient infected with HIV-1.
  • the patients need not satisfy the patient characteristics specified for the use in treating HIV infection. 7.
  • Pharmaceutical Compositions and Kits The compounds of the present invention may be provided in the form of a pharmaceutical composition.
  • the pharmaceutical composition comprises a compound of the present invention as the sole active ingredient.
  • the compounds of the present invention may also be provided together with any of the other drug compounds described herein as suitable for use in the present invention, either in separate pharmaceutical compositions or together in a single pharmaceutical composition.
  • compositions comprising one or more compounds as described herein, which can be administered by the same route.
  • pharmaceutical compositions comprising a compound of the present invention, which is suitable for oral administration, alone or further comprising one or more drug compounds for HIV therapy or cancer therapy.
  • pharmaceutical compositions for intravenous administration which comprise a compound of the present invention that is suitable for intravenous administration alone or a compound of the present invention that is suitable for intravenous administration together with another drug that is suitable for intravenous administration.
  • the pharmaceutical compositions of the invention may furthermore be provided with instructions for use.
  • kits wherein two or more drugs are provided in two or more separate pharmaceutical compositions, each of which being formulated for the respective appropriate route of administration.
  • one of the drugs is a compound of invention, and the other one or more drugs are as specified elsewhere in the present application.
  • the kits of the invention may furthermore contain instructions for use.
  • the pharmaceutical compositions according to the present invention may optionally be provided with instructions for use in the treatment of HIV or cancer, as the case may be. Such instructions may involve instructions for co-administration with one or more other active components as specified above.
  • Such instructions for use may be given in the form of a printed patient leaflet, product labelling, or the like, or by means of oral or written instructions of the treating physician.
  • the grant of a marketing authorization for one of the compounds of the present invention for use in combination with at least one other component for the treatment of HIV or cancer may also be regarded as an embodiment of the present invention.
  • the pharmaceutical compositions described above may comprise further active agents or combinations of active agents. It is, for instance, contemplated to provide a pharmaceutical composition for use in the treatment of HIV, the treatment being in combination with an immune checkpoint inhibitor, wherein the pharmaceutical composition comprises a compound of the present invention together with one or more drugs for ART.
  • the pharmaceutical compositions of the present invention are not restricted to any particular type of administration. Instead, it is advantageous to identify and select an appropriate administration form for each drug to be administered. In some embodiments, a compound of the invention is administered orally.
  • a compound of the invention is administered in capsular form or tablet form. In some embodiments, a compound of the invention is administered orally as a capsule or as a tablet.
  • the pharmaceutical compositions of the present invention may comprise one or more pharmaceutically acceptable excipients such as fillers, binders, disintegrants, lubricants, or glidants in addition to a compound of the present invention and optionally one or more further active agents. 8.
  • Flash column chromatography was performed on silica gel 60 or a Biotage Isolera Four using Silicycle Siliasep columns (pre-packed with spherical silica 25 ⁇ m) or Biotage ZIP® columns (pre-packed with spherical silica 60 ⁇ m) and reagent grade heptane, EtOAc, DCM or MeOH as eluent for normal phase chromatographic purification or water and MeCN (0.1% FA for acidic or 0.1% saturated aqueous NH3 for basic) for reverse phase chromatographic purification.
  • UPLC-MS (MSP1 - BEH C18 Short Basic 2to98) Instrument: Waters Acquity UPLC H-Class system; Column: XBridge BEH C181.7 ⁇ m 2.1 x 50 mm; eluent A: water + 0.1% saturated aqueous NH3, eluent B: MeCN + 0.1% saturated aqueous NH3; gradient: 0.2-2.5min 2-98% B with A, 2.5-3.0 min 98% B; flow 1.0 mL/min; temperature: 50 °C; PDA: 190-450 nm.
  • UPLC-MS (CSH C18 Short Acid 2to95) Instrument: Waters Acquity UPLC H-Class system; Column: Acquity CSH C181.7 ⁇ m 2.1 x 50 mm; eluent A: water, eluent B: MeCN, eluent C: 2 vol % NH3 (28%) in water, eluent D: 2 vol % FA in water; gradient: 0-1.2 min 2-95% B with A and 5% D throughout, 1.2-1.4 min 95% B; flow 0.8 ml/min; temperature: 40 °C; PDA: 215-350 nm.
  • UPLC-MS (CSH C18 Long Acid 2to95) Instrument: Waters Acquity UPLC H-Class system; Column: Acquity CSH C181.7 ⁇ m 2.1 x 50 mm; eluent A: water, eluent B: MeCN, eluent C: 2 vol % NH3 (28%) in water, eluent D: 2 vol % FA in water; gradient: 0-4.0 min 2-95% B with A and 5% D throughout, 4.0-4.6 min 95% B; flow 0.8 ml/min; temperature: 40 °C; PDA: 215-350 nm.
  • UPLC-MS (BEH C18 Short Basic 2to95) Instrument: Waters Acquity UPLC H-Class system; Column: XBridge BEH C82.5 ⁇ m 2.1 x 50 mm; eluent A: water, eluent B: MeCN, eluent C: 2 vol % NH3 (28%) in water, eluent D: 2 vol % FA in water; gradient: 0-1.2 min 2-95% B with A and 5% C throughout, 1.2-1.4 min 95% B; flow 0.8 ml/min; temperature: 40 °C; PDA: 215-350 nm.
  • UPLC-MS (BEH C18 Long Basic 2to95) Instrument: Waters Acquity UPLC H-Class system; Column: XBridge BEH C182.5 ⁇ m 2.1 x 50 mm; eluent A: water, eluent B: MeCN, eluent C: 2 vol % NH3 (28%) in water, eluent D: 2 vol % FA in water; gradient: 0-4.0 min 2-95% B with A and 5% C throughout, 4.0-4.6 min 95% B; flow 0.8 ml/min; temperature: 40 °C; PDA: 215-350 nm.
  • UPLC-MS (3 min standard) Analyses were performed on a UPLC Acquity and SQD Waters system. Masslynx software was used to launch and analyse experiments using OALogin and automatic or manual integrations. Details of the method used are listed in Table 1 below. Table 1: UPLC-MS mass spectra were recorded on a SQ detector Acquity Waters (Waters Corporation, Waters Milford, 34 Maple St., Milford, USA) equipped with software Empower 2 pro in a positive and negative ionization. Preparative HPLC: (standard gradient) Column: Xbridge® Prep C185 ⁇ M OBDTM 19x150 mm Flowrate: 24 mL/min.
  • Example 1 Building block synthesis of tert-butyl ((5S,8S,10aR)-8-((4-fluorobenzyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate Step 1: 3-allyl 8-methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxylate To a solution of methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate (1.00 g, 2.93 mmol) in DCM (40 mL) and DIPEA (1.28 mL, 7.
  • Step 2 (5S,8S,10aR)-3-((allyloxy)carbonyl)-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid
  • 3-allyl 8-methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6- oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxylate 930 mg, 2.19 mmol
  • THF 10 mL
  • water 10 mL
  • lithium hydroxide monohydrate 275 mg, 6.56 mmol
  • Step 3 allyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-8-((4-fluorobenzyl)carbamoyl)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3(4H)-carboxylate
  • 5S,8S,10aR -3-((allyloxy)carbonyl)-5-((tert-butoxycarbonyl)amino)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid
  • Step 4 tert-butyl ((5S,8S,10aR)-8-((4-fluorobenzyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate
  • a solution of allyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-8-((4- fluorobenzyl)carbamoyl)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3(4H)-carboxylate (1.40 g, 2.70 mmol) in degassed EtOAc-DCM (50:50) was added tetrakistriphenyl phosphine palladium (0) (312 mg, 0.270 mmol) and stirred at room temperature for 3 hours under N2.
  • Example 2 Building block synthesis of tert-butyl ((5S,8S,10aR)-6-oxo-8-(((R)-3,4,6,7-tetrahydro-2H-chromen-4-yl)carbamoyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate
  • Step 1 3-benzyl 8-methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxylate
  • Step 2 benzyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-8-(((R)-chroman-4-yl)carbamoyl)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3(4H)-carboxylate
  • 3-benzyl 8-methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6- oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxylate (2.80 g, 5.91 mmol) in THF (100 mL) and water (25 mL), was added lithium hydroxide monohydrate (298 mg, 7.09 mmol) at room temperature.
  • Step 3 benzyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-8-(((R)-chroman-4-yl)carbamoyl)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3(4H)-carboxylate
  • 5S,8S,10aR -3-((benzyloxy)carbonyl)-5-((tert-butoxycarbonyl)amino)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid
  • (R)- chroman-4-amine hydrochloride 580 mg, 3.12 mmol
  • DIPEA 1.48 mL, 8.52 mmol
  • Step 4 tert-butyl ((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate
  • benzyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-8-(((R)-chroman-4- yl)carbamoyl)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3(4H)-carboxylate 890 mg, 1.50 mmol) in EtOH (100 mL) under an atmosphere of nitrogen, was added 10% Pd/C (25 mg) at room temperature.
  • Example 3 Building block synthesis of (5S,8S,10aR)-N-((R)-chroman-4-yl)-5-((S)-2-(methyl((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)amino)propanamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride Step 1: 3-Allyl 8-methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxylate A solution of methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate
  • Step 2 (5S,8S,10aR)-3-((Allyloxy)carbonyl)-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid
  • a solution of 3-allyl 8-methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6- oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxylate (6.77 g, 15.9 mmol) and lithium hydroxide monohydrate (2.00 g, 47.7 mmol) in THF (40 mL) and water (40 mL) was stirred at room temperature for 3 hours.
  • Step 3 allyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-8-(((R)-chroman-4-yl)carbamoyl)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3(4H)-carboxylate
  • 5S,8S,10aR -3-((Allyloxy)carbonyl)-5-((tert-butoxycarbonyl)amino)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid
  • DIPEA 5.75 mL, 33.0 mmol
  • (R)-chroman-4-amine hydrochloride (2.94 g, 15.8 mmol
  • Step 4 allyl (5S,8S,10aR)-5-amino-8-(((R)-chroman-4-yl)carbamoyl)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3(4H)-carboxylate hydrochloride
  • a solution of allyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-8-(((R)-chroman-4- yl)carbamoyl)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3(4H)-carboxylate (3.40 g, 6.27 mmol) in 4 M HCl/dioxane (30 mL) was stirred at room temperature for 3 hours.
  • Step 5 allyl (5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-5-((S)-2-(methyl((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)amino)propanamido)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3(4H)-carboxylate
  • allyl (5S,8S,10aR)-5-amino-8-(((R)-chroman-4-yl)carbamoyl)-6- oxooctahydropyrrolo[1,2-a][1,5]diazocine-3(4H)-carboxylate hydrochloride (2.90 g, 6.06 mmol) in DCM (150 mL) was added DIPEA (3.16 mL, 18.2 mmol) and N-methyl-N-
  • Step 7 tert-butyl ((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)-L-alaninate
  • K2CO3 91.2 g, 660 mmol
  • the mixture was stirred for 5 minutes at room temperature and 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (32.7 g, 220 mmol) and potassium iodide (36.5 g, 220 mmol) were added.
  • Step 8 tert-butyl N-methyl-N-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)-L-alaninate
  • tert-butyl ((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)-L-alaninate (26.0 g, 101 mmol) in DCM (1L) was added formaldehyde solution (37% wt in water, 22.6 mL, 303 mmol) and the mixture stirred at room temperature for 15 minutes.
  • Sodium triacetoxyborohydride (64.2 g, 303 mmol) was added portion wise and the mixture stirred at room temperature for 2 hours.
  • Step 9 N-methyl-N-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)-L-alanine
  • 1H NMR (400 MHz, CDCl3) ⁇ [ppm] 1.69 (d, 3H), 2.26 (s, 3H), 3.01 (s, 3H), 4.33-4.55 (m, 3H).
  • Example 4a Synthesis of (5S,8S,10aR)-N8-((R)-chroman-4-yl)-N3-methyl-5-((S)-2-(methylamino)propanamido)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide (Compound 4) 2,2,2-trifluoroacetate salt
  • Step 1 methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(methylcarbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocine-8-carboxylate (500mg, 1.39
  • Methylcarbamic chloride 150 mg, 1.52 mmol
  • TEA 600 ⁇ L, 4.21 mmol
  • UPLC analysis 3 min standard
  • More methylcarbamic chloride 28 mg, 0.28 mmol
  • the reaction was stirred for 10 min and the reaction mixture was diluted with water (5 mL) and phases were separated. Aqueous layer was extracted with more DCM (5 mL) and the combined organic layers were dried over MgSO4 and concentrated to dryness.
  • Step 2 (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(methylcarbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(methylcarbamoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate (98.4 mg, 0.243 mmol) was dissolved in THF (1.5 ml). The resulting solution was treated with LiOH 2M (803 ⁇ L).
  • Step 3 tert-butyl ((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-(methylcarbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(methylcarbamoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (82.8 mg, 0.211 mmol) and (R)- chroman-4-amine hydrochloride (49.1 mg, 0.262 mmol) were dissolved in DMF (1 ml).
  • Step 4 (5S,8S,10aR)-5-amino-N8-((R)-chroman-4-yl)-N3-methyl-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide 2,2,2-trifluoroacetate tert-butyl ((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-(methylcarbamoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (82 mg) was dissolved in 1 ml of TFA/DCM 9:1.
  • Step 5 tert-butyl ((S)-1-(((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-(methylcarbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (5S,8S,10aR)-5-amino-N8-((R)-chroman-4-yl)-N3-methyl-6-oxooctahydropyrrolo[1,2- a][1,5]diazocine-3,8(4H)-dicarboxamide 2,2,2-trifluoroacetate (70 mg, 0.130 mmol) and N- (tert-butoxycarbonyl)-N-methyl-L-alanine (32 mg, 0.154 mmol) was dissolved in DMF (0.5 ml).
  • Step 6 (5S,8S,10aR)-N8-((R)-chroman-4-yl)-N3-methyl-5-((S)-2-(methylamino)propanamido)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide 2,2,2-trifluoroacetate tert-butyl ((S)-1-(((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-(methylcarbamoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (54.4 mg, 0.090) was treated with a mixture of TFA/DCM 9:1 (0.3 ml).
  • Example 4b Synthesis of (5S,8S,10aR)-N8-((R)-chroman-4-yl)-N3-methyl-5-((S)-2-(methyl((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)amino)propanamido)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide (Compound 4-PRO, prodrug of Compound 4) Step 1: (5S,8S,10aR)-N8-((R)-chroman-4-yl)-N3-methyl-5-((S)-2-(methyl((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)amino)propanamido)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dica
  • Step 3 methyl (5S,8S,10aR)-3-acetyl-5-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate methyl (5S,8S,10aR)-3-acetyl-5-amino-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8- carboxylate 2,2,2-trifluoroacetate (4.15 g, 10.2 mmol) and acid (2.47 g, 11.9 mmol) was dissolved in DCM (50.0 ml).
  • Step 4 (5S,8S,10aR)-3-acetyl-5-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid methyl (5S,8S,10aR)-3-acetyl-5-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate (2.57 g) was dissolved in THF (40 mL).
  • Step 5 tert-butyl ((S)-1-(((5S,8S,10aR)-3-acetyl-8-(((R)-chroman-4-yl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (5S,8S,10aR)-3-acetyl-5-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (2.58 g, 5.11 mmol) was dissolved in DCM (15 mL) and N-(tert-butoxycarbonyl)-N-methyl-L-alanine (1.25 g, 6.66 mmol) was added.
  • Step 6 (5S,8S,10aR)-3-acetyl-N-((R)-chroman-4-yl)-5-((S)-2-(methylamino)propanamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride tert-butyl ((S)-1-(((5S,8S,10aR)-3-acetyl-8-(((R)-chroman-4-yl)carbamoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (1.38 g, 2.24) was dissolved in DCM (10 mL).
  • Example 6 The preparation of compound 5-MET (metabolite) is disclosed in Example 6 (step 6).
  • Example 6 Synthesis of (5S,8S,10aR)-3-acetyl-N-((R)-chroman-4-yl)-5-((S)-2-(isobutylamino)propanamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (Compound 6)
  • Step 1 tert-butyl isobutyl-L-alaninate
  • KOAc 170 mg, 1.73 mmol
  • Step 2 isobutyl-L-alanine To solution of tert-butyl isobutyl-L-alaninate (100 mg, 0.497 mmol) in THF (10 mL), MeOH (2 mL) and water (1 mL) was added LiOH.H2O (104 mg, 2.48 mmol) and the mixture stirred at room temperature for 1 hour. Reaction mixture was heated at 60 °C for 6 hours.
  • Step 3 Methyl (5S,8S,10aR)-3-acetyl-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate
  • DIPEA 430 ⁇ L, 2.469 mmol
  • acetyl chloride 105 ⁇ L, 1.477 mmol
  • Step 4 (5S,8S,10aR)-3-Acetyl-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid
  • methyl (5S,8S,10aR)-3-acetyl-5-((tert-butoxycarbonyl)amino)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate 390 mg, 1.017 mmol
  • 2 M lithium hydroxide aqueous solution (3.05 mL, 6.102 mmol
  • Step 5 tert-Butyl ((5S,8S,10aR)-3-acetyl-8-(((R)-chroman-4-yl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate
  • a solution of (5S,8S,10aR)-3-acetyl-5-((tert-butoxycarbonyl)amino)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid 195 mg, 0.528 mmol
  • DCM 5 mL
  • DIPEA 370 ⁇ L, 2.12 mmol
  • (R)-chroman-4-amine hydrochloride 108 mg, 0.582 mmol
  • reaction mixture was stirred at room temperature for 1 hour. Reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO3 solution. The aqueous layer was washed with DCM. The combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude residue was purified by column chromatography on silica gel 60 eluting with MeOH-DCM (5:95) and further purified by reverse phase chromatography (Biotage Isolera, 60 g, C18 SNAP Ultra Biotage cartridge) using water containing 0.1% FA and MeCN containing 0.1% FA (90:10 to 30:70) to give the desired compound (204 mg, 77%) as a white foam.
  • Step 7 (5S,8S,10aR)-3-acetyl-N-((R)-chroman-4-yl)-5-((S)-2-(isobutylamino)propanamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide
  • isobutyl-L-alanine 43.9 mg, 0.242 mmol
  • 5S,8S,10aR)-3-acetyl-5-amino-N- ((R)-chroman-4-yl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride (96 mg, 0.220 mmol) and TEA (0.196 mL, 1.41 mmol) in DCM (5 mL) was added HATU (100 mg, 0.264 mmol) and the mixture stirred at room temperature for 16 hours.
  • Reaction mixture was diluted with DCM and washed with water. Organics were dried over Na2SO4, filtered and concentrated under reduced pressure.
  • the crude residue was purified by flash column chromatography on silica gel 60 (eluent: 95:5 DCM:MeOH with few drops of 1M NH3 in MeOH).
  • the crude product was further purified by trituration with Et2O and solids collected by filtration and dried under vacuum.
  • the crude product was further purified by flash column chromatography on silica gel 60 (eluent: 9:1 EtOAc:MeOH).
  • the crude product was further purified by trituration with Et2O and solids collected by filtration and dried under vacuum.
  • Residue was further purified by SCX-2 (1 g, 6 mL) cartridge loading and washing with MeOH and eluting with 1 M NH3/MeOH. Product fractions were concentrated and diluted with water then freeze dried to give the desired product (23.5 mg, 21%) as a white solid.
  • Step 2 methyl (5S,8S,10aR)-5-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3-(methylcarbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate methyl (5S,8S,10aR)-5-amino-3-(methylcarbamoyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocine-8-carboxylate 2,2,2-trifluoroacetate (205 mg, 0.487 mmol) and N-(tert- butoxycarbonyl)-N-methyl-L-alanine (110 mg) was dissolved in DMF (2.0 mL).
  • Step 3 (5S,8S,10aR)-5-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3-(methylcarbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid methyl (5S,8S,10aR)-5-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3- (methylcarbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate (163 mg, 0.330 mmol) was dissolved in THF (2 mL).
  • Step 4 tert-butyl ((2S)-1-(((5S,8S,10aR)-8-((2,3-dihydrobenzofuran-3-yl)carbamoyl)-3-(methylcarbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (5S,8S,10aR)-5-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3- (methylcarbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (25.7 mg, 0.054 mmol) and racemic 2,3-dihydrobenzofuran-3-amine (12 mg, 0.069 mmol) were dissolved in DMF (0.25 m
  • Step 5 (5S,8S,10aR)-N8-(2,3-dihydrobenzofuran-3-yl)-N3-methyl-5-((S)-2-(methylamino)propanamido)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide 2,2,2-trifluoroacetate tert-butyl ((2S)-1-(((5S,8S,10aR)-8-((2,3-dihydrobenzofuran-3-yl)carbamoyl)-3- (methylcarbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2- yl)(methyl)carbamate (21.8 mg, 0.0372 mmol) was treated with 1 mL of a mixture of TFA/DCM 9
  • Step 6 tert-butyl ((5S,8S,10aR)-8-((2,3-dihydrobenzofuran-3-yl)carbamoyl)-3-(methylcarbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(methylcarbamoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (50 mg, 0.127 mmol) and 2,3- dihydrobenzofuran-3-amine hydrochloride (27 mg, 0.156 mmiol) were dissolved in DMF (0.5 ml).
  • Step 7 (5S,8S,10aR)-5-amino-N8-(2,3-dihydrobenzofuran-3-yl)-N3-methyl-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide 2,2,2-trifluoroacetate
  • a mixture of 9:1 TFA/DCM (1 mL) was added to tert-butyl ((5S,8S,10aR)-8-((2,3- dihydrobenzofuran-3-yl)carbamoyl)-3-(methylcarbamoyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazocin-5-yl)carbamate.
  • Example 8 General synthetic route A towards sulfonamide derivatives
  • Example 9 Synthesis of (5S,8S,10aR)-N-((R)-chroman-4-yl)-5-((S)-2-(methylamino)propanamido)-6-oxo-3-(phenylsulfonyl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (Compound 9) hydrochloride salt and itsprodrug Step 1: tert-butyl ((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-6-oxo-3-(phenylsulfonyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate To a solution of tert-butyl ((5S,8S,10aR)-8-(((R)-chroman-4-yl
  • Step 2 (5S,8S,10aR)-5-amino-N-((R)-chroman-4-yl)-6-oxo-3-(phenylsulfonyl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride
  • tert-butyl ((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-6-oxo-3- (phenylsulfonyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (229 mg, 0.382 mmol) in MeOH (3 mL) was added 4 M HCl/dioxane (3 mL) and the mixture stirred at room temperature for 18 hours.
  • Step 4 (5S,8S,10aR)-N-((R)-chroman-4-yl)-5-((S)-2-(methylamino)propanamido)-6-oxo-3-(phenylsulfonyl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamidehydrochloride
  • tert-butyl ((S)-1-(((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-6-oxo-3- (phenylsulfonyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2- yl)(methyl)carbamate (210 mg, 0.307 mmol) in MeOH (3 mL) was added 4 M HCl/dioxane (3 mL) and the
  • Step 2 (5S,8S,10aR)-5-amino-N-((R)-chroman-4-yl)-3-((4-fluorophenyl)sulfonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride
  • tert-butyl ((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-((4- fluorophenyl)sulfonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (280 mg, 0.454 mmol) in MeOH (3 mL) was added 4 M HCl/dioxane (3 mL) and the mixture stir
  • Step 3 tert-butyl ((S)-1-(((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-((4-fluorophenyl)sulfonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate To a solution of (5S,8S,10aR)-5-amino-N-((R)-chroman-4-yl)-3-((4-fluorophenyl)sulfonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride (157 mg, 0.284 mmol) in DCM (10 mL) was added DIPEA (148 ⁇ L, 0.852 mmol) and N-(
  • Step 3 tert-butyl ((S)-1-(((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-(isopropylsulfonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate
  • To a solution of (5S,8S,10aR)-5-amino-N-((R)-chroman-4-yl)-3-(isopropylsulfonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride 40 mg, 0.080 mmol
  • DCM 5 mL
  • DIPEA 42 ⁇ L, 0.240 mmol
  • the reaction mixture was diluted with DCM and washed with saturated aqueous NH4Cl solution.
  • the aqueous layer was extracted with DCM.
  • the combined organics were dried over Na2SO4, filtered and concentrated.
  • the crude residue was purified by flash column chromatography on silica gel 60 using heptane:EtOAc (3:7 to 0:1).
  • the residue was purified further by reverse phase chromatography (Biotage Isolera, 12 g, C18 SNAP Ultra Biotage cartridge) using MeCN containing 0.1% FA and water containing 0.1% FA (30:70 to 80:20) and product saturated with brine and extracted with EtOAc.
  • Step 4 (5S,8S,10aR)-N-((R)-chroman-4-yl)-3-(isopropylsulfonyl)-5-((S)-2-(methylamino)propanamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride
  • tert-butyl ((S)-1-(((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3- (isobutylsulfonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2- yl)(methyl)carbamate (42 mg, 0.063 mmol) in MeOH (3 mL) was added 4 M HCl/dioxane (3 m
  • Step 2 (5S,8S,10aR)-N8-((R)-chroman-4-yl)-N3-(3-methoxypropyl)-5-((S)-2-(methylamino)propanamido)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide hydrochloride
  • Example 13 Synthesis of (5S,8S,10aR)-N-((R)-chroman-4-yl)-3-(ethylsulfonyl)-5-((S)-2-(methylamino)propanamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (Compound 13) and its prodrug Step 1: methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(ethylsulfonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate To a solution of methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate (500 g, 1.46
  • Step 2 (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(ethylsulfonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid
  • a solution of methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(ethylsulfonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate (279 mg, 643.6 mmol) and lithium hydroxide monohydrate (81.02 mg, 1.93 mmol) in THF (4 mL) and water (4 mL) was stirred at room temperature for 2 hours.
  • Step 3 tert-butyl ((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-(ethylsulfonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate
  • To a solution of (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(ethylsulfonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (266 mg, 0.634 mmol) in DCM (20 mL) was added DIPEA (246 mg,
  • Step 4 (5S,8S,10aR)-5-amino-N-((R)-chroman-4-yl)-3-(ethylsulfonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride
  • tert-butyl ((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-(ethylsulfonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate 230 mg, 0.418 mmol
  • 4 M HCl/dioxane 10 mL
  • Step 5 ((5S,8S,10aR)-N-((R)-chroman-4-yl)-3-(ethylsulfonyl)-5-((S)-2-(methyl((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)amino)propanamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide
  • To a solution of (5S,8S,10aR)-5-amino-N-((R)-chroman-4-yl)-3-(ethylsulfonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride 150 mg, 30.8 ⁇ mol
  • DCM 10 mL
  • DIPEA 0.27 mL, 1.54 mmol
  • HATU 141 mg, 369 ⁇ mol
  • the reaction mixture was concentrated and diluted with EtOAc, washed with water, NaHCO3 (saturated solution), water, brine, dried over Na2SO4, filtered and concentrated.
  • Step 6 tert-butyl ((S)-1-(((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-(ethylsulfonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate
  • To a solution (5S,8S,10aR)-5-amino-N-((R)-chroman-4-yl)-3-(ethylsulfonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride (40 mg, 0.080 mmol) in DCM (5 mL) was added DIPEA (42 ⁇ L, 0.240 mmol) and N-(tert-butoxycarbonyl)-N-
  • the reaction mixture was diluted with DCM and washed with saturated aqueous NH4Cl solution.
  • the aqueous layer was extracted with DCM.
  • the combined organics were dried over Na2SO4, filtered and concentrated.
  • the crude residue was purified by flash column chromatography on silica gel 60 using heptane:EtOAc (3:7 to 0:1).
  • the residue was purified further by reverse phase chromatography (Biotage Isolera, 12 g, C18 SNAP Ultra Biotage cartridge) using MeCN containing 0.1% FA and water containing 0.1% FA (30:70 to 80:20) and product saturated with brine and extracted with EtOAc.
  • Step 7 (5S,8S,10aR)-N-((R)-chroman-4-yl)-3-(ethylsulfonyl)-5-((S)-2-(methylamino)propanamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide tert-butyl ((S)-1-(((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-(ethylsulfonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (40 mg, 0.097 mmol) in
  • Step 3 tert-butyl ((5S,8S,10aR)-3-(cyclopropylsulfonyl)-8-((4-fluorobenzyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate
  • HATU 722 mg, 1.90 mmol
  • 4-fluorophenyl)methanamine (213 mg, 11.2 mmol)
  • (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(cyclopropylsulfonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid 700 mg, 1.62 mmol
  • DIPEA 0.87 mL, 629 mg, 4.87 mmol
  • Step 5 (5S,8S,10aR)-3-(cyclopropylsulfonyl)-N-(4-fluorobenzyl)-5-((S)-2-(methyl((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)amino)propanamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide HATU (274.3 g, 721.4 mmol) was added to a solution of N-methyl-N-((5-methyl-2-oxo-1,3- dioxol-4-yl)methyl)-L-alanine (158.9 mg, 631.2 mmol) and DIPEA (388 mg, 0.52 mL, 3.01 mmol) in DCM (6.5 mL) at ambient temperature.
  • Step 6 tert-butyl ((S)-1-(((5S,8S,10aR)-3-(cyclopropylsulfonyl)-8-((4-fluorobenzyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (5S,8S,10aR)-3-(cyclopropylsulfonyl)-N-(4-fluorobenzyl)-5-((S)-2-(methyl((5-methyl-2-oxo- 1,3-dioxol-4-yl)methyl)amino)propanamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8- carboxamide (120 mg, 188.8 ⁇ mol) was stirred in 0.07 M NH3 in
  • Step 3 tert-butyl ((S)-1-(((5S,8S,10aR)-8-((4-fluorobenzyl)carbamoyl)-3-(oxetan-3-yl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate
  • N-(tert-butoxycarbonyl)-N-methyl-L-alanine 24 mg, 0.12 mmol
  • DCM 2 mL
  • DIPEA 54 ⁇ L, 0.33 mmol
  • Step 4 (5S,8S,10aR)-N-(4-fluorobenzyl)-5-((S)-2-(methylamino)propanamido)-3-(oxetan-3-yl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide
  • tert-butyl ((S)-1-(((5S,8S,10aR)-8-((4-fluorobenzyl)carbamoyl)-3-(oxetan-3- yl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2- yl)(methyl)carbamate (60 mg, 0.104 mmol) in MeCN (2 mL) was added pTSA.H2O (119 mg, 0.624 mmol) and the mixture stirred at room temperature
  • Step 2 (5S,8S,10aR)-5-amino-N-((R)-chroman-4-yl)-3-(oxetan-3-yl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide
  • tert-butyl ((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-(oxetan-3-yl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate 172 mg, 0.334 mmol
  • MeCN 5 mL
  • pTSA.H2O 381 mg, 2.004 mmol
  • Step 3 tert-butyl ((S)-1-(((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-(oxetan-3-yl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate To a solution of N-(tert-butoxycarbonyl)-N-methyl-L-alanine (35 mg, 0.173 mmol) in DCM (5 mL) was added HATU (78 mg, 0.204 mmol) and DIPEA (0.082 mL, 0.471 mmol).
  • Step 4 (5S,8S,10aR)-N-((R)-chroman-4-yl)-5-((S)-2-(methylamino)propanamido)-3-(oxetan-3-yl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide
  • tert-butyl ((S)-1-(((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-(oxetan-3- yl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2- yl)(methyl)carbamate (90 mg, 0.150 mmol) in MeCN (2 mL) was added pTSA.H2O (171 mg, 0.900 mmol) and the mixture stirred
  • Example 18A Synthesis of (5S,8S,10aR)-N-((R)-chroman-4-yl)-5-((S)-2-(methylamino)propanamido)-6-oxo-3-(2,2,2-trifluoroethyl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide
  • Compound18 hydrochloride salt and its prodrug
  • Step 1 Methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxo-3-(2,2,2-trifluoroethyl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate
  • Step 2 (5S,8S,10aR)-5-((tert-Butoxycarbonyl)amino)-6-oxo-3-(2,2,2-trifluoroethyl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylicacid
  • methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxo-3-(2,2,2- trifluoroethyl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate 250 mg, 0.590 mmol
  • THF 3 mL
  • water 3 mL
  • Step 3 tert-Butyl ((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-6-oxo-3-(2,2,2-trifluoroethyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate
  • To a solution of (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxo-3-(2,2,2- trifluoroethyl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (245 mg, 0.598 mmol) in DCM (10 mL) was added DIPEA (312 ⁇ L, 1.79 mmol) and (R)-chroman-4-amine hydrochloride (133 mg, 0.718 mmol).
  • Example 18B Synthesis of (5S,8S,10aR)-N-((R)-chroman-4-yl)-5-((S)-2-(methylamino)propanamido)-6-oxo-3-(2,2,2-trifluoroethyl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (Compound18)
  • HPLC Chrolith TFA
  • Instrument Agilent 1260 Infinity II
  • Column Chromolith RP-18e 50 - 4.6 mm
  • eluent A water + 0.1% TFA
  • eluent B MeCN + 0.1% TFA
  • gradient 0-7.0 min 1-99 % B with A, 7.0-8.0 min 99 % B
  • temperature 40 °C
  • DAD HS 220, 254, 298 nm.
  • Acetonitrile (20.0 L) was filled into the reactor through the feed vessel B.
  • the stirrer was started and the jacket temperature was set to 20 °C and the condenser to 3 °C.
  • Methyl (5S,8S,10aR)-5- ⁇ [(tert-butoxy)carbonyl]amino ⁇ -6-oxo-decahydropyrrolo[1,2- a][1,5]diazocine-8-carboxylate I (2.00 kg, 5.52 mol) was added through the manway and dissolved. A clear orange solution arose. Then, DIPEA (1.88 L) was added. Afterwards, the reaction mixture was cooled to 1 °C (external temperature: -5 °C).
  • reaction mixture was transferred into a 160 L mixing vessel and the reaction was rinsed with 5 L water.
  • the reaction mixture was extracted once with 20 L MTBE and twice with 10 L MTBE each.
  • the combined organic layers were washed twice with 10 L brine each. Afterwards, the organic layer was filtered over anhydrous sodium sulfate (4.00 kg, 28.2 mol) and evaporated to residue obtaining the desired product methyl (5S,8S,10aR)-5- ⁇ [(tert-butoxy)carbonyl]amino ⁇ -6-oxo-3-(2,2,2- trifluoroethyl)-decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate (2.33 kg, 94.7 %) as a brown oil.
  • Step 2 (5S,8S,10aR)-5- ⁇ [(Tert-butoxy)carbonyl]amino ⁇ -6-oxo-3-(2,2,2-trifluoroethyl)- decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (III) A 25 L reactor was inertized with nitrogen.
  • Methyl (5S,8S,10aR)-5- ⁇ [(tert-butoxy)carbonyl]amino ⁇ -6- oxo-3-(2,2,2-trifluoroethyl)-decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate (2.67 kg, 5.69 mol) was dissolved in THF (12.0 L) and filled into the reactor through the feed vessel B. The stirrer was started, and the jacket temperature was set to 25 °C and the condenser to 3 °C. Additionally, the nitrogen flow was set to 200 L/h. LiOH (420 g, 17.2 mol) was dissolved in water (12.0 L) and the solution was added through the feed vessel B within 30 min.
  • reaction mixture was stirred overnight for 20 hours at 25 °C. After reaction completion the jacket temperature was set to 20 °C.
  • the reaction mixture was acidified with HCl (37 %) (1.50 L, 49.0 mol) to pH 4. Afterwards, the reaction mixture was transferred into a 160 L mixing vessel and 9 L MTBE were added and stirred for 15 min. The layers were separated, and the aqueous layer was washed with 9 L MTBE again.
  • the combined organic layers were extracted twice with 6 L water each time and once with 6 L brine.
  • a suction strainer was prepared with sodium sulfate (4.00 kg, 28.2 mol) and the organic layer was subsequently filtered.
  • Step 3 Tert-butyl N-[(5S,8S,10aR)-8- ⁇ [(4R)-3,4-dihydro-2H-1-benzopyran-4-yl]carbamoyl ⁇ -6-oxo-3- (2,2,2-trifluoroethyl)-decahydropyrrolo[1,2-a][1,5]diazocin-5-yl]carbamate (V)
  • a 65 L reactor was inertized with nitrogen. dichloromethane (17.0 L) was filled into the reactor through the feed vessel B. The stirrer was started, and the jacket temperature was set to 22 °C and the condenser to 3°C.
  • reaction mixture was stirred for 15 min at an internal temperature of 22 °C. After 15 min 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (875 g, 4.56 mol) and 1-hydroxybenzotriazole hydrate (700 g, 4.57 mol) were added through the manway to the reaction mixture. The clear orange reaction solution was stirred for 3 hours at an internal temperature of 22 °C. After reaction completion the reaction mixture was transferred into the 160 L mixing vessel and the reactor was rinsed with 3 L dichloromethane. 18 L water were added, and the mixture was stirred for 10 min. The layers were separated. The organic layer was extracted twice with 18 L of water each.
  • Step 4 (5S,8S,10aR)-5-Amino-N-[(4R)-3,4-dihydro-2H-1-benzopyran-4-yl]-6-oxo-3-(2,2,2- trifluoroethyl)-decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (VI) A 65 L reactor was inertized with nitrogen.
  • the stirrer was started, the jacket temperature was set to 22 °C and the condenser to 3 °C.6 N HCl (9.00 L, 54.0 mol) was added within 15 min. A clear yellow solution was obtained.
  • the reaction mixture was stirred for additional 2 hours at an internal temperature of 22 °C. After complete conversion the jacket temperature was set to 0 °C and the reaction mixture was cooled to 5 °C. Then, MTBE (10.0 L) were added to the reaction mixture. Afterwards, the reaction mixture was basified using 6 N NaOH (9.10 L, 54.6 mol) until pH 12 was adjusted. Thereby, the internal temperature varied between 5 °C and 8 °C. The mixture was stirred for 15 min and transferred into the 160 L mixing vessel.
  • the reactor was rinsed with MTBE (15.0 L). The layers were separated, and the organic layer was extracted four times with 8 L of water each, followed by a single extraction with 10 L of brine. The filtrate was evaporated to yield the first crop of the desired product (563 g). The aqueous layer still contained product. Therefore, it was extracted with 15 L of MTBE. Again, the layers were separated, and the organic layer was filtered through sodium sulfate (2.00 kg, 14.1 mol). The filtrate was evaporated to afford the second crop of the desired product (1.05 kg).
  • Step 5 Tert-butyl N-[(1S)-1- ⁇ [(5S,8S,10aR)-8- ⁇ [(4R)-3,4-dihydro-2H-1-benzopyran-4-yl]carbamoyl ⁇ -6- oxo-3-(2,2,2-trifluoroethyl)-decahydropyrrolo[1,2-a][1,5]diazocin-5-yl]carbamoyl ⁇ ethyl]-N- methylcarbamate (VII) A 65 L reactor was inertized with nitrogen.
  • N- ⁇ -Tert-butyloxycarbonyl-N- ⁇ -methyl-L-alanine (720 g, 3.54 mol) was dissolved in THF (10.0 L) and filled into the reactor through the feed vessel B.
  • the stirrer was started, and the jacket temperature was set to 22 °C, the condenser to 3 °C.
  • DIPEA (1.20 L, 7.06 mol)
  • 1-hydroxybenzotriazole hydrate 600 g, 3.92 mol
  • 1- ethyl-3-(3-dimethylaminopropyl)-carbo diimide hydrochloride (750 g, 3.91 mol) were added.
  • the reaction mixture was stirred for 15 min at 22 °C internal temperature.
  • Step 6 (5S,8S,10aR)-N-[(4R)-3,4-dihydro-2H-1-benzopyran-4-yl]-5-[(2S)-2- (methylamino)propanamido]-6-oxo-3-(2,2,2-trifluoroethyl)-decahydropyrrolo[1,2- a][1,5]diazocine-8-carboxamide (VIII)
  • a 65 L reactor was inertized with nitrogen.
  • Step 7 MTBE solvate formation, melting, evaporation and homogenization of (5S,8S,10aR)-N-[(4R)- 3,4-dihydro-2H-1-benzopyran-4-yl]-5-[(2S)-2-(methylamino)propanamido]-6-oxo-3-(2,2,2- trifluoroethyl)-decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide Part a) – MTBE solvate formation Combined batches of obtained (5S,8S,10aR)-N-[(4R)-3,4-dihydro-2H-1-benzopyran-4-yl]-5- [(2S)-2-(methylamino)propanamido]-6-oxo-3-(2,2,2-trifluoroethyl)-decahydropyrrolo[1,2- a][1,5]diazocine-8-carboxamide (3.
  • the mixture of white solids was suspended in MTBE (5.50 L). The suspension was heated to 60 °C. After stirring for three hours by rotating the flask at this temperature, heating was stopped, and the suspension was continued to stir overnight at room temperature. The suspension was filtered with suction and the filter cake was washed with 1 L of MTBE.
  • the oil started to foam. Between a pressure of 100 to 70 mbar, the vacuum was interrupted with a stream of nitrogen up to a pressure of 150 mbar. This process was repeated until a stable foam was obtained. Samples were taken to analyze the content of residual MTBE. Afterwards, the vacuum was reduced to 1 mbar. Then, heating was stopped, and the foam was kept overnight for 20 hours at room temperature under a pressure of 1 mbar. Subsequently, the material was transferred into the vacuo drying oven and further dried at 50 °C and 1 mbar over a period of 3 days. From each portion, 5 g were combined, mixed, and the content of MTBE was determined by NMR.
  • Example 18C Synthesis of a deuterated compound and metabolite Analytical methods HPLC (Chromolith TFA) Instrument: Agilent 1260 Infinity II; Column: Chromolith RP-18e 50 - 4.6 mm; eluent A: water + 0.1% TFA, eluent B: MeCN + 0.1% TFA; gradient: 0-7.0 min 1-99 % B with A, 7.0-8.0 min 99 % B; flow 2.0 mL/min; temperature: 40 °C; DAD HS: 220, 254, 298 nm.
  • HPLC Chrolith TFA
  • Step BB-1 3-[(2,3,4,5,6-2H5)phenoxy]propane nitrile
  • phenol-2,3,4,5,6-2H5 (10.0 g, 101 mmol)
  • prop-2-enennitrile (66.9 ml, 1009 mmol)
  • potassium carbonate (1.39 g, 10.1 mmol)
  • tert-butanol 0.959 mL, 10.1 mmol
  • the reaction mixture was concentrated under reduced pressure.
  • the crude material was poured into DCM and water/2M NaOH solution. The layers were separated. The organic layer was washed with water and a small amount of 2M NaOH twice.
  • Step BB-2 3,4-dihydro(5,6,7,8-2H4)-2H-1-benzopyran-4-one 3-[(2,3,4,5,6-2H5)phenoxy]propanenitrile (13.2 g, 86.7 mmol) was dissolved in DCM (70 mL) and cooled to 0 °C. Then, TFA-d, 99.5% isotop D (50.0 g, 435 mmol) and TfOH (11.4 ml, 130 mmol) were added. The orange solution was stirred over the weekend at room temperature. After reaction completion the reaction mixture was evaporated to residue. The residue was poured in cold D2O to change the pH value with concentrated NaOH solution to pH 7. The color changed from red to yellow, then to orange.
  • the aqueous layer changed from a clear solution to turbid. DCM was added, the layers were separated, and the aqueous layer was extracted twice with DCM. The combined organic layers were washed twice with sat. aqueous NaHCO3 solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure obtaining the desired product 3,4- dihydro(5,6,7,8-2H4)-2H-1-benzopyran-4-one (12.3 g, 84.0 %) as orange oil in crude form.
  • Step BB-3 N-[(4E)-3,4-dihydro(3,3,5,6,7,8-2H6)-2H-1-benzopyran-4-ylidene]hydroxylamine 3,4-dihydro(5,6,7,8-2H4)-2H-1-benzopyran-4-one (16.0 g, 105 mmol) was dissolved in EtOH (70 mL). Afterwards, hydroxylammonium chloride (18.3 g, 263 mmol) was dissolved in water (25 mL) and the solution was added slowly to the reaction mixture. After 10 min, sodium acetate trihydrate (35.8 g, 263 mmol) was dissolved in water (25 mL) and the solution was added slowly to the reaction mixture.
  • Step BB-4 3,4-dihydro(3,3,5,6,7,8-2H6)-2H-1-benzopyran-4-amine
  • Hydrogenation setup o Starting material: 16.2 g o 1,0 w% catalyst load (corresponds to formally dry catalyst Pd-C 5%) o Solvent: methanol (160 mL) o Reductive hydrogenation conditions: 3.0 - 3.1 bar / room temperature (for 16 hours) o Observed hydrogen consumption: 3.7 L (95.9 % of theory) Work-up: After filtration, the solution was evaporated to dryness. The residue was dissolved in 100 mL MTBE, filtered, and evaporated to residue giving 13.2 g yellow oil as crude product.
  • Step BB-5 (4R)-3,4-dihydro(3,3,5,6,7,8-2H6)-2H-1-benzopyran-4-amine
  • the enantiomers of 3,4-dihydro(3,3,5,6,7,8-2H6)-2H-1-benzopyran-4-amine hydrochloride were separated by chiral SFC.
  • Step 1-D tert-Butyl N-[(5S,8S,10aR)-8- ⁇ [(4R)-3,4-dihydro(3,3,5,6,7,8-2H6)-2H-1-benzopyran- 4-yl]carbamoyl ⁇ -6-oxo-3-(2,2,2-trifluoroethyl)-decahydropyrrolo[1,2-a][1,5]diazocin-5- yl]carbamate (V-D) (5S,8S,10aR)-5- ⁇ [(tert-butoxy)carbonyl]amino ⁇ -6-oxo-3-(2,2,2-trifluoroethyl)-decahydropyrrolo[1,2- a][1,5]diazocine-8-carboxylic acid (10.0 g, 23.9 mmol) was dissolved in DCM (200 mL) at 22 °C.
  • Step 2-D (5S,8S,10aR)-5-Amino-N-[(4R)-3,4-dihydro(3,3,5,6,7,8-2H6)-2H-1-benzopyran-4-yl]-6-oxo-3- (2,2,2-trifluoroethyl)-decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide
  • VI-D Tert-butyl N-[(5S,8S,10aR)-8- ⁇ [(4R)-3,4-dihydro(3,3,5,6,7,8-2H6)-2H-1-benzopyran-4- yl]carbamoyl ⁇ -6-oxo-3-(2,2,2-trifluoroethyl)-decahydropyrrolo[1,2-a][1,5]diazocin-5- yl]carbamate (11.4 g, 20.0 mmol) was dissolved in ethyl acetate (50
  • Step 3-D tert-Butyl N-[(1S)-1- ⁇ [(5S,8S,10aR)-8- ⁇ [(4R)-3,4-dihydro(3,3,5,6,7,8-2H6)-2H-1- benzopyran-4-yl]carbamoyl ⁇ -6-oxo-3-(2,2,2-trifluoroethyl)-decahydropyrrolo[1,2- a][1,5]diazocin-5-yl]carbamoyl ⁇ ethyl]-N-methylcarbamate (VII-D) (2S)-2- ⁇ [(tert-butoxy)carbonyl](methyl)amino ⁇ propanoic acid (3.78 g, 18.6 mmol) was dissolved in THF (100) at 22 °C.
  • Step 4-D (5S,8S,10aR)-N-[(4R)-3,4-Dihydro(3,3,5,6,7,8-2H6)-2H-1-benzopyran-4-yl]-5-[(2S)-2- (methylamino)propanamido]-6-oxo-3-(2,2,2-trifluoroethyl)-decahydropyrrolo[1,2-a][1,5]diazocine- 8-carboxamide (VIII-D) Tert-butyl N-[(1S)-1- ⁇ [(5S,8S,10aR)-8- ⁇ [(4R)-3,4-dihydro(3,3,5,6,7,8-2H6)-2H-1-benzopyran-4- yl]carbamoyl ⁇ -6-oxo-3-(2,2,2-trifluoroethyl)-decahydropyrrolo[1,2-a][1,5]diazocin-5- yl]carbam
  • Step 2 (5S,8S,10aR)-5-amino-3-(2,2-difluoropropyl)-N-(4-fluorobenzyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride
  • a solution of tert-butyl ((5S,8S,10aR)-3-(2,2-difluoropropyl)-8-((4-fluorobenzyl)carbamoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (248 mg, 0.484 mmol) in 4 M HCl/dioxane (2 mL) and MeOH (2 mL) was stirred at room temperature for 3 hours.
  • Step 3 tert-butyl ((S)-1-(((5S,8S,10aR)-3-(2,2-difluoropropyl)-8-((4-fluorobenzyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate
  • To a solution of (5S,8S,10aR)-5-amino-3-(2,2-difluoropropyl)-N-(4-fluorobenzyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride 195 mg, 0.434 mmol
  • DCM 6 mL
  • DIPEA 227 ⁇ L, 1.30 mmol
  • Step 4 (5S,8S,10aR)-3-(2,2-difluoropropyl)-N-(4-fluorobenzyl)-5-((S)-2-(methylamino)propanamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride
  • Example 20 Synthesis of (5S,8S,10aR)-N-(4-fluorobenzyl)-5-((S)-2-(methylamino)propanamido)-6-oxo-3-(3,3,3-trifluoro-2,2-dimethylpropyl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide(Compound 20) hydrochloride salt
  • Step 1 tert-butyl ((5S,8S,10aR)-8-((4-fluorobenzyl)carbamoyl)-6-oxo-3-(3,3,3-trifluoro-2,2-dimethylpropyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate
  • a solution of tert-butyl ((5S,8S,10aR)-8-((4-fluorobenzyl)carbamoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate 250 mg, 0.732 mmol
  • TEA 255 ⁇ L, 1.83 mmol
  • 3,3,3-trifluoro-2,2-dimethylpropyl trifluoromethanesulfonate 261 mg, 0.952 mmol.
  • the reaction mixture was stirred at 80 °C for 3 days. Additional 3,3,3-trifluoro-2,2-dimethylpropyl trifluoromethanesulfonate (50 mg, 0.182 mmol) and TEA (255 ⁇ L, 1.83 mmol) were added. The reaction mixture was heated to 80 °C for 18 hours. The reaction mixture was quenched with water, extracted with EtOAc, dried over Na2SO4, filtered and concentrated.
  • Step 2 (5S,8S,10aR)-5-amino-N-(4-fluorobenzyl)-6-oxo-3-(3,3,3-trifluoro-2,2-dimethylpropyl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride
  • Step 3 tert-butyl ((S)-1-(((5S,8S,10aR)-8-((4-fluorobenzyl)carbamoyl)-6-oxo-3-(3,3,3-trifluoro-2,2-dimethylpropyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate To a solution of (5S,8S,10aR)-5-amino-N-(4-fluorobenzyl)-6-oxo-3-(3,3,3-trifluoro-2,2- dimethylpropyl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride (30 mg, 0.06
  • Step 2 (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(isopropylcarbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid
  • a mixture of methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(isopropylcarbamoyl)- 6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate 65 mg, 0.15 mmol
  • THF 1.5 mL
  • water 1.0 mL
  • Step 4 (5S,8S,10aR)-5-amino-N8-((R)-chroman-4-yl)-N3-isopropyl-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide Tert-butyl ((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-(isopropylcarbamoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (83 mg, 0.15 mmol) was dissolved in TFA (0.5 mL) and stirred at ambient temperature for 1 hour.
  • Step 7 (5S,8S,10aR)-N8-((R)-chroman-4-yl)-N3-isopropyl-5-((S)-2-(methyl((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)amino)propanamido)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide
  • HATU 100 mg, 0.264 mmol
  • Example 22 Synthesis of (5S,8S,10aR)-N8-((R)-chroman-4-yl)-N3-cyclohexyl-5- ((S)-2-(methylamino)propanamido)-6-oxooctahydropyrrolo[1,2- a][1,5]diazocine-3,8(4H)-dicarboxamide (Compound 22) hydrochloride salt
  • the compound was synthesized in the same manner as previous compound using cyclohexyl isocyanate instead of isopropyl isocyanate.
  • Table 2 The analytical data and yield of each intermediate are reported in Table 2 below.
  • Step 2 (5S,8S,10aR)-5-((S)-2-aminopropanamido)-N8-((R)-chroman-4-yl)-N3-methyl-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide hydrochloride tert-Butyl ((S)-1-(((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-(methylcarbamoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)carbamate (55 mg, 0.094 mmol) was dissolved in MeOH (2 mL) and 4 M HCl/dioxane (2 mL) was added and the mixture stirred at room temperature for
  • Step 3 (5S,8S,10aR)-N8-((R)-chroman-4-yl)-5-((S)-2-(isopropylamino)propanamido)-N3-methyl-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide
  • To a suspension of (5S,8S,10aR)-5-((S)-2-aminopropanamido)-N8-((R)-chroman-4-yl)-N3- methyl-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide hydrochloride (49 mg, 0.094 mmol) in DCM was added acetone (14 ⁇ L, 0.188 mmol) and sodium triacetoxyborohydride (40 mg, 0.188 mmol), and the mixture stirred at room temperature for 18
  • Step 3 tert-butyl ((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-(2-(methylsulfonyl)acetyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate
  • a solution of (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(2-(methylsulfonyl)acetyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid 150 mg, 0.328 mmol
  • (R)- chroman-4-amine hydrochloride 80 mg, 0.427 mmol
  • DMF 1.0 ml
  • Step 4 (5S,8S,10aR)-5-amino-N-((R)-chroman-4-yl)-3-(2-(methylsulfonyl)acetyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide 2,2,2-trifluoroacetate tert-butyl ((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-(2-(methylsulfonyl)acetyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (255 mg, 0.547 mmol) was treated with a 9:1 mixture of TFA/DCM (1 ml).
  • Step 5 tert-butyl ((S)-1-(((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-(2-(methylsulfonyl)acetyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate N-(tert-butoxycarbonyl)-N-methyl-L-alanine (31mg, 0.147 mmol) and HATU ( 81.3mg) were dissolved in DMF (0.5 ml), DIPEA (73.7 ⁇ L).
  • Step 6 (5S,8S,10aR)-N-((R)-chroman-4-yl)-5-((S)-2-(methylamino)propanamido)-3-(2-(methylsulfonyl)acetyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide2,2,2-trifluoroacetate
  • Step 3 tert-butyl ((5S,8S,10aR)-3-(2-fluoroacetyl)-8-(((R)-1-(4-fluorophenyl)ethyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate
  • To a solution of (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(2-fluoroacetyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (370 mg, 0.955 mmol) in DCM (20 mL) was added (R)-1-(4-fluorophenyl)ethan-1-amine (159 mg, 1.15 mmol), DIPEA (500 ⁇ L, 2.87 mmol) and then HATU (545 mg, 1.43
  • Step 4 (5S,8S,10aR)-5-amino-3-(2-fluoroacetyl)-N-((R)-1-(4-fluorophenyl)ethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride
  • a solution of tert-butyl ((5S,8S,10aR)-3-(2-fluoroacetyl)-8-(((S)-1-(4- fluorophenyl)ethyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (486 mg, 0.956 mmol) in 4 M HCl/dioxane (3 mL) and MeOH (3 mL) was stirred at room temperature for 18 hours.
  • Step 3 tert-butyl ((S)-1-(((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-(2-fluoroacetyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)carbamate
  • To a solution of (5S,8S,10aR)-5-amino-N-((R)-chroman-4-yl)-3-(2-fluoroacetyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride 100 mg, 0.220 mmol
  • DIPEA tert-butoxycarbonyl
  • Step 4 (5S,8S,10aR)-5-((S)-2-Aminopropanamido)-N-((R)-chroman-4-yl)-3-(2-fluoroacetyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamidehydrochloride
  • Step 3 tert-Butyl ((S)-1-(((5S,8S,10aR)-3-(2-fluoroacetyl)-8-(((R)-7-fluorochroman-4-yl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate To a solution of N-(tert-butoxycarbonyl)-N-methyl-L-alanine (114 mg, 0.561 mmol) in DCM (20 mL) was added HATU (252 mg, 0.521 mmol) and DIPEA (355 ⁇ L, 2.04 mmol).
  • Step 4 (5S,8S,10aR)-5-Amino-3-(2-fluoroacetyl)-N-((R)-7-fluorochroman-4-yl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride
  • tert-butyl ((S)-1-(((5S,8S,10aR)-3-(2-fluoroacetyl)-8-(((R)-7-fluorochroman-4- yl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2- yl)(methyl)carbamate (103 mg, 0.166 mmol) in MeOH (5 mL) was added 4 M HCl/dioxane (0.449 mL, 1.66 mmol) and the reaction
  • Example 28 Synthesis of (5S,8S,10aR)-N8-((R)-chroman-4-yl)-N3-cyclopropyl-5-((S)-2-(methylamino)propanamido)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide (Compound 28) and its prodrug Step 1: tert-butyl ((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-(cyclopropylcarbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate To a solution of tert-butyl ((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-6- oxo
  • Step 2 (5S,8S,10aR)-5-amino-N8-((R)-chroman-4-yl)-N3-cyclopropyl-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide
  • Step 3 tert-butyl ((S)-1-(((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-(cyclopropylcarbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate
  • To a mixture of (5S,8S,10aR)-5-amino-N8-((R)-chroman-4-yl)-N3-cyclopropyl-6- oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide 90 mg, 0.188 mmol
  • DIPEA 98.4 ⁇ L, 0.565 mmol
  • Step 4 (5S,8S,10aR)-N8-((R)-chroman-4-yl)-N3-cyclopropyl-5-((S)-2-(methylamino)propanamido)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide
  • Step 5 (5S,8S,10aR)-N8-((R)-chroman-4-yl)-N3-cyclopropyl-5-((S)-2-(methyl((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)amino)propanamido)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide
  • 5S,8S,10aR)-5-amino-N8-((R)-chroman-4-yl)-N3-cyclopropyl-6- oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide hydrochloride (26.5 mg, 0.0554 mmol), DIPEA (0.029 mL, 0.0166 mmol) and N-methyl-N-((5-methyl-2-
  • Step 2 (5S,8S,10aR)-5-amino-N-((R)-chroman-4-yl)-3-(cyanomethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide formate
  • a solution of tert-butyl ((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-(cyanomethyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate 99 mg, 0.199 mmol
  • FA 2 mL
  • Step 3 tert-butyl ((S)-1-(((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-(cyanomethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate
  • HATU tert-butoxycarbonyl-N-methyl-L-alanine
  • Step 4 (5S,8S,10aR)-N-((R)-chroman-4-yl)-3-(cyanomethyl)-5-((S)-2-(methylamino)propanamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide formate
  • Step 2 (5S,8S,10aR)-5-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid
  • a solution of methyl (5S,8S,10aR)-5-((S)-2-((tert- butoxycarbonyl)(methyl)amino)propanamido)-3-(3-methylbutanoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate (2.54 g, 4.97 mmol) in THF (125 mL) was added a solution of lithium hydroxide monohydrate (1.25 g, 29.9 mmol) in water (25 mL) and the mixture stirred for 3 hours at room temperature.
  • Step 3 tert-butyl methyl((2S)-1-(((5S,8S,10aR)-3-(3-methylbutanoyl)-6-oxo-8-(thiochroman-4-ylcarbamoyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)carbamate
  • 5S,8S,10aR -5-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3- (3-methylbutanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (125 mg, 0.251 mmol), thiochroman-4-amine hydrochloride (55.9 mg, 0.277 mmol) and DIPEA (0.180 mL, 1.01 mmol)
  • Step 1 Methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxo-3-pivaloyldecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate
  • DIPEA 408 ⁇ L, 2.34 mmol
  • pivaloyl chloride 174 ⁇ L, 1.41 mmol
  • Step 2 (5S,8S,10aR)-5-((tert-Butoxycarbonyl)amino)-6-oxo-3-pivaloyldecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid
  • a solution of methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxo-3- pivaloyldecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate 380 mg, 0.890 mmol
  • 1 M lithium hydroxide aqueous solution 5.36 mL, 5.36 mmol
  • Step 3 tert-Butyl ((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-6-oxo-3-pivaloyldecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate
  • HATU (217 mg, 0.571 mmol)
  • DIPEA 307 ⁇ L, 1.76 mmol
  • (R)-chroman-4-amine hydrochloride 90.0 mg, 0.484 mmol).
  • Step 4 (5S,8S,10aR)-5-Amino-N-((R)-chroman-4-yl)-6-oxo-3-pivaloyldecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride
  • tert-butyl ((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-6-oxo-3- pivaloyldecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (220 mg, 0.405 mmol) in MeOH (1.5 mL) was added 4 M HCl/dioxane (5 mL).
  • Step 5 tert-butyl ((S)-1-(((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-6-oxo-3-pivaloyldecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(ethyl)carbamate
  • HATU 0.28 g, 0.74 mmol
  • DIPEA 0.27 mL, 1.56 mmol
  • Step 6 (5S,8S,10aR)-N-((R)-chroman-4-yl)-5-((S)-2-(ethylamino)propanamido)-6-oxo-3-pivaloyldecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide
  • Step 1 (R)-4-benzyl-3-((R)-2-fluoro-3-methylbutanoyl)oxazolidin-2-one
  • (R)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one 7.00 g, 26.8 mmol
  • a 1 M NaHMDS/THF solution 29.5 mL, 29.5 mmol
  • the reaction mixture was added to a solution of N-fluoro-N(phenylsulfonyl)benzenesulfonamide (11.0 g, 34.8 mmol) in anhydrous THF (200 mL), at –78 °C. After 3 hours, the mixture was warmed to room temperature, and quenched with saturated aqueous NH4Cl solution and extracted with EtOAc. The combined organics were dried (MgSO4), filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel 60 using heptane-EtOAc (19:1 to 9:1).
  • Step 2 (R)-2-fluoro-3-methylbutanoic acid To a solution of (R)-4-benzyl-3-((R)-2-fluoro-3-methylbutanoyl)oxazolidin-2-one (2.51 g, 8.99 mmol) in THF (100 mL) was added lithium hydroxide monohydrate (1.51 g, 36.0 mmol) and an aqueous solution of hydrogen peroxide (6.99 g, 71.9 mmol, 35% w/w solution), at room temperature and the mixture stirred for 4 hours. The mixture was diluted with water and treated with sodium thiosulfate (15 g). Volatiles were removed under reduced pressure and the aqueous solution was washed with EtOAc.
  • the aqueous layer was acidified with conc. HCl and extracted with DCM. The combined organics were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude reside was dissolved in DCM, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude reside was dissolved in Et2O, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by Kugelrohr short path distillation to give the desired product (365 mg, 33%) as a colourless oil.
  • Step 3 tert-butyl ((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-((R)-2-fluoro-3-methylbutanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate To a mixture of tert-butyl ((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate To a mixture of tert-butyl ((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-y
  • Step 5 tert-butyl ((S)-1-(((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-((R)-2-fluoro-3-methylbutanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate To a mixture of (5S,8S,10aR)-5-amino-N-((R)-chroman-4-yl)-3-((R)-2-fluoro-3- methylbutanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride (200 mg, 0.402 mmol), N-(tert-butoxycarbonyl)-N-methyl-L-alanine (90.0 mg, 0.443
  • Step 5 (5S,8S,10aR)-N-((R)-chroman-4-yl)-3-(2-fluoro-2-methylpropanoyl)-5-((S)-2-(methyl((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)amino)propanamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide
  • Step 2 (5S,8S,10aR)-5-amino-N-((R)-chroman-4-yl)-3-(2-methoxy-2-methylpropanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride
  • a solution of tert-butyl ((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-(2-methoxy-2- methylpropanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (387 mg, 0.693 mmol) in 4 M HCl/dioxane (10 mL) and MeOH (1 mL) was stirred at room temperature for 16 hours.
  • Step 4 (5S,8S,10aR)-N-((R)-chroman-4-yl)-3-(2-methoxy-2-methylpropanoyl)-5-((S)-2-(methylamino)propanamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride
  • Step 5 (5S,8S,10aR)-N-((R)-chroman-4-yl)-3-(2-methoxy-2-methylpropanoyl)-5-((S)-2-(methyl((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)amino)propanamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide
  • Step 2 (5S,8S,10aR)-5-amino-N-((R)-chroman-4-yl)-3-(1-hydroxycyclopropane-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide
  • Step 4 (5S,8S,10aR)-N-((R)-chroman-4-yl)-3-(1-hydroxycyclopropane-1-carbonyl)-5-((S)-2-(methylamino)propanamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide
  • Step 5 (5S,8S,10aR)-N-((R)-chroman-4-yl)-3-(1-hydroxycyclopropane-1-carbonyl)-5-((S)-2-(methyl((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)amino)propanamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide
  • 5S,8S,10aR)-N-((R)-chroman-4-yl)-3-(1-hydroxycyclopropane-1-carbonyl)-5- ((S)-2-(methylamino)propanamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8- carboxamide 79 mg, 0.150 mmol
  • K3PO4 64 mg, 0.300 mmol
  • KI 27 mg, 0.165 mmol
  • Example 36 Synthesis of (5S,8S,10aR)-N-((R)-chroman-4-yl)-3-(3-hydroxyoxetane-3-carbonyl)-5-((S)-2-(methylamino)propanamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (Compound 36) Step 1: tert-butyl ((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-(3-hydroxyoxetane-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate To a solution of 3-hydroxyoxetane-3-carboxylic acid (54 mg, 0.458 mmol) in a mixture of DCM (2 mL) and DMF (2 mL) was added HA
  • Step 2 (5S,8S,10aR)-5-amino-N-((R)-chroman-4-yl)-3-(3-hydroxyoxetane-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide
  • Step 4 (5S,8S,10aR)-N-((R)-chroman-4-yl)-3-(3-hydroxyoxetane-3-carbonyl)-5-((S)-2-(methylamino)propanamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide
  • tert-butyl ((S)-1-(((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-(3- hydroxyoxetane-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1- oxopropan-2-yl)(methyl)carbamate (47 mg, 0.073 mmol) in MeCN (2 mL) was added pTSA (42 mg, 0.219
  • Example 37 Synthesis of (5S,8S,10aR)-N-((R)-chroman-4-yl)-5-((S)-2-(methylamino)propanamido)-6-oxo-3-(3,3,3-trifluoro-2,2-dimethylpropanoyl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide(Compound 37) hydrochloride salt and its prodrug Step 1: tert-butyl ((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-6-oxo-3-(3,3,3-trifluoro-2,2-dimethylpropanoyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate To a solution of 3,3,3-trifluoro-2,2-dimethylpropanoic acid (436 mg, 2.79 mmol) in
  • Step 2 (5S,8S,10aR)-5-amino-N-((R)-chroman-4-yl)-6-oxo-3-(3,3,3-trifluoro-2,2-dimethylpropanoyl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamidehydrochloride
  • Step 4 (5S,8S,10aR)-N-((R)-chroman-4-yl)-5-((S)-2-(methylamino)propanamido)-6-oxo-3-(3,3,3-trifluoro-2,2-dimethylpropanoyl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride
  • Step 2 (5S,8S,10aR)-5-amino-N-((R)-7-fluorochroman-4-yl)-6-oxo-3-pivaloyldecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide
  • tert-butyl ((5S,8S,10aR)-8-(((R)-7-fluorochroman-4-yl)carbamoyl)-6-oxo-3- pivaloyldecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (0.21 g, 0.38 mmol) in MeOH (3 mL) was added 4 M HCl/dioxane (1 mL) and the mixture stirred at room temperature for 3 hours.
  • Step 3 tert-butyl ((S)-1-(((5S,8S,10aR)-8-(((R)-7-fluorochroman-4-yl)carbamoyl)-6-oxo-3-pivaloyldecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate
  • N-(tert-butoxycarbonyl)-N-methyl-L-alanine 96.7 mg, 0.476 mmol
  • DCM 5 mL
  • DIPEA DIPEA
  • Step 4 (5S,8S,10aR)-N-((R)-7-fluorochroman-4-yl)-5-((S)-2-(methylamino)propanamido)-6-oxo-3-pivaloyldecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride
  • Step 2 (5S,8S,10aR)-5-amino-N-((R)-chroman-4-yl)-3-(2,2-difluoropropyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride
  • a solution of tert-butyl ((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-(2,2-difluoropropyl)- 6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate 100 mg, 0.186 mmol
  • 4 M HCl/dioxane (2 mL) and MeOH (1 mL) was stirred at room temperature for 90 minutes.
  • Step 4 (5S,8S,10aR)-N-((R)-chroman-4-yl)-3-(2,2-difluoropropyl)-5-((S)-2-(methylamino)propanamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride
  • Step 2 tert-butyl ((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-6-oxo-3-((S)-1,1,1-trifluoropropan-2-yl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate
  • DIPEA 68.4 ⁇ L, 0.393
  • Step 3 (5S,8S,10aR)-5-amino-N-((R)-chroman-4-yl)-6-oxo-3-((S)-1,1,1-trifluoropropan-2-yl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride
  • Step 5 (5S,8S,10aR)-N-((R)-chroman-4-yl)-5-((S)-2-(methylamino)propanamido)-6-oxo-3-((S)-1,1,1-trifluoropropan-2-yl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride
  • Step 2 (5S,8S,10aR)-5-amino-N-((R)-chroman-4-yl)-6-oxo-3-((R)-1,1,1-trifluoropropan-2-yl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride
  • Step 3 tert-butyl ((S)-1-(((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-6-oxo-3-((R)-1,1,1-trifluoropropan-2-yl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate To a solution of (5S,8S,10aR)-5-amino-N-((R)-chroman-4-yl)-6-oxo-3-((R)-1,1,1- trifluoropropan-2-yl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride (30 mg, 0.0611 mmol) in DCM (3 mL) was added DIPEA (32 ⁇ L, 0.183 mmol) and N-
  • Step 2 (5S,8S,10aR)-5-amino-N8-((R)-chroman-4-yl)-6-oxo-N3-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide hydrochloride
  • a mixture of tert-butyl ((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-6-oxo-3-((tetrahydro- 2H-pyran-4-yl)carbamoyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (6.24 g, 10.7 mmol) in 4 M HCl/dioxane (30 mL) was stirred at room temperature for 3 hours.
  • Step 3 tert-butyl ((S)-1-(((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-6-oxo-3-((tetrahydro-2H-pyran-4-yl)carbamoyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate To a solution of (5S,8S,10aR)-5-amino-N8-((R)-chroman-4-yl)-6-oxo-N3-(tetrahydro-2H- pyran-4-yl)octahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide hydrochloride (205 mg, 393 mmol) in DCM (8 mL) was added DIPEA (0.
  • Step 4 (5S,8S,10aR)-N8-((R)-chroman-4-yl)-5-((S)-2-(methylamino)propanamido)-6-oxo-N3-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide hydrochloride
  • Example 42b Synthesis of (5S,8S,10aR)-N8-((R)-chroman-4-yl)-5-((S)-2-(methyl((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)amino)propanamido)-6-oxo-N3-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide Step 1: (5S,8S,10aR)-N8-((R)-chroman-4-yl)-5-((S)-2-(methyl((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)amino)propanamido)-6-oxo-N3-(tetrahydro-2H-pyran-4-yl)octahydropyrrolo[1,2-a][
  • Step 2 (5S,8S,10aR)-5-amino-N8-((R)-chroman-4-yl)-N3-(2-fluoroethyl)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide hydrochloride
  • Step 3 tert-butyl ((S)-1-(((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-((2-fluoroethyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate To a mixture of (5S,8S,10aR)-5-amino-N8-((R)-chroman-4-yl)-N3-(2-fluoroethyl)-6- oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide hydrochloride (840 mg, 1.74 mmol), DIPEA (909 ⁇ L, 5.22mmol) and N-(tert-butoxycarbonyl)
  • Step 4 (5S,8S,10aR)-N8-((R)-chroman-4-yl)-N3-(2-fluoroethyl)-5-((S)-2-(methylamino)propanamido)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide hydrochloride Tert-butyl ((S)-1-(((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-((2- fluoroethyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1- oxopropan-2-yl)(methyl)carbamate (1.05 g, 1.66 mmol), was dissolved in MeOH (5.0 mL) and added 4N
  • Example 43b Synthesis of (5S,8S,10aR)-N8-((R)-chroman-4-yl)-N3-(2-fluoroethyl)-5-((S)-2-(methyl (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)amino)propanamido)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide Step 1 :(5S,8S,10aR)-N8-((R)-chroman-4-yl)-N3-(2-fluoroethyl)-5-((S)-2-(methyl((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)amino)propanamido)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4
  • Step 2 (5S,8S,10aR)-5-amino-N8-((R)-chroman-4-yl)-N3-methyl-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide hydrochloride (5S,8S,10aR)-5-amino-N8-((R)-chroman-4-yl)-N3-methyl-6-oxooctahydropyrrolo[1,2- a][1,5]diazocine-3,8(4H)-dicarboxamide (170mg, 0.330 mmol) was dissolved in MeOH (3 mL) and 4 M HCl/dioxane (3 mL) and the mixture stirred at room temperature for 3 hours.
  • Step 3 tert-butyl ((S)-1-(((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-(methylcarbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)carbamat
  • 5S,8S,10aR)-5-amino-N8-((R)-chroman-4-yl)-N3-methyl-6- oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide hydrochloride 50 mg, 0.111 mmol
  • (tert-butoxycarbonyl)-L-alanine 25 mg, 0133) in DCM
  • Step 4 (5S,8S,10aR)-5-((S)-2-aminopropanamido)-N8-((R)-chroman-4-yl)-N3-methyl-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide hydrochloride tert-Butyl ((S)-1-(((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-(methylcarbamoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)carbamate (55 mg, 0.094 mmol) was dissolved in MeOH (2 mL) and 4 M HCl/dioxane (2 mL) was added and the mixture stirred at room temperature for
  • Step 5 (5S,8S,10aR)-N8-((R)-chroman-4-yl)-5-((S)-2-(isobutylamino)propanamido)-N3-methyl-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide
  • Step 6 tert-butyl ((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)-L-alaninate
  • K2CO3 (4.56 g, 33.0 mmol)
  • 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (1.63 g, 11.0 mmol)
  • KI (1.83 g, 11.0 mmol
  • Step 7 tert-butyl N-isobutyl-N-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)-L-alaninate
  • isobutyraldehyde 107 ⁇ L, 1.17 mmol
  • sodium triacetoxyborohydride 247 mg, 1.17 mmol
  • Step 8 N-isobutyl-N-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)-L-alanine hydrochloride
  • a solution of tert-Butyl N-isobutyl-N-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)-L-alaninate (62 mg, 0.198 mmol) in 4 M HCl/dioxane (2 mL) was stirred at room temperature for 18 hours. Additional 4 M HCl/dioxane (2 mL) was added and stirring was continued for 24 hours.
  • Step 9 ((5S,8S,10aR)-N8-((R)-chroman-4-yl)-5-((S)-2-(isobutyl((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)amino)propanamido)-N3-methyl-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide
  • 5S,8S,10aR)-5-amino-N8-((R)-chroman-4-yl)-N3-methyl-6- oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide 71 mg, 0.157 mmol) in DCM (5 mL) was added N-isobutyl-N-((5-methyl-2-oxo-1,3-diox
  • Step 2 ((5S,8S,10aR)-5-amino-N-((R)-chroman-4-yl)-3-(methylsulfonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride
  • a solution of tert-butyl ((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-(methylsulfonyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (117 mg, 0.218 mmol) in 4 M HCl/dioxane (5 mL) was stirred at room temperature for 1 hour.
  • Step 3 tert-butyl ((S)-1-(((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-3-(methylsulfonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate
  • N-(tert-butoxycarbonyl)-N-methyl-L-alanine 24.1 mg, 0.119 mmol
  • HATU 53.3 mg, 0.140 mmol
  • Step 4 (5S,8S,10aR)-N-((R)-chroman-4-yl)-5-((S)-2-(methylamino)propanamido)-3-(methylsulfonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamidehydrochloride
  • Step 2 (5S,8S,10aR)-5-amino-3-(3,3-difluorocyclobutane-1-carbonyl)-N-(4-fluorobenzyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamidehydrochloride
  • Step 3 tert-butyl ((S)-1-(((5S,8S,10aR)-3-(3,3-difluorocyclobutane-1-carbonyl)-8-((4-fluorobenzyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate To a solution of N-(tert-butoxycarbonyl)-N-methyl-L-alanine (106 mg, 0.520 mmol) in DCM (5 mL) was added HATU (234 mg, 0.614 mmol) and the mixture stirred at room temperature.
  • Step 4 (5S,8S,10aR)-3-(3,3-difluorocyclobutane-1-carbonyl)-N-(4-fluorobenzyl)-5-((S)-2-(methylamino)propanamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride
  • Step 2 (5S,8S,10aR)-5-amino-N8-(4-fluorobenzyl)-N3-isopropyl-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide hydrochloride
  • Step 3 tert-butyl ((S)-1-(((5S,8S,10aR)-8-((4-fluorobenzyl)carbamoyl)-3-(isopropylcarbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate
  • To a solution of (5S,8S,10aR)-5-amino-N8-(4-fluorobenzyl)-N3-isopropyl-6- oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide hydrochloride 60 mg, 0.132 mmol
  • DCM 4 mL
  • DIPEA 69 ⁇ L, 0.396 mmol
  • Step 4 (5S,8S,10aR)-N8-(4-fluorobenzyl)-N3-isopropyl-5-((S)-2-(methylamino)propanamido)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxamide hydrochloride
  • Step 2 (5S,8S,10aR)-N-((R)-chroman-4-yl)-5-((S)-2-(methylamino)propanamido)-6-oxo-3-pivaloyldecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide hydrochloride
  • a solution of tert-butyl ((S)-1-(((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-6-oxo-3- pivaloyldecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2- yl)(methyl)carbamate (119 mg, 0.190 mmol) in 4 M HCl/dioxane (3 mL) and MeOH (1 mL) was stirred at room temperature for 90 minutes.
  • Example 49a Synthesis of (5S,8S,10aR)-N-((R)-chroman-4-yl)-5-((S)-2-(methylamino)propanamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (Compound 49) dihydrochloride salt Step 1: benzyl (5S,8S,10aR)-5-amino-8-(((R)-chroman-4-yl)carbamoyl)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3(4H)-carboxylate hydrochloride A solution of benzyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-8-(((R)-chroman-4- yl)carbamoyl)-6-oxooctahydropyrrolo[1,2-a][
  • Step 2 benzyl (5S,8S,10aR)-5-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-8-(((R)-chroman-4-yl)carbamoyl)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3(4H)-carboxylate
  • HATU a solution of N-(tert-butoxycarbonyl)-N-methyl-L-alanine (63 mg, 0.312 mmol) in DCM (5 mL) was added HATU (140 mg, 0.369 mmol) and DIPEA (0.148 mL, 0.852 mmol).
  • Step 3 tert-butyl ((S)-1-(((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate
  • benzyl (5S,8S,10aR)-5-((S)-2-((tert- butoxycarbonyl)(methyl)amino)propanamido)-8-(((R)-chroman-4-yl)carbamoyl)-6- oxooctahydropyrrolo[1,2-a][1,5]diazocine-3(4H)-carboxylate 142 mg, 0.210 mmol
  • IMS mL
  • Step 4 (5S,8S,10aR)-N-((R)-chroman-4-yl)-5-((S)-2-(methylamino)propanamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide dihydrochloride
  • tert-butyl ((S)-1-(((5S,8S,10aR)-8-(((R)-chroman-4-yl)carbamoyl)-6- oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (97 mg, 0.178 mmol) in MeOH (1 mL) was added 4 M HCl/dioxane (0.481 mL) and the reaction mixture stirred at room temperature for 18 hours.
  • the reaction mixture was concentrated under reduced pressure and the residue purified by Biotage SCX-2 cartridge (5 g, 25 mL) loading and washing with MeOH and eluting with 2 M NH3/MeOH. Product fractions were combined and concentrated under reduced pressure. The solids were dissolved in MeOH (1mL) and in 4M HCl/dioxane (0.481 mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue triturated with Et2O. Solids were collected by filtration, dried under vacuum, dissolved in water:MeCN (2:1) and freeze dried to give the desired compound (51 mg, 55%) as a beige solid.
  • Example 49b Synthesis of (5S,8S,10aR)-5-amino-N- (R)-chroman-4-yl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide dihydrochloride
  • Step 1 (5S,8S,10aR)-5-amino-N-((R)-chroman-4-yl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide
  • benzyl (5S,8S,10aR)-5-amino-8-(((R)-chroman-4-yl)carbamoyl)-6- oxooctahydropyrrolo[1,2-a][1,5]diazocine-3(4H)-carboxylate hydrochloride (55 mg, 0.104 mmol) in IMS (5 mL) was added 10% Palladium on Carbon (5 mg, 50% wet)
  • the reaction mixture was degassed with nitrogen and placed under an atmosphere of hydrogen and stirred at room temperature for 18 hours.
  • the reaction mixture was filtered through Celite and washed with MeOH and the filtrate concentrated under reduced pressure.
  • the crude residue was purified by reverse phase chromatography (Biotage Isolera, 12 g, C18 SNAP Ultra Biotage cartridge) using water containing 0.1% saturated aqueous NH3 and MeCN containing 0.1% saturated aqueous NH3 (90:10 to 50:50) to give the desired compound (17 mg) as a beige solid.
  • UPLC-MS: (BEH C18 Short Basic 2to95) Rt 0.53 min., 77% (UV).
  • Biological examples Biological Example 1 Cell-free IAP binding results Compounds were evaluated in duplicate in a competitive binding assay where compounds compete with a fluorescently labeled peptide probe (ARPFAQ-K(5-FAM)-NH2) for binding to the BIR3 domain of human IAP family proteins cIAP1, cIAP2 and XIAP. The peptide probes’ binding to the BIR3 domain increases fluorescence polarization. Compounds were assessed in dose responses at 10 different concentrations, and IC50 was determined. Test compounds were dissolved in DMSO to make 10 mM DMSO stocks.
  • ARPFAQ-K(5-FAM)-NH2 fluorescently labeled peptide probe
  • ⁇ cIAP2-BIR3-his (RBC Cat# APT-11-372): human recombinant cIAP2 (amino acids 244- 349; GenBank Accession No.
  • Reactions were set up at room temperature for 60min using the following conditions: ⁇ 5 nM ARPFAQ-K(5-FAM)-NH2 ⁇ 20 nM cIAP1-BIR3 ⁇ 45 nM cIAP2-BIR3 or ⁇ 30 nM XIAP-BIR3 ⁇ IAP Buffer: 100 mM potassium phosphate, pH 7.5; 0.1 % BSA, 0.005% Triton X-100, 0.5% DMSO Fluorescence Polarization was measured on an EnVision machine and mP values calculated. The signal of reaction control (DMSO) was set as a 100% activity, and the signal of background (no IAP but ligand in the buffer) was set as a 0% activity (or 100% inhibition).
  • DMSO signal of reaction control
  • % activity ⁇ [Signal] ⁇ [Background signal] ⁇ / ⁇ [DMSO control signal] ⁇ [Background signal] ⁇ 100.
  • Table 3 Table 3: IC50 values of binding to BIR3 domains of human cIAP1, cIAP2 and XIAP
  • Table 3 demonstrates that all tested compounds show strong binding to one or several of the tested human IAP family proteins. Accordingly, the compounds of the present invention show high IAP inhibitory activity.
  • Biological Example 2 In vitro HIV reactivation using latent reporter cell line(2D10) The experiment analyzed the ability of compounds at reactivating latent HIV using the well- characterized latent T cell line 2D10 (Pearson R, Kim YK, Hokello J, Lassen K, Friedman J, Tyagi M, et al. (2008) J Virol 82(24): 12291–12303. PMID: 18829756). This cell line contains part of the HIV genome and the GFP reporter gene and is unable to produce infective HIV particles.
  • Drug titration studies were conducted using individual test compounds as single agents.
  • Cells (100,000-250,000 cells/100 ⁇ L) were treated in duplicate for 48-72h with increasing compound concentrations (0, 0.2, 2, 20 ⁇ M).
  • Cells were analyzed for GFP expression by flow cytometry counting all cells per replicate, and reported as normalized %GFP+ cells. Normalization was done by subtraction of the DMSO control background activity from activity observed in the treated conditions.
  • Table 4 below shows the HIV reactivation values at 20 ⁇ M for a number of compounds according to the present invention. It is apparent that these compounds as single agents possess the capacity of reactivating latent HIV in the latent GFP reporter cell line 2D10 (e.g.
  • BLT In vivo efficacy results (BLT) – HIV Humanized BLT mice were generated by implanting 1-mm3 pieces of human fetal liver and thymus tissues (Advanced Bioscience Resources) under the kidney capsule in 6 to 8-week-old female NSG mice (immunodeficient NOD scid gamma mice [NOD.Cg- PrkdcscidIl2rgtm1Wjl/SzJ], purchased from the Jackson Laboratories).
  • CD34+ human hematopoietic stem cells were purified from autologous fetal liver tissue, isolated by magnetic bead selection for CD34+ cells (Miltenyi), phenotyped cytometrically for engraftment success (CD34+, HLA DR-), and cryopreserved until injection (200,000 CD34+ cells) into mice 3 weeks after thymus/liver implantation. Human reconstitution was verified by flow cytometry (CD45+, CD3+, CD4+ and CD8+) in peripheral blood of the mice. Each cohort was produced with tissues from a single donor.
  • BLT mice T cell education occurs in the human thymic tissue, resulting in complete systemic reconstitution of all major human hematopoietic lineages including T, B, monocyte/macrophage, dendritic, and natural killer cells.
  • the extensive systemic and genital mucosal reconstitution with human lymphoid cells renders female humanized BLT mice susceptible to both vaginal and rectal HIV infection.
  • R5 HIV JR-CSF
  • Humanized mice were infected with JR-CSF (200 ng of p24) for 2 weeks and viral replication quantified weekly by qPCR.
  • BLT mice were treated with an ART cocktail (tenofovir disoproxil fumarate [TDF], emtricitabine [FTC], and raltegravir [RAL]) delivered via drinking water as described in Satheesan et al.2018 (HIV replication and latency in a humanized NSG mouse model during suppressive oral combinational antiretroviral therapy, J Virol.2018 Mar 14;92(7):e02118-17, https://doi.org/10.1128/JVI.02118-17) for a total of 8 weeks and HIV RNA plasma titers were determined weekly by qPCR as described in Bobardt et al.2020 (The inhibitor of apoptosis proteins antagonist Debio 1143 promotes the PD-1 blockade-mediated HIV load reduction in blood and tissues of humanized mice.
  • ART cocktail tenofovir disoproxil fumarate [TDF], emtricitabine [FTC], and raltegravir [RAL]
  • mice Upon sacrifice of mice, latent organ reservoirs were assessed via detection of HIV-1 DNA copies in CD4+ cells in spleen, liver, lung, lymph nodes, thymic organoid as described in Satheesan et al.2018. Mean viral RNA plasma titers per group are shown on Figure 3, expressed as HIV-1 RNA copy number per mL of plasma. After infection, an expected fast rise of viral RNA plasma titers was observed, which was quickly and efficiently suppressed with ART treatment to undetectable levels. Titers remained undetectable also during the 4-week treatment period with vehicles, Compound 18-PRO, anti-PD-1 or the combination.
  • IC50 shift method Selected compounds were tested in a CYP3A4 IC50 shift assay. The compounds were pre-incubated for 0 or 30 minutes at six concentrations with human liver microsomes (0.3 mg/mL in 0.1M phosphate buffer pH 7.4, 1% DMSO) with 1 mM NADPH. A CYP3A4-specific substrate (midazolam, 4 ⁇ M) was added to the samples, after which a secondary incubation was conducted. Enzymatic reactions were terminated by adding ice- cold MeCN after 10 min.
  • the compounds for which the direct inhibition IC50 was not reached at the maximum concentration of 100 ⁇ M are considered to have no relevant interaction with CYP3A4 and thus their time-dependent inhibition (TDI; calculated as IC50 fold shift) was not determined (n.d.).
  • TDI time-dependent inhibition
  • the remaining compounds showed a direct inhibition IC50 between 20 and 100 ⁇ M and are thus considered as having a negligible risk of direct inhibition of CYP3A4, with respect to the free active concentrations in vivo at an effective dose.
  • the IC50 fold shift of the compounds of the invention was below 2 and therefore these compounds are also considered as having a low risk of time-dependent inhibition of CYP3A4; in particular, the compounds of the invention showed less time-dependent inhibition (TDI) of CYP3A4 than xevinapant.
  • TDI time-dependent inhibition
  • Biological Example 5 In vitro IC50 in the MDA-MB-231 human cancer cell lineusing alamarBlue cytotoxicity assay Cytotoxicity assays were performed in 96-well microtiter plates, the inner wells receiving 190 ⁇ L of culture medium with a predefined number of MDA-MB-231 cells.
  • the cells were treated for 1 hour with 100 nM compound 18 or xevinapant in triplicates with a final DMSO concentration of 0.01%.
  • the cell culture medium was diluted 1:4 with Acetonitril supplemented with internal standards and 1% formic acid.
  • the cells were washed with PBS and detached with Trypsin. The generated cell pellet was lysed for 15 minutes at room temperature by resuspending with 200 ⁇ L medium that was pre- diluted 1:4 with Acetonitril supplemented with internal standards and 1% formic acid.
  • Compound 18 displays 3-fold higher cellular permeability compared to xevinapant.
  • Aspects according to the invention relates to the following aspects: .
  • R1 is selected from the group consisting of 7.
  • R3 represents a group selected from and most preferably 8.
  • R 1 is selected from the group consisting of and preferably R 1 is R 2 is as specified in aspect 1; R 2a represents CH 3 ; R 4 is as specified in aspect 1; R 6 represents C 1-6 alkyl, which is optionally substituted by 1, 2 or 3 Cl and/or F atoms or R 6 represents a 4 to 6-membered heterocycle containing 1 oxygen atom; and X is O or S.
  • R1 is selected from the group consisting of NH and preferably R 1 is R 2 and R 4 are as specified in aspect 1;
  • R 2a represents CH 3 ;
  • R 3 is selected from the group consisting of the following formulae IIa, IIb and IIc: wherein R 12 is selected from CH 3 , CF 3 , OH, O-CH 3, H and F; and
  • X is O or S. 10.
  • R1 is selected from the group consisting of preferably R 1 is R 2 is selected from iPr, iBu, Cpr and CH 2 -Cpr; R 2a represents CH 3 ; R 4 is as specified in aspect 1; R 6 is as specified in aspect 1 and preferably CH 3 or CH 2 F; and X is O or S. 11.
  • R1 is selected from the group consisting of and preferably R 1 is R 2 is CH 3 ; R 2a represents CH 3 ; R 4 is as specified in aspect 1; R 6 is CH 3 , CH 2 F, CHF 2 , CH 2 CH(CH 3 ) 2 or CHFCH(CH 3 ) 2 ; and X is O or S. 12.
  • R 1 is selected from the group consisting of and preferably R 1 is R 2 is as specified in aspect 1; R 2a represents CH 3 ; R 4 is as specified in aspect 1; R 8 is H; R 9 is as specified in aspect 1 and preferably represents a group selected from linear or branched C 1-4 alkyl, optionally substituted with 1 or 2 substituents independently selected from F, Cl and O-CH 3 , C 3-6 cycloalkyl and saturated 6-membered heterocycle containing 1 oxygen atom; and X is O or S. 13.
  • R9 is a group selected from linear or branched C 1-4 alkyl, optionally substituted with 1 or 2 substituents independently selected from F, Cl and O-CH 3 , C 3-6 cycloalkyl and saturated 6-membered heterocycle containing 1 oxygen atom, preferably R9 is a group selected from C 1-2 alkyl, optionally substituted with 1 F substituent or C 3-4 cycloalkyl, and more preferably R 9 is a group selected from 2- fluoroethyl and cyclopropyl. 14.
  • R 1 is selected from the group consisting of preferably R 1 R 2 is as specified in aspect 1; R 2a represents CH 3 ; R 4 is as specified in aspect 1; and R 10 is as specified in aspect 1 and it preferably represents a group selected from C 1-4 alkyl, which is optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl and phenyl, which is optionally substituted by an F or Cl atom; and X is O or S.
  • R 1 is selected from the group consisting of R 2 is as specified in aspect 1; R 2a represents CH 3 ; R 4 is as specified in aspect 1; and R 11 is as specified in aspect 1 and it preferably represents a group selected from H and linear or branched C 1-5 alkyl, which is optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl and cyano, or R 11 preferably represents a 4 to 6- membered heterocycle containing 1 oxygen atom; and X is O or S. 17.
  • R11 is a group selected from linear or branched C 1-5 alkyl, which is optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl and cyano, preferably R11 is a group selected from C 1-2 alkyl, which is optionally substituted by 1, 2 or 3 F substituents, and more preferably R 11 is 2,2,2- trifluoroethyl.
  • R 2 is CH 3 ; R 4 is H; and X is O. 19.
  • R 2 represents a group selected from H, CH 3 , Et, iPr, iBu, Cpr and CH 2 -Cpr, preferably CH 3 , Et, iPr, or iBu, further preferably CH 3 ;
  • R 2a is CH 3 ;
  • R 3 is as specified in aspect 1;
  • R 4 is H or F, preferably H; and
  • X is O or S, preferably O. 20.
  • R 3 is preferably a R 9 group or R 11 group, most preferably as specified in aspect 13 or 17.
  • R 3 is preferably a R 9 group or R 11 group, most preferably as specified in aspect 13 or 17.
  • X is O.
  • 26 The compound or pharmaceutically acceptable salt, tautomer, prodrug or metabolite thereof according to any one of aspects 1 to 5, wherein R 2 is as specified in aspect 1; R 2a represents CH 3 ; R 4 and R 5 are as specified in aspect 1; and R6 represents a C 2-6 alkyl, which is optionally substituted by 1, 2 or 3 substituents independently selected from F and Cl. 27.
  • R 2 is as specified in aspect 1;
  • R 2a represents CH 3 ;
  • R 4 and R 5 are as specified in aspect 1;
  • R 11 represents a group selected from H and C 3-6 alkyl, which is optionally substituted by 1, 2 or 3 substituents independently selected from F, Cl and an oxygen atom bonded to 2 different carbon atoms to form an oxygen-containing heterocycle having 4-7 ring members.
  • the compound or pharmaceutically acceptable salt, tautomer, prodrug or metabolite thereof according to any one of aspects 1-5, 7, 26, 28 or 29, wherein R 5 is not H and R 1 is present in the R-enantiomeric form: in the R 1 groups shown in aspect 1; and the R 1 group shown in aspects 26, 28 or 29. 31.
  • a pharmaceutical composition or kit comprising the compound or pharmaceutically acceptable salt, tautomer, prodrug or metabolite thereof according to any one of the preceding aspects. 37.
  • a process for manufacturing a compound according to any one of aspects 1 to 35 which comprises the step of reacting the intermediate of formula 1-1 1-1 with intermediate of formula 1-2 1-2, to obtain intermediate of formula 1-3 1-3 and the step of subjecting intermediate 1-3 to deprotection, wherein R 1 , R 2 , R 3a and R 3 have the same meanings as specified in any of aspects 1 to 35 above.
  • the process of aspect 39 further comprising the step of subjecting the deprotected intermediate 1-3 to a) solvate formation, preferably methyl tert-butyl ether solvate formation, and b) at least one of melting, evaporation and homogenization.
  • any reference to the compound or pharmaceutically acceptable salt, tautomer, prodrug or metabolite of the invention may be understood as referring not only to the respective compound or pharmaceutically acceptable salt, tautomer, prodrug or metabolite, but also to a polymorph, hydrate, solvate, or ester thereof.

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Abstract

La présente invention concerne des composés I qui sont actifs en tant qu'inhibiteurs d'IAP et qui peuvent être utilisés pour le traitement d'infections par le VIH et/ou du cancer. La présente invention concerne également des compositions pharmaceutiques comprenant de tels composés, des procédés de fabrication et des procédés d'utilisation de ceux-ci.
PCT/EP2023/084910 2022-12-09 2023-12-08 Inhibiteurs d'iap, leurs procédés de fabrication et leurs utilisations WO2024121395A1 (fr)

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