Antibiotic macrocyclic peptides

Abstract

The present invention provides compounds of formula (I); (I) wherein Y, R1, R2, R3, m, and n are as described herein, as well as pharmaceutically acceptable salts thereof. Further, the present invention is concerned with the manufacture of the compounds of formula (I), pharmaceutical compositions comprising them and their use as medicaments for the treatment of diseases and infections caused by bacteria.

Description

[0001] Case 39858

[0002] Antibiotic Macrocyclic Peptides

[0003] Field of the Invention

[0004] The present invention provides compounds which exhibit activity against bacteria, in particular against Gram-negative bacteria like Acinetobacter baumannii, their manufacture, pharmaceutical compositions comprising them and their use as medicaments for the treatment of diseases and infections caused by bacteria.

[0005] Background of the Invention

[0006] Acinetobacter baumannii is a Gram-negative, aerobic, nonfermenting bacterium recognized over the last decades as an emerging pathogen with very limited treatment options.

[0007] A. baumannii is considered to be a serious threat by the US Centers for Disease Control and Prevention and belongs to the so called ‘ESKAPE’ pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species & E. coli) that currently cause the majority of nosocomial infections and effectively “escape” the activity of antimicrobial agents.

[0008] A. baumannii is most often encountered in intensive care units and surgical wards, where extensive antibiotic use has enabled selection for resistance against all known antimicrobials and where it causes infections that include bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection.

[0009] A. baumannii has an exceptional ability to upregulate and acquire resistance determinats and shows an environmental persistence that allows its survival and spread in the nosocomial setting, making this organism a frequent cause of outbreaks of infection and an endemic, health care-associated pathogen.

[0010] Due to increasing antibiotic resistance to most if not all available therapeutic options, Multi-Drug Resistant (MDR) A. baumannii infections, especially those caused by Carbapenem resistant A. baumannii (CRAB), are extremely difficult or even impossible to treat with high mortality rate as well as increased morbidity and length of stay in intensive care unit.

[0011] CNE / 16.12.2025Acinetobacter baumannii has been defined and still remains “a prime example of a mismatch between unmet medical needs and the current antimicrobial research and development pipeline” according to the Antimicrobial Availability Task Force (AATF) of the Infectious Diseases Society of America (IDSA). Thus, there is a high demand and need to identify compounds suitable for the treatment of diseases and infections caused by Acinetobacter baumannii.

[0012] WO2017 / 072062, WO2019185572, and WO2019206853 disclose peptide macrocycles that are active against Acinetobacter baumannii. However, there is still a high unmet medical need for further compounds that are suitable for the treatment of diseases and infections caused by Acinetobacter baumannii, for example in order to overcome potential future resistances to the antibiotic compounds disclosed in the prior art.

[0013] Summary of the Invention

[0014] The present invention provides novel peptide macrocycles that are highly active against Acinetobacter baumannii, including against MDR strains of Acinetobacter baumannii.

[0015] More particularly, in a first aspect, the present invention provides a compound of formula (I)

[0016]

[0017] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Y, R1, R2, R3, m and n are as described herein.

[0018] The present invention further provides processes for manufacturing the compounds of formula (I), pharmaceutical compositions comprising them and their use as medicaments for the treatment of diseases and infections caused by certain bacteria.Detailed description of the invention

[0019] Definitions

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, suitable methods and materials are described below.

[0021] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0022] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0023] The nomenclature used in this Application is based on IUPAC systematic nomenclature, unless indicated otherwise. Biovia Draw 22.1 was employed to generate IUPAC chemical names.

[0024] Any open valency appearing on a carbon, oxygen, sulfur or nitrogen atom in the structures herein indicates the presence of a hydrogen atom, unless indicated otherwise.

[0025] The term “pharmaceutically acceptable salts” denotes salts which are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts. Acid addition salts are those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoricacid, and organic acids selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicyclic acid. Base addition salts are those pharmaceutically acceptable salts formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, purines, piperazine, piperidine, N-ethylpiperidine, and polyamine resins.

[0026] The term “parent compound” as used herein refers to compounds of the invention in a zwitterionic (“inner salt”) state, provided that the compounds have both a basic and an acidic functionality.

[0027] Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al. Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511). The prefixes D and L or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or L designating that the compound is levorotatory. A compound prefixed with (+) or D is dextrorotatory.

[0028] The term "heteroaryl" refers to a mono- or bicyclic ring system having a total of 5 to 14 ring members, preferably, 5 to 10 ring members, preferably, 5 to 9 ring members, more preferably 5 to 8 ring members, in particular 5 to 7 ring members or 5 to 6 ring members,wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms. Preferably, “heteroaryl” refers to a 5 to 10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. Most preferably, “heteroaryl” refers to a 5-10 membered heteroaryl, 5-9 membered heteroaryl, 5-8 membered heteroaryl, 5-7 membered heteroaryl, or 5-6 membered heteroaryl comprising 1 to 3 heteroatoms independently selected from O, S and N. Some non-limiting examples of heteroaryl include spiro[cyclopropane-l,3'-indoline], pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridy), pyrazinyl, pyrimidinyl, indol-l-yl, lH-indol-2-yl, lH-indol-3-yl, lH-indol-4-yl, lH-indol-5-yl, lH-indol-6-yl, lH-indol-7-yl, l,2-benzoxazol-3-yl, l,2-benzoxazol-4-yl, l,2-benzoxazol-5-yl, 1,2-benzoxazol-6-yl, l,2-benzoxazol-7-yl, lH-indazol-3-yl, lH-indazol-4-yl, lH-indazol-5-yl, 1H-indazol-6-yl, lH-indazol-7-yl, pyrazolyl (e.g., pyrazol-l-yl, lH-pyrazol-3-yl, lH-pyrazol-4-yl, or lH-pyrazol-5-yl), pyrazolo[l,5-a]pyridine, 2H-pyrazolo[4,3-b]pyridine, [l,2,4]triazolo[l,5-a]pyridine, lH-pyrrolo[2,3-b]pyridine, imidazolyl (e.g., imidazol-l-yl, lH-imidazol-2-yl, 1H-imidazol-4-yl, or lH-imidazol-5-yl), thienyl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, or thiazol-5-yl), thiadiazolyl, pyridazinyl (e.g., pyridazin-3-yl or pyridazin-4-yl), l,2,4-triazol-4-yl, 1,2,4-triazol-l-yl, 4H-l,2,4-triazol-3-yl, trizaol-2-yl, 2H-triazolyl, 4,5,6,7-tetrahydroindazol-2-yl, 6,7-dihydro-4H-pyrano[4,3-c]pyrazol-2-yl, 3-oxo-lJT-isobenzofuranyl, 3-oxoisoindolinyl, 1,1-dioxo-2,3-dihydrobenzothiophenyl, benzofurazan-4-yl, tetrazolyl, isoxazolyl, and pyrrolyl.

[0029] Particularly preferred, yet non-limiting examples of heteroaryl are imidazolyl, thienyl, thiazolyl, thiadiazolyl, pyridyl, pyrazolyl, pyridazinyl, 3-oxo-lJT-isobenzofuranyl, 3-oxoisoindolinyl, and 1,1 -di oxo-2, 3-dihydrobenzothiophenyl.

[0030] The term “heterocyclyl” refers to a saturated or partly unsaturated mono- or bicyclic ring system of 3 to 14 ring atoms, for example 3 to 12 ring atoms, 3 to 10 ring atoms, 3 to 8 ring atoms, or 3 to 6 ring atoms, in particular 3, 4, 5 or 6 ring atoms, wherein 1, 2, 3, or 4 of said ring atoms are heteroatoms selected from N, O and S, the remaining ring atoms being carbon.

[0031] Preferably, 1 to 3, more preferably 1 to 2 of said ring atoms are selected from N, O and S, the remaining ring atoms being carbon. “Bicyclic heterocyclyl” refers to heterocyclic moieties consisting of two cycles having two ring atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms. “Bicyclic heterocyclyl” also refers to spirocyclic moieties, i.e., wherein the two rings are connected via one common ring atom. Some non-limiting examples of heterocyclyl groups include oxohexahydropyrimidinyl, oxopiperidyl, l,l-dioxo-l,2-thiazolidinyl, 1,1-dioxothianyl, pyrrolidinyl, piperazinyl, 3,6-diazabicyclo[3.1.1]heptanyl, 5-azaspiro[2.4]heptanyl, 4,7-diazaspiro[2.5]octanyl, 1,7-diazaspiro[4.4]nonanyl, l,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridinyl, azetidinyl, pyrrolidinyl, oxetanyl, 5-azaspiro[2.5]octan-5-yl, piperidyl, 3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrol-2-yl, 2-azaspiro[3.3]heptan-2-yl, 2,6-diazaspiro[3.3]heptanyl, 2-azaspiro[3.4]octane, 2-azaspiro[3.5]nonan-2-yl, 1,2-dihydropyridiynl, piperidyl, thietanyl, 2,5-dihydro-lH-pyrrolyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridine, 1,2-dihydropyridine, 3,8-diazabicyclo[3.2.1]octanyl, 2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4-b][1,4]oxazinyl, 8-oxa-2,5-diazaspiro[3.5]nonanyl, 2,8-diazaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decan-3-onyl, 9-oxa-2,6-diazaspiro[4.5]decanyl, 4-oxa-l,9-diazaspiro[5.5]undecanyl, 4-oxa-l,8-diazaspiro[5.5]undecanyl, 2,6,9-triazaspiro[4.5]decanyl, 2,6,9-triazaspiro[4.5]decan-8-onyl, 2,6-diazaspiro[4.5]decanyl, and 2,3,4,4a,5,6,7,7a-octahydro-lH-pyrrolo[3,4-b]pyridinyl. Some preferred, yet non-limiting examples of heterocyclyl groups include oxohexahydropyrimidinyl, oxopiperidyl, l,l-dioxo-l,2-thiazolidinyl, 1,1-dioxothianyl, pyrrolidinyl, piperazinyl, 3,6-diazabicyclo[3.1.1]heptanyl, 5-azaspiro[2.4]heptanyl, 4,7-diazaspiro[2.5]octanyl, 1,7-diazaspiro[4.4]nonanyl, l,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridinyl, 2, 3, 4, 4a, 5, 6, 7,7a-octahydropyrrolo[3,4-b][l,4]oxazine, 8-oxa-2,5-diazaspiro[3.5]nonanyl, 2,8-diazaspiro[4.5]decanyl, 2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4-b][1,4]oxazinyl, 9-oxa-2,6-diazaspiro[4.5]decanyl, 4-oxa-l,9-diazaspiro[5.5]undecanyl, 4-oxa-l,8-diazaspiro[5.5]undecanyl, 2,6,9-triazaspiro[4.5]decanyl, 2,6-diazaspiro[4.5]decanyl, and 2,3,4,4a,5,6,7,7a-octahydro-lZ7-pyrrolo[3,4-b]pyridine.

[0032] The term "aryl" refers to a mono- or bicyclic carbocyclic ring system having a total of 6 to 10 ring members (“Ce-Cio-aryl”), preferably 6 to 9 ring members, more preferably 6 to 8 ring members, wherein at least one ring in the system is aromatic. Some non-limiting examples of aryl include phenyl, 9H-fluorenyl, and 3 -oxoindanyl. A particularly preferred, yet non-limiting example of aryl is phenyl.

[0033] The term “halo”, “halogen”, and “halide” are used interchangeably herein and denote fluoro, chloro, bromo, or iodo. Particular examples of halogen are fluoro, chloro, and bromo.

[0034] The term “alkyl” denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms (“Ci-6-alkyl”). In particular embodiments, alkyl has 1 to 4 carbon atoms, and in more particular embodiments 1 to 3 carbon atoms, for example 1, 2, or 3 carbon atoms.

[0035] Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. A particular, yet non-limiting example of alkyl is methyl.The term “alkoxy” denotes a group of the formula -O-R’, wherein R’ is an alkyl group as defined herein. Non-limiting examples of alkoxy moieties include methoxy, ethoxy, isopropoxy, and tert-butoxy. A particular, yet non-limiting example of alkoxy is methoxy (-OCH3).

[0036] The term “haloalkyl” refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a halogen atom, preferably fluoro. Preferably, “haloalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms of the alkyl group have been replaced by a halogen atom, most preferably fluoro. Preferred, yet non-limiting examples of haloalkyl are trifluoromethyl (CF3), difluoromethyl (CHF2), 1,1-difluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl. Particularly, yet non-limiting examples of haloalkyl are trifluoromethyl (CF3) and difluoromethyl (CHF2).

[0037] The term “haloalkoxy” refers to an alkoxy group as defined herein, wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by a halogen atom, preferably fluoro. Preferably, “haloalkoxy” refers to an alkoxy group wherein 1, 2 or 3 hydrogen atoms of the alkoxy group have been replaced by a halogen atom, most preferably fluoro. Particularly preferred, yet non-limiting examples of haloalkoxy are trifluoromethoxy, difluoromethoxy, 1,1-difluoroethoxy, 2,2-difluoroethoxy, and 2,2,2-trifluoroethoxy. Further particularly preferred, yet non-limiting examples of haloalkoxy are trifluoromethoxy and difluoromethoxy.

[0038] The term “cycloalkyl” refers to a saturated mono- or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms (“Cs-io-cycloalkyl”). In some preferred embodiments, the cycloalkyl group is a monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. “Bicyclic cycloalkyl” refers to cycloalkyl moieties consisting of two saturated carbocycles having two carbon atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic moieties, i.e., the two rings are connected via one common ring atom. Preferably, the cycloalkyl group is a monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., of 3, 4, 5 or 6 carbon atoms. Some non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, l-bicyclo[l.l.l]pentanyl, bicyclo[3.1.0]hexanyl, norbornanyl, and l-bicyclo[2.2.2]octanyl. Particularly preferred, yet nonlimiting examples of cycloalkyl are cyclopropyl and bicyclo[l.l.l]pentanyl.

[0039] The term “hydroxy” refers to an -OH group.

[0040] The term “amino” refers to an -NH2 group.The term “cyano” refers to a -CN (nitrile) group.

[0041] The term “hydroxyalkyl” refers to an alkyl group, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a hydroxy group. Preferably, “hydroxyalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms, in particular 1 hydrogen atom, of the alkyl group have been replaced by a hydroxy group. Particularly preferred, yet non-limiting examples of hydroxyalkyl are hydroxymethyl, 2-hydroxy ethyl, 3-hydroxypropyl, and 4-hydroxybutyl.

[0042] The term “aminoalkyl” refers to an alkyl group, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an amino group. Preferably, “aminoalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms, in particular 1 hydrogen atom, of the alkyl group have been replaced by an amino group. Particularly preferred, yet non-limiting examples of aminoalkyl are aminomethyl, 2-aminoethyl, 3 -aminopropyl, and 4-aminobutyl.

[0043] The term “protecting group” denotes the group which selectively blocks a reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Protecting groups can be removed at the appropriate point. Exemplary protecting groups are amino-protecting groups, carboxy -protecting groups or hydroxy-protecting groups, as can be found, for example, in T. W. Greene and P. G. M. Wuts, “Protective groups in Organic Synthesis”, 2nd ed., John Wiley & Sons, Inc., New York, NY, 1991, chapter 7; E. Haslam, “Protecting groups in Organic Chemistry”, J. G. W. McOmie, Ed., Plenum Press, New York, NY, 1973, Chapter 5, and T. W. Greene, “Protective groups in Organic Synthesis”, John Wiley and Sons, New York, NY, 1981.

[0044] The terms “pharmaceutical composition” and “pharmaceutical formulation” (or “formulation”) are used interchangeably and denote a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable excipients to be administered to a mammal, e.g., a human in need thereof.

[0045] The term “pharmaceutically acceptable” denotes an attribute of a material which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neitherbiologically nor otherwise undesirable and is acceptable for veterinary as well as human pharmaceutical use.

[0046] The terms “pharmaceutically acceptable excipient”, “pharmaceutically acceptable carrier” and “therapeutically inert excipient” can be used interchangeably and denote any pharmaceutically acceptable ingredient in a pharmaceutical composition having no therapeutic activity and being non-toxic to the subject administered, such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants, carriers, diluents or lubricants used in formulating pharmaceutical products.

[0047] The term “therapeutically effective amount” denotes an amount of a compound or molecule of the present invention that, when administered to a subject, (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein. The therapeutically effective amount will vary depending on the compound, the disease state being treated, the severity of the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors.

[0048] The term “treating” or “treatment” of a disease state includes inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms, or relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.

[0049] Compounds of the Invention

[0050] In a first aspect, the present invention provides a compound of formula (I)

[0051]

[0052] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0053] Y is CH or N;

[0054] A is selected from the group consisting of phenyl, pyridyl, and thienyl;

[0055] B and C are each independently selected from the group consisting of:

[0056] (i) 5- to 14-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon;

[0057] (ii) Ce-io-aryl;

[0058] (iii) 3- to 14-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon; and

[0059] (iv) C3-10-cycloalkyl;

[0060] m is an integer selected from the group consisting of 1, 2, and 3;

[0061] n is an integer selected from the group consisting of 1, 2, and 3;

[0062] p is an integer selected from the group consisting of 0, 1, and 2;

[0063] L is selected from the group consisting of a covalent bond, –CH2–, –(CH2)2– and –C1-6-alkyl-CO–*; wherein the asterisk indicates the point of attachment of L to ring B;

[0064] L1is selected from the group consisting of a covalent bond, –CH2–, –(CH2)2– and –COO–(CH2)p–*; wherein the asterisk indicates the point of attachment of L1to ring C;

[0065] R1is selected from the group consisting of hydrogen, halogen, Ci-6-alkyl, amino-C1-6-alkyl, Ci-6-alkoxy, halo-Ci-6-alkyl, halo-Ci-6-alkoxy, Cs-io-cycloalkyl, Ci-6-alkyl-O- CH2-, and C3-io-cycloalkyl-0-CH2-;R2

[0066]

[0067] is halogen or a group%;

[0068] R3is selected from the group consisting of halogen, Ci-6-alkyl-COR9, C2-6-alkenyl-

[0069]

[0070] COR10, C1-6-alkyl-NR13R14, -CO-CO-NR15R16, and a group;

[0071] R4is selected from the group consisting of hydrogen, halogen, NH2, COOH, SO2OH, and lH-tetrazol-5-yl;

[0072] R5is selected from the group consisting of hydrogen, halogen, and Ci-6-alkyl;

[0073] R6is selected from the group consisting of hydrogen, halogen, Ci-6-alkyl, Ci-6-alkoxy, amino-Ci-6-alkyl, hydroxy-Ci-6-alkyl, halo-Ci-6-alkyl, Ci-6-alkoxy-Ci-6-alkyl, NH2, icL1>C

[0074]

[0075] OH, oxo, COOR17, -CO-NH2, -CO-NH-Ci-6-alkyl, and a group

[0076] R7is selected from the group consisting of hydrogen, NH2, halogen, and Ci-6-alkyl; R8is selected from the group consisting of hydrogen and cyano;

[0077] R9and R10are selected from the group consisting of OH2NR11R12, and Ci-6-alkoxy;

[0078] R11and R12are each independently selected from the group consisting of hydrogen, C1-6- alkyl, hydroxy-Ci-6-alkyl, and amino-Ci-6-alkyl;

[0079] R13and R14are each independently selected from the group consisting of hydrogen, C1-6- alkyl, and halo-Ci-6-alkyl;

[0080] R15and R16are each independently selected from the group consisting of hydrogen and Ci- 6-alkyl; and

[0081] R17is selected from the group consisting of hydrogen and Ci-6-alkyl.

[0082] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0083] Y is CH or N;

[0084] A is selected from the group consisting of phenyl, pyridyl, and thienyl;B is selected from the group consisting of:

[0085] (i) 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon;

[0086] (ii) Ce-io-aryl;

[0087] (iii) 3- to 10-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon; and

[0088] (iv) C3-10-cycloalkyl;

[0089] m is an integer selected from the group consisting of 1, 2, and 3;

[0090] n is an integer selected from the group consisting of 1, 2, and 3;

[0091] L is selected from the group consisting of a covalent bond, -CH2-, and -Ci-6-alkyl- CO-*; wherein the asterisk indicates the point of attachment of L to ring B;

[0092] R1is selected from the group consisting of hydrogen, halogen, Ci-6-alkyl, amino-C1-6-alkyl, Ci-6-alkoxy, halo-Ci-6-alkyl, halo-Ci-6-alkoxy, Cs-io-cycloalkyl, Ci-6-alkyl-O- CH2-, and C3-io-cycloalkyl-0-CH2-;

[0093]

[0094] R3is selected from the group consisting of Ci-6-alkyl-COR9, C2-6-alkenyl-COR10, and a

[0095]

[0096] R4is selected from the group consisting of hydrogen, halogen, NH2, COOH, SO2OH, and lH-tetrazol-5-yl;

[0097] R5is selected from the group consisting of hydrogen, halogen, and Ci-6-alkyl;

[0098] R6is selected from the group consisting of hydrogen, Ci-6-alkyl, Ci-6-alkoxy, amino-Ci- 6-alkyl, NH2, and -CO-NH-Ci-6-alkyl;

[0099] R7is selected from the group consisting of hydrogen, halogen, and Ci-6-alkyl;

[0100] R8is selected from the group consisting of hydrogen and cyano;

[0101] R9and R10are selected from the group consisting of OH2NR11R12, and Ci-6-alkoxy; and R11and R12are each independently selected from the group consisting of hydrogen, C1-6- alkyl, hydroxy-Ci-6-alkyl, and amino-Ci-6-alkyl.In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein when R2is halogen or R4is hydrogen, halogen or NH2, then R3is Ci-6-alkyl-COR9and R9is OH.

[0102] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Y is N.

[0103] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of formula (I) is a compound of formula (la):

[0104]

[0105] (la)

[0106] wherein the variables are as defined herein.

[0107] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of formula (I) is a compound of formula (lb):

[0108]

[0109] wherein the variables are as defined herein.

[0110] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of formula (I) is a compound of formula (Ic):

[0111]

[0112] wherein the variables are as defined herein.

[0113] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1is selected from the group consisting of hydrogen, halogen, Ci-6-alkyl, and halo-Ci-6-alkyl.

[0114] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1is selected from the group consisting of hydrogen, fluoro, chloro, methyl, and difluoromethyl.

[0115] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1is selected from the group consisting of halogen and Ci-6-alkyl.

[0116] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1is selected from the group consisting of chloro and methyl.

[0117] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0118] A is selected from the group consisting of phenyl and pyridyl;

[0119]

[0120] R4is selected from the group consisting of hydrogen, halogen, NH2, and COOH; and R5is hydrogen.

[0121] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0122] A is selected from the group consisting of phenyl and pyridyl;

[0123]

[0124] R4is selected from the group consisting of hydrogen, fluoro, NH2, and COOH; and R5is hydrogen.

[0125] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0126] A is phenyl;

[0127]

[0128] R4is COOH; and

[0129] R5is hydrogen.

[0130] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0131]

[0132] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0133] B is selected from the group consisting of:

[0134] (i) 5- to 14-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon;

[0135] (ii) Ce-io-aryl;

[0136] (iii) 3- to 14-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon; and

[0137] (iv) C3-10-cycloalkyl;

[0138] C is selected from the group consisting of:

[0139] (i) 5- to 14-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon;

[0140] (ii) 3- to 14-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon; and

[0141] (iii) C3-10-cycloalkyl;

[0142] P is 2;

[0143] L is selected from the group consisting of a covalent bond, -CH2-, and

[0144] -Ci-6-alkyl-CO-*; wherein the asterisk indicates the point of attachment of L to ring B;

[0145] L1is selected from the group consisting of a covalent bond, -CH2-, -(CH2)2- and -COO-(CH2)p-*; wherein the asterisk indicates the point of attachment of L1to ring C;

[0146] R3is selected from the group consisting of halogen, Ci-6-alkyl-COR9, C2-6-alkenyl-

[0147]

[0148] COR10, C1-6-alkyl-NR13R14, -CO-CO-NR15R16, and a group;

[0149] R6is selected from the group consisting of hydrogen, halogen, Ci-6-alkyl, Ci-6-alkoxy, amino-Ci-6-alkyl, hydroxy-Ci-6-alkyl, halo-Ci-6-alkyl, Ci-6-alkoxy-Ci-6-alkyl, NH2,

[0150]

[0151] OH, oxo, COOR17, -CO-NH2, -CO-NH-Ci-6-alkyl, and a groupR7is selected from the group consisting of hydrogen, NH2, halogen, and Ci-6-alkyl; R8is selected from the group consisting of hydrogen and cyano;

[0152] R9is selected from the group consisting of OH2NR11R12, and Ci-6-alkoxy;

[0153] R10is selected from the group consisting of OH2NR11R12, and Ci-6-alkoxy;

[0154] R11is selected from the group consisting of Ci-6-alkyl and hydroxy-Ci-6-alkyl;

[0155] R12is selected from the group consisting of Ci-6-alkyl and amino-Ci-6-alkyl;

[0156] R13is selected from the group consisting of hydrogen, Ci-6-alkyl, and halo-Ci-6-alkyl; R14is selected from the group consisting of hydrogen and Ci-6-alkyl;

[0157] R15is Ci-6-alkyl;

[0158] R16is Ci-6-alkyl; and

[0159] R17is selected from the group consisting of hydrogen and Ci-6-alkyl.

[0160] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0161] B is selected from the group consisting of cyclopropyl, azetidinyl, imidazolyl, thienyl, thiazolyl, thiadiazolyl, piperidyl, oxopyrrolidinyl, pyridyl, pyrazolyl, phenyl, oxohexahydropyrimidinyl, oxopiperidyl, pyridazinyl, l,l-dioxo-l,2-thiazolidinyl, 1,1-dioxothianyl, pyrrolidinyl, piperazinyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3-oxo- l / Z-isobenzofuranyl, 3-oxoindanyl, 5-azaspiro[2.4]heptanyl, 4,7- diazaspiro[2.5]octanyl, 3-oxoisoindolinyl, l,l-dioxo-2,3-dihydrobenzothiophenyl, l,7-diazaspiro[4.4]nonanyl, l,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridinyl, 2,5- dihydro-lH-pyrrolyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridine, 1,2- dihydropyridine, lH-l,2,4-triazolyl, 1,2,5-oxadiazolyl, triazolyl, pyrrolyl, 3,8- diazabicyclo[3.2.1]octanyl, 2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4-b][1,4]oxazinyl, 8-oxa-2,5-diazaspiro[3.5]nonanyl, 2,8-diazaspiro[4.5]decanyl, 2,8- diazaspiro[4.5]decan-3-onyl, 9-oxa-2,6-diazaspiro[4.5]decanyl, 4-oxa-l,9- diazaspiro[5.5]undecanyl, 4-oxa-l,8-diazaspiro[5.5]undecanyl, 2,6,9- triazaspiro[4.5]decanyl, 2,6,9-triazaspiro[4.5]decan-8-onyl, 2,6- diazaspiro[4.5]decanyl, and 2,3,4,4a,5,6,7,7a-octahydro-1H-pyrrolo[3,4-b]pyridinyl; C is selected from the group consisting of cyclopropyl, oxetanyl, and imidazolyl;

[0162] P is 2;

[0163] L is selected from the group consisting of a covalent bond, -CH2-, and -CH2-CO-*;

[0164] wherein the asterisk indicates the point of attachment of L to ring B;L1is selected from the group consisting of a covalent bond, -CH2-, -(CH2)2- and -COO-(CH2)p-*; wherein the asterisk indicates the point of attachment of L1to ring C;

[0165] R3is selected from the group consisting of bromo, -CH2-COR9, -CH=CH-COR10,

[0166] B

[0167]

[0168] R8

[0169] Ci-4-alkyl-NR13R14, -CO-CO-NR15R16, and a group

[0170] R6is selected from the group consisting of hydrogen, fluoro, methyl, methoxy, aminomethyl, 2-hydroxyethyl, hydroxymethyl, fluoromethyl, trifluoromethyl, 2- fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, methoxymethyl, 2-methoxyethyl, NH2, OH, oxo, COOR17, -CO-NH2, and -CO-NH- methyl

[0171]

[0172] methyl;, and a group

[0173] R7is selected from the group consisting of hydrogen, NH2, fluoro, and methyl;

[0174] R8is selected from the group consisting of hydrogen and cyano;

[0175] R9is selected from the group consisting of OH2NR11R12, and ethoxy;

[0176] R10is selected from the group consisting of OH2NR11R12, and ethoxy;

[0177] R11and R12are both methyl; or R11is 2-hydroxyethyl and R12is selected from the group consisting of 2-aminoethyl and 3-amino-n-propyl;

[0178] R13is selected from the group consisting of hydrogen, methyl, and 2,2,2-trifluoroethyl; R14is selected from the group consisting of hydrogen and methyl;

[0179] R15is methyl;

[0180] R16is methyl; and

[0181] R17is selected from the group consisting of hydrogen and methyl.

[0182] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0183] B is selected from the group consisting of:

[0184] (i) 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, the remaining atoms being carbon; and(n) 3- to 10-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, the remaining atoms being carbon;

[0185] L is selected from the group consisting of a covalent bond, -CH2-, and

[0186] -CH2-CO-*; wherein the asterisk indicates the point of attachment of L to ring B; R3is selected from the group consisting of Ci-6-alkyl-COR9and a group

[0187]

[0188] R6is selected from the group consisting of hydrogen, oxo, Ci-6-alkyl, and halo-Ci-6- alkyl;

[0189] R7is hydrogen;

[0190] R8is hydrogen;

[0191] R9is NR11R12;

[0192] R11is Ci-6-alkyl; and

[0193] R12is Ci-6-alkyl.

[0194] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0195] B is selected from the group consisting of pyrrolidinyl, oxopyrrolidinyl, piperidyl, pyridyl, pyrazolyl, 2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4-b][1,4]oxazinyl, 1,7- diazaspiro[4.4]nonanyl, and 9-oxa-2,6-diazaspiro[4.5]decanyl;

[0196] L is selected from the group consisting of a covalent bond, -CH2-, and

[0197] -CH2-CO-*; wherein the asterisk indicates the point of attachment of L to ring B;

[0198]

[0199] R3is selected from the group consisting of-CH2-COR9and a group

[0200] R6is selected from the group consisting of hydrogen, oxo, methyl, and 2,2- difluoroethyl;

[0201] R7is hydrogen;

[0202] R8is hydrogen;R9is NR11R12;

[0203] R11is methyl; and

[0204] R12is methyl.

[0205] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0206] B is selected from the group consisting of:

[0207]

[0208] wherein a wavy line indicates the point of attachment of ring B to linker L;

[0209] L is selected from the group consisting of a covalent bond, -CH2-, and

[0210] -CH2-CO-*; wherein the asterisk indicates the point of attachment of L to ring B;

[0211] R6( B )

[0212]

[0213] rr7R3is selected from the group consisting of-CH2-COR9and a group

[0214] R6is selected from the group consisting of hydrogen, methyl, and 2,2-difluoroethyl; R7is hydrogen;

[0215] R8is hydrogen;

[0216] R9is NR11R12;

[0217] R11is methyl; and

[0218] R12is methyl.

[0219] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0220] B is a 7- to 14-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon;L is selected from the group consisting of a covalent bond, -CH2-, and -Ci-6-alkyl-CO-*; wherein the asterisk indicates the point of attachment of L to ring B;

[0221] B

[0222]

[0223] R8

[0224] R3is a group

[0225] R6is selected from the group consisting of hydrogen, halogen, Ci-6-alkyl, Ci-6-alkoxy, amino-Ci-6-alkyl, hydroxy-Ci-6-alkyl, halo-Ci-6-alkyl, Ci-6-alkoxy-Ci-6-alkyl, NH2,

[0226]

[0227] OH, oxo, COOR17, -CO-NH2, -CO-NH-Ci-6-alkyl, and a group

[0228] R7is selected from the group consisting of hydrogen, NH2, halogen, and Ci-6-alkyl; R8is selected from the group consisting of hydrogen and cyano.

[0229] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0230] B is a 7- to 14-membered fused bicyclic or spirocyclic bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon; L is -Ci-6-alkyl-CO-*; wherein the asterisk indicates the point of attachment of L to ring B;

[0231] B

[0232]

[0233] R8

[0234] R3is a group

[0235] R6is selected from the group consisting of hydrogen, halogen, Ci-6-alkyl, NH2, and oxo; R7is hydrogen, halogen, and Ci-6-alkyl; and

[0236] R8is hydrogen.

[0237] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:B is selected from the group consisting of 5-azaspiro[2.4]heptanyl, 4,7- diazaspiro[2.5]octanyl, 2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4-b][1,4]oxazine, 8- oxa-2,5-diazaspiro[3.5]nonanyl, l,7-diazaspiro[4.4]nonanyl, 2,8- diazaspiro[4.5]decanyl, 2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4-b][1,4]oxazinyl, 9- oxa-2,6-diazaspiro[4.5]decanyl, 4-oxa-l,9-diazaspiro[5.5]undecanyl, 4-oxa-l,8- diazaspiro[5.5]undecanyl, 2,6,9-triazaspiro[4.5]decanyl, 2,6-diazaspiro[4.5]decanyl, and 2,3,4,4a,5,6,7,7a-octahydro-1H-pyrrolo[3,4-b]pyridine;

[0238] L is -CH2-CO-*; wherein the asterisk indicates the point of attachment of L to ring B;

[0239] B

[0240]

[0241] R8

[0242] R3is a group

[0243] R6is selected from the group consisting of hydrogen, fluoro, methyl, NH2, and oxo; R7is hydrogen, fluoro, and methyl; and

[0244] R8is hydrogen.

[0245] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0246] B is selected from the group consisting of:

[0247] (i) 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon;

[0248] (ii) C6-10-aryl; and

[0249] (iii) 3- to 10-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon;

[0250] L is selected from the group consisting of a covalent bond, -CH2-, and -Ci-6-alkyl- CO-*; wherein the asterisk indicates the point of attachment of L to ring B;

[0251] R3is selected from the group consisting of Ci-6-alkyl-COR9, C2-6-alkenyl-COR10, and a

[0252] 1, B

[0253] LXI

[0254]

[0255] groupR6is selected from the group consisting of hydrogen, Ci-6-alkyl, Ci-6-alkoxy, amino-Ci-6-alkyl, NH2, and -CO-NH-Ci-6-alkyl;

[0256] R7is selected from the group consisting of hydrogen, halogen, and Ci-6-alkyl;

[0257] R8is selected from the group consisting of hydrogen and cyano;

[0258] R9is selected from the group consisting of OH and NR11R12;

[0259] R10is NR11R12;

[0260] R11is selected from the group consisting of Ci-6-alkyl and hydroxy-Ci-6-alkyl; and R12is selected from the group consisting of Ci-6-alkyl and amino-Ci-6-alkyl.

[0261] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0262] B is selected from the group consisting of imidazolyl, thienyl, thiazolyl, thiadiazolyl, piperidyl, oxopyrrolidinyl, pyridyl, pyrazolyl, phenyl, oxohexahydropyrimidinyl, oxopiperidyl, pyridazinyl, l,l-dioxo-l,2-thiazolidinyl, 1,1-dioxothianyl, pyrrolidinyl, piperazinyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3-oxo-1H-isobenzofuranyl, 3- oxoindanyl, 5-azaspiro[2.4]heptanyl, 4,7-diazaspiro[2.5]octanyl, 3-oxoisoindolinyl, 1, l-dioxo-2,3-dihydrobenzothiophenyl, l,7-diazaspiro[4.4]nonanyl, and l,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridinyl;

[0263] L is selected from the group consisting of a covalent bond, -CH2-, and -CH2-CO-*;

[0264] wherein the asterisk indicates the point of attachment of L to ring B;

[0265] R3is selected from the group consisting of-CH2-COR9, -CH=CH-COR10, and a group

[0266] B

[0267]

[0268] R8

[0269] R6is selected from the group consisting of hydrogen, methyl, methoxy, aminomethyl, NH2, and -CO-NH-methyl;

[0270] R7is selected from the group consisting of hydrogen, fluoro, and methyl;

[0271] R8is selected from the group consisting of hydrogen and cyano;

[0272] R9is selected from the group consisting of OH and NR11R12;

[0273] R10is NR11R12;

[0274] R11and R12are both methyl; or R11is 2-hydroxyethyl and R12is 3-amino-n-propyl.In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0275] B is selected from the group consisting of:

[0276]

[0277]

[0278] wherein a wavy line indicates the point of attachment of ring B to linker L; L is selected from the group consisting of a covalent bond, -CH2-, and -CH2-CO-*;

[0279] wherein the asterisk indicates the point of attachment of L to ring B;

[0280] R3is selected from the group consisting of-CH2-COR9, -CH=CH-COR10, and a group

[0281]

[0282] R6is selected from the group consisting of hydrogen, methyl, methoxy, aminomethyl, NH2, and -CO-NH-methyl;

[0283] R7is selected from the group consisting of hydrogen, fluoro, and methyl;

[0284] R8is selected from the group consisting of hydrogen and cyano;

[0285] R9is selected from the group consisting of OH and NR11R12;

[0286] R10is NR11R12;

[0287] R11and R12are both methyl; or R11is 2-hydroxyethyl and R12is 3-amino-n-propyl.

[0288] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0289] B is selected from the group consisting of:

[0290] (i) 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, the remaining atoms being carbon; and

[0291] (ii) 3- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, the remaining atoms being carbon;L is -CH2-;

[0292] R3is selected from the group consisting of Ci-6-alkyl-COR9and a group

[0293]

[0294] R6is selected from the group consisting of hydrogen and Ci-6-alkyl;

[0295] R7is hydrogen;

[0296] R8is hydrogen;

[0297] R9is NR11R12;

[0298] R11is Ci-6-alkyl; and

[0299] R12is Ci-6-alkyl.

[0300] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0301] B is selected from the group consisting of oxopyrrolidinyl, pyridyl, and pyrazolyl; L is -CH2-;

[0302]

[0303] R3is selected from the group consisting of-CH2-COR9and a group

[0304] R6is selected from the group consisting of hydrogen and methyl;

[0305] R7is hydrogen;

[0306] R8is hydrogen;

[0307] R9is NR11R12;

[0308] R11is methyl; and

[0309] R12is methyl.

[0310] In a further particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0311] B is selected from the group consisting of:

[0312]

[0313] wherein a wavy line indicates the point of attachment of ring B to linker L;

[0314] L is -CH2-;

[0315]

[0316] R3is selected from the group consisting of-CH2-COR9and a group

[0317] R6is selected from the group consisting of hydrogen and methyl;

[0318] R7is hydrogen;

[0319] R8is hydrogen;

[0320] R9is NR11R12;

[0321] R11is methyl; and

[0322] R12is methyl.

[0323] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m is 2 and n is 3.

[0324] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Y is N, m is 2 and n is 3.

[0325] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0326] Y isN;

[0327] A is selected from the group consisting of phenyl and pyridyl;

[0328] B is selected from the group consisting of:

[0329] (i) 5- to 14-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon;

[0330] (ii) Ce-io-aryl;(iii) 3- to 14-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon; and

[0331] (iv) C3-10-cycloalkyl;

[0332] C is selected from the group consisting of:

[0333] (i) 5- to 14-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon;

[0334] (ii) 3- to 14-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon; and

[0335] (iii) C3-10-cycloalkyl;

[0336] is 2;

[0337] is 3;

[0338] is 2;

[0339] L is selected from the group consisting of a covalent bond, -CH2-, and -Ci-6-alkyl- CO-*; wherein the asterisk indicates the point of attachment of L to ring B;

[0340] L1is selected from the group consisting of a covalent bond, –CH2–, –(CH2)2– and –COO–(CH2)p–*; wherein the asterisk indicates the point of attachment of L1to ring C;

[0341] R1is selected from the group consisting of hydrogen, halogen, Ci-6-alkyl, and halo-Ci-6- alkyl;

[0342] R

[0343] R2is halogen or a group

[0344]

[0345] R3is selected from the group consisting of halogen, Ci-6-alkyl-COR9, C2-6-alkenyl-

[0346] (,BL\ |

[0347]

[0348] COR10, C1-6-alkyl-NR13R14, -CO-CO-NR15R16, and a group

[0349] R4is selected from the group consisting of hydrogen, halogen, NH2, and COOH;

[0350] R5is hydrogen;R6is selected from the group consisting of hydrogen, halogen, Ci-6-alkyl, Ci-6-alkoxy, amino-Ci-6-alkyl, hydroxy-Ci-6-alkyl, halo-Ci-6-alkyl, Ci-6-alkoxy-Ci-6-alkyl, NH2,

[0351]

[0352] OH, oxo, COOR17, -CO-NH2, -CO-NH-Ci-6-alkyl, and a group

[0353] R7is selected from the group consisting of hydrogen, NH2, halogen, and Ci-6-alkyl; R8is selected from the group consisting of hydrogen and cyano;

[0354] R9is selected from the group consisting of OH2NR11R12, and Ci-6-alkoxy;

[0355] R10is selected from the group consisting of OH2NR11R12, and Ci-6-alkoxy;

[0356] R11is selected from the group consisting of Ci-6-alkyl and hydroxy-Ci-6-alkyl;

[0357] R12is selected from the group consisting of Ci-6-alkyl and amino-Ci-6-alkyl;

[0358] R13is selected from the group consisting of hydrogen, Ci-6-alkyl, and halo-Ci-6-alkyl; R14is selected from the group consisting of hydrogen and Ci-6-alkyl;

[0359] R15is Ci-6-alkyl;

[0360] R16is Ci-6-alkyl; and

[0361] R17is selected from the group consisting of hydrogen and Ci-6-alkyl.

[0362] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0363] Y isN;

[0364] A is selected from the group consisting of phenyl and pyridyl;

[0365] B is selected from the group consisting of cyclopropyl, azetidinyl, imidazolyl, thienyl, thiazolyl, thiadiazolyl, piperidyl, oxopyrrolidinyl, pyridyl, pyrazolyl, phenyl, oxohexahydropyrimidinyl, oxopiperidyl, pyridazinyl, l,l-dioxo-l,2-thiazolidinyl, 1,1-dioxothianyl, pyrrolidinyl, piperazinyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3-oxo-1H-isobenzofuranyl, 3-oxoindanyl, 5-azaspiro[2.4]heptanyl, 4,7- diazaspiro[2.5]octanyl, 3-oxoisoindolinyl, l,l-dioxo-2,3-dihydrobenzothiophenyl, l,7-diazaspiro[4.4]nonanyl, l,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridinyl, 2,5- dihydro-lH-pyrrolyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridine, 1,2- dihydropyridine, lH-l,2,4-triazolyl, 1,2,5-oxadiazolyl, triazolyl, pyrrolyl, 3,8- diazabicyclo[3.2.1]octanyl, 2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4-b][1,4]oxazinyl, 8-oxa-2,5-diazaspiro[3.5]nonanyl, 2,8-diazaspiro[4.5]decanyl, 2,8- diazaspiro[4.5]decan-3-onyl, 9-oxa-2,6-diazaspiro[4.5]decanyl, 4-oxa-l,9-diazaspiro[5.5]undecanyl, 4-oxa-l,8-diazaspiro[5.5]undecanyl, 2,6,9- triazaspiro[4.5]decanyl, 2,6,9-triazaspiro[4.5]decan-8-onyl, 2,6- diazaspiro[4.5]decanyl, and 2,3,4,4a,5,6,7,7a-octahydro-1H-pyrrolo[3,4-b]pyridinyl; C is selected from the group consisting of cyclopropyl, oxetanyl, and imidazolyl; m is 2;

[0366] n is 3;

[0367] P is 2;

[0368] L is selected from the group consisting of a covalent bond, -CH2-, and -CH2-CO-*;

[0369] wherein the asterisk indicates the point of attachment of L to ring B;

[0370] L1is selected from the group consisting of a covalent bond, –CH2–, –(CH2)2– and –COO–(CH2)p–*; wherein the asterisk indicates the point of attachment of L1to ring C;

[0371] R1is selected from the group consisting of hydrogen, fluoro, chloro, methyl, and difluoromethyl;

[0372]

[0373] R2is bromo or a group

[0374] R3is selected from the group consisting of bromo, -CH2-COR9, -CH=CH-COR10,

[0375] B

[0376]

[0377] R8

[0378] Ci-4-alkyl-NR13R14, -CO-CO-NR15R16, and a group

[0379] R4is selected from the group consisting of hydrogen, fluoro, NH2, and COOH;

[0380] R5is hydrogen;

[0381] R6is selected from the group consisting of hydrogen, fluoro, methyl, methoxy, aminomethyl, 2-hydroxyethyl, hydroxymethyl, fluoromethyl, trifluoromethyl, 2- fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, methoxymethyl, 2-methoxyethyl, NH2, OH, oxo, COOR17, -CO-NH2, and -CO-NH-

[0382]

[0383] methyl;, and a groupR7is selected from the group consisting of hydrogen, NH2, fluoro, and methyl;

[0384] R8is selected from the group consisting of hydrogen and cyano;

[0385] R9is selected from the group consisting of OH2NR11R12, and ethoxy;

[0386] R10is selected from the group consisting of OH2NR11R12, and ethoxy;

[0387] R11and R12are both methyl; or R11is 2-hydroxyethyl and R12is selected from the group consisting of 2-aminoethyl and 3-amino-n-propyl;

[0388] R13is selected from the group consisting of hydrogen, methyl, and 2,2,2-trifluoroethyl; R14is selected from the group consisting of hydrogen and methyl;

[0389] R15is methyl;

[0390] R16is methyl; and

[0391] R17is selected from the group consisting of hydrogen and methyl.

[0392] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0393] Y isN;

[0394] A is phenyl;

[0395] B is selected from the group consisting of:

[0396] (i) 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, the remaining atoms being carbon; and

[0397] (ii) 3- to 10-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, the remaining atoms being carbon;

[0398] m is 2;

[0399] n is 3;

[0400] L is selected from the group consisting of a covalent bond, -CH2-, and

[0401] -CH2-CO-*; wherein the asterisk indicates the point of attachment of L to ring B; R1is selected from the group consisting of halogen and Ci-6-alkyl;

[0402] R1

[0403]

[0404] is a groupR3is selected from the group consisting of Ci-6-alkyl-COR9and a group

[0405]

[0406] R4is COOH;

[0407] R5is hydrogen;

[0408] R6is selected from the group consisting of hydrogen, oxo, Ci-6-alkyl, and halo-Ci-6- alkyl;

[0409] R7is hydrogen;

[0410] R8is hydrogen;

[0411] R9is NR11R12;

[0412] R11is Ci-6-alkyl; and

[0413] R12is Ci-6-alkyl.

[0414] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0415] Y isN;

[0416] A is phenyl;

[0417] B is selected from the group consisting of pyrrolidinyl, oxopyrrolidinyl, piperidyl, pyridyl, pyrazolyl, 2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4-b][1,4]oxazinyl, 1,7- diazaspiro[4.4]nonanyl, and 9-oxa-2,6-diazaspiro[4.5]decanyl;

[0418] m is 2;

[0419] n is 3;

[0420] L is selected from the group consisting of a covalent bond, -CH2-, and

[0421] -CH2-CO-*; wherein the asterisk indicates the point of attachment of L to ring B; R1is selected from the group consisting of chloro and methyl;

[0422] R4

[0423]

[0424]

[0425] R3is selected from the group consisting of-CH2-COR9and a group; R4is COOH;

[0426] R5is hydrogen;

[0427] R6is selected from the group consisting of hydrogen, oxo, methyl, and 2,2- difluoroethyl;

[0428] R7is hydrogen;

[0429] R8is hydrogen;

[0430] R9is NR11R12;

[0431] R11is methyl; and

[0432] R12is methyl.

[0433] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0434] Y isN;

[0435] A is selected from the group consisting of phenyl and pyridyl;

[0436] B is selected from the group consisting of:

[0437] (i) 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon;

[0438] (ii) C6-10-aryl; and

[0439] (iii) 3- to 10-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon;

[0440] m is 2;

[0441] n is 3;

[0442] L is selected from the group consisting of a covalent bond, -CH2-, and -Ci-6-alkyl- CO-*; wherein the asterisk indicates the point of attachment of L to ring B;

[0443] R1is selected from the group consisting of hydrogen, halogen, Ci-6-alkyl, and halo-Ci-6- alkyl;R4

[0444] ( A )

[0445] R2is halogen or a group

[0446]

[0447] x;

[0448] R3is selected from the group consisting of Ci-6-alkyl-COR9, C2-6-alkenyl-COR10, and a R6

[0449] ( B )

[0450]

[0451] R?

[0452] group;

[0453] R4is selected from the group consisting of hydrogen, halogen, NH2, and COOH;

[0454] R5is hydrogen;

[0455] R6is selected from the group consisting of hydrogen, Ci-6-alkyl, Ci-6-alkoxy, amino-Ci- 6-alkyl, NH2, and -CO-NH-Ci-6-alkyl;

[0456] R7is selected from the group consisting of hydrogen, halogen, and Ci-6-alkyl;

[0457] R8is selected from the group consisting of hydrogen and cyano;

[0458] R9is selected from the group consisting of OH and NR11R12;

[0459] R10is NR11R12;

[0460] R11is selected from the group consisting of Ci-6-alkyl and hydroxy-Ci-6-alkyl; and R12is selected from the group consisting of Ci-6-alkyl and amino-Ci-6-alkyl.

[0461] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0462] Y isN;

[0463] A is selected from the group consisting of phenyl and pyridyl;

[0464] B is selected from the group consisting of imidazolyl, thienyl, thiazolyl, thiadiazolyl, piperidyl, oxopyrrolidinyl, pyridyl, pyrazolyl, phenyl, oxohexahydropyrimidinyl, oxopiperidyl, pyridazinyl, l,l-dioxo-l,2-thiazolidinyl, 1,1-dioxothianyl, pyrrolidinyl, piperazinyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3-oxo-1H-isobenzofuranyl, 3- oxoindanyl, 5-azaspiro[2.4]heptanyl, 4,7-diazaspiro[2.5]octanyl, 3-oxoisoindolinyl, 1, l-dioxo-2,3-dihydrobenzothiophenyl, l,7-diazaspiro[4.4]nonanyl, and l,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridinyl;

[0465] m is 2;

[0466] n is 3;L is selected from the group consisting of a covalent bond, -CH2-, and -CH2-CO-*; wherein the asterisk indicates the point of attachment of L to ring B;

[0467] R1is selected from the group consisting of hydrogen, fluoro, chloro, methyl, and difluoromethyl;

[0468]

[0469] R2is bromo or a group

[0470] R3is selected from the group consisting of-CH2-COR9, -CH=CH-COR10, and a group

[0471] B

[0472]

[0473] R8

[0474] R4is selected from the group consisting of hydrogen, fluoro, NH2, and COOH;

[0475] R5is hydrogen;

[0476] R6is selected from the group consisting of hydrogen, methyl, methoxy, aminomethyl, NH2, and -CO-NH-methyl;

[0477] R7is selected from the group consisting of hydrogen, fluoro, and methyl;

[0478] R8is selected from the group consisting of hydrogen and cyano;

[0479] R9is selected from the group consisting of OH and NR11R12;

[0480] R10is NR11R12;

[0481] R11and R12are both methyl; or R11is 2-hydroxyethyl and R12is 3-amino-n-propyl.

[0482] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0483] Y isN;

[0484] A is phenyl;

[0485] B is selected from the group consisting of:

[0486] (i) 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, the remaining atoms being carbon; and

[0487] (ii) 3- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, the remaining atoms being carbon;

[0488] is 2;n is 3;

[0489] L is -CH2-;

[0490] R1is selected from the group consisting of halogen and Ci-6-alkyl;

[0491] R4

[0492] ( A )

[0493] R2is a group

[0494]

[0495] x;

[0496] R3is selected from the group consisting of Ci-6-alkyl-COR9and a group

[0497]

[0498] R4is COOH;

[0499] R5is hydrogen;

[0500] R6is selected from the group consisting of hydrogen and Ci-6-alkyl;

[0501] R7is hydrogen;

[0502] R8is hydrogen;

[0503] R9is NR11R12;

[0504] R11is Ci-6-alkyl; and

[0505] R12is Ci-6-alkyl.

[0506] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0507] Y isN;

[0508] A is phenyl;

[0509] B is selected from the group consisting of oxopyrrolidinyl, pyridyl, and pyrazolyl; m is 2;

[0510] n is 3;

[0511] L is -CH2-;

[0512] R1is selected from the group consisting of chloro and methyl;R4

[0513] ( A )

[0514] R2is a group

[0515]

[0516] x;

[0517] R6( B )

[0518]

[0519] rr7R3is selected from the group consisting of-CH2-COR9and a group

[0520] R4is COOH;

[0521] R5is hydrogen;

[0522] R6is selected from the group consisting of hydrogen and methyl;

[0523] R7is hydrogen;

[0524] R8is hydrogen;

[0525] R9is NR11R12;

[0526] R11is methyl; and

[0527] R12is methyl.

[0528] In one embodiment, the present invention provides a compound of formula (I) as described herein, selected from the group consisting of:

[0529] 4-[(l IS, 14S,17S)- 14-(4- Aminobutyl)- 11 -(3-aminopropyl)-25-chl oro-16-methyl- 12, 15,18-tri oxo- 17-[[2-[(2-oxopyrrolidin- 1 -yl)methyl]- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0530] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16,25-dimethyl-12,15,18-trioxo-17- [[2-[(2-oxopyrrolidin- 1 -yl)m ethyl]- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0531] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-[(l- methylpyrazol-3-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0532] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-[(l- methylpyrazol-4-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;4-[(l IS, 14S,17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 16-methyl-12, 15,18-tri oxo-17-[[2-(2- oxo-3 -piperidyl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0533] 4-[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 1 l-(3-aminopropyl)- 16-methyl-12, 15,18-tri oxo-17-[[2-(3- oxo-lH-isobenzofuran-4-yl)-lH-indol-3-yl]methyl]-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0534] 4-[(l IS, 14S,17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 16-methyl-12, 15,18-tri oxo-17-[[2-(3- oxoindan-4-yl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0535] 4-[(l IS, 14S,17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 16-methyl-12, 15,18-tri oxo-17-[[2-(3- thienylmethyl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0536] 4-[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 1 l-(3-aminopropyl)- 16-methyl-12, 15,18-tri oxo-17-[[2- (thiazol-5-ylmethyl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0537] 4-[(l IS, 14S,17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 16-methyl-12, 15,18-tri oxo-17-[[2-[(2- oxopyrrolidin- 1 -yl)m ethyl]- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0538] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-17-[[2-[(l-methylpyrazol- 4-yl)methyl]- lH-indol-3 -yl]methyl]- 12,15,18-tri oxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0539] 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-17-[(2-benzyl-1H-indol-3-yl)methyl]-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0540] 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-17-[[2-(1,1-dioxo-2,3-dihydrobenzothiophen-7-yl)-1H-indol-3-yl]methyl]-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0541] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-17-[[2-(lH-imidazol-2-ylmethyl)-lH- indol-3 -yl]methyl]- 16-methyl- 12,15,18-tri oxo-2 -thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-17-[[2-(lH-imidazol-4-ylmethyl)-lH- indol-3 -yl]methyl]- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0542] 4- [( 11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 17-[[2-(2-methoxy-6-methyl-phenyl)- lH-indol-3 -yl]methyl]- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0543] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-17-[[2-(2-methoxyphenyl)-lH-indol- 3 -yl]methyl]- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0544] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-(5-cyano-3-fluoro-2-methoxy- phenyl)- lH-indol-3 -yl]methyl]- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0545] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[(l,l-dioxo-l,2-thi azolidin-2- yl)methyl]- lH-indol-3 -yl]methyl]- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0546] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-(dimethylamino)-2-oxo- ethyl]-lH-indol-3-yl]methyl]-16,25-dimethyl-12,15,18-trioxo-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0547] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-(dimethylamino)-2-oxo- ethy 1] - lH-indol-3 -yl]methyl]- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0548] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-(dimethylamino)-2-oxo- ethyl]-lH-indol-3-yl]methyl]-25-fluoro-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0549] 4- [( 11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25-(difluorom ethyl)- 16-methyl- 12,15,18-trioxo-17-[[2-[(2-oxopyrrolidin-l-yl)methyl]-lH-indol-3-yl]methyl]-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0550] 4- [( 11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25-(difluorom ethyl)- 16-methyl- 17- [[2-[(l-methylpyrazol-3-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4- [( 11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25-(difluorom ethyl)- 16-m ethyl- 17- [[2-[(l-methylpyrazol-4-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0551] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-(difluoromethyl)-17-[[2-[2- (dimethylamino)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16-methyl-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0552] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-chloro-16-methyl-17-[[2-[(l- methylpyrazol-3-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0553] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-chloro-16-methyl-17-[[2-[(l- methylpyrazol-4-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0554] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-chloro-17-[[2-[2-(dimethylamino)- 2-oxo-ethyl]- lH-indol-3 -yl]methyl]- 16-m ethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0555] 4-[(l IS, 14S,17S)- 14-(4- Aminobutyl)- 11 -(3-aminopropyl)-25-fluoro-l 6-m ethyl- 12, 15,18-tri oxo- 17-[[2-[(2-oxopyrrolidin- 1 -yl)methyl]- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0556] 4-[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 11 -(3-aminopropyl)-25-fluoro-l 6-m ethyl- 17-[[2-[(l- methylpyrazol-3-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0557] 4-[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 11 -(3-aminopropyl)-25-fluoro-l 6-m ethyl- 17-[[2-[(l- methylpyrazol-4-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0558] 4-[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 1 l-(3-aminopropyl)-16,25-dimethyl- 12, 15,18-tri oxo-17- [[2-(4-pyridylmethyl)-lH-indol-3-yl]methyl]-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0559] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16,25-dimethyl-12,15,18-trioxo-17- [ [2-(4-piperi dy 1)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17-[[2-(1,2,5-thiadiazol-3-ylmethyl)-1H-indol-3-yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0560] 4-[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 1 l-(3-aminopropyl)- 16-methyl-12, 15,18-tri oxo-17-[[2-(2- oxohexahydropyrimidin-5-yl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0561] 4-[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 1 l-(3-aminopropyl)- 16-methyl-12, 15,18-tri oxo-17-[[2-(4- piperidyl)-lH-indol-3-yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;

[0562] 4-[(l IS, 14S,17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 16-methyl-12, 15,18-tri oxo-17-[[2-(4- pyridylmethyl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0563] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16-methyl-17-[[2-(l-methyl-2-oxo-3- piperidyl)- lH-indol-3 -yl]methyl]- 12,15,18-tri oxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0564] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16-methyl-17-[[2-(2-methyl-3-oxo- isoindolin-4-yl)- lH-indol-3 -yl]methyl]- 12,15,18-tri oxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0565] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-(l,l-dioxothian-2-yl)-lH- indol-3 -yl]methyl]- 16-methyl- 12,15,18-tri oxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0566] 4-[( 11 S, 14 S, 17 S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 17- [ [2 - (3 -methoxypyridazin-4-yl)- lH-indol-3 -yl]methyl]- 16-methyl- 12,15,18-tri oxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0567] 4- [( 11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25-(difluorom ethyl)- 16-methyl- 12.15.18-trioxo-17-[[2-(4-piperidyl)-lH-indol-3-yl]methyl]-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0568] 4- [( 11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25-(difluorom ethyl)- 16-methyl- 12.15.18-trioxo-17-[[2-(4-pyridylmethyl)-lH-indol-3-yl]methyl]-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0569] 4-[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 1 l-(3-aminopropyl)-25-chloro-l 6-methyl- 12, 15,18-tri oxo- 17- [ [2-(4-piperi dy 1)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;4-[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 11 -(3-aminopropyl)-25-chloro-l 6-methyl- 12, 15,18-trioxo- 17-[[2-(4-pyridylmethyl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0570] 4-[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 11 -(3-aminopropyl)-25-fluoro-l 6-methyl- 12, 15,18-trioxo- 17- [ [2-(4-piperi dy 1)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0571] 4-[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 11 -(3-aminopropyl)-25-fluoro-l 6-methyl- 12, 15,18-trioxo- 17-[[2-(4-pyridylmethyl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0572] 2-[3-[[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-22-bromo-25-chloro-16-methyl- 12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa- l(25),3(8),4,6,21,23-hexaen-17-yl]methyl]-lH-indol-2-yl]acetic acid;

[0573] 2-[3-[[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-chloro-16-methyl-12,15,18- trioxo-22-(3 -pyridyl)-2-thia-4, 10,13,16,19-pentazatricyclo[ 19.4.0.03,8]pentacosa- l(25),3(8),4,6,21,23-hexaen-17-yl]methyl]-lH-indol-2-yl]acetic acid;

[0574] 2-[3 -[[(11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-22-(6-amino-3 -pyridyl)-25- chloro-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa- l(25),3(8),4,6,21,23-hexaen-17-yl]methyl]-lH-indol-2-yl]acetic acid;

[0575] 2-[3-[[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-chloro-22-(2-fluoro-4- pyridyl)- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-17-yl]methyl]-lH-indol-2- yl] acetic acid;

[0576] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[(E)-3-(dimethylamino)-3-oxo- prop- 1 -enyl]- lH-indol-3 -yl]methyl]- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0577] 4-[(l IS, 14S,17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 16-methyl-12, 15,18-tri oxo-17-[[2-(2- oxo-2-piperazin- 1 -yl-ethyl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; trihydrochloride;

[0578] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16,25-dimethyl-12,15,18-trioxo-17- [[2-(2-oxo-2-piperazin- 1 -yl-ethyl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-[2-(4- methylpiperazin-l-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0579] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16-methyl-17-[[2-[2-[4- (methylcarbamoyl)-l-piperidyl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0580] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-(l,7-diazaspiro[4.4]nonan- 7-yl)-2-oxo-ethyl]- lH-indol-3 -yl]methyl]- 16-m ethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0581] 4-[(l 1 S, 14S, 17 S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 17-[[2-[2-(2,2-dimethylpiperazin- 1 - yl)-2-oxo-ethyl]- lH-indol-3 -yl]methyl]- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0582] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-[(3R)-3-aminopyrrolidin-l- yl]-2-oxo-ethyl]- lH-indol-3 -yl]methyl]- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0583] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-[3-aminopropyl(2- hydroxyethyl)amino]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-l 6-methyl- 12, 15, 18-tri oxo-2 -thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0584] 4- [( 11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25-(difluorom ethyl)- 16-methyl- 12,15,18-trioxo-17-[[2-(2-oxo-2-piperazin-l-yl-ethyl)-lH-indol-3-yl]methyl]-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0585] 4- [( 11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25-(difluorom ethyl)- 16-methyl- 17- [[2-[2-(4-methylpiperazin-l-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]- 12, 15, 18-tri oxo-2 -thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0586] 4-[(l IS, 14S,17S)- 14-(4- Aminobutyl)- 11 -(3-aminopropyl)-25-chl oro-16-methyl- 12, 15, 18-tri oxo- 17-[[2-(2-oxo-2-piperazin- 1 -yl-ethyl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-chloro-16-methyl-17-[[2-[2-(4- methylpiperazin-l-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4, 10, 13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1(25), 3(8), 4, 6, 21, 23-hexaen-22- yl]benzoic acid;

[0587] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l 1 -(3-aminopropyl)-25-fluoro-16-m ethyl- 12, 15,18-trioxo- 17-[[2-(2-oxo-2-piperazin- 1 -yl-ethyl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0588] 4-[(l IS, 14S,17S)- 14-(4- Aminobutyl)- 11 -(3-aminopropyl)-25-fluoro- 16-m ethyl- 17-[[2-[2-(4- methylpiperazin-l-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4, 10, 13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1(25), 3(8), 4, 6, 21, 23-hexaen-22- yl]benzoic acid;

[0589] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-17-[[2-[2-(4-amino-l-piperidyl)-2-oxo-ethyl]-lH-indol-3- yl]methyl]-l 1 -(3-aminopropyl)-16-methyl-12, 15,18-tri oxo-2 -thia-4,10,13, 16, 19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0590] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-17-[[2-[2-[4-(aminomethyl)-l-piperidyl]-2-oxo-ethyl]-lH- indol-3-yl]methyl]-l 1 -(3-aminopropyl)-16-methyl-12, 15,18-tri oxo-2 -thia-4,10,13, 16, 19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0591] 4-[(llS,14S,17S)-17-[[2-[2-[(4aR,7aR)-l,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridin-6-yl]- 2-oxo-ethyl]- lH-indol-3 -yl]methyl]- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 16-methyl- 12, 15,18-tri oxo-2 -thia-4,10,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;

[0592] 4-[(llS,14S,17S)-17-[[2-[2-[(4aS,7aS)-l,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridin-6-yl]-2- oxo-ethyl]-lH-indol-3-yl]methyl]-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16-methyl- 12, 15,18-tri oxo-2 -thia-4,10,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;

[0593] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-(3,6- diazabicyclo[3.1.1 ]heptan-6-yl)-2-oxo-ethyl]- lH-indol-3 -yl]methyl]- 16-m ethyl- 12,15,18- tri oxo-2-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1(25), 3(8), 4, 6, 21,23- hexaen-22-yl]benzoic acid;

[0594] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-(4,7-diazaspiro[2.5]octan-4- yl)-2-oxo-ethyl]- lH-indol-3 -yl]methyl]- 16-methyl- 12,15,18-tri oxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;4-[(11S,14S,17S)-17-[[2-[2-[(7R)-7-amino-5-azaspiro[2.4]heptan-5-yl]-2-oxo-ethyl]-lH-indol-3- yl]methyl]-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0595] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-(5-azaspiro[2.4]heptan-5- yl)-2-oxo-ethyl]- lH-indol-3 -yl]methyl]- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0596] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-(3,8- diazabicyclo[3.2.1]octan-8-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16-methyl-12,15,18- trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;

[0597] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-(4-methoxycarbonyl-l- piperidyl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16-methyl-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0598] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-[(3S)-3-aminopyrrolidin-l- yl]-2-oxo-ethyl]- lH-indol-3 -yl]methyl]- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0599] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[(E)-2-carboxyvinyl]-lH- indol-3 -yl]methyl]- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0600] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[(E)-3-ethoxy-3-oxo-prop-l- enyl]- lH-indol-3 -yl]methyl]- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0601] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-(2-ethoxy-2-oxo-ethyl)-lH- indol-3 -yl]methyl]- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0602] 4-[(l IS, 14S,17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 16-methyl-12, 15,18-tri oxo-17-[[2-(2- pyridylmethyl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0603] 4-[(l IS, 14S,17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 16-methyl-12, 15,18-tri oxo-17-[[2-(3- pyridylmethyl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-17-[[2-[(l- methylimidazol-2-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0604] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16-methyl-17-[[2-[(3-methyl-4- pyridyl)methyl]- lH-indol-3 -yl]methyl]- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0605] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16-methyl-17-[[2-[(4-methyl-l,2,5- oxadiazol-3-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0606] 4-[(l IS, 14S,17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 16-methyl-12, 15,18-tri oxo-17-[(2- tetrahydropyran-4-yl- lH-indol-3 -yl)methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0607] 4-[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 1 l-(3-aminopropyl)- 16-methyl-12, 15,18-tri oxo-17-[[2- (lH-pyrazol-4-ylmethyl)-lH-indol-3-yl]methyl]-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0608] 4-[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 1 l-(3-aminopropyl)- 16-methyl-12, 15,18-tri oxo-17-[[2- (lH-pyrrol-3-ylmethyl)-lH-indol-3-yl]methyl]-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0609] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-17-[[2-[(l- methylimidazol-4-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0610] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-17-[[2-[(l-methylpyrazol- 3-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0611] 4-[(l IS, 14S,17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 16-methyl-l 7-[[2-[(l -methyltri azol-4- yl)methyl]- lH-indol-3 -yl]methyl]- 12,15,18-tri oxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0612] 4-[(l IS, 14S,17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 16-methyl-l 7-[[2-[(2-methyl- 1,2,4- triazol-3 -yl)methyl]- lH-indol-3 -yl]methyl]- 12,15,18-tri oxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0613] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[(2-cyclopropyl-lH-indol-3- yl)methyl]- 16-methyl- 12,15,18-tri oxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-(2-methoxy-3-pyridyl)-lH- indol-3 -yl]methyl]- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0614] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-(4-carboxyphenyl)-lH-indol- 3 -yl]methyl]- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0615] 4-[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 1 l-(3-aminopropyl)- 16-methyl-12, 15,18-tri oxo-17-[[2-(2- oxo- IH-pyri din-3 -yl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0616] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-(2-hydroxyphenyl)-lH-indol- 3 -yl]methyl]- 16-methyl- 12,15,18-tri oxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0617] 4- [( 11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 17-[[2-(2-hydroxy-6-methyl-phenyl)- lH-indol-3 -yl]methyl]- 16-methyl- 12,15,18-tri oxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0618] 4-[(llS,14S,17S)-14-(4-aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-[2-[(5R)-9-oxa- 2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0619] 4-[(llS,14S,17S)-14-(4-aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-[2-[(5S)-9-oxa- 2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0620] 4-[(llS,14S,17S)-14-(4-aminobutyl)-ll-(3-aminopropyl)-16-methyl-17-[[2-[2-[(5R)-9-oxa-2,6- diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0621] 4-[(llS,14S,17S)-14-(4-aminobutyl)-ll-(3-aminopropyl)-16-methyl-17-[[2-[2-[(5S)-9-oxa-2,6- diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0622] 4-[(llS,14S,17S)-14-(4-aminobutyl)-ll-(3-aminopropyl)-25-(difluoromethyl)-16-methyl-17-[[2- [2-[(5R)-9-oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;

[0623] 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-25-(difluoromethyl)-16-methyl-17-[[2-[2-[(5S)-9-oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-1H-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;

[0624] 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-25-chloro-16-methyl-17-[[2-[2-[(5R)-9-oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-1H-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0625] 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-25-chloro-16-methyl-17-[[2-[2-[(5S)-9-oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-1H-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0626] 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-16,25-dimethyl-12,15,18-trioxo-17-[[2-[2-oxo-2-(8-oxo-2,6,9-triazaspiro[4.5]decan-2-yl)ethyl]-1H-indol-3-yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0627] 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-16,25-dimethyl-17-[[2-[2-(9-methyl-8-oxo-2,6,9-triazaspiro[4.5]decan-2-yl)-2-oxo-ethyl]-1H-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0628] 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-16,25-dimethyl-12,15,18-trioxo-17-[[2-[2-oxo-2-[(5R)-1,7-diazaspiro[4.4]nonan-7-yl]ethyl]-1H-indol-3-yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0629] 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-16,25-dimethyl-12,15,18-trioxo-17-[[2-[2-oxo-2-[(5S)-1,7-diazaspiro[4.4]nonan-7-yl]ethyl]-1H-indol-3-yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0630] 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-16,25-dimethyl-12,15,18-trioxo-17-[[2-[2-oxo-2-[2-(trifluoromethyl)piperazin-1-yl]ethyl]-1H-indol-3-yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0631] 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-16,25-dimethyl-12,15,18-trioxo-17-[[2-[2-oxo-2-[3-(trifluoromethyl)piperazin-1-yl]ethyl]-1H-indol-3-yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0632] 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-16,25-dimethyl-17-[[2-[2-(4-oxa-1,8-diazaspiro[5.5]undecan-8-yl)-2-oxo-ethyl]-1H-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0633] 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-16,25-dimethyl-17-[[2-[2-(4-oxa-1,9-diazaspiro[5.5]undecan-9-yl)-2-oxo-ethyl]-1H-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0634] 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-16,25-dimethyl-17-[[2-[2-(8-oxa-2,5-diazaspiro[3.5]nonan-2-yl)-2-oxo-ethyl]-1H-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0635] 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-16,25-dimethyl-17-[[2-[2-[(5R)-6-methyl-9-oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-1H-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;

[0636] 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-16,25-dimethyl-17-[[2-[2-[(5S)-6-methyl-9-oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-1H-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;

[0637] 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-16-methyl-17-[[2-[2-[(5R)-6-methyl-9-oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-1H-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0638] 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-16-methyl-17-[[2-[2-[(5S)-6-methyl-9-oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-1H-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4, 10, 13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa-l (25), 3(8), 4, 6, 21, 23-hexaen-22- yl]benzoic acid;

[0639] 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-17-[[2-[2-(3-carbamoylpiperazin-1-yl)-2-oxo-ethyl]-1H-indol-3-yl]methyl]-16,25-dimethyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0640] 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-17-[[2-[2-(4,7-diazaspiro[2.5]octan-7-yl)-2-oxo-ethyl]-1H-indol-3-yl]methyl]-16,25-dimethyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0641] 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-17-[[2-[2-[(3R)-3-(methoxymethyl)piperazin-1-yl]-2-oxo-ethyl]-1H-indol-3-yl]methyl]-16,25-dimethyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;

[0642] 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-17-[[2-[2-[(3S)-3-(hydroxymethyl)piperazin-1-yl]-2-oxo-ethyl]-1H-indol-3-yl]methyl]-16,25-dimethyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;

[0643] 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-17-[[2-[2-[(3S)-3-(methoxymethyl)piperazin-1-yl]-2-oxo-ethyl]-1H-indol-3-yl]methyl]-16,25-dimethyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;

[0644] 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-17-[[2-[2-[3-(fluoromethyl)piperazin-1-yl]-2-oxo-ethyl]-1H-indol-3-yl]methyl]-16,25-dimethyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa- 1(25), 3(8), 4, 6, 2 l,23-hexaen-22- yl]benzoic acid;

[0645] 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-17-[[2-[2-[3-aminopropyl(2-hydroxyethyl)amino]-2-oxo-ethyl]-1H-indol-3-yl]methyl]-16,25-dimethyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-l (25), 3(8), 4, 6, 2 l,23-hexaen-22- yl]benzoic acid;

[0646] 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-25-chloro-16-methyl-17-[[2-[2-(4-oxa-1,9-diazaspiro[5.5]undecan-9-yl)-2-oxo-ethyl]-1H-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-l (25), 3(8), 4, 6, 2 l,23-hexaen-22- yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-chloro-16-methyl-17-[[2-[2-(8- oxa-2,5-diazaspiro[3.5]nonan-2-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2- thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0647] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-17-[[2-[2-[(3S,4R)-3-amino-4-fluoro-pyrrolidin-l-yl]-2- oxo-ethyl]-lH-indol-3-yl]methyl]-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18-trioxo-2- thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0648] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-17-[[2-[2-[(3S,4R)-3-amino-4-hydroxy-pyrrolidin-l-yl]-2- oxo-ethyl]-lH-indol-3-yl]methyl]-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18-trioxo-2- thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0649] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-17-[[2-[2-[(3S,4S)-3-amino-4-fluoro-pyrrolidin-l-yl]-2- oxo-ethyl]-lH-indol-3-yl]methyl]-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18-trioxo-2- thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0650] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-17-[[2-[2-[(3S,4S)-3-amino-4-hydroxy-pyrrolidin-l-yl]-2- oxo-ethyl]-lH-indol-3-yl]methyl]-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18-trioxo-2- thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0651] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-17-[[2-[2-[2-aminoethyl(2-hydroxyethyl)amino]-2-oxo- ethyl]-lH-indol-3-yl]methyl]-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0652] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-17-[[2-[2-[4-amino-4-(hydroxymethyl)-l-piperidyl]-2- oxo-ethyl]-lH-indol-3-yl]methyl]-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18-trioxo-2- thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0653] 4-[(llS,14S,17S)-17-[[2-[2-[(4aR,7aR)-3,4,4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4-b][l,4]oxazin- 6-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-14-(4-aminobutyl)-l 1 -(3 -aminopropyl)- 16,25- dimethyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;4-[(llS,14S,17S)-17-[[2-[2-[(4aR,7aR)-3,4,4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4-b][l,4]oxazin- 6-yl]-2-oxo-ethyl]- lH-indol-3 -yl]methyl]- 14-(4-aminobutyl)- 11 -(3 -aminopropyl)- 16-methyl- 12, 15,18-tri oxo-2 -thia-4, 10, 13, 16,19-pentazatri cyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0654] 4-[(llS,14S,17S)-17-[[2-[2-[(4aR,7aR)-3,4,4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4-b][l,4]oxazin- 6-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-14-(4-aminobutyl)-l l-(3-aminopropyl)-25- (difluoromethyl)- 16-methyl- 12,15,18-tri oxo-2 -thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0655] 4-[(llS,14S,17S)-17-[[2-[2-[(4aR,7aR)-3,4,4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4-b][l,4]oxazin- 6-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-14-(4-aminobutyl)-ll-(3-aminopropyl)-25-chloro- 16-methyl- 12, 15,18-tri oxo-2 -thia-4, 10, 13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;

[0656] 4-[(llS,14S,17S)-17-[[2-[2-[(4aS,7aS)-3,4,4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4-b][l,4]oxazin- 6-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-14-(4-aminobutyl)-l l-(3-aminopropyl)- 16,25- dimethyl- 12, 15,18-tri oxo-2-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;

[0657] 4-[(llS,14S,17S)-17-[[2-[2-[(4aS,7aS)-3,4,4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4-b][l,4]oxazin- 6-yl]-2-oxo-ethyl]- lH-indol-3 -yl]methyl]- 14-(4-aminobutyl)- 11 -(3 -aminopropyl)- 16-methyl- 12, 15,18-tri oxo-2 -thia-4, 10, 13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;

[0658] 4-[(llS,14S,17S)-17-[[2-[2-[(4aS,7aS)-3,4,4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4-b][l,4]oxazin- 6-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-14-(4-aminobutyl)-l l-(3-aminopropyl)-25- (difluorom ethyl)- 16-methyl- 12,15,18-tri oxo-2 -thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0659] 4-[(llS,14S,17S)-17-[[2-[2-[(4aS,7aS)-3,4,4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4-b][l,4]oxazin- 6-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-14-(4-aminobutyl)-ll-(3-aminopropyl)-25-chloro- 16-methyl- 12, 15,18-tri oxo-2 -thia-4, 10, 13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;

[0660] 4-[(llS,14S,17S)-17-[[cis-2-[2-(3,4,4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4-b][l,4]oxazin-6-yl)-2- oxo-ethyl]-lH-indol-3-yl]methyl]-14-(4-aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl- 12, 15,18-tri oxo-2 -thia-4, 10, 13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;4-[( 11 S, 14S, 17 S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 17-[[2-[2-(9,9-difluoro-2,6- diazaspiro[4.5]decan-2-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16,25-dimethyl-12,15,18- trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;

[0661] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18-trioxo-17- [[2-[2-oxo-2-[(3R)-3-(hydroxymethyl)piperazin-l-yl]ethyl]-lH-indol-3-yl]methyl]-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0662] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-(dimethylamino)-2-oxo- acetyl]-lH-indol-3-yl]methyl]-16,25-dimethyl-12,15,18-trioxo-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0663] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l 1 -(3-aminopropyl)- 16,25-dimethyl- 12, 15,18-trioxo-l 7- [[2-[(3-oxo-2,8-diazaspiro[4.5]decan-2-yl)methyl]-lH-indol-3-yl]methyl]-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0664] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l 1 -(3-aminopropyl)- 16,25-dimethyl- 12, 15,18-trioxo-l 7- [[2-(piperazin- 1 -ylmethyl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0665] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[(dimethylamino)methyl]-lH- indol-3 -yl]methyl]- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0666] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-17-[[2-(aminomethyl)-lH-indol-3-yl]methyl]-l l-(3- aminopropyl)- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0667] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-(3-aminopropyl)-lH-indol-3- yl]methyl]- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0668] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-17-[[2-(4-Aminobutyl)-lH-indol-3-yl]methyl]-l l-(3- aminopropyl)- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0669] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-17-[[2-(2-aminoethyl)-lH-indol-3-yl]methyl]-l l-(3- aminopropyl)- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18-trioxo-17- [[2-(4-piperidylmethyl)-lH-indol-3-yl]methyl]-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0670] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-(azetidin-3-ylmethyl)-lH- indol-3 -yl]methyl]- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0671] 4-[(l IS, 14S,17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 16,25-dimethyl- 12, 15,18-tri oxo-17- [[2-(pyrrolidin-3-ylmethyl)-lH-indol-3-yl]methyl]-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0672] 4-[(l IS, 14S,17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 16,25-dimethyl- 12, 15,18-tri oxo-17- [ [2-( 1,2,3,6-tetrahydropyridin-5-yl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0673] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-(2,5-dihydro-lH-pyrrol-3-yl)- lH-indol-3 -yl]methyl]- 16,25-dimethyl- 12,15,18-tri oxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0674] 4-[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 1 l-(3-aminopropyl)- 17-[(2 -bromo- lH-indol-3-yl)methyl]- 16,25-dimethyl-12,15,18-trioxo-2-thia-4,10,13,16, 19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;

[0675] 4-[(l IS, 14S,17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 16,25-dimethyl- 17-[[2-(l -methyl-4- piperidyl)- lH-indol-3 -yl]methyl]- 12,15,18-tri oxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0676] 4-[(l IS, 14S,17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 16,25-dimethyl- 12, 15,18-tri oxo-17- [ [2- [ 1 -(2,2,2-trifluoroethyl)-4-piperidyl]- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0677] 4-[(l IS, 14S,17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 16,25-dimethyl- 12, 15,18-tri oxo-17- [ [2-( 1,2,3,6-tetrahydropyridin-4-yl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0678] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[l-(2-hydroxyethyl)-4- piperi dy 1 ] - lH-indol-3 -yl]methyl]- 16,25-dimethyl- 12,15,18-tri oxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0679] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[l-(2-methoxyethyl)-4- piperi dy 1 ] - lH-indol-3 -yl]methyl]- 16,25-dimethyl- 12,15,18-tri oxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[l-(2-imidazol-l- ylethoxycarbonyl)-4-piperidyl]-lH-indol-3-yl]methyl]-16,25-dimethyl-12,15,18-trioxo-2- thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[0680] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18-trioxo-17- [[2-[l-(3,3,3-trifluoropropyl)-4-piperidyl]-lH-indol-3-yl]methyl]-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0681] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[l-(2,2-difluoroethyl)-4- piperi dy 1 ] - lH-indol-3 -yl]methyl]- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0682] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[l-(2-fluoroethyl)-4- piperi dy 1 ] - lH-indol-3 -yl]methyl]- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0683] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-[l-(oxetan-3- ylmethyl)-4-piperidyl]- lH-indol-3 -yl]methyl]- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0684] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[l-(2-imidazol-l-ylethyl)-4- piperi dy 1 ] - lH-indol-3 -yl]methyl]- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0685] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-(l-cyclopropyl-4-piperidyl)- lH-indol-3 -yl]methyl]- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0686] 4-[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 1 l-(3-aminopropyl)- 16,25-dimethyl- 12, 15,18-tri oxo-17- [[2-[(2,2,2-trifluoroethylamino)methyl]- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; or a pharmaceutically acceptable salt or stereoisomer thereof.

[0687] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, selected from the group consisting of:

[0688] 4-[(l IS, 14S,17S)- 14-(4- Aminobutyl)- 11 -(3-aminopropyl)-25-chl oro-16-methyl- 12, 15,18-tri oxo- 17-[[2-[(2-oxopyrrolidin- 1 -yl)methyl]- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-[(l- methylpyrazol-3-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0689] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-[(l- methylpyrazol-4-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0690] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-(dimethylamino)-2-oxo- ethyl]-lH-indol-3-yl]methyl]-16,25-dimethyl-12,15,18-trioxo-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; and 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18-trioxo-17- [[2-(4-pyridylmethyl)-lH-indol-3-yl]methyl]-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; or a pharmaceutically acceptable salt or stereoisomer thereof.

[0691] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, which is 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-chloro-16-methyl-12,15,18-trioxo-17-[[2-[(2-oxopyrrolidin-l-yl)methyl]-lH-indol-3-yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0692] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, which is 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)- 16.25-dimethyl-17-[[2-[(l-methylpyrazol-3-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0693] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, which is 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)- 16.25-dimethyl-17-[[2-[(l-methylpyrazol-4-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0694] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, which is 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-(dimethylamino)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16,25-dimethyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0695] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, which is 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18-trioxo-17-[[2-(4-pyridylmethyl)-lH-indol-3-yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0696] In one embodiment, the present invention provides pharmaceutically acceptable salts of the compounds according to formula (I) as described herein, especially hydrochloride salts, more particularly dihydrochloride salts. In a further particular embodiment, the present invention provides compounds according to formula (I) as described herein as free bases or acids.

[0697] In some embodiments, the compounds of formula (I) are isotopically-labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number. Such isotopically-labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of this disclosure. Examples of isotopes that can be incorporated into the compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, such as, but not limited to,2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,31P,32P,35S,18F,36C1,123I, and125I, respectively. Certain isotopically-labeled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.3H, and carbon-14, i.e.,14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. For example, a compound of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.

[0698] Substitution with heavier isotopes, such as deuterium, i.e.2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Therefore, deuterated versions of the compounds disclosed herein are to be understood to be within the scope of the present invention. For example, compounds of formula (I) wherein 1-6 hydrogen atoms, for example 1, 2, 3, 4, 5 or 6 hydrogen atoms, are replaced with deuterium atoms are understood to be within the scope of the present invention.Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the nonlabeled reagent previously employed.

[0699] Manufacturing Processes

[0700] The compounds of the present invention can be prepared by any conventional means. Suitable processes for synthesizing these compounds as well as their starting materials are provided in the schemes below and in the examples. All substituents, in particular R1, R2, R3, R5, R6, R11, R12, R13, m, n, and Y are as defined above unless otherwise indicated. Furthermore, and unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to a person of ordinary skill in organic chemistry.

[0701] 1. General synthesis of the aldehyde intermediate

[0702] The aldehyde intermediate of formula (II) can be prepared following standard methods known in the art, particularly according to methods as described in the examples.

[0703] PG

[0704]

[0705] In compound (II), PG is a suitable amino protecting group, such as 9-fluorenylmethoxy-carbonyl, and X, Y, R1and R2are as defined herein.

[0706] 2. General synthesis of the tripeptide

[0707] The tripeptide of formula (III), wherein R3is as defined herein, can be prepared following standard methods known in the art. PG is a suitable protective group, e. g., 9-fluorenylmethoxycarbonyl, Ra is lower alkyl, preferably methyl or allyl, Rb is tertbutoxycarbonyl or hydrogen, m and n

[0708]

[0709] The tripeptide (III) can for example be synthesized from dipeptide (IV) and N-methyltryptophan derivative (V) as follows:

[0710]

[0711] a) In the first step, dipeptide (IV) is reacted with N-methyltryptophan derivative (V) in an amide coupling reaction, using reagents and methods known in the art. For instance, the reaction is performed in the presence of N, N’-diisopropylcarbodiimide and either l-hydroxy-7-azabenzotriazole or 2-hydroxypyridine-N-oxide in a suitable solvent, e. g., dichloromethane, tetrahydrofuran, tert-butyl-m ethyl ether, or N, N-dimethylacetamide, at temperatures between -40°C and + 40°C.

[0712] b) In the second step, the protective group (PG) is removed, using methods and reagents known in the art. Suitable reagents for the deprotection reaction are bases such as with a base, preferably a primary or amine such as diethylamine, dicyclohexylamine or tert-amylamine, and the reaction is performed in a suitable solvent, e. g., acetonitrile, at temperatures between -40°C and +50°C. After completion of this step, In a particular embodiment, the N-protected dipeptides are protected with 9-fluorenylmethyloxy carbonyl.

[0713] Dipeptides (IV) are either commercially available or can be produced using procedures known in the art.

[0714] N-Methyltry ptophan derivatives (V) can be produced following standard methods known in the art, particularly according to methods as described in the examples.3. General procedure for the assembly of macrocyclic intermediate (VIII)

[0715] The intermediates of formula (VIII) can be obtained, for example starting from the compounds of formula (II) and of formula (III) according to Scheme 1. PG is a protective group, e. g., 9-fluorenylmethoxycarbonyl, Rais lower alkyl, preferably methyl or allyl, Rbis tert-butoxycarbonyl or hydrogen, m, n, Y, R1, R2and R3are as defined herein.

[0716] Scheme 1

[0717] Step a

[0718] Step b Step c

[0719]

[0720] (VII) (VIII)

[0721] In scheme 1, step a, aldehyde of formula (II) is coupled with the tripeptide of formula (III) in a reductive amination reaction, producing intermediate (VI). This reaction is performed e. g., in the presence of a suitable reducing agent, e. g., sodium cyanoborohydride or sodium triacetoxyborohydride, in a solvent like toluene or dichloromethane, in the presence of a carboxylic acid selected from acetic acid and propionic acid, at temperatures between 0°C and 50°C.In scheme 1, step b, the amine protective group (PG) and the ester are removed, using methods and reagents known in the art, producing intermediate (VII). In the case where Rais allyl, the reaction can be accomplished in the presence of a palladium catalyst, e. g., tetrakis(triphenylphosphine)palladium(0) and abase, e. g., diethylamine, in a solvent such as acetonitrile, at temperatures between 0°C and 50°C. In the case where Rais methyl, the reaction can be accomplished in the presence of lithium bromide and a base, e. g., diethylamine, in a solvent such as acetonitrile, at temperatures between 0°C and 80°C.

[0722] In scheme 1, step c, intermediate of formula (VIII) is finally obtained through cyclisation of intermediate (VII) using methods and reagents known in the art. For instance, the reaction is performed in the presence of coupling reagents such as l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or carbonyldiimidazole, or N, N’ -diisopropylcarbodiimide and l-hydroxy-7-azabenzotriazole, or 1 -hydroxybenzotriazole and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, in a solvent such as dichloromethane of N, N-dimethylformamide, at temperatures between -20°C and +40°C.

[0723] 4. General procedure for the installation of the carboxylic acid subunit

[0724] Intermediates of formula (VIII) in which R2is as defined before except that R2is not a halogen, are represented by general structure (Vlllb). Alternatively to scheme 1, intermediates (Vlllb) can also be produced from intermediate of formula (Villa) as shown in scheme 2. In scheme 2, Rbis tert-butoxycarbonyl or hydrogen, m, n, R1, R3, R5, R6, Y, are as defined before. Hal is a halogen, preferably Br or I.

[0725] Scheme 2

[0726]

[0727] (Vina) (vmb)In scheme 2, halo-macrocycle (Villa) is reacted with boronic acid (IXa) or dioxoborolane (IXb) to produce compounds of formula (Vlllb). Particular, yet non-limiting examples of protected carboxylic acids are alkyl esters, such as methyl ester and tert-butyl ester.

[0728] R5'

[0729] R5

[0730] OH

[0731]

[0732] (IXa) (IXb)

[0733] The reaction is performed in the presence of a suitable palladium catalyst, e. g., tetrakis(triphenylphosphine)palladium(0), [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), cataCXiumA-Pd-G3 or bis(tri-tert-butylphosphine)palladium(0), in a solvent such as water, 1,4-dioxane, toluene, N, N-dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran or mixtures thereof, in the presence of a base, e. g., sodium carbonate or potassium phosphate, at temperatures between 20°C and 150°C, optionally under microwave irradiation.

[0734] The intermediates of formula (Villa) can be prepared following standard methods known in the art, particularly according to methods as described in the examples.

[0735] 5. General procedure for the installation of the carboxamide subunit

[0736] Intermediates of formula (VIII) in which R3is Ci-6-alkyl-CONR1'R12or -CH=CH-CONR11R12, are represented by general structure (Ville). Alternatively to scheme 1, intermediates (Ville) can also be produced from intermediate of formula (VIIIc) as shown in scheme 2. In scheme 3, Rbis tert-butoxycarbonyl or hydrogen, m, n, R1, R2, R11, R12, R13, and Y are as defined before, L’ is -(CH2)I-6- or -CH=CH-

[0737] Scheme 3Step a

[0738] (vnic) (vind)

[0739]

[0740] (Vine)

[0741] In Scheme 3, step a, the ester group in intermediate (VIIIc) is hydrolyzed, producing carboxylic acid (Vllld). This reaction is performed in the presence of a base, e. g., lithium hydroxide or sodium hydroxide, in a solvent, e. g., water, methanol, tetrahydrofuran, or mixtures thereof, at temperatures between 0°C and 60°C.

[0742] In Scheme 3, step b, the carboxylic acid is reacted with a suitable amine of formula HN(Rn)(R12), producing amide derivative (Ville). This reaction is performed in the presence of a suitable coupling reagent, e. g., O-(7-azabenzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate or carbonyldiimidazole, optionally in the presence of a base, e. g., N, N-diisopropylethylamine, in a suitable solvent, e. g., dichloromethane of N, N-dimethylformamide, at temperatures between 0°C and 40°C.

[0743] The aldehyde intermediate of formula (VIIIc) can be prepared following standard methods known in the art, particularly according to methods as described in the examples.

[0744] 6. General procedure for the cleavage of the protective groupsIn scheme 4, the protecting groups in intermediate (VIII) are cleaved using methods and reagents known in the art, producing compounds of general formula (I). Rbis tertbutoxycarbonyl or hydrogen, R1, R2, R3and Y are as defined before. For instance, a global deprotection can be performed using hydrochloric acid in a suitable solvent or solvent mixture, e. g., 1,4-dioxane, or water / tetrahydrofuran, at temperatures between 0°C and 60°C.

[0745] Scheme 4

[0746]

[0747] Alternatively, the protective groups can be cleaved using trifluoroacetic acid in dichloromethane at temperatures between 0°C and 50°C, followed by evaporation of the solvent and hydrolysis in water or aqueous hydrochloric acid at room temperature. By this sequence, for example the following protecting groups may be removed:

[0748] • a tert-butoxycarbonyl group on the indole nitrogen (in the case where Rbis tertbutoxycarbonyl)

[0749] • the two tert-butoxycarbonyl groups at the aminoalkyl subunits

[0750] • a tert-butyl ester at R2

[0751] In a particular embodiment, where the R2substituent of intermediate (VIII) is contains a methyl ester group, intermediate (VIII) is first hydrolyzed with a base, e. g., sodium hydroxide, in a suitable solvent mixture, e. g., water / tetrahydrofuran or water / ethanol, at temperatures between 20°C and 100°C. This procedure also cleaves the tert-butoxy carbonyl group from the indole nitrogen. In a second step, the remaining protecting groups are cleaved using hydrochloric acid in a suitable solvent mixture, e. g., water / tetrahydrofuran, at temperaturesbetween 0°C and 50°C. By this sequence of deprotection reactions compounds of formula (I) are produced.

[0752] In one aspect, the present invention provides a process of manufacturing a compound of formula (I) described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the process is as described in any one of schemes 1 to 4.

[0753] In one aspect, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, when manufactured according to any one of the processes described herein.

[0754] Pharmaceutical Compositions

[0755] Another aspect of the invention provides pharmaceutical compositions or medicaments comprising the compounds of the invention and a therapeutically inert carrier, diluent or pharmaceutically acceptable excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments.

[0756] Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.

[0757] The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0758] In a preferred embodiment, there is provided a pharmaceutical composition comprising one or more compounds of the invention, wherein said pharmaceutical composition is suitable for intravenous administration.

[0759] The compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may comprisecomponents conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents, antioxidants, and further active agents. They can also comprise still other therapeutically valuable substances.

[0760] A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel H. C. et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, Philadelphia; Gennaro A. R. et al, Remington: The Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe R. C, Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

[0761] The dosage at which compounds of the invention can be administered can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of intravenous administration a daily dosage of about 1 to 2000 mg per person of a compound of general formula (I) should be appropriate, although the above upper limit can also be exceeded when necessary.

[0762] An example of a suitable intravenous dosage form is a sterile aqueous solution comprising about 1 mg to about 1000 mg of a compound of the invention. Such a sterile aqueous solution for intravenous administration may be obtained e.g. by dissolving about 1 mg to about 1000 mg of a parent compound of the invention in sterile water for injection (SWFI, e.g. about 50 mL) and adjusting the pH to 4-8, preferably around 5 by addition of aqueous hydrochloric acid solution. Alternatively, about 1 mg to about 1000 mg of a pharmaceutically acceptable salt of a compound of the invention, for example of a hydrochloric acid salt, may be dissolved in SWFI, followed by adjusting the pH to 4-8, preferably around 5 by addition of aqueous sodium hydroxide solution. The procedure is completed by terminal sterilisation using methods known in the art. In some instances, it may be necessary to add a stabilizer to the final solution in order to prevent APIdecomposition over time. A suitable stabilizer may be methionine. An exemplary, yet nonlimiting intravenous dosage form is as follows:

[0763] Component Amount Function

[0764] API (free base) 1.043 mmol API

[0765] HCI QS to pH 5.3

[0766] Methionine 196,9 mg Stabilizer

[0767] Water for Injection 33 mL Solvent

[0768]

[0769] The sterile aqueous solution may need to be diluted with SWFI prior to intravenous administration. The SWFI may contain 5-10% wt / wt of dextrose and / or 0.9% wt / wt of sodium chloride.

[0770] In one aspect, the present invention provides an aqueous pharmaceutical composition comprising:

[0771] (i) a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof; and

[0772] (ii) methionine.

[0773] An example of an aerosol formulation can be prepared by dissolving the compound, for example 10 to 100 mg, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such as sodium chloride, if desired. The solution may be filtered, e.g., using a 0.2 μm filter, to remove impurities and contaminants.

[0774] Uses

[0775] The compounds of the present invention exhibit potent and selective antibacterial activity against members of the baumannii–calcoaceticus complex of opportunistic bacterial pathogens. Thus, the compounds of the present invention can be used, either alone or in combination with other drugs, for the treatment of diseases caused by infections with members of said ABC complex of pathogens.

[0776] In one aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, for use as a therapeutically active substance, in particular for use as an antibiotic.In one aspect, the present invention provides a method for the treatment of diseases caused by infections with members of the A. baumannii–calcoaceticus complex of pathogens in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof

[0777] In one embodiment, said diseases caused by infections with members of the A. baumannii–calcoaceticus complex of pathogens are selected from bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection.

[0778] Members of the A. baumannii–calcoaceticus complex of pathogens are notorious for causing invasive infections in hospitalized patients and patients with critical illness, most commonly hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP) and / or bloodstream infections (BSI). Thus, in a preferred embodiment, said diseases caused by infections with members of the ABC complex of pathogens are selected from HABP, VABP and / or BSI.

[0779] In one embodiment, said member from the A. baumannii–calcoaceticus complex of pathogens is multi drug resistant (MDR).

[0780] In one embodiment, said member from the A. baumannii–calcoaceticus complex of pathogens is Acinetobacter baumannii.

[0781] In a preferred embodiment, said member from the A. baumannii–calcoaceticus complex of pathogens is carbapenem-resistant baumannii (CRAB).

[0782] In one embodiment, said member from the A. baumannii–calcoaceticus complex of pathogens is colistin-resistant and / or polymyxin B-resistant.

[0783] In a preferred embodiment, said member from the A. baumannii–calcoaceticus complex of pathogens is colistin-resistant and / or polymyxin B-resistant CRAB.

[0784] In one embodiment, said member from the A. baumannii–calcoaceticus complex of pathogens is MDR Acinetobacter baumannii.

[0785] In one embodiment, said member from the A. baumannii–calcoaceticus complex of pathogens is colistin-resistant and / or polymyxin B-resistant Acinetobacter baumannii.In one embodiment, said subject is a critically ill hospitalized subject with limited treatment options.

[0786] In one embodiment, the present invention provides a method for the treatment of HABP, VABP and / or BSI caused by infections with colistin-resistant and / or polymyxin B-resistant Acinetobacter baumannii in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof

[0787] In one embodiment, the present invention provides a method for the treatment of HABP, VABP and / or BSI caused by infections with colistin-resistant and / or polymyxin B-resistant Acinetobacter baumannii in a critically ill hospitalized subject with limited treatment options, comprising administering to the critically ill hospitalized subject with limited treatment options a therapeutically effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof

[0788] In one aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, for use in a method of treatment described herein.

[0789] In one aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, in a method of treatment described herein.

[0790] In one aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, for the manufacture of a medicament for the treatment of diseases caused by bacterial infections as described herein.

[0791] Numbered Clauses

[0792] The invention is further described by the following numbered clauses:

[0793] 1. A compound of formula (I)

[0794]

[0795] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0796] Y is CH or N;

[0797] A is selected from the group consisting of phenyl, pyridyl, and thienyl;

[0798] B and C are each independently selected from the group consisting of:

[0799] (i) 5- to 14-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon;

[0800] (ii) Ce-io-aryl;

[0801] (iii) 3- to 14-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon; and

[0802] (iv) C3-10-cycloalkyl;

[0803] m is an integer selected from the group consisting of 1, 2, and 3;

[0804] n is an integer selected from the group consisting of 1, 2, and 3;

[0805] p is an integer selected from the group consisting of 0, 1, and 2;

[0806] L is selected from the group consisting of a covalent bond, –CH2–, –(CH2)2– and –C1-6-alkyl-CO–*; wherein the asterisk indicates the point of attachment of L to ring B;

[0807] L1is selected from the group consisting of a covalent bond, –CH2–, –(CH2)2– and –COO–(CH2)p–*; wherein the asterisk indicates the point of attachment of L1to ring C;

[0808] R1is selected from the group consisting of hydrogen, halogen, Ci-6-alkyl, amino-C1-6-alkyl, Ci-6-alkoxy, halo-Ci-6-alkyl, halo-Ci-6-alkoxy, Cs-io-cycloalkyl, Ci-6-alkyl-O- CH2-, and C3-io-cycloalkyl-0-CH2-;R4

[0809] ( A )

[0810] R2is halogen or a group

[0811]

[0812] x;

[0813] R3is selected from the group consisting of halogen, Ci-6-alkyl-COR9, C2-6-alkenyl- R6

[0814]

[0815] COR10, C1-6-alkyl-NR13R14, -CO-CO-NR15R16, and a group;

[0816] R4is selected from the group consisting of hydrogen, halogen, NH2, COOH, SO2OH, and lH-tetrazol-5-yl;

[0817] R5is selected from the group consisting of hydrogen, halogen, and Ci-6-alkyl;

[0818] R6is selected from the group consisting of hydrogen, halogen, Ci-6-alkyl, Ci-6-alkoxy, amino-Ci-6-alkyl, hydroxy-Ci-6-alkyl, halo-Ci-6-alkyl, Ci-6-alkoxy-Ci-6-alkyl, NH2,

[0819]

[0820] OH, oxo, COOR17, -CO-NH2, -CO-NH-Ci-6-alkyl, and a group;

[0821] R7is selected from the group consisting of hydrogen, NH2, halogen, and Ci-6-alkyl; R8is selected from the group consisting of hydrogen and cyano;

[0822] R9and R10are selected from the group consisting of OH2NR11R12, and Ci-6-alkoxy;

[0823] R11and R12are each independently selected from the group consisting of hydrogen, C1-6- alkyl, hydroxy-Ci-6-alkyl, and amino-Ci-6-alkyl;

[0824] R13and R14are each independently selected from the group consisting of hydrogen, C1-6- alkyl, and halo-Ci-6-alkyl;

[0825] R15and R16are each independently selected from the group consisting of hydrogen and Ci- 6-alkyl; and

[0826] R17is selected from the group consisting of hydrogen and Ci-6-alkyl

[0827] 2. The compound of formula (I) according to clause 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein when R2is halogen or R4is hydrogen, halogen or NH2, then R3is Ci-6-alkyl-COR9and R9is OH.3. The compound of formula (I) according to clause 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Y is N.

[0828] 4. The compound of formula (I) according to any one of clauses 1 to 3, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of formula (I) is a compound of formula (la):

[0829]

[0830] (la).

[0831] 5. The compound of formula (I) according to any one of clauses 1 to 4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1is selected from the group consisting of hydrogen, halogen, Ci-6-alkyl, and halo-Ci-6-alkyl.

[0832] 6. The compound of formula (I) according to any one of clauses 1 to 4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1is selected from the group consisting of hydrogen, fluoro, chloro, methyl, and difluoromethyl.

[0833] 7. The compound of formula (I) according to any one of clauses 1 to 4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1is selected from the group consisting of halogen and Ci-6-alkyl.

[0834] 8. The compound of formula (I) according to any one of clauses 1 to 4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1is selected from the group consisting of chloro and methyl.

[0835] 9. The compound of formula (I) according to any one of clauses 1 to 8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0836] A is selected from the group consisting of phenyl and pyridyl;

[0837]

[0838] R2is halogen or a group

[0839] R4is selected from the group consisting of hydrogen, halogen, NH2, and COOH; and R5is hydrogen.

[0840] The compound of formula (I) according to any one of clauses 1 to 8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0841] A is selected from the group consisting of phenyl and pyridyl;

[0842]

[0843] R2is bromo or a group

[0844] R4is selected from the group consisting of hydrogen, fluoro, NH2, and COOH; and R5is hydrogen.

[0845] The compound of formula (I) according to any one of clauses 1 and 3 to 8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0846] A is phenyl;

[0847] R1

[0848] R2is a group

[0849]

[0850] R4is COOH; and

[0851] R5is hydrogen.

[0852] The compound of formula (I) according to any one of clauses 1 and 3 to 8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0853] O

[0854] R2is a group

[0855]

[0856] The compound of formula (I) according to any one of clauses 1 to 12, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0857] B is selected from the group consisting of:

[0858] (i) 5- to 14-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon;

[0859] (ii) Ce-io-aryl;

[0860] (iii) 3- to 14-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon; and

[0861] (iv) C3-10-cycloalkyl;

[0862] C is selected from the group consisting of:

[0863] (i) 5- to 14-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon;

[0864] (ii) 3- to 14-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon; and

[0865] (iii) C3-10-cycloalkyl;

[0866] P is 2;

[0867] L is selected from the group consisting of a covalent bond, -CH2-, and

[0868] -Ci-6-alkyl-CO-*; wherein the asterisk indicates the point of attachment of L to ring B;

[0869] L1is selected from the group consisting of a covalent bond, -CH2-, -(CH2)2- and -COO-(CH2)p-*; wherein the asterisk indicates the point of attachment of L1to ring C;

[0870] R3is selected from the group consisting of halogen, Ci-6-alkyl-COR9, C2-6-alkenyl-

[0871]

[0872] COR10, C1-6-alkyl-NR13R14, -CO-CO-NR15R16, and a group;

[0873] R6is selected from the group consisting of hydrogen, halogen, Ci-6-alkyl, Ci-6-alkoxy, amino-Ci-6-alkyl, hydroxy-Ci-6-alkyl, halo-Ci-6-alkyl, Ci-6-alkoxy-Ci-6-alkyl, NH2,

[0874]

[0875] OH, oxo, COOR17, -CO-NH2, -CO-NH-Ci-6-alkyl, and a groupR7is selected from the group consisting of hydrogen, NH2, halogen, and Ci-6-alkyl; R8is selected from the group consisting of hydrogen and cyano;

[0876] R9is selected from the group consisting of OH2NR11R12, and Ci-6-alkoxy;

[0877] R10is selected from the group consisting of OH2NR11R12, and Ci-6-alkoxy;

[0878] R11is selected from the group consisting of Ci-6-alkyl and hydroxy-Ci-6-alkyl;

[0879] R12is selected from the group consisting of Ci-6-alkyl and amino-Ci-6-alkyl;

[0880] R13is selected from the group consisting of hydrogen, Ci-6-alkyl, and halo-Ci-6-alkyl; R14is selected from the group consisting of hydrogen and Ci-6-alkyl;

[0881] R15is Ci-6-alkyl;

[0882] R16is Ci-6-alkyl; and

[0883] R17is selected from the group consisting of hydrogen and Ci-6-alkyl.

[0884] The compound of formula (I) according to any one of clauses 1 to 12, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0885] B is selected from the group consisting of cyclopropyl, azetidinyl, imidazolyl, thienyl, thiazolyl, thiadiazolyl, piperidyl, oxopyrrolidinyl, pyridyl, pyrazolyl, phenyl, oxohexahydropyrimidinyl, oxopiperidyl, pyridazinyl, l,l-dioxo-l,2-thiazolidinyl, 1,1-dioxothianyl, pyrrolidinyl, piperazinyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3-oxo-1H-isobenzofuranyl, 3-oxoindanyl, 5-azaspiro[2.4]heptanyl, 4,7- diazaspiro[2.5]octanyl, 3-oxoisoindolinyl, l,l-dioxo-2,3-dihydrobenzothiophenyl, l,7-diazaspiro[4.4]nonanyl, l,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridinyl, 2,5- dihydro-lH-pyrrolyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridine, 1,2- dihydropyridine, lH-l,2,4-triazolyl, 1,2,5-oxadiazolyl, triazolyl, pyrrolyl, 3,8- diazabicyclo[3.2.1]octanyl, 2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4-b][1,4]oxazinyl, 8-oxa-2,5-diazaspiro[3.5]nonanyl, 2,8-diazaspiro[4.5]decanyl, 2,8- diazaspiro[4.5]decan-3-onyl, 9-oxa-2,6-diazaspiro[4.5]decanyl, 4-oxa-l,9- diazaspiro[5.5]undecanyl, 4-oxa-l,8-diazaspiro[5.5]undecanyl, 2,6,9- triazaspiro[4.5]decanyl, 2,6,9-triazaspiro[4.5]decan-8-onyl, 2,6- diazaspiro[4.5]decanyl, and 2,3,4,4a,5,6,7,7a-octahydro-1H-pyrrolo[3,4-b]pyridinyl; C is selected from the group consisting of cyclopropyl, oxetanyl, and imidazolyl;

[0886] P is 2;

[0887] L is selected from the group consisting of a covalent bond, -CH2-, and -CH2-CO-*;

[0888] wherein the asterisk indicates the point of attachment of L to ring B;L1is selected from the group consisting of a covalent bond, -CH2-, -(CH2)2-, and -COO-(CH2)p-*; wherein the asterisk indicates the point of attachment of L1to ring C;

[0889] R3is selected from the group consisting of bromo, -CH2-COR9, -CH=CH-COR10,

[0890] B

[0891]

[0892] R8

[0893] Ci-4-alkyl-NR13R14, -CO-CO-NR15R16, and a group

[0894] R6is selected from the group consisting of hydrogen, fluoro, methyl, methoxy, aminomethyl, 2-hydroxyethyl, hydroxymethyl, fluoromethyl, trifluoromethyl, 2- fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, methoxymethyl, 2-methoxyethyl, NH2, OH, oxo, COOR17, -CO-NH2, and -CO-NH- methyl

[0895]

[0896] methyl;, and a group

[0897] R7is selected from the group consisting of hydrogen, NH2, fluoro, and methyl;

[0898] R8is selected from the group consisting of hydrogen and cyano;

[0899] R9is selected from the group consisting of OH2NR11R12, and ethoxy;

[0900] R10is selected from the group consisting of OH2NR11R12, and ethoxy;

[0901] R11and R12are both methyl; or R11is 2-hydroxyethyl and R12is selected from the group consisting of 2-aminoethyl and 3-amino-n-propyl;

[0902] R13is selected from the group consisting of hydrogen, methyl, and 2,2,2-trifluoroethyl; R14is selected from the group consisting of hydrogen and methyl;

[0903] R15is methyl;

[0904] R16is methyl; and

[0905] R17is selected from the group consisting of hydrogen and methyl.

[0906] The compound of formula (I) according to any one of clauses 1 to 12, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0907] B is selected from the group consisting of:

[0908]

[0909]

[0910] wherein a wavy line indicates the point of attachment of ring B to linker L;

[0911] L is selected from the group consisting of a covalent bond, -CH2-, and -CH2-CO-*;

[0912] wherein the asterisk indicates the point of attachment of L to ring B;

[0913] R3is selected from the group consisting of-CH2-COR9, -CH=CH-COR10, and a group

[0914]

[0915] R6is selected from the group consisting of hydrogen, methyl, methoxy, aminomethyl, NH2, and -CO-NH-methyl;

[0916] R7is selected from the group consisting of hydrogen, fluoro, and methyl;

[0917] R8is selected from the group consisting of hydrogen and cyano;

[0918] R9is selected from the group consisting of OH and NR11R12;

[0919] R10is NR11R12;

[0920] R11and R12are both methyl; or R11is 2-hydroxyethyl and R12is 3-amino-n-propyl.

[0921] The compound of formula (I) according to any one of clauses 1 to 12, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0922] B is selected from the group consisting of:

[0923] (i) 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, the remaining atoms being carbon; and

[0924] (ii) 3- to 10-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, the remaining atoms being carbon;

[0925] L is selected from the group consisting of a covalent bond, -CH2-, and

[0926] -CH2-CO-*; wherein the asterisk indicates the point of attachment of L to ring B;R3is selected from the group consisting of Ci-6-alkyl-COR9and a group

[0927]

[0928] R6is selected from the group consisting of hydrogen, oxo, Ci-6-alkyl, and halo-Ci-6- alkyl;

[0929] R7is hydrogen;

[0930] R8is hydrogen;

[0931] R9is NR11R12;

[0932] R11is Ci-6-alkyl; and

[0933] R12is Ci-6-alkyl.

[0934] 17. The compound of formula (I) according to any one of clauses 1 to 12, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0935] B is selected from the group consisting of pyrrolidinyl, oxopyrrolidinyl, piperidyl, pyridyl, pyrazolyl, 2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4-b][1,4]oxazinyl, 1,7- diazaspiro[4.4]nonanyl, and 9-oxa-2,6-diazaspiro[4.5]decanyl;

[0936] L is selected from the group consisting of a covalent bond, -CH2-, and

[0937] -CH2-CO-*; wherein the asterisk indicates the point of attachment of L to ring B;

[0938]

[0939] R3is selected from the group consisting of-CH2-COR9and a group

[0940] R6is selected from the group consisting of hydrogen, oxo, methyl, and 2,2- difluoroethyl;

[0941] R7is hydrogen;

[0942] R8is hydrogen;

[0943] R9is NR11R12;

[0944] R11is methyl; and

[0945] R12is methyl.18. The compound of formula (I) according to any one of clauses 1 to 12, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0946]

[0947] wherein a wavy line indicates the point of attachment of ring B to linker L;

[0948] L is selected from the group consisting of a covalent bond, -CH2-, and

[0949] -CH2-CO-*; wherein the asterisk indicates the point of attachment of L to ring B;

[0950] R6( )

[0951]

[0952] R3is selected from the group consisting of-CH2-COR9and a group

[0953] R6is selected from the group consisting of hydrogen, methyl, and 2,2-difluoroethyl; R7is hydrogen;

[0954] R8is hydrogen;

[0955] R9is NR11R12;

[0956] R11is methyl; and

[0957] R12is methyl.

[0958] The compound of formula (I) according to any one of clauses 1 to 12, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0959] B is a 7- to 14-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon;

[0960] L is selected from the group consisting of a covalent bond, -CH2-, and

[0961] -Ci-6-alkyl-CO-*; wherein the asterisk indicates the point of attachment of L to ring B;R3

[0962]

[0963] R6is selected from the group consisting of hydrogen, halogen, Ci-6-alkyl, Ci-6-alkoxy, amino-Ci-6-alkyl, hydroxy-Ci-6-alkyl, halo-Ci-6-alkyl, Ci-6-alkoxy-Ci-6-alkyl, NH2,

[0964]

[0965] OH, oxo, COOR17, -CO-NH2, -CO-NH-Ci-6-alkyl, and a group

[0966] R7is selected from the group consisting of hydrogen, NH2, halogen, and Ci-6-alkyl; R8is selected from the group consisting of hydrogen and cyano.

[0967] The compound of formula (I) according to clause 19, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0968] B is a 7- to 14-membered fused bicyclic or spirocyclic bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon; L is -Ci-6-alkyl-CO-*; wherein the asterisk indicates the point of attachment of L to

[0969]

[0970] R6is selected from the group consisting of hydrogen, halogen, Ci-6-alkyl, NH2, and oxo; R7is hydrogen, halogen, and Ci-6-alkyl; and

[0971] R8is hydrogen.

[0972] The compound of formula (I) according to clause 20, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0973] B is selected from the group consisting of 5-azaspiro[2.4]heptanyl, 4,7- diazaspiro[2.5]octanyl, 2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4-b][1,4]oxazine, 8- oxa-2,5-diazaspiro[3.5]nonanyl, l,7-diazaspiro[4.4]nonanyl, 2,8- diazaspiro[4.5]decanyl, 2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4-b][1,4]oxazinyl, 9-oxa-2,6-diazaspiro[4.5]decanyl, 4-oxa-l,9-diazaspiro[5.5]undecanyl, 4-oxa-l,8- diazaspiro[5.5]undecanyl, 2,6,9-triazaspiro[4.5]decanyl, 2,6-diazaspiro[4.5]decanyl, and 2,3,4,4a,5,6,7,7a-octahydro-1H-pyrrolo[3,4-b]pyridine;

[0974] L is -CH2-CO-*; wherein the asterisk indicates the point of attachment of L to ring B;

[0975] B

[0976]

[0977] R8

[0978] R3is a group

[0979] R6is selected from the group consisting of hydrogen, fluoro, methyl, NH2, and oxo; R7is hydrogen, fluoro, and methyl; and

[0980] R8is hydrogen.

[0981] The compound of formula (I) according to any one of clauses 1 to 21, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m is 2 and n is 3.

[0982] The compound of formula (I) according to clause 1 or 4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0983] Y isN;

[0984] A is selected from the group consisting of phenyl and pyridyl;

[0985] B is selected from the group consisting of:

[0986] (i) 5- to 14-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon;

[0987] (ii) Ce-io-aryl;

[0988] (iii) 3- to 14-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon; and

[0989] (iv) C3-10-cycloalkyl;

[0990] C is selected from the group consisting of:

[0991] (i) 5- to 14-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon;

[0992] (ii) 3- to 14-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon; and

[0993] (iii) C3-10-cycloalkyl;

[0994] is 2;is 3;

[0995] is 2;

[0996] L is selected from the group consisting of a covalent bond, -CH2-, and -Ci-6-alkyl- CO-*; wherein the asterisk indicates the point of attachment of L to ring B;

[0997] L1is selected from the group consisting of a covalent bond, –CH2–, –(CH2)2– and –COO–(CH2)p–*; wherein the asterisk indicates the point of attachment of L1to ring C;

[0998] R1is selected from the group consisting of hydrogen, halogen, Ci-6-alkyl, and halo-Ci-6- alkyl;

[0999] R1

[1000] R2is halogen or a group

[1001]

[1002] R3is selected from the group consisting of halogen, Ci-6-alkyl-COR9, C2-6-alkenyl-

[1003] B

[1004]

[1005] COR10, C1-6-alkyl-NR13R14, -CO-CO-NR15R16, and a group J8R4is selected from the group consisting of hydrogen, halogen, NH2, and COOH;

[1006] R5is hydrogen;

[1007] R6is selected from the group consisting of hydrogen, halogen, Ci-6-alkyl, Ci-6-alkoxy, amino-Ci-6-alkyl, hydroxy-Ci-6-alkyl, halo-Ci-6-alkyl, Ci-6-alkoxy-Ci-6-alkyl, NH2,

[1008]

[1009] OH, oxo, COOR17, -CO-NH2, -CO-NH-Ci-6-alkyl, and a group

[1010] R7is selected from the group consisting of hydrogen, NH2, halogen, and Ci-6-alkyl; R8is selected from the group consisting of hydrogen and cyano;

[1011] R9is selected from the group consisting of OH2NR11R12, and Ci-6-alkoxy;

[1012] R10is selected from the group consisting of OH2NR11R12, and Ci-6-alkoxy;

[1013] R11is selected from the group consisting of Ci-6-alkyl and hydroxy-Ci-6-alkyl;

[1014] R12is selected from the group consisting of Ci-6-alkyl and amino-Ci-6-alkyl;

[1015] R13is selected from the group consisting of hydrogen, Ci-6-alkyl, and halo-Ci-6-alkyl;R14is selected from the group consisting of hydrogen and Ci-6-alkyl;

[1016] R15is Ci-6-alkyl;

[1017] R16is Ci-6-alkyl; and

[1018] R17is selected from the group consisting of hydrogen and Ci-6-alkyl.

[1019] 24. The compound of formula (I) according to clause 1 or 4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[1020] Y isN;

[1021] A is selected from the group consisting of phenyl and pyridyl;

[1022] B is selected from the group consisting of cyclopropyl, azetidinyl, imidazolyl, thienyl, thiazolyl, thiadiazolyl, piperidyl, oxopyrrolidinyl, pyridyl, pyrazolyl, phenyl, oxohexahydropyrimidinyl, oxopiperidyl, pyridazinyl, l,l-dioxo-l,2-thiazolidinyl, 1,1-dioxothianyl, pyrrolidinyl, piperazinyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3-oxo- IJT-isobenzofuranyl, 3-oxoindanyl, 5-azaspiro[2.4]heptanyl, 4,7- diazaspiro[2.5]octanyl, 3-oxoisoindolinyl, l,l-dioxo-2,3-dihydrobenzothiophenyl, l,7-diazaspiro[4.4]nonanyl, l,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridinyl, 2,5- dihydro-lH-pyrrolyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridine, 1,2- dihydropyridine, lH-l,2,4-triazolyl, 1,2,5-oxadiazolyl, triazolyl, pyrrolyl, 3,8- diazabicyclo[3.2.1]octanyl, 2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4-b][1,4]oxazinyl, 8-oxa-2,5-diazaspiro[3.5]nonanyl, 2,8-diazaspiro[4.5]decanyl, 2,8- diazaspiro[4.5]decan-3-onyl, 9-oxa-2,6-diazaspiro[4.5]decanyl, 4-oxa-l,9- diazaspiro[5.5]undecanyl, 4-oxa-l,8-diazaspiro[5.5]undecanyl, 2,6,9- triazaspiro[4.5]decanyl, 2,6,9-triazaspiro[4.5]decan-8-onyl, 2,6- diazaspiro[4.5]decanyl, and 2,3,4,4a,5,6,7,7a-octahydro-17 / -pyrrolo[3,4-b]pyridinyl; C is selected from the group consisting of cyclopropyl, oxetanyl, and imidazolyl; m is 2;

[1023] n is 3;

[1024] P is 2;

[1025] L is selected from the group consisting of a covalent bond, -CH2-, and -CH2-CO-*;

[1026] wherein the asterisk indicates the point of attachment of L to ring B;

[1027] L1is selected from the group consisting of a covalent bond, –CH2–, –(CH2)2– and –COO–(CH2)p–*; wherein the asterisk indicates the point of attachment of L1to ring C;R1is selected from the group consisting of hydrogen, fluoro, chloro, methyl, and difluoromethyl;

[1028]

[1029] R2is bromo or a group

[1030] R3is selected from the group consisting of bromo, -CH2-COR9, -CH=CH-COR10,

[1031] B

[1032]

[1033] R8

[1034] Ci-4-alkyl-NR13R14, -CO-CO-NR15R16, and a group

[1035] R4is selected from the group consisting of hydrogen, fluoro, NH2, and COOH;

[1036] R5is hydrogen;

[1037] R6is selected from the group consisting of hydrogen, fluoro, methyl, methoxy, aminomethyl, 2-hydroxyethyl, hydroxymethyl, fluoromethyl, trifluoromethyl, 2- fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, methoxymethyl, 2-methoxyethyl, NH2, OH, oxo, COOR17, -CO-NH2, and -CO-NH-

[1038]

[1039] methyl;, and a group

[1040] R7is selected from the group consisting of hydrogen, NH2, fluoro, and methyl;

[1041] R8is selected from the group consisting of hydrogen and cyano;

[1042] R9is selected from the group consisting of OH2NR11R12, and ethoxy;

[1043] R10is selected from the group consisting of OH2NR11R12, and ethoxy;

[1044] R11and R12are both methyl; or R11is 2-hydroxyethyl and R12is selected from the group consisting of 2-aminoethyl and 3-amino-n-propyl;

[1045] R13is selected from the group consisting of hydrogen, methyl, and 2,2,2-trifluoroethyl; R14is selected from the group consisting of hydrogen and methyl;

[1046] R15is methyl;

[1047] R16is methyl; and

[1048] R17is selected from the group consisting of hydrogen and methyl.The compound of formula (I) according to clause 1 or 4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[1049] Y isN;

[1050] A is phenyl;

[1051] B is selected from the group consisting of:

[1052] (i) 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, the remaining atoms being carbon; and

[1053] (ii) 3- to 10-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, the remaining atoms being carbon;

[1054] m is 2;

[1055] n is 3;

[1056] L is selected from the group consisting of a covalent bond, -CH2-, and

[1057] -CH2-CO-*; wherein the asterisk indicates the point of attachment of L to ring B; R1is selected from the group consisting of halogen and Ci-6-alkyl;

[1058] R4

[1059] ( A )

[1060] R2is a group

[1061]

[1062] ;

[1063] R3is selected from the group consisting of Ci-6-alkyl-COR9and a group

[1064]

[1065] R4is COOH;

[1066] R5is hydrogen;

[1067] R6is selected from the group consisting of hydrogen, oxo, Ci-6-alkyl, and halo-Ci-6- alkyl;

[1068] R7is hydrogen;

[1069] R8is hydrogen;

[1070] R9is NR11R12;

[1071] R11is Ci-6-alkyl; and

[1072] R12is Ci-6-alkyl.The compound of formula (I) according to clause 1 or 4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[1073] Y isN;

[1074] A is phenyl;

[1075] B is selected from the group consisting of pyrrolidinyl, oxopyrrolidinyl, piperidyl, pyridyl, pyrazolyl, 2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4-b][1,4]oxazinyl, 1,7- diazaspiro[4.4]nonanyl, and 9-oxa-2,6-diazaspiro[4.5]decanyl;

[1076] m is 2;

[1077] n is 3;

[1078] L is selected from the group consisting of a covalent bond, -CH2-, and

[1079] -CH2-CO-*; wherein the asterisk indicates the point of attachment of L to ring B; R1is selected from the group consisting of chloro and methyl;

[1080] R4

[1081]

[1082] R3is selected from the group consisting o

[1083]

[1084] f CH2-COR9and a R4is COOH;

[1085] R5is hydrogen;

[1086] R6is selected from the group consisting of hydrogen, oxo, methyl, and 2,2- difluoroethyl;

[1087] R7is hydrogen;

[1088] R8is hydrogen;

[1089] R9is NR11R12;

[1090] R11is methyl; and

[1091] R12is methyl.

[1092] The compound of formula (I) according to clause 1, selected from the group consisting of: 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-chloro-16-methyl-12,15,18- trioxo-17-[[2-[(2-oxopyrrolidin-l-yl)methyl]-lH-indol-3-yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1093] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18- trioxo-17-[[2-[(2-oxopyrrolidin-l-yl)methyl]-lH-indol-3-yl]methyl]-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1094] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-[(l- methylpyrazol-3-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1095] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-[(l- methylpyrazol-4-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1096] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17- [[2-(2-oxo-3-piperidyl)-lH-indol-3-yl]methyl]-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17-[[2-(3-oxo-1H-isobenzofuran-4-yl)-1H-indol-3-yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17-[[2-(3-oxoindan-4-yl)-1H-indol-3-yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17-[[2-(3-thienylmethyl)-1H-indol-3-yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17-[[2-(thiazol-5-ylmethyl)-1H-indol-3-yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17-[[2-[(2-oxopyrrolidin-1-yl)methyl]-1H-indol-3-yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-17-[[2-[(l- methylpyrazol-4-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1097] 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-17-[(2-benzyl-1H-indol-3-yl)methyl]-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-(l,l-dioxo-2,3- dihy drobenzothi ophen-7-yl)-lH-indol-3-yl]methyl]-l 6-methyl-12, 15, 18-tri oxo-2 -thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1098] 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-17-[[2-(1H-imidazol-2-ylmethyl)-1H-indol-3-yl]methyl]-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-17-[[2-(1H-imidazol-4-ylmethyl)-1H-indol-3-yl]methyl]-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-17-[[2-(2-methoxy-6-methyl-phenyl)-1H-indol-3-yl]methyl]-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-17-[[2-(2-methoxyphenyl)-1H-indol-3-yl]methyl]-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-(5-cyano-3-fluoro-2- methoxy-phenyl)-lH-indol-3-yl]methyl]-16-methyl- 12, 15, 18-tri oxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1099] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[(l,l-dioxo-l,2- thiazolidin-2-yl)methyl]-lH-indol-3-yl]methyl]-16-methyl- 12, 15, 18-tri oxo-2 -thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-17-[[2-[2-(dimethylamino)-2-oxo-ethyl]-1H-indol-3-yl]methyl]-16,25-dimethyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-17-[[2-[2-(dimethylamino)-2-oxo-ethyl]-1H-indol-3-yl]methyl]-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-(dimethylamino)-2- oxo-ethyl]-lH-indol-3-yl]methyl]-25-fluoro-16-methyl-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1100] - [( 11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25-(difluorom ethyl)- 16-methyl- 12,15,18-trioxo-17-[[2-[(2-oxopyrrolidin-l-yl)methyl]-lH-indol-3-yl]methyl]-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1101] - [( 11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25-(difluorom ethyl)- 16-methyl- 17-[[2-[(l-methylpyrazol-3-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1102] - [( 11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25-(difluorom ethyl)- 16-methyl- 17-[[2-[(l-methylpyrazol-4-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1103] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-(difluoromethyl)-17-[[2-[2- (dimethylamino)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16-methyl-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1104] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-chloro-16-methyl-17-[[2-[(l- methylpyrazol-3-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1105] 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-25-chloro-16-methyl-17-[[2-[(1-methylpyrazol-4-yl)methyl]-1H-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1106] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-chloro-17-[[2-[2-(dimethylamino)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16-methyl-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1107] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-fluoro-16-methyl-12,15,18-trioxo-17-[[2-[(2-oxopyrrolidin-l-yl)methyl]-lH-indol-3-yl]methyl]-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1108] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-fluoro-16-methyl-17-[[2-[(l-methylpyrazol-3-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1109] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-fluoro-16-methyl-17-[[2-[(l-methylpyrazol-4-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1110] -[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16,25-dimethyl-12,15,18- trioxo- 17-[[2-(4-pyridylmethyl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16,25-dimethyl-12,15,18- trioxo- 17- [ [2-(4-piperi dy 1)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17- [[2-(l,2,5-thiadiazol-3-ylmethyl)-lH-indol-3-yl]methyl]-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17- [[2-(2-oxohexahydropyrimidin-5-yl)-lH-indol-3-yl]methyl]-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17- [ [2-(4-piperi dy 1)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;4-[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 11 -(3-aminopropyl)-16-methyl-12, 15,18-trioxo- 17- [[2-(4-pyridylmethyl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-16-methyl-17-[[2-(1-methyl-2-oxo-3-piperidyl)-1H-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-16-methyl-17-[[2-(2-methyl-3-oxo-isoindolin-4-yl)-1H-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-17-[[2-(1,1-dioxothian-2-yl)-1H-indol-3-yl]methyl]-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-17-[[2-(3-methoxypyridazin-4-yl)-1H-indol-3-yl]methyl]-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-25-(difluoromethyl)-16-methyl-12,15,18-trioxo-17-[[2-(4-piperidyl)-1H-indol-3-yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-25-(difluoromethyl)-16-methyl-12,15,18-trioxo-17-[[2-(4-pyridylmethyl)-1H-indol-3-yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-25-chloro-16-methyl-12,15,18-trioxo-17-[[2-(4-piperidyl)-1H-indol-3-yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-25-chloro-16-methyl-12,15,18-trioxo-17-[[2-(4-pyridylmethyl)-1H-indol-3-yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-25-fluoro-16-methyl-12,15,18-trioxo-17-[[2-(4-piperidyl)-1H-indol-3-yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-25-fluoro-16-methyl-12,15,18-trioxo-17-[[2-(4-pyridylmethyl)-1H-indol-3-yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;2-[3 -[ [( 11 S, 14 S, 17 S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-22-bromo-25-chloro- 16- methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa- l(25),3(8),4,6,21,23-hexaen-17-yl]methyl]-lH-indol-2-yl]acetic acid;

[1111] 2-[3-[[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-chloro-16-methyl- 12,15,18-trioxo-22-(3 -pyridyl)-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-17-yl]methyl]-lH- indol-2-yl]acetic acid;

[1112] 2-[3 -[[(11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-22-(6-amino-3 -pyridyl)-25- chloro- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-17-yl]methyl]-lH- indol-2-yl]acetic acid;

[1113] 2-[3-[[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-chloro-22-(2-fluoro-4- pyridyl)- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-17-yl]methyl]-lH- indol-2-yl]acetic acid;

[1114] 44-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[(E)-3-(dimethylamino)-3-oxo-prop-l-enyl]-lH-indol-3-yl]methyl]-l 6-methyl-12, 15, 18-tri oxo-2 -thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1115] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l 1 -(3-aminopropyl)- 16-methyl-12, 15, 18-trioxo- 17- [[2-(2-oxo-2-piperazin- 1 -yl-ethyl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; trihydrochloride;

[1116] 4-[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 11 -(3-aminopropyl)- 16,25-dimethyl- 12, 15, 18- trioxo- 17-[[2-(2-oxo-2-piperazin-l -yl-ethyl)- lH-indol-3-yl]methyl]-2 -thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1117] 4-[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 11 -(3-aminopropyl)- 16,25-dimethyl- 17-[[2-[2-(4- methylpiperazin-l-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]- 12, 15, 18-tri oxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1118] 4-[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 11 -(3-aminopropyl)- 16-methyl-17-[[2-[2-[4- (methylcarbamoyl)- l-piperidyl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]- 12, 15, 18-tri oxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen- 22-yl]benzoic acid;

[1119] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-(l,7- diazaspiro[4.4]nonan-7-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16-methyl-12,15,18- trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;

[1120] -[(l 1 S, 14S, 17 S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 17-[[2-[2-(2,2- dimethylpiperazin-l-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16-methyl-12,15,18- trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;

[1121] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-[(3R)-3- aminopyrrolidin- 1 -yl]-2-oxo-ethyl]- lH-indol-3 -yl]methyl]- 16-methyl- 12,15,18-trioxo- 2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen- 22-yl]benzoic acid;

[1122] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-[3-aminopropyl(2- hydroxyethyl)amino]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16-methyl-12,15,18-tri oxo-2- thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen- 22-yl]benzoic acid;

[1123] - [( 11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25-(difluorom ethyl)- 16-methyl- 12,15,18-trioxo-17-[[2-(2-oxo-2-piperazin-l-yl-ethyl)-lH-indol-3-yl]methyl]-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1124] - [( 11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25-(difluorom ethyl)- 16-methyl- 17-[[2-[2-(4-methylpiperazin-l-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18- trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;

[1125] -[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 1 l-(3-aminopropyl)-25-chloro-l 6-methyl- 12, 15, 18- trioxo-17-[[2-(2-oxo-2-piperazin-l-yl-ethyl)-lH-indol-3-yl]methyl]-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1126] -[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 11 -(3-aminopropyl)-25-chloro-l 6-methyl- 17-[[2-[2- (4-methylpiperazin-l-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1127] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-fluoro-16-methyl-12,15,18-trioxo-17-[[2-(2-oxo-2-piperazin-l-yl-ethyl)-lH-indol-3-yl]methyl]-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1128] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-fluoro-16-methyl-17-[[2-[2-(4-methylpiperazin-l-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1129] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-17-[[2-[2-(4-amino-l-piperidyl)-2-oxo-ethyl]-lH-indol-3 -yl]methyl]- 11 -(3 -aminopropyl)- 16-m ethyl- 12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1130] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-17-[[2-[2-[4-(aminomethyl)-l-piperidyl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-ll-(3-aminopropyl)-16-methyl-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1131] -[(llS,14S,17S)-17-[[2-[2-[(4aR,7aR)-l,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridin- 6-yl]-2-oxo-ethyl]- lH-indol-3 -yl]methyl]- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 16- methyl-12, 15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[1132] 4-[(11S,14S,17S)-17-[[2-[2-[(4aS,7aS)-1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridin-6-yl]-2-oxo-ethyl]-1H-indol-3-yl]methyl]-14-(4-Aminobutyl)-11-(3-aminopropyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[1133] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-(3,6- diazabicyclo[3.1.1 ]heptan-6-yl)-2-oxo-ethyl]- lH-indol-3 -yl]methyl]- 16-methyl- 12, 15,18-trioxo-2-thia-4,l 0,13, 16,19-pentazatricy clo[l 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;

[1134] -[( 11 S, 14S, 17 S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 17- [ [2- [2-(4,7- diazaspiro[2.5]octan-4-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;

[1135] -[(llS,14S,17S)-17-[[2-[2-[(7R)-7-amino-5-azaspiro[2.4]heptan-5-yl]-2-oxo-ethyl]-lH- indol-3 -yl]methyl]- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 16-m ethyl- 12,15,18-trioxo- 2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen- 22-yl]benzoic acid;

[1136] -[( 11 S, 14S, 17 S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 17-[[2-[2-(5- azaspiro[2.4]heptan-5-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16-methyl-12,15,18- trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;

[1137] -[( 11 S, 14S, 17 S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 17-[[2-[2-(- diazabicyclo[3.2.1]octan-8-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16-methyl-12,15,18- trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;

[1138] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-(4-methoxy carbonyl-1-piperidyl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16-methyl-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1139] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-[(3S)-3- aminopyrrolidin- 1 -yl]-2-oxo-ethyl]- lH-indol-3 -yl]methyl]- 16-methyl- 12,15,18-trioxo- 2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen- 22-yl]benzoic acid;

[1140] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[(E)-2-carboxyvinyl]- lH-indol-3 -yl]methyl]- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-17-[[2-[(E)-3-ethoxy-3-oxo-prop-1-enyl]-1H-indol-3-yl]methyl]-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-17-[[2-(2-ethoxy-2-oxo-ethyl)-1H-indol-3-yl]methyl]-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17- [[2-(2 -pyridylmethyl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17-[[2-(3-pyridylmethyl)-1H-indol-3-yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-17-[[2-[(l- methylimidazol-2-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1141] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-17-[[2-[(3-methyl-4- pyridyl)methyl]- lH-indol-3 -yl]methyl]- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-17-[[2-[(4-methyl- l,2,5-oxadiazol-3-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1142] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17- [(2-tetrahydropyran-4-yl- lH-indol-3 -yl)methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17- [[2-(lH-pyrazol-4-ylmethyl)-lH-indol-3-yl]methyl]-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17- [[2-(lH-pyrrol-3-ylmethyl)-lH-indol-3-yl]methyl]-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-17-[[2-[(l- methylimidazol-4-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1143] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-17-[[2-[(l- methylpyrazol-3-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1144] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-17-[[2-[(l- methyltriazol-4-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1145] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16-methyl-17-[[2-[(2-methyl- l,2,4-triazol-3-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19- pentazatri cyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[(2-cyclopropyl-lH-indol-3- yl)methyl]- 16-m ethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatri cyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-(2-methoxy-3-pyridyl)- lH-indol-3 -yl]methyl]- 16-m ethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatri cyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-(4-carboxyphenyl)-lH- indol-3 -yl]methyl]- 16-m ethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatri cyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17- f[2-(2-oxo- IH-pyri din-3 -yl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatri cyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[( 11 S, 14 S, 17 S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 17 - [ [2 - (2 -hy droxyphenyl)- 1 H- indol-3 -yl]methyl]- 16-m ethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatri cyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4- [( 11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 17-[[2-(2-hydroxy-6-methyl- phenyl)-lH-indol-3-yl]methyl]-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19- pentazatri cyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-[2-[(5R)- 9-oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18- trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;

[1146] 4-[(llS,14S,17S)-14-(4-aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-[2-[(5S)- 9-oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[1147] 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-16-methyl-17-[[2-[2-[(5R)-9-oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-1H-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[1148] -[(llS,14S,17S)-14-(4-aminobutyl)-ll-(3-aminopropyl)-16-methyl-17-[[2-[2-[(5S)-9- oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18- trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;

[1149] -[(llS,14S,17S)-14-(4-aminobutyl)-ll-(3-aminopropyl)-25-(difluoromethyl)-16-methyl- 17-[[2-[2-[(5R)-9-oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-lH-indol-3- yl]methyl]- 12, 15,18-tri oxo-2-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;

[1150] -[(llS,14S,17S)-14-(4-aminobutyl)-ll-(3-aminopropyl)-25-(difluoromethyl)-16-methyl- 17-[[2-[2-[(5S)-9-oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-lH-indol-3- yl]methyl]- 12, 15,18-tri oxo-2 -thia-4,10,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;

[1151] -[(l IS, 14S,17S)- 14-(4-aminobutyl)-l 1 -(3-aminopropyl)-25-chl oro-16-methyl-l 7-[[2-[2- [(5R)-9-oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-1H-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[1152] 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-25-chloro-16-methyl-17-[[2-[2-[(5S)-9-oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-1H-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[1153] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18- trioxo-17-[[2-[2-oxo-2-(8-oxo-2,6,9-triazaspiro[4.5]decan-2-yl)ethyl]-lH-indol-3- yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;

[1154] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-[2-(9- methyl-8-oxo-2,6,9-triazaspiro[4.5]decan-2-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;

[1155] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18- trioxo-17-[[2-[2-oxo-2-[(5R)-l,7-diazaspiro[4.4]nonan-7-yl]ethyl]-lH-indol-3- yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;

[1156] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18- trioxo-17-[[2-[2-oxo-2-[(5S)-l,7-diazaspiro[4.4]nonan-7-yl]ethyl]-lH-indol-3- yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;

[1157] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18- trioxo-17-[[2-[2-oxo-2-[2-(trifluoromethyl)piperazin-l-yl]ethyl]-lH-indol-3-yl]methyl]- 2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen- 22-yl]benzoic acid;

[1158] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18- trioxo-17-[[2-[2-oxo-2-[3-(trifluoromethyl)piperazin-l-yl]ethyl]-lH-indol-3-yl]methyl]- 2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen- 22-yl]benzoic acid;

[1159] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-[2-(4- oxa-l,8-diazaspiro[5.5]undecan-8-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18- trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;

[1160] -[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16,25-dimethyl-17-[[2-[2-(4- oxa- 1,9-diazaspiro[5.5]undecan-9-yl)-2-oxo-ethyl]- lH-indol-3 -yl]methyl]- 12,15,18- trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;

[1161] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-[2-(8- oxa-2,5-diazaspiro[3.5]nonan-2-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18- trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;

[1162] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-[2-[(5R)- 6-methyl-9-oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12, 15, 18-trioxo-2-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;

[1163] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-[2-[(5S)- 6-methyl-9-oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]- 12, 15, 18-trioxo-2-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;

[1164] -[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16-methyl-17-[[2-[2-[(5R)-6- methyl-9-oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]- 12, 15,18-trioxo-2-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;

[1165] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-17-[[2-[2-[(5S)-6- methyl-9-oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]- 12, 15,18-trioxo-2-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;

[1166] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-(3- carbamoylpiperazin-l-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16,25-dimethyl- 12, 15,18-trioxo-2-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;

[1167] -[( 11 S, 14S, 17 S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 17- [ [2- [2-(4,7- diazaspiro[2.5]octan-7-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16,25-dimethyl- 12, 15,18-trioxo-2-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;

[1168] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-[(3R)-3- (methoxymethyl)piperazin-l-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16,25-dimethyl- 12, 15,18-trioxo-2-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;

[1169] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-[(3S)-3- (hydroxymethyl)piperazin-l-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16,25-dimethyl- 12, 15,18-trioxo-2-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;

[1170] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-[(3S)-3- (methoxymethyl)piperazin-l-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16,25-dimethyl-12, 15, 18-trioxo-2-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;

[1171] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-[3- (fluoromethyl)piperazin-l-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16,25-dimethyl- 12, 15, 18-trioxo-2-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;

[1172] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-[3-aminopropyl(2- hydroxyethyl)amino]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16,25-dimethyl-12,15,18- trioxo-2-thia-4, 10, 13, 16,19-pentazatri cyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;

[1173] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-chloro-16-methyl-17-[[2-[2- (4-oxa-l,9-diazaspiro[5.5]undecan-9-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18- trioxo-2-thia-4, 10, 13, 16,19-pentazatri cyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;

[1174] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-chloro-16-methyl-17-[[2-[2- (8-oxa-2,5-diazaspiro[3.5]nonan-2-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18- trioxo-2-thia-4, 10, 13, 16,19-pentazatri cyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;

[1175] -[(llS,14S,17S)-14-(4-Aminobutyl)-17-[[2-[2-[(3S,4R)-3-amino-4-fluoro-pyrrolidin-l- yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18- trioxo-2-thia-4, 10, 13, 16,19-pentazatri cyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;

[1176] -[(llS,14S,17S)-14-(4-Aminobutyl)-17-[[2-[2-[(3S,4R)-3-amino-4-hydroxy-pyrrolidin-l- yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18- trioxo-2-thia-4, 10, 13, 16,19-pentazatri cyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;

[1177] -[(llS,14S,17S)-14-(4-Aminobutyl)-17-[[2-[2-[(3S,4S)-3-amino-4-fluoro-pyrrolidin-l- yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18- trioxo-2-thia-4, 10, 13, 16,19-pentazatri cyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;

[1178] -[(llS,14S,17S)-14-(4-Aminobutyl)-17-[[2-[2-[(3S,4S)-3-amino-4-hydroxy-pyrrolidin-l- yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-l l-(3-aminopropyl)-16,25-dimethyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;

[1179] -[(llS,14S,17S)-14-(4-Aminobutyl)-17-[[2-[2-[2-aminoethyl(2-hydroxyethyl)amino]-2- oxo-ethyl]-lH-indol-3-yl]methyl]-l l-(3-aminopropyl)-16,25-dimethyl-12,15,18-trioxo- 2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen- 22-yl]benzoic acid;

[1180] -[(llS,14S,17S)-14-(4-Aminobutyl)-17-[[2-[2-[4-amino-4-(hydroxymethyl)-l-piperidyl]- 2-oxo-ethyl]-lH-indol-3-yl]methyl]-l l-(3-aminopropyl)-l 6,25-dimethyl- 12, 15, 18- trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;

[1181] -[(llS,14S,17S)-17-[[2-[2-[(4aR,7aR)-3,4,4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4- b][l,4]oxazin-6-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-14-(4-aminobutyl)-ll-(3- aminopropyl)- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-17-[[2-[2-[(4aR,7aR)-3,4,4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4- b][l,4]oxazin-6-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-14-(4-aminobutyl)-l l-(3- aminopropyl)- 16-m ethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-17-[[2-[2-[(4aR,7aR)-3,4,4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4- b][l,4]oxazin-6-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-14-(4-aminobutyl)-l l-(3- aminopropyl)-25-(difluorom ethyl)- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-17-[[2-[2-[(4aR,7aR)-3,4,4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4- b][l,4]oxazin-6-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-14-(4-aminobutyl)-l l-(3- aminopropyl)-25-chloro- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-17-[[2-[2-[(4aS,7aS)-3,4,4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4- b][l,4]oxazin-6-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-14-(4-aminobutyl)-l l-(3- aminopropyl)- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-17-[[2-[2-[(4aS,7aS)-3,4,4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4- b][l,4]oxazin-6-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-14-(4-aminobutyl)-l l-(3-aminopropyl)- 16-m ethyl- 12,15,18-tri oxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-17-[[2-[2-[(4aS,7aS)-3,4,4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4- b][l,4]oxazin-6-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-14-(4-aminobutyl)-l l-(3- aminopropyl)-25-(difluorom ethyl)- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-17-[[2-[2-[(4aS,7aS)-3,4,4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4- b][l,4]oxazin-6-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-14-(4-aminobutyl)-l l-(3- aminopropyl)-25-chloro- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-17-[[cis-2-[2-(3,4,4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4-b][l,4]oxazin-6- yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-14-(4-aminobutyl)-ll-(3-aminopropyl)-16,25- dimethyl-12, 15,18-tri oxo-2 -thia-4,10,13, 16,19-pentazatricy clo[l 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;

[1182] -[( 11 S, 14S, 17 S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 17-[[2-[2-(9,9-difluoro-2,6- diazaspiro[4.5]decan-2-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16,25-dimethyl- 12, 15,18-tri oxo-2-thia-4,l 0,13, 16,19-pentazatricy clo[l 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;

[1183] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18- trioxo-17-[[2-[2-oxo-2-[(3R)-3-(hydroxymethyl)piperazin-l-yl]ethyl]-lH-indol-3- yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;

[1184] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-(dimethylamino)-2- oxo-acetyl]-lH-indol-3-yl]methyl]- 16, 25-dimethyl- 12, 15,18-tri oxo-2 -thia- 4,10,13, 16,19-pentazatricy clo[l 9.4.0.03,8]pentacosa- 1(25), 3(8), 4, 6, 21, 23-hexaen-22- yl]benzoic acid;

[1185] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18- trioxo-17-[[2-[(3-oxo-2,8-diazaspiro[4.5]decan-2-yl)methyl]-lH-indol-3-yl]methyl]-2- thia-4, 10, 13, 16,19-pentazatricy clo[l 9.4.0.03,8]pentacosa- 1(25), 3(8), 4, 6, 21,23-hexaen- 22-yl]benzoic acid;

[1186] -[(l IS, 14S,17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 16, 25-dimethyl- 12, 15,18- trioxo- 17-[[2-(piperazin- 1 -ylmethyl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;4-[( 11 S, 14S, 17 S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 17-[[2- [(dimethylamino)methyl]-lH-indol-3-yl]methyl]-16,25-dimethyl-12,15,18-trioxo-2- thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen- 22-yl]benzoic acid;

[1187] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-17-[[2-(aminomethyl)-lH-indol-3-yl]methyl]-l l-(3- aminopropyl)- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-(3-aminopropyl)-lH- indol-3 -yl]methyl]- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-17-[[2-(4-Aminobutyl)-lH-indol-3-yl]methyl]-l 1- (3 -aminopropyl)- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-17-[[2-(2-aminoethyl)-lH-indol-3-yl]methyl]-l l-(3- aminopropyl)- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[(l IS, 14S,17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 16,25-dimethyl- 12, 15,18- trioxo- 17-[[2-(4-piperidylmethyl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-(azetidin-3-ylmethyl)- lH-indol-3 -yl]methyl]- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[(l IS, 14S,17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 16,25-dimethyl- 12, 15,18- trioxo- 17-[[2-(pyrrolidin-3 -ylmethyl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 1 l-(3-aminopropyl)-l 6,25-dimethyl- 12, 15, 18- trioxo-17-[[2-(l,2,3,6-tetrahydropyridin-5-yl)-lH-indol-3-yl]methyl]-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1188] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-(2,5-dihydro-lH-pyrrol- 3-yl)- lH-indol-3-yl]methyl]-l 6,25-dimethyl- 12, 15,18-trioxo-2-thia-4, 10,13, 16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;-[(l IS, 14S,17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 17-[(2 -bromo- lH-indol-3- yl)methyl]- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-(l- methyl-4-piperidyl)- lH-indol-3 -yl]methyl]- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 1 l-(3-aminopropyl)-l 6,25-dimethyl- 12, 15, 18- trioxo-17-[[2-[l-(2,2,2-trifluoroethyl)-4-piperidyl]-lH-indol-3-yl]methyl]-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1189] -[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 1 l-(3-aminopropyl)-l 6,25-dimethyl- 12, 15, 18- trioxo-17-[[2-(l,2,3,6-tetrahydropyridin-4-yl)-lH-indol-3-yl]methyl]-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1190] -[(l IS, 14S, 17 S)-14-(4- Aminobutyl)- 1 l-(3-aminopropyl)-17-[[2-[l-(2 -hydroxy ethyl)-4- piperi dy 1 ] - lH-indol-3 -yl]methyl]- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(l IS, 14S, 17 S)-14-(4- Aminobutyl)- 1 l-(3-aminopropyl)-17-[[2-[l-(2 -methoxy ethyl)-4- piperi dy 1 ] - lH-indol-3 -yl]methyl]- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[l-(2-imidazol-l- ylethoxycarbonyl)-4-piperidyl]-lH-indol-3-yl]methyl]-16,25-dimethyl-12,15,18-trioxo- 2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen- 22-yl]benzoic acid;

[1191] -[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 1 l-(3-aminopropyl)-l 6,25-dimethyl- 12, 15, 18- trioxo-17-[[2-[l-(3,3,3-trifluoropropyl)-4-piperidyl]-lH-indol-3-yl]methyl]-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1192] -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[l-(2,2-difluoroethyl)-4- piperidyl]- lH-indol-3 -yl]methyl]- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[l-(2-fluoroethyl)-4- piperi dy 1 ] - lH-indol-3 -yl]methyl]- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-[l- (oxetan-3-ylmethyl)-4-piperidyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1193] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[l-(2-imidazol-l- ylethyl)-4-piperidyl]-lH-indol-3-yl]methyl]-16,25-dimethyl-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1194] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-(l-cyclopropyl-4- piperidyl)- lH-indol-3 -yl]methyl]- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18- trioxo-17-[[2-[(2,2,2-trifluoroethylamino)methyl]-lH-indol-3-yl]methyl]-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acidor a pharmaceutically acceptable salt or stereoisomer thereof.

[1195] The compound of formula (I) according to clause 1, selected from the group consisting of: 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-chloro-16-methyl-12,15,18- trioxo-17-[[2-[(2-oxopyrrolidin-l-yl)methyl]-lH-indol-3-yl]methyl]-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1196] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-[(l- methylpyrazol-3-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;

[1197] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-[(l- methylpyrazol-4-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;44-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-17-[[2-[2-(dimethylamino)-2-oxo-ethyl]-1H-indol-3-yl]methyl]-16,25-dimethyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(l IS, 14S,17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 16,25-dimethyl- 12, 15,18- trioxo- 17-[[2-(4-pyridylmethyl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; or a pharmaceutically acceptable salt or stereoisomer thereof.

[1198] A pharmaceutical composition comprising a compound according to any of clauses 1 to 28, or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more pharmaceutically acceptable excipients.

[1199] A compound according to any of clauses 1 to 28, or a pharmaceutically acceptable salt or stereoisomer thereof, for use as therapeutically active substance.

[1200] A method for the treatment of diseases caused by infections with members of the A. baumannii–calcoaceticus complex of pathogens in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) according to any one of clauses 1 to 28, or of a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition according to clause 29.

[1201] A compound of formula (I) according to any of clauses 1 to 28, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to clause 29 for use in the method according to clause 31.

[1202] Use of a compound of formula (I) according to any of clauses 1 to 28, or of a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition according to clause 29 in the method according to clause 31.

[1203] Use of a compound according to any of clauses 1 to 28, or of a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of diseases caused by infections with members of the A. baumannii–calcoaceticus complex of pathogens in a subject.Examples

[1204] The invention will be more fully understood by reference to the following examples. They should however not be construed as limiting the scope of the invention.

[1205] All examples and intermediates were prepared under nitrogen atmosphere if not specified otherwise.

[1206] Abbreviations used

[1207] Abbreviations: aq. = aqueous; Boc = tert-butoxycarbonyl; DMSO = dimethyl sulfoxide; MS = mass spectrometry; HPLC = high-performance liquid chromatography; NMR = nuclear magnetic resonance spectroscopy; CAS-RN = Chemical Abstracts Service Registry Number.

[1208] Intermediate 1

[1209] 9H-Fluoren-9-ylmethyl N-[[6-bromo-3-(difluoromethyl)-2-[(3-formyl-2-pyridyl)-sulfanyl] phenyl] methyljcarbamate

[1210]

[1211] Step 1: 6-Bromo-3-(difluoromethyl)-2-fluoro-benzaldehyde

[1212] To a solution of 4-bromo-l-difluoromethyl-2-fluorobenzene (4.18 mL, 31.1 mmol) in anhydrous tetrahydrofuran (50 mL) was added dropwise lithium diisopropylamide solution (2 M in tetrahydrofuran, 17.1 mL, 34.2 mmol) over a period of 40 min while maintaining the internal temperature below -70°C, then after 60 min at -70 °C N, N-dimethylformamide (4.8 mL, 62 mmol) was added at -70°C, then after another 10 min the reaction mixture was poured onto ice water (200 mL) and extracted with ethyl acetate (4×60 mL). The combined organics were dried over sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by chromatography (SiO2 petroleum ether / ethyl acetate 9:1) to produce the title compound (8.0 g, 86%). Yellow oil,1H NMR (400 MHz, CDCl3) 8 ppm 10.20 (s, 1 H), 7.72 -7.88 (m, 2 H), 7.27 (t, J= 53.8 Hz, 1H).

[1213] Step 2: Methyl 2-[3-bromo-6-(difluoromethyl)-2-formyl-phenyl]sulfanylpyridine-3-carboxylate

[1214]

[1215] ine-3 -carboxylate

[1216] To a solution of 2-mercaptonicotinic acid (5.4 g, 34. 8 mmol) in N, N-dimethylformamide (80 mL) was added sodium hydride (60% dispersion in mineral oil, 2.4 g, 60 mmol) at 0°C under a nitrogen atmosphere, and the solution was stirred at 25°C for 30 min, then 6-bromo-3-(difhioromethyl)-2-fluoro-benzaldehyde (8.0 g, 31.6 mmol) was added dropwise. The solution was heated at 80°C for 3 h, then cooled to room temperature and treated with potassium carbonate (12.2 g, 88.5 mmol) and iodomethane (5.51 mL, 88.5 mmol) at 25°C, then after 30 min the reaction mixture was poured into the ice water (300 mL) and s extracted with ethyl acetate (3×80 mL). The organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by flash chromatography system ( Si O2 column, petroleum ether / ethyl acetate 7:3) to produce the title compound (5.0 g, 36%). Yellow solid, MS: 401.9 [M+H]+.

[1217]

[1218] Step 3: Methyl 2-[3-bromo-2-[(E)-tert-butylsulfinyliminomethyl]-6-(difluoromethyl)phenyl]sulfanylpyridine-3-carboxylate

[1219] To a solution of methyl 2-[3-bromo-6-(difluoromethyl)-2-formyl-phenyl]sulfanylpyridine-3-carboxylate (8.5 g, 21.1 mmol) in tetrahydrofuran (20 mL) were added 2-methylpropane-2-sulfinamide (2.56 g, 21.1 mmol) and titanium(IV) ethoxide (21.7 mL, 106 mmol), then the solution was stirred at 70°C for 2 h. After cooling, the solution was treated with water (20 mL), insoluble material was removed by filtration, and the filter cake was washed with ethyl acetate (80 mL). The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to produce the title compound (6.6 g, 67%). Orange oil, MS: 505.0 [M+H]+.

[1220] Step 4: N-[[6-Bromo-3-(difluoromethyl)-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]-methyl]-2-methyl-propane-2-sulfinamide

[1221]

[1222]

[1223] -2-methyl-:-2-sulfinamide

[1224] To a solution of methyl 2-[3-bromo-2-[(E)-tert-butylsulfinyliminomethyl]-6-(difluoromethyl) phenyl]sulfanylpyridine-3-carboxylate (6.6 g, 13.0 mmol) in tetrahydrofuran (60 mL) was added slowly of lithium aluminum hydride solution (2.5 M in tetrahydrofuran, 29.3 mL, 73.1 mmol) at -40°C, then after 2 h the reaction mixture was treated with 20 g of sodium sulfate decahydrate slowly, and a lot of bubbles were formed, then the mixture was formed a lot of white suspension. The solid was filtered off and the filter cake was washed with dichloromethane (40 mL). Thefiltrate was concentrated under reduced pressure to produce the title compound (6.2 g, 99%), which was used directly in next step. Yellow solid, MS: 479.1 [M+H]+.

[1225]

[1226] -( Aminomethyl)-3 -bromo-6-i -3-hydrochloride

[1227] To a solution of N-[[6-bromo-3-(difluoromethyl)-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl] phenyl]methyl]-2-methyl-propane-2-sulfinamide (6.2 g, 12.9 mmol) in 1,4-dioxane (5 mL) was added hydrogen chloride solution (0.7 M in 1,4-dioxane, 20 mL, 14 mmol) at 25°C, then after 2 h the solution was concentrated under reduced pressure to produce the title compound (5.0 g, quant.). Yellow solid, MS: 375.1 [M+H]+.

[1228] 6: 9H-Fluoren-9-ylmethyl N-[[6-bromo-3-(difluoromethyl)-2-[[3-(hydroxymethyl)-2-

[1229]

[1230] To a solution of [2-[2-(aminomethyl)-3-bromo-6-(difluoromethyl)phenyl]sulfanyl-3 -pyridyl] methanol; hydrochloride (5.0 g, 12.2 mmol) in saturated aqueous sodium hydrogen carbonate solution (60 mL) and tetrahydrofuran (60 mL) was added N-(9-fluorenylmethoxycarbonyl-oxy)succinimide (4.3 g, 12.8 mmol) at 25 °C, then after 2 h the solution was partitioned between water (60 mL) and ethyl acetate (30 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography (SiO2; petroleum ether / ethyl acetate 2:1) to produce the title compound (8.0 g, 88%). Yellow solid, MS: 597.1 [M+H]+.

[1231] 7: 9H-Fluoren-9-ylmethylN-[[6-bromo-3-(difluoromethyl)-2-[(3-formyl-2-

[1232]

[1233] To a solution of 9H-fluoren-9-ylmethyl N-[[6-bromo-3-(difluoromethyl)-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]methyl]carbamate (0.7 g, 1.17 mmol) in 1,2-di chloroethane (15 mL) was added manganese(IV) oxide (2.04 g, 23.4 mmol), and the black suspension was stirred at 50°C for 16 h. Insoluble material was removed by filtration, and the filtrate was concentrated to give a residue, which was triturated in ethyl acetate (20 mL) to produce the title compound (470 mg, 64%). White solid, MS: 595.2 [M+H]+.

[1234] Intermediate 2

[1235] tert-Butyl 3-[(2S)-3-methoxy-2-(methylamino)-3-oxo-propyl]-2-(4-pyridylmethyl)indole-l-carboxylate

[1236]

[1237] Step 1: Methyl (3S)-1-(4-pyridyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate

[1238] To a solution of L-tryptophan methyl ester (5.00 g, 22.9 mmol) in dichloromethane (50 mL) were added 4-pyridinecarboxaldehyde (2.4 mL, 25.2 mmol) and trifluoroacetic acid (2.55 mL, 34.4 mmol) at 0-5°C under a nitrogen atmosphere, and the solution was stirred at 25°C for 10 h, then the solution was concentrated under reduced pressure to give the title compound (5.2 g, 74%), which was used directly in the next step. Yellow solid, MS: 308.2 [M+H]+.

[1239] Step 2: Methyl (3S)-2-methyl-1-(4-pyridyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole-3-carboxylate

[1240] To a solution of methyl (3S)-l-(4-pyridyl)-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indole-3-carboxylate (5.2 g, 16.9 mmol) in methanol (50 mL) was added paraformaldehyde (2.29 g, 25.4 mmol) in portions at 25°C, and the mixture was heated at 40 °C for 1 h, then the solution was cooled to 25°C and sodium cyanoborohydride (3.19 g, 50.8 mmol) was added in portions, then after 16 h volatile material was removed by distillation under reduced pressure. The residue was purified by flash chromatography (SiO2, ethyl acetate) to produce the title compound (4.2 g, 77%). Yellow solid, MS: 322.2 [M+H]+.

[1241] Step 3: Methyl (2S)-2-(methylamino)-3-[2-(4-pyridylmethyl)-1H-indol-3-yl]propanoate

[1242] To a solution of methyl (3S)-2-methyl-l-(4-pyridyl)-l,3,4,9-tetrahydropyrido[3,4-b]indole-3-carboxylate (4.0 g, 12.5 mmol) in methanol (50 mL) was added palladium(O) (10% on activated charcoal, 2.5 g), and the mixture was stirred under a hydrogen atmosphere (22.5 Psi) at 40°C, then after 20 h the catalyst was filtered off and the filtrate was concentrated under reduced pressure to give a residue, which was purified by flash chromatography (SiO2; petroleum ether / ethyl acetate 2:1) to produce the title compound (2.7 g, 59%). Yellow oil, MS: 324.2 [M+H]+.

[1243] Step 4: Methyl (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-[2-(4-pyridylmethyl)-lH-indol-3-

[1244]

[1245] To a mixture of methyl (2S)-2-(methylamino)-3-[2-(4-pyridylmethyl)-lH-indol-3-yl]propanoate (1.9 g, 5.88 mmol) in tetrahydrofuran (10 mL) and saturated aq. sodium hydrogen carbonate solution (10.0 mL) was added N-(9-fluorenylmethoxycarbonyloxy)succinimide (4.36 g, 12.9 mmol) at 25°C, then after 2 h the reaction mixture was partitioned between water (20 mL) and ethyl acetate (20 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered, and evaporated. Flash chromatography of the residue (SiO2; petroleum ether / ethyl acetate 2:1) produced the title compound (2.4 g, 49%). Yellow solid, MS: 546.4 [M+H]+.

[1246] 5: tert-Butyl 3-F(2S)-2-F9H-fluoren-9-' -3 -methoxy-3 -oxo-

[1247]

[1248] I-2-C4-;-l -carboxylate

[1249] To a solution of methyl (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-[2-(4-pyridylmethyl)-lH-indol-3-yl]propanoate (2.3 g, 4.22 mmol) in acetonitrile (30 mL) were added di-tert-butyl-dicarbonate (1.7 g, 8.43 mmol) and 4-dimethylaminopyridine (51 mg, 0.42 mmol) at 0°C. After removal of the ice bath the solution was stirred at 25°C for 16 h, then partitioned between water (30 mL) and ethyl acetate (30 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography (SiO2: petroleum ether / ethyl acetate 2:1) to produce the title compound (2.2 g, 55%). Yellow solid, MS: 646.4 [M+H]+.

[1250]

[1251] 6: tert-Butyl 3- i-3 -methoxy-2-(methylamino)-3 -oxo-

[1252]

[1253] -2-(4-i 1-carboxylate

[1254] To a solution of tert-butyl 3-[(2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-methoxy-3-oxo-propyl]-2-(4-pyridylmethyl)indole-l-carboxylate (2.0 g, 3.1 mmol) in acetonitrile (20 mL) was added diethylamine (6.25 mL, 61.9 mmol) at 25°C, then after 2 h the reaction mixture was partitioned between water (30 mL) and ethyl acetate (30 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography (SiO2; dichloromethane / methanol 93:7) to produce the title compound (720 mg, 55%). Yellow oil, MS: 424.3 [M+H]+.

[1255] Intermediate 3

[1256] tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo-propyl]-2-benzyl-indole-l-carboxylate

[1257]

[1258] Step 1: (3S)-1-Phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid

[1259] To a solution of L-tryptophan (20.0 g, 97.9 mmol) in water (75 mL) and ethanol (200 mL) were added concentrated sulfuric acid (4.9 g, 50.0 mmol) and benzaldehyde (9.95 mL, 97.9 mmol) at 25 °C, and the solution was heated at 100°C for 16 h, then concentrated under reduced pressure. The residue was taken up in ice-water (200 mL), and the pH of the solution was adjusted to 6~7 by progressive adding solid sodium hydrogen carbonate. The precipitate which had formed was collected by filtration, and the filter cake was triturated in acetonitrile (500 mL) to produce the title compound (18.0 g, 31%). Yellow solid, MS: 293.2 [M+H]+.

[1260] Step 2: (3S)-2-Methyl-1-phenyl-1,3,4,9-tetrahydropyrido[3,4-b]indole-3-carboxylic acid

[1261] To a solution of (3S)-l-phenyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indole-3-carboxylic acid (18.0 g, 61.6 mmol) in methanol (180 mL) was added paraformaldehyde (12.7 g, 129 mmol,) at 25°C, and the solution was stirred at 40°C for 1 h. The solution was cooled to 25 °C and sodium cyanoborohydride (1.24 g, 19.8 mmol) was added slowly, then the solution was stirred at 40°C for 3 h, then concentrated under reduced pressure. The residue was taken up in ice-water (200 mL), and the pH of the solution was adjusted to 5-6 by progressive adding aq. hydrochloric acid solution (1 M). The solution was then extracted with ethyl acetate (3×200 mL), the organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the title compound (9.00 g, 24%). Yellow solid, MS: 307.2 [M+H]+.

[1262] Step 3: (2S)-3-(2-Benzyl-lH-indol-3-yl)-2-(methylamino)propanoic acid

[1263] To a solution of (3S)-2-methyl-l-phenyl-l,3,4,9-tetrahydropyrido[3,4-b]indole-3-carboxylic acid (5.0 g, 16.3 mmol) in methanol (10 mL) was added palladium(O) (10% on activated charcoal, 3.0 g) at 25 °C, then the black suspension was stirred under a hydrogen atmosphere (25 Psi) at 25°C. After 4 h the catalyst was filtered off and the filtrate was concentrated under reduced pressure to produce the title compound (4.0 g, 66%). Yellow oil, MS: 309.2 [M+H]+.

[1264]

[1265] 4: ( 2 S)-3 -(2-Benzyl- lH-indol-3 -yD-2-l acid

[1266] To a solution of (2S)-3-(2-benzyl-lH-indol-3-yl)-2-(methylamino)propanoic acid (4.00 g, 13.0 mmol) in dichloromethane (10 mL) and methanol (10 mL) were added N, N- diisopropylethylamine (9.04 mL, 51.9 mmol) and di-tert-butyl-dicarbonate (1.85 g, 38.9 mmol) at 25°C, then after 16 h the reaction mixture was partitioned between water (10 mL) and dichloromethane (25 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (SiCh, petroleum ether / ethyl acetate 2: 1) produced the title compound 5.00 g, 33%). Yellow oil, MS: 309.2 [M- Boc+H]+.

[1267]

[1268] 5: Allyl (2S)-3-(2-benzyl-lH-indol-3-yl)-2-

[1269] To a solution of (2S)-3-(2-benzyl-lH-indol-3-yl)-2-[tert-butoxycarbonyl(methyl)amino] propanoic acid (5.00 g, 12.2 mmol) in N, N-dimethylformamide (70 mL) were added allyl bromide (2.96 mL, 34.3 mmol) and diisopropylethylamine (11.9 mL, 68.6 mmol) at 25°C,, then after 2 h the reaction mixture was partitioned between water (70 mL) and ethyl acetate (100 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure.

[1270] Chromatography of the residue (SiO₂; petroleum ether / ethyl acetate 3:1) produced the title compound (600 mg, 11%). Yellow oil, MS: 471.2 [M+Na]+.

[1271]

[1272] 6: Allyl (2S)-3-(2-benzyl-lH-indol-3-yl)-2-i

[1273] To a solution of allyl (2S)-3-(2-benzyl-lH-indol-3-yl)-2-[tert-butoxycarbonyl(methyl)amino] propanoate (500 mg, 1.11 mmol) in 1,4-dioxane (0.2 mL)was added hydrogen chloride solution (4 M in 1,4-dioxane, 41 mL, 164 mmol) at 25°C, then the reaction mixture was concentrated to produce the title compound (500 mg, 99%), which was used directly in the next step. Yellow oil, MS: 349.2 [M+H]+.

[1274] 7: Allyl (2S)-3-(2-benzyl-lH-indol-3-yl)-2-[9H-fluoren-9-vlmethoxvcarbonvl(methvl)-

[1275]

[1276] >

[1277] To a solution of allyl (2S)-3-(2-benzyl-lH-indol-3-yl)-2-(methylamino)propanoate (500 mg, 1.43 mmol) in tetrahydrofuran (12 mL) and saturated aqueous sodium hydrogen carbonate solution (12 mL) was added N-(9-fluorenylmethoxycarbonyloxy)succinimide (629 mg, 1.87 mmol) at 25°C, then after 2 h the solution was partitioned between water (20 mL) and ethylacetate (50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by flash chromatography system (SiO2 column, petroleum ether / ethyl acetate 2:1) to produce the title compound (390 mg, 35%). Yellow oil, MS: 571.4 [M+H]+.

[1278] 8: tert-Butyl 3-r 2S)-3-allvloxv-2-F9H-fluoren-9-'

[1279]

[1280] -3-oxo- -2-benzyl-indole- 1 -carboxylate

[1281] To a solution of allyl (2S)-3-(2-benzyl-lH-indol-3-yl)-2-[9H-fluoren-9-ylmethoxycarbonyl (methyl)amino]propanoate (420 mg, 0.74 mmol) in dichloromethane (8 mL) were added N, N-diisopropylethylamine (0.19 mL, 1.1 mmol), di-tert-butyl-dicarbonate (193 mg, 0.88 mmol) and 4-dimethylaminopyridine (18 mg, 0.15 mmol) at 25°C, then after 2 h the solution was concentrated to give a residue, which was purified by flash chromatography (SiO2; petroleum ether / ethyl acetate 6:1) to produce the title compound (350 mg, 58%). White solid, MS: 693.2 [M+Na]+.

[1282] Step 9: tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo-propyl]-2-benzyl-indole-l-carboxylate

[1283] To a solution of tert-butyl 3-[(2S)-3-allyloxy-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl) amino]-3-oxo-propyl]-2-benzyl-indole-l-carboxylate (350 mg, 0.52 mmol) in acetonitrile (3 mL) was added di ethylamine (0.27 mL, 2.61 mmol) at 25°C, then after 2 h the solution was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2; petroleum ether / ethyl acetate 2:1) to produce the title compound (210 mg, 85%). Light yellow oil, MS: 449.3 [M+H]+.

[1284] Intermediate 4

[1285] tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo-propyl]-2-(3-thienylmethyl)indole-l-carboxylate

[1286]

[1287] 1: Methyl (3S)-1-(3-thienyl)-2,3,4,9-tetrahydro-1H-i

[1288]

[1289] ,4-b]indole-3 -carboxylate

[1290] To a suspension of L-tryptophan methyl ester hydrochloride (5.00 g, 19.6 mmol) in 1,2-dichloroethane (50 mL) was added 3-thiophenecarboxaldehyde (1.72 mL, 19.6 mmol) at 25°C, and the suspension was heated to 80 °C under a nitrogen atmosphere and stirred for 16 h. After cooling the solid was collected by filtration and the filter cake was washed with ethyl acetate (3x10 mL) and dried to produce the title compound (6.8 g, 95%). Light yellow solid, MS: 313.1 [M+H]+.

[1291]

[1292] 2: Methyl (3S)-2-methyl-l-(3-thienyl)-l,3,4,9-i;-3 -carboxylate

[1293] The title compound was produced in analogy to intermediate 2, step 2, from methyl (3S)-l-(3-thienyl)-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indole-3-carboxylate. Light yellow solid, MS: 327.1 [M+H]+.

[1294] 3: Methyl (2S)-2-(methylamino)-3-r2-(3-thienylmethyl)-lH-indol-3-

[1295]

[1296] The title compound was produced in analogy to intermediate 2, step 3, from methyl (3S)-2-methyl-l-(3-thienyl)-l,3,4,9-tetrahydropyrido[3,4-b]indole-3-carboxylate. Light yellow solid, MS: 329.1 [M+H]+.

[1297] 4: Methyl (2S)-2- -(2-ni -3 -F2-(3 -thienylmethyl)- IH-indol-

[1298]

[1299] To a solution of methyl (2S)-2-(methylamino)-3-[2-(3-thienylmethyl)-lH-indol-3-yl]propanoate (1.10 g, 2.95 mmol) in dichloromethane (16 mL) were added triethylamine (0.66 mL, 4.72 mmol) and 2-nitrobenzenesulfonyl chloride (784 mg, 3.54 mmol) in turn at 0°C. After removal of the ice bath, the solution was stirred at 25°C for 4 h, then partitioned between water and dichloromethane. The organic layer was washed with brine (10 mL), dried over sodium sulfate,and concentrated under reduced pressure to give a residue, which purified by flash chromatography (SiO2; petroleum ether / ethyl acetate 2:1) to produce the title compound (1.10 g, 64%). Light brown oil, MS: 514.2 [M+H]+.

[1300]

[1301] 5: tert-Butyl 3-r(2S)-3-methoxy-2-| -(2-ni 1-3 -oxo-i 2-(3 -thienylmethyl)indole- 1 -carboxylate

[1302] To a solution of methyl (2S)-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-[2-(3-thienyl methyl) -lH-indol-3-yl]propanoate (1.10 g, 1.88 mmol) in ethyl acetate (10 mL) were added di -tert-butyl -dicarbonate (411 mg, 1.88 mmol) and 4-dimethylaminopyridine (23 mg, 0.19 mmol) at 25°C, then after 3 h the solution was concentrated to give a residue, which was purified by flash chromatography (SiO2; petroleum ether / ethyl acetate 3:1) to produce the title compound (1.00 g, 79%). Light yellow oil, MS: 636.2 [M+Na]+.

[1303] Step 6: (2S)-3-[l-tert-Butoxycarbonyl-2-(3-thienylmethyl)indol-3-yl]-2-[methyl-(2-nitrophenyl) sulfonyl-amino]propanoic acid

[1304] To a solution of tert-butyl 3-[(2S)-3-methoxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]-2-(3-thienylmethyl)indole-l-carboxylate (1.00 g, 1.63 mmol) in acetonitrile (10 mL) and water (0.4 mL) were added triethylamine (2.27 mL, 16.3 mmol) and lithium bromide (1.41 g, 16.3 mmol) at 2 °C, and the mixture was stirred at 50°C for 20 h. After cooling the mixture was partitioned between water (10 mL) and ethyl acetate (10 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, and concentrated to produce the title compound (950 mg, 82%), which was used directly in the next step. Light yellow solid, MS: 622.2 [M+Na]+.

[1305] Step 7: tert-Butyl 3-[(2S)-3-allyloxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]-2-(3 -thienylmethyl)indole- 1 -carboxylate

[1306] To a solution of (2S)-3-[l-tert-butoxycarbonyl-2-(3-thienylmethyl)indol-3-yl]-2-[methyl-(2-nitrophenyl)sulfonyl-amino]propanoic acid (0.95 g, 1.33 mmol) in N, N-dimethylformamide (10 mL) were added triethylamine (0.55 mL, 3.99 mmol) and allyl bromide (161 mg, 1.33 mmol) in turn at 0°C. After removal of the ice bath, the solution was stirred at 25°C for 3 h, then partitioned between water (20 mL) and ethyl acetate (20 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography (SiO2, petroleum ether / ethyl acetate 3:1)to produce the title compound (500 mg, 53%). Light yellow solid, MS: 640.2 [M+H]+.

[1307] Step 8: tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo-propyl]-2-(3-thienylmethyl)indole-1-carboxylate

[1308] To a solution of tert-butyl 3-[(2S)-3-allyloxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]-2-(3-thienylmethyl)indole-l-carboxylate (500 mg, 0.78 mmol) in N, N-dimethylformamide (5 mL) were added potassium carbonate (324 mg, 2.34 mmol) and sodium thiophenolate (276 mg, 2.5 mmol) at 0°C, then after 2 h the reaction mixture was partitioned between water (10 mL) and ethyl acetate (10 mL). The organic layer was washed with water (5 mL) and brine (5 mL) in turn, dried over sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by preparative thin-layer chromatography (ethyl acetate / petroleum ether 3: 1) to produce the title compound (350. mg, 89%). Light yellow oil, MS: 455.2 [M+H]+.

[1309] The following Intermediates (Int.) were produced in analogy to intermediate 4, replacing 3-thiophenecarboxaldehyde in step 1 by the appropriate aldehyde:

[1310] Int. Name Aldehyde MS (m / z)

[1311] 5 tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo- 1 -Methylpyrazole-3 - 453.1 propyl]-2-[(l-methylpyrazol-3-yl)methyl]indole-l- carbaldehyde [M+H]+carboxylate

[1312] XN-N

[1313] \ / x-J.

[1314] N— < r N

[1315] H> O t J

[1316] —

[1317]

[1318] Int. Name Aldehyde MS (m / z) 6 tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo- l-Methylpyrazole-4- 453.2 propyl]-2-[(l-methylpyrazol-4-yl)methyl]indole-l- carbaldehyde [M+H]+carboxylate

[1319] QV K N

[1320] 7 tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo- Thiazole-5- 456.2 propyl]-2-(thiazol-5-ylmethyl)indole-l -carboxylate carbaldehyde [M+H]+o

[1321] H \ ff \

[1322] 8 tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo- l-(2-Trimethylsilyl- 569.4 propyl]-2-[[l-(2-trimethylsilylethoxymethyl)imidazol- ethoxymethyl)- [M+H]+4-yl]methyl]indole- 1 -carboxylate imidazole-4- carbaldehyde (CAS- RN 163807-98-5)

[1323] H 1 N.

[1324] > V

[1325] \\!

[1326]

[1327] Int. Name Aldehyde MS (m / z)

[1328] 9 tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo- l-[[2-(Trimethyl- 569.3 propyl]-2-[[l-(2-trimethylsilylethoxymethyl)imidazol- silyl)ethoxy]methyl]- [M+H]+2-yl]methyl]indole- 1 -carboxylate lH-imidazole-2- carboxaldehyde (CAS- oK"" A' \ /

[1329] Si RN 101226-42-0)

[1330] oz'" / X

[1331] OCX )

[1332] H > N J

[1333]

[1334] Intermediate 10

[1335] tert-Butyl 3-[(2S)-3-methoxy-2-(methylamino)-3-oxo-propyl]-2-(l,2,5-thiadiazol-3-ylmethyl)indole-l-carboxylate

[1336]

[1337] The title compound was produced in analogy to intermediate 2, replacing 4-pyridinecarboxaldehyde in step 1 by l,2,5-thiadiazole-3-carbaldehyde (CAS-RN 75238-60-7). Light yellow oil, MS: 431.2 [M+H]+.

[1338] Intermediate 11

[1339] tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo-propyl]-2-(2-methoxyphenyl)indole-l-carboxylate

[1340]

[1341] Step 1: Methyl (2S)-2-(tert-butoxycarbonylamino)-3-r2-(2-methoxyphenyl)-lH-indol-3-yl1-propanoate

[1342] To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(lH-indol-3-yl)propanoate (CAS-RN 33900-28-6; 5.00 g, 15.7 mmol) and 2-methoxyphenylboronic acid (4.77 g, 31.4 mmol) in acetic acid (50 mL) were added copper(II) acetate (0.33 g, 1.57 mmol) and palladium(II) acetate (0.57 g, 0.79 mmol) at 25°C, and the mixture was stirred at 40°C for 4 h, then partitioned between saturated aq. sodium hydrogen carbonate solution (500 mL) and ethyl acetate (100 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate, and evaporated. The residue was purified by flash chromatography (SiO₂; petroleum ether / ethyl acetate 4:1), followed by preparative HPLC (Phenomenex Luna Cl 8 150*25mm*10pm column; gradient from 0.05% aq. hydrochloric acid solution to acetonitrile), to produce the title compound (600 mg, 9%). White solid, MS: 447.2 [M+Na]+.

[1343] Step 2: Methyl (2S)-2-amino-3-r2-(2-methoxyphenyl)-lH-indol-3-yl]propanoate; hydrochloride

[1344] To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[2-(2-methoxyphenyl)-lH-indol-3-yl]propanoate (0.6 g, 1.41 mmol) in 1,4-dioxane (2 mL) was added hydrogen chloride solution (2 M in 1,4-dioxane, 5.0 mL, 10.0 mmol) at 0°C, and then the solution was stirred at 25°C, then the mixture was evaporated to produce the title compound (0.50 g, 92%). Light yellow solid, MS: 325.1 [M+H]+.

[1345] Step 3: Methyl (2S)-3-r2-(2-methoxyphenyl)-lH-indol-3-yl]-2-r(2-nitrophenyl)sulfonyl-aminolpropanoate

[1346] The title compound was produced in analogy to intermediate 4, step 4, from methyl (2S)-2-amino-3-[2-(2-methoxyphenyl)-lH-indol-3-yl]propanoate; hydrochloride. Light yellow solid, MS: 510.2 [M+H]+-4: Methyl (2S)-3-F2-(2-] i- lH-indol-3-vl]-2- -(2-ni

[1347]

[1348] To a solution of methyl (2S)-3-[2-(2-methoxyphenyl)-lH-indol-3-yl]-2-[(2-nitrophenyl)-sulfonylamino]propanoate (530 mg, 1.04 mmol) in ethyl acetate (5 mL) were added potassium carbonate (216 mg, 1.56 mmol) and tetrabutylammonium bromide (34 mg, 0.1 mmol) in turn at 25°C, then iodomethane (0.06 mL, 1.04 mmol) was added slowly and the reaction was stirred at 40°C for 16 h. After cooling the suspension was partitioned between water (10 mL) and ethyl acetate (10 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to produce the title compound (0.50 g, 89%). Light yellow solid, MS: 524.2 [M+H]+.

[1349] 5: tert-Butyl 3-r(2S)-3-methoxy-2-| -(2-ni 1-3 -oxo-i

[1350]

[1351] 2-(2-i;-l -carboxylate

[1352] The title compound was produced in analogy to intermediate 4, step 5, from methyl (2S)-3-[2-(2-methoxyphenyl)-lH-indol-3-yl]-2-[methyl-(2 -nitrophenyl) sulfonyl-amino]propanoate. Light yellow solid, MS: 646.2 [M+Na]+.

[1353] 6: (2S)-3- -tert-Butoxycarbonyl-2-(2-

[1354]

[1355] -3-V11-2- -(2-

[1356]

[1357] sulfonyl-

[1358]

[1359] The title compound was produced in analogy to intermediate 4, step 6, from tert-butyl 3-[(2S)-3-methoxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]-2-(2-methoxyphenyl)indole-1 -carboxylate. Light yellow solid, MS: 632.2 [M+Na]+.

[1360]

[1361] 7: tert-Butyl 3-r(2S)-3-allyloxy-2- -(2-ni -3-oxo- 1-2- (2-:

[1362]

[1363] -I -carboxylate

[1364] The title compound was produced in analogy to intermediate 4, step 7, from (2S)-3-[l-tert-butoxycarbonyl-2-(2-methoxyphenyl)indol-3-yl]-2-[methyl-(2-nitrophenyl)sulfonyl-amino]propanoic acid. Light yellow solid, MS: 672.2 [M+Na]+.

[1365] 8: tert-Butyl 3- i-3 -allyloxy -2-(methylamino)-3 -oxo-i

[1366]

[1367] -2-(2-

[1368]

[1369] :-l -carboxylate

[1370] The title compound was produced in analogy to intermediate 4, step 8, from tert-butyl 3-[(2S)-3-allyloxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]-2-(2-methoxyphenyl)indole-l- carboxylate. Light yellow oil, MS: 465.2 [M+H]+.

[1371] Intermediate 12

[1372] tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo-propyl]-2-(2-methoxy-6-methyl- phenyl) indole-l-carboxylate

[1373]

[1374] 1: Methyl (2S)-2-(tert-butoxycarbonylamino)-3-r2-(2-methoxy-6-methyl-

[1375]

[1376] i-lH-indol-

[1377]

[1378] 3--

[1379] To a mixture of N-[(l,l-dimethylethoxy)carbonyl]-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-L-tryptophan methyl ester (CAS-RN 1198605-52-5; 1.30 g, 2.93 mmol) and 2-bromo-l- methoxy-3-methyl-benzene (882 mg, 4.39 mmol) in tetrahydrofuran (26 mL) and water (2.6 mL) were added potassium carbonate (1.22 g, 8.82 mmol) and bis-triphenylphosphine-palladium(II) chloride (75 mg, 0.15 mmol) at 20 °C, and the mixture was heated at 80°C for 2 h, then partitioned water (50 mL) and ethyl acetate (30 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by flash chromatography (SiO₂; petroleum ether / ethyl acetate 3:1) to produce the title compound (1.30 g, 71%). Yellow solid, MS: 339.2 [M-Boc+H]+.

[1380] 2: Methyl (2S)-2-amino-3-12-(2-methoxv-6-methyl-i

[1381]

[1382] i-lH-indol-3-

[1383]

[1384] hydrochloride

[1385] The title compound was produced in analogy to intermediate 11, step 2, from methyl (2S)-2- (tert-butoxycarbonylamino)-3-[2-(2-methoxy-6-methyl-phenyl)-lH-indol-3-yl]propanoate.

[1386] Yellow solid, MS: 339.2 [M+H]+.

[1387] Step 3: Methyl (2S)-3-r2-(2-methoxy-6-rnethyl-phenyl)-lH-indol-3-yl]-2-l(2-

[1388]

[1389] The title compound was produced in analogy to intermediate 4, step 4, from methyl (2S)-2-amino-3-[2-(2-methoxy-6-methyl-phenyl)-lH-indol-3-yl]propanoate; hydrochloride. Yellow oil, MS: 524.2 [M+H]+.

[1390] 4: Methyl (2S)-3-F2-(2-methoxy-6-methyl- i-lH-indol-3-yll-2- -(2-

[1391]

[1392] The title compound was produced in analogy to intermediate 11, step 4, from methyl (2S)-3-[2-(2-methoxy-6-methyl-phenyl)-lH-indol-3-yl]-2-[(2-nitrophenyl)sulfonylamino]propanoate. Yellow solid, MS: 538.1 [M+H]+.

[1393]

[1394] 5: tert-Butyl 3-r(2S)-3-methoxy-2-| -(2-ni 1-3 -oxo-i 2-(2-methoxy-6-methyl-i

[1395]

[1396] ;-l -carboxylate

[1397] The title compound was produced in analogy to intermediate 2, step 5, from methyl (2S)-3-[2-(2-methoxy-6-methyl-phenyl)-lH-indol-3-yl]-2-[methyl-(2-nitrophenyl)sulfonyl-amino]propanoate. Yellow solid, MS: 538.2 [M-Boc+H]+.

[1398] -tert-Butoxycarbonyl-2-(2-methoxy-6-methyl-

[1399]

[1400] -3-V11-2- -(2-

[1401]

[1402] acid

[1403] The title compound was produced in analogy to intermediate 4, step 6, from tert-butyl 3-[(2S)-3-methoxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]-2-(2-methoxy-6-methyl-phenyl)indole-l -carboxylate. Black oil, MS: 524.1 [M+H-Boc]+.

[1404]

[1405] -3-oxo- 1-2- (2-methoxy-6-methyl-

[1406]

[1407] :-l -carboxylate

[1408] The title compound was produced in analogy to intermediate 4, step 7, from (2S)-3-[l-tert-butoxycarbonyl-2-(2-methoxy-6-methyl-phenyl)indol-3-yl]-2-[methyl-(2-nitrophenyl)sulfonyl-amino]propanoic acid. White solid, MS: 564.2 [M+H-Boc]+.

[1409] Step 8: tert-Butyl 3-r(2S)-3-allyloxy-2-(methylamino)-3-oxo-propyl]-2-(2-methoxy-6-methyl- yl) indole- 1 -carboxylate

[1410] The title compound was produced in analogy to intermediate 4, step 8, from tert-butyl 3-[(2S)-3-allyloxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]-2-(2-methoxy-6-methyl-phenyl)indole-l -carboxylate. Yellow oil, MS: 479.3 [M+H]+.

[1411] The following Intermediates (Int.) were produced in analogy to intermediate 12, replacing 2-bromo-l-m ethoxy-3 -methylbenzene by the appropriate starting material:

[1412] Int. Name Starting material MS (m / z)

[1413] 13 tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo- 7-Bromo- 1 -indanone 489.3 propyl]-2-(3-oxoindan-4-yl)indole-l-carboxylate (CAS-RN 125114-77- [M+H]+

[1414] 4)

[1415] Vs0

[1416] J

[1417] y

[1418] 14 tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo- 7-Bromo-3H- 491.1 propyl]-2-(3-oxo-lH-isobenzofuran-4-yl)indole-l- isobenzofuran-l-one [M+H]+carboxylate (CAS-RN 105694-44- 8)

[1419] H \

[1420] N X

[1421]

[1422] Int. Name Starting material MS (m / z)

[1423] 15 tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo- 3 -Bromo-5 -fluoro-4- 508.4 propyl]-2-(5-cyano-3-fluoro-2-methoxy-phenyl)indole- methoxy -benzonitrile [M+H]+1 -carboxylate (CAS-RN 1898216- 35-7)

[1424] O N

[1425] ^0 / / /

[1426] H \ O F

[1427] zNAX

[1428] >-0

[1429] 16 tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo- 7-Bromo-2,3- 525.3 propyl]-2-(l,l-dioxo-2,3-dihydrobenzothiophen-7- dihydrobenzo- [M+H]+yl)indole- 1 -carboxylate thiophene 1,1 -di oxide (CAS-RN 1334625- 0

[1430] y,o 45-4)

[1431] kA / w

[1432] °*S >

[1433] / V0*

[1434] >-o

[1435]

[1436] Intermediate 17

[1437] tert-Butyl 3-[(2S)-3-methoxy-2-(methylamino)-3-oxo-propyl]-2-(3-methoxypyridazin-4-yl)indole-l-carboxylate

[1438]

[1439] Step 1: Methyl (2S)-2-(tert-butoxycarbonylamino)-3-12-(6-chloro-3-methoxy-pyridazin-4-yl)-lH-indol-3-yllpropanoate

[1440] The title compound was produced in analogy to intermediate 12, step 1, replacing 2-bromo-l-methoxy-3 -methylbenzene by 6-chloro-4-iodo-3-methoxy-pyridazine. Yellow solid, MS: 461.2 [M+H]+.

[1441] Step 2: Methyl (2S)-2-(tert-butoxycarbonylamino)-3-12-(3-methoxypyridazin-4-yl)-lH-indol-3-yllpropanoate

[1442] To a mixture of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[2-(6-chloro-3-methoxy-pyridazin-4-yl)-lH-indol-3-yl]propanoate (1.00 g, 2.17 mmol) in isopropyl acetate (50 mL) was added palladium(O) (10% on activated charcoal, 700 mg), and the mixture was stirred under a hydrogen atmosphere (20 Psi) at 25°C for 10 h, then the catalyst was filtered off. The filtrate was concentrated and purified by flash chromatography (SiO₂; petroleum ether / ethyl acetate 2:1) to produce the title compound 190 mg, 21%). Light yellow solid, MS: 427.2 [M+H]+.

[1443] Step 3: Methyl (2S)-2-amino-3-r2-(3-methoxypyridazin-4-yl)-lH-indol-3-yl]propanoate; hydrochloride

[1444] The title compound was produced in analogy to intermediate 11, step 2, from methyl (2S)-2-(tert-butoxycarbonylamino)-3-[2-(3-methoxypyridazin-4-yl)-lH-indol-3-yl]propanoate. Light yellow solid, MS: 327.1 [M+H]+.

[1445] Step 4: Methyl (2S)-3-12-(3-methoxypyridazin-4-yl)-lH-indol-3-yl1-2-l(2-nitrophenyDsulfonylaminolpropanoate

[1446] The title compound was produced in analogy to intermediate 4, step 4, from methyl (2S)-2-amino-3-[2-(3-methoxypyridazin-4-yl)-lH-indol-3-yl]propanoate;hydrochloride. Light yellow solid, MS: 512.0 [M+H]+.Step 5: Methyl (2S)-3-12-(3-methoxypyridazin-4-yl)-lH-indol-3-yl1-2-lmethyl-(2-nitrophenyDsulfonyl-aminolpropanoate

[1447] The title compound was produced in analogy to intermediate 11, step 4, from methyl (2S)-3-[2-(3-methoxypyridazin-4-yl)-lH-indol-3-yl]-2-[(2-nitrophenyl)sulfonylamino]propanoate. Light yellow solid, MS: 526.1 [M+H]+.

[1448] Step 6: tert-Butyl 3-r(2S)-3-methoxy-2-lmethyl-(2-nitrophenyl)sulfonyl-amino1-3-oxo-propyl1-2-(3-methoxypyridazin-4-yl)indole-l -carboxylate

[1449] The title compound was produced in analogy to intermediate 2, step 5, from methyl (2S)-3-[2-(3-methoxypyridazin-4-yl)-lH-indol-3-yl]-2-[methyl-(2-nitrophenyl)sulfonyl-amino]propanoate. Light yellow solid, 626.3 [M+H]+.

[1450] Step 7: tert-Butyl 3-l(2S)-3-methoxy-2-(methylamino)-3-oxo-propyl1-2-(3-methoxypyridazin-4-yl) indole- 1 -carboxylate

[1451] The title compound was produced in analogy to intermediate 4, step 8, from tert-butyl 3-[(2S)-3-methoxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]-2-(3-methoxypyridazin-4-yl)indole-l -carboxylate. Light yellow oil, MS: 441.2 [M+H]+.

[1452] Intermediate 18

[1453] tert-Butyl 3-[(2S)-3-methoxy-2-(methylamino)-3-oxo-propyl]-2-(2-methyl-3-oxo-isoindolin-4-yl)indole-l-carboxylate

[1454]

[1455] The title compound was produced in analogy to intermediate 17, steps 1 & 3-7, replacing 6-chloro-4-iodo-3-methoxy-pyridazine in step 1 by 7-bromo-2-methyl-isoindolin-l-one (CAS-RN 1330763-93-3). Light yellow solid, MS: 478.2 [M+H]+.Intermediate 19

[1456] tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo-propyl]-2-[(E)-3-ethoxy-3-oxo-prop-l-enyl]indole-l-carboxylate

[1457] 1: Ethyl (2S)-2-(tert-butoxycarbonvlamino)-3-r2-r(E)-3-ethoxv-3-oxo-prop-l-envll-lH-

[1458]

[1459] indol-3-

[1460] To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(lH-indol-3-yl)propanoate (CAS-RN 33900-28-6; 10.0 g, 31.41 mmol) and palladium(II) acetate (1.41 g, 6.28 mmol) in 1,4-dioxane (220 mL) and acetic acid (80 mL) were added ethyl acrylate (13.5 mL, 126 mmol) and 1,4-benzoquinone (6.79 g, 62.8 mmol) at 20°C, then the mixture was stirred at 80°C for 20 h. After cooling the reaction mixture was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by chromatography (SiO₂; petroleum ether / ethyl acetate 3:1) to produce the title compound (11.0 g, 38%), which contained ca. 40% of starting material. White solid, MS: 317.2 [M-Boc+H]+.

[1461] Step 2: Methyl (2S)-2-amino-3-[2-[(E)-3-ethoxy-3-oxo-prop-l-enyl]-lH-indol-3-yl]propanoate; hydrochloride

[1462] The title compound was produced in analogy to intermediate 11, step 2, from methyl (2S)-2-(tert-butoxycarbonylamino)-3-[2-[(E)-3-ethoxy-3-oxo-prop-l-enyl]-lH-indol-3-yl]propanoate. Light yellow solid, MS: 317.2 [M+H]+.

[1463] 3: Methyl (2S)-3- i-3-ethoxy-3-oxo-prop-l-enyll-lH-indol-3-vll-2-

[1464]

[1465]

[1466] The title compound was produced in analogy to intermediate 4, step 4, from methyl (2S)-2-amino-3-[2-[(E)-3-ethoxy-3-oxo-prop-l-enyl]-lH-indol-3-yl]propanoate;hydrochloride. Lightyellow solid, MS: 502.1 [M+H]+.

[1467] 4: Methyl (2S)-3-F2- i-3 -ethoxy-3 -oxo-prop- 1 -i |-lH-indol-3-yll-2- -(2-

[1468]

[1469] The title compound was produced in analogy to intermediate 11, step 4, from methyl (2S)-3-[2-[(E)-3-ethoxy-3-oxo-prop-l-enyl]-lH-indol-3-yl]-2-[(2-nitrophenyl)sulfonylamino]propanoate. Light yellow solid, MS: 516.1 [M+H]+.

[1470]

[1471] 5: tert-Butyl 2- F (E)-3 -ethoxy-3 -oxo-prop- 1 -enyll-3 - F(2 S)-3 -methoxy -2- -(2-

[1472]

[1473] -3-oxo-propyl]indole-1-carboxylate

[1474] The title compound was produced in analogy to intermediate 2, step 5, from methyl (2S)-3-[2-[(E)-3-ethoxy-3-oxo-prop-l-enyl]-lH-indol-3-yl]-2-[methyl-(2-nitrophenyl)sulfonyl-amino]propanoate. Light yellow oil, MS: 516.1 [M-Boc+H]+.

[1475] 6: (2S)-3-Fl-tert-Butoxycarbonyl-2-F(E)-3-ethoxy-3-oxo-prop-l-i -3-V11-2-I

[1476]

[1477] (2-ni ic acid

[1478] The title compound was produced in analogy to intermediate 4, step 6, from tert-butyl 2-[(E)-3-ethoxy-3-oxo-prop-l-enyl]-3-[(2S)-3-methoxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]indole-l -carboxylate. Light yellow solid, MS: 602.2 [M+H]+.

[1479]

[1480] -3-oxo- 1-2- i-3 -ethoxy-3 -oxo-prop- 1-enyllindole-l -carboxylate

[1481] The title compound was produced in analogy to intermediate 4, step 7, from (2S)-3-[l-tert-butoxycarbonyl-2-[(E)-3-ethoxy-3-oxo-prop-l-enyl]indol-3-yl]-2-[methyl-(2-nitrophenyl)sulfonyl-amino]propanoic acid. Light yellow oil, MS: 642.2 [M+H]+.

[1482]

[1483] 8: tert-Butyl 3- i-3 -allyloxy-2-(methylamino)-3 -oxo-i

[1484]

[1485] -2- F (E)-3 -ethoxy-3 -oxo- i- 1 -enyllindole- 1 -carboxylate

[1486] The title compound was produced in analogy to intermediate 4, step 8, from tert-butyl 3-[(2S)-3-allyloxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]-2-[(E)-3-ethoxy-3-oxo-prop-l-enyl]indole-l -carboxylate. Light yellow oil, MS: 457.2 [M+H]+.Intermediate 20

[1487] tert-Butyl 3-[(2S)-3-methoxy-2-(methylamino)-3-oxo-propyl]-2-(l-methyl-2-oxo-3- piperidyl) indole-l-carboxylate

[1488] O 7

[1489] „N

[1490] H

[1491] N

[1492]

[1493] 1: Methyl (2S)-2-(tert-butoxvcarbonvlamino)-3-r2-(l-methyl-2-oxo-3-pvridvl)-lH-indol-3-

[1494]

[1495] To a mixture of N-[(l,l-dimethylethoxy)carbonyl]-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-L-tryptophan methyl ester (CAS-RN 1198605-52-5; 1.0 g, 2.25 mmol) in toluene (20 mL) and water (2 mL) were added 3-bromo-l-methyl-pyridin-2-one (508 mg, 2.7 mmol), potassium phosphate (956 mg, 4.5 mmol) and bis(tri-tert-butyl-phosphine)palladium(0) (115 mg, 0.23 mmol) at 20 °C, then the mixture was heated at 80°C for 2 h. After cooling, the reaction mixture was partitioned between water (10 mL) and ethyl acetate (15 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography (SiO₂; petroleum ether / ethyl acetate 2:1) to produce the title compound (560 mg, 50%). Light yellow solid, MS: 426.2 [M+H]+.

[1496] 2: Methyl (2S)-2-(tert-butoxycarbonylamino)-3-r2-(l-methyl-2-oxo-3-piperidyl)-lH-indol-

[1497]

[1498] 3--

[1499] To a mixture of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[2-(l-methyl-2-oxo-3-pyridyl)-lH- indol-3-yl]propanoate (560 mg, 1.32 mmol) in methanol (20 mL) were added palladium (10% on activated charcoal, 560 mg) and palladium(II) hydroxide (10% on activated charcoal, 560 mg) under nitrogen atmosphere, and the mixture was stirred under a hydrogen atmosphere (30 Psi) at 25°C for 10 h. After 10 h the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to produce the title compound (560 mg, 79%). Light yellow solid, MS: 430.3 [M+H]+.

[1500] 3: Methyl (2S)-2-amino-3-r2-(l-methyl-2-oxo-3-pi i-lH-indol-3-hydrochloride

[1501] The title compound was produced in analogy to intermediate 11, step 2, from methyl (2S)-2-(tert-butoxycarbonylamino)-3-[2-(l-methyl-2-oxo-3-piperidyl)-lH-indol-3-yl]propanoate. Light yellow solid, MS: 330.2 [M+H]+.

[1502] 4: Methyl (2S)-3-r2-(T-methyl-2-oxo-3-pi i-lH-indol-3-yll-2-r(2-

[1503]

[1504] The title compound was produced in analogy to intermediate 4, step 4, from methyl (2S)-2-amino-3-[2-(l-methyl-2-oxo-3-piperidyl)-lH-indol-3-yl]propanoate; hydrochloride. Light yellow solid, MS: 515.2 [M+H]+.

[1505] 5: Methyl (2S)-2- -(2-ni -3 - [2 -f 1 -methyl-2-oxo-3 -

[1506]

[1507] i-lH-indol-3-

[1508] The title compound was produced in analogy to intermediate 11, step 4, from methyl (2S)-3-[2-(l-methyl-2-oxo-3-piperidyl)-lH-indol-3-yl]-2-[(2-nitrophenyl)sulfonylamino]propanoate. Light yellow solid, MS: 529.2 [M+H]+.

[1509]

[1510] 6: tert-Butyl 3-r(2S)-3-methoxy-2-| -(2-ni 1-3 -oxo-i 2-( 1 -methyl-2-oxo-3 -pi

[1511]

[1512] ;-l -carboxylate

[1513] The title compound was produced in analogy to intermediate 4, step 5, from methyl (2S)-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-[2-(l-methyl-2-oxo-3-piperidyl)-lH-indol-3-yl]propanoate. Light yellow solid, MS: 629.2 [M+H]+.

[1514] Step 7: tert-Butyl 3-r(2S)-3-methoxy-2-(methylamino)-3-oxo-propyl]-2-(l-methyl-2-oxo-3- idyl) indole- 1 -carboxylate

[1515] The title compound was produced in analogy to intermediate 4, step 8, from tert-butyl 3-[(2S)-3-methoxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]-2-(l-methyl-2-oxo-3-piperidyl)indole-l -carboxylate. Light yellow oil, MS: 444.2 [M+H]+.

[1516] Intermediate 21

[1517] tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo-propyl]-2-(l-tert-butoxycarbonyl-2-oxo-3-piperidyl)indole-l-carboxylate

[1518]

[1519] Step 1: Methyl (2S)-3-r2-(2-benzyloxy-3-pyridyl)-lH-indol-3-yl1-2-(tert-butoxycarbonyl-amino)propanoate

[1520] The title compound was produced in analogy to intermediate 20, step 1, replacing 3 -bromo- 1-methyl-pyridin-2-one with 2-benzyloxy-3 -bromo-pyridine. Light yellow solid, MS: 502.2 [M+H]+.

[1521] Step 2: Methyl (2S)-2-(tert-butoxycarbonylamino)-3-r2-(2-oxo-3-piperidyl)-lH-indol-3-yllpropanoate

[1522] To a mixture of methyl (2S)-3-[2-(2-benzyloxy-3-pyridyl)-lH-indol-3-yl]-2-(tert-butoxy-carbonylamino)propanoate (1700 mg, 3.39 mmol) in methanol (70 mL) was added palladium hydroxide (10% on activated charcoal, 1.7 g), and the mixture was stirred under a hydrogen atmosphere (30 Psi) at 25°C. After 10 h the catalyst was filtered off and the filter cake was washed with methanol (100 mL). The filtrate was concentrated to produce the title compound (1.20 g, 83%). Light yellow oil, MS: 316.1 [M+H-Boc]+.

[1523] Step 3: Methyl (2S)-2-amino-3-12-(2-oxo-3-piperidyl)-lH-indol-3-yl1propanoate; hydrochloride

[1524] The title compound was produced in analogy to intermediate 11, step 2, from methyl (2S)-2-(tert-butoxycarbonylamino)-3-[2-(2-oxo-3-piperidyl)-lH-indol-3-yl]propanoate. Light yellow solid, MS: 316.1 [M+H]+.

[1525] Step 4: Methyl (2S)-2-r(2-nitrophenyl)sulfonylamino1-3-r2-(2-oxo-3-piperidyl)-lH-indol-3-yl1 propanoate

[1526] The title compound was produced in analogy to intermediate 4, step 4, from methyl (2S)-2-amino-3-[2-(2-oxo-3-piperidyl)-lH-indol-3-yl]propanoate; hydrochloride. Light yellow solid, MS: 501.1 [M+H]+.5: Methyl (2S)-2- -(2-ni -3-F2-(2-oxo-3-pi I-IH-

[1527]

[1528] indol-3-

[1529] The title compound was produced in analogy to intermediate 11, step 4, from methyl (2S)-2-[(2-nitrophenyl)sulfonylamino]-3-[2-(2-oxo-3-piperidyl)-lH-indol-3-yl]propanoate. Yellow solid, MS: 515.1 [M+H]+.

[1530] 6: tert-Butyl 2-(2-tert-butoxy-2-oxo-ethyl)-3-F(2S)-3-methoxy-2-

[1531]

[1532]

[1533] -3 -oxo-i:-l -carboxylate

[1534] To a solution of methyl (2S)-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-[2-(2-oxo-3-piperidyl)-lH-indol-3-yl]propanoate (1.00 g, 1.94 mmol) in dichloromethane (15 mL) were added N, N-diisopropylethylamine (0.85 mL, 4.86 mmol), 4-dimethylaminopyridine (190 mg, 1.55 mmol) and di-tert-butyl-dicarbonate (2.23 mL, 9.72 mmol) in turn at 25°C, then after 16 h the reaction mixture was partitioned between dichloromethane (20 mL) and water (10 mL). The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by chromatography (petroleum ether / ethyl acetate = 1: 1) to produce the title compound (1.00 g, 71%). Light yellow solid, MS: 615.3 [M-Boc+H]+.

[1535] 7: (2S)-3- -tert-Butoxycarbonyl-2-(2-oxo-3

[1536]

[1537] -3-yl]-2-Fmethyl-(2-

[1538]

[1539] sulfonyl-:

[1540]

[1541] acid

[1542] The title compound was produced in analogy to intermediate 4, step 6, from methyl tert-butyl 2-(l-tert-butoxycarbonyl-2-oxo-3-piperidyl)-3-[(2S)-3-methoxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]indole-l -carboxylate. Light yellow solid, MS: 601.2 [M+H]+.

[1543]

[1544] 8: tert-Butyl 3-F(2S)-3-allyloxy-2- -(2-ni -3-oxo- 1-2- (2-oxo-3-pi

[1545]

[1546] ;-l -carboxylate

[1547] The title compound was produced in analogy to intermediate 4, step 7, from (2S)-3-[l-tert-butoxycarbonyl-2-(2-oxo-3-piperidyl)indol-3-yl]-2-[methyl-(2-nitrophenyl)sulfonyl-amino]propanoic acid. Light yellow solid, MS: 641.2 [M+H]+.

[1548]

[1549] 9: tert-Butyl 3-F(2S)-3-allyloxy-2- -(2-ni -3-oxo- 1-2- ( 1 -tert-butoxycarbonyl-2-oxo-3 -pi

[1550]

[1551] ;-l -carboxylateTo a solution of tert-butyl 3-[(2S)-3-allyloxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]-2-(2-oxo-3-piperidyl)indole-l-carboxylate (700 mg, 1.09 mmol) in dichloromethane (15 mL) were added 4-dimethylaminopyridine (267 mg, 2.19 mmol) and di-tert-butyl-dicarbonate (1.25 mL, 5.46 mmol) at 25°C, then after 10 h the reaction mixture was partitioned between dichloromethane (20 mL) and water (10 mL). The organic layer was washed with brine (5 mL), dried over sodium sulfate, and concentrated to give a residue, which was purified by chromatography (petroleum ether / ethyl acetate = 3: 1) to produce the title compound (500 mg, 61%). Light yellow solid, MS: 741.2 [M-Boc+H]+.

[1552] Step 10: tert-Butyl 3-r(2S)-3-allyloxy-2-(methylamino)-3-oxo-propyl]-2-(l-tert-butoxycarbonyl-2-oxo -3 -piperidyl)indole-l -carboxylate

[1553] The title compound was produced in analogy to intermediate 4, step 8, from tert-butyl 3-[(2S)-3-allyloxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]-2-(l-tert-butoxycarbonyl-2-oxo-3-piperidyl)indole-l-carboxylate. Light yellow oil, MS: 556.4 [M+H]+.

[1554] Intermediate 22

[1555] Di-tert-butyl-5-[l-tert-butoxycarbonyl-3-[(2S)-3-methoxy-2-(methylamino)-3-oxo-propyl] indol-2-yl]-2-oxo-hexahydropyrimidine-l,3-dicarboxylate

[1556]

[1557] Step 1: Methyl (2S)-3-r2-(2-benzyloxypyrimidin-5-yl)-lH-indol-3-yl]-2-(tert-butoxy-carbonylamino) propanoate

[1558] The title compound was produced in analogy to intermediate 20, step 1, replacing 3 -bromo- 1-methyl-pyridin-2-one by 2-benzyloxy-5-bromo-pyrimidine. Light brown solid, MS: 503.3 [M+H]+.

[1559] 2: Methvl(2S)-2-(tert-butoxvcarbonvlamino)-3-r2-(2-' idin-5-vl)-lH-indol-3-

[1560]

[1561] The title compound was produced in analogy to intermediate 20, step 2, from methyl (2S)-3-[2-(2-benzyloxypyrimidin-5-yl)-lH-indol-3-yl]-2-(tert-butoxycarbonylamino)propanoate. White solid, MS: 417.2 [M+H]+.

[1562]

[1563] -5 -yl)- 1 H-indol-3 -■ hydrochloride

[1564] The title compound was produced in analogy to intermediate 11, step 2, from methyl (2S)-2-(tert-butoxycarbonylamino)-3-[2-(2-oxohexahydropyrimidin-5-yl)-lH-indol-3-yl]propanoate. Yellow solid, MS: 317.1 [M+H]+.

[1565] 4: Methyl (2S)-2- |-3-F2-C2-< -5-vl)-lH-

[1566]

[1567] indol-3-

[1568] The title compound was produced in analogy to intermediate 4, step 4, from methyl (2S)-2-amino-3-[2-(2-oxohexahydropyrimidin-5-yl)-lH-indol-3-yl]propanoate; hydrochloride.

[1569] Orange solid, MS: 502.1, [M+H]+.

[1570] 5: Methyl (2S)-2- -(2-ni -3-F2-f2-1

[1571]

[1572] 5-yl)-lH-indol-3-’

[1573] To a solution of methyl (2S)-2-[(2-nitrophenyl)sulfonylamino]-3-[2-(2-oxohexahydropyrimidin-5-yl)-lH-indol-3-yl]propanoate (550 mg, 1.1 mmol) in N, N-dimethylformamide (5 mL) was added l,8-diazabicyclo[5.4.0]undec-7-ene (0.33 mL, 2.19 mmol) and iodomethane (0.14 mL, 2.19 mmol) at 25°C, then after 16 h the solution was partitioned between water (5 mL) and ethyl acetate (3×15 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by chromatography (SiO₂ column, dichloromethane / methanol 9:1) to produce the title compound (500 mg, 78%). Yellow solid, MS: 516.1 [M+H]+.

[1574] 6: Di -tert-butyl 5-1 -tert-butoxy carbonyl-3 -

[1575]

[1576] i-3-methoxy-2-|

[1577]

[1578] -(2-

[1579]

[1580] -3-oxo-

[1581]

[1582] -2-yl]-2-oxo-

[1583]

[1584] 1,3-dicarboxylate

[1585] To a solution of methyl (2S)-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-[2-(2-oxohexahydro pyrimidin-5-yl)-lH-indol-3-yl]propanoate (490 mg, 0.95 mmol) in tetrahydrofuran (5 mL) anddichloromethane (3 mL) was added 4-(dimethylamino)pyridine (46.5 mg, 0.38 mmol) and di-tert-butyl -di carb onate (830 mg, 3.8 mmol) at 25°C, then after 3 h the solution was concentrated under reduced pressure. Chromatography of the residue (SiO₂ column, petroleum ether / ethyl acetate 3:1) produced the title compound (370 mg, 46%). Yellow solid, MS: 716.4 [M-Boc+H]+.

[1586] Step 7: Di-tert-butyl-5-ri-tert-butoxycarbonyl-3-r(2S)-3-methoxy-2-(methylamino)-3-oxo- yl] indol-2-yl]-2-oxo-hexahydropyrimidine-l,3-dicarboxylate

[1587] The title compound was produced in analogy to intermediate 4, step 8, from di -tert-butyl 5-[l-tert-butoxycarbonyl-3-[(2S)-3-methoxy-2-[methyl-(2-nitro phenyl)sulfonyl-amino]-3-oxo-propyl]indol-2-yl]-2-oxo-hexahydropyrimidine-l,3-dicarboxylate. Yellow solid, MS: 631.4 [M+H]+.

[1588] Intermediate 23

[1589] tert-Butyl 3-[(2S)-3-methoxy-2-(methylamino)-3-oxo-propyl]-2-[l-(2-trimethylsilyl-ethoxycarbonyl)-4-piperidyl]indole-l-carboxylate

[1590] o

[1591] o

[1592] H

[1593] N

[1594] o

[1595]

[1596] 1: 2-Trimethylsilylethyl 4-1 i-2-(tert-butoxycarbonylamino)-3-methoxy-3-oxo-

[1597]

[1598] - 1 H-indol-2-yl] -3, 6-dihy dro-2H-i;-l -carboxylate

[1599] The title compound was produced in analogy to intermediate 20, step 1, replacing 3 -bromo- 1-methyl-pyridin-2-one by 2-trimethylsilylethyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyridine-1 -carboxylate (CAS-RN 375854-77-6). Light yellow oil, MS: 544.3 [M+H]+.

[1600] 2: 2-Trimethylsilylethyl 4-r3-r(2S)-2-(tert-butoxycarbonylamino)-3-methoxy-3-oxo-

[1601]

[1602] -lH-indol-2-;-l -carboxylate

[1603] The title compound was produced in analogy to intermediate 20, step 2, from 2-trimethylsilylethyl 4-[3-[(2S)-2-(tert-butoxycarbonylamino)-3-methoxy-3-oxo-propyl]-lH-indol-2-yl]-3,6-dihydro-2H-pyridine-l-carboxylate. Light yellow oil, MS: 568.4 [M+Na]+.

[1604]

[1605] 3: 2-Trimethylsilylethyl 4-1 i-2-amino-3 -methoxy-3 -oxo-

[1606]

[1607] -lH-indol-2- ine-1 -carboxylate

[1608] The title compound was produced in analogy to intermediate 11, step 2, from 2-trimethylsilylethyl 4-[3-[(2S)-2-(tert-butoxycarbonylamino)-3-methoxy-3-oxo-propyl]-lH-indol-2-yl]piperidine-l -carboxylate. Light yellow solid, MS: 446.3 [M+H]+.

[1609]

[1610] 4: 2-Trimethylsilylethyl 4-1 i-3 -methoxy -2-

[1611]

[1612] -3-oxo-

[1613]

[1614] -lH-indol-2- ine-1 -carboxylate

[1615] The title compound was produced in analogy to intermediate 4, step 4, from 2-trimethylsilylethyl 4-[3-[(2S)-2-amino-3-methoxy-3-oxo-propyl]-lH-indol-2-yl]piperidine-l-carboxylate. Light yellow solid, MS: 603.3 [M-C2H4+H]+.

[1616]

[1617] 5: 2-Trimethylsilylethyl 4-1 i-3 -methoxy -2-

[1618]

[1619] -(2-ni -3-oxo-i -lH-indol-2-

[1620]

[1621] ine-1 -carboxylate

[1622] The title compound was produced in analogy to intermediate 11, step 4, from 2-trimethylsilylethyl 4-[3-[(2S)-3-methoxy-2-[(2-nitrophenyl)sulfonylamino]-3-oxo-propyl]-lH-indol-2-yl]piperidine-l -carboxylate. Light yellow solid, 617.3 [M-C2H4+H]+.

[1623]

[1624] 6: tert-Butyl 3-r(2S)-3-methoxy-2-| -(2-ni 1-3 -oxo-i 2-ri-(2-trimethylsilylethoxycarbonyl)-4-pi

[1625]

[1626] ;-l -carboxylate

[1627] The title compound was produced in analogy to intermediate 4, step 5, from 2-trimethylsilylethyl 4-[3-[(2S)-3-methoxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]-lH-indol-2-yl]piperidine-l -carboxylate. Light yellow solid, MS: 717.4 [M-C2H4+H]+.

[1628] 7: tert-Butyl 3-r(2S)-3-methoxy-2-(methylamino)-3-oxo-

[1629]

[1630] -2-[l-(2-trimethylsilylethoxycarbonyl)-4-pi

[1631]

[1632] ;-l -carboxylate

[1633] The title compound was produced in analogy to intermediate 4, step 8, from tert-butyl 3-[(2S)-3-methoxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]-2-[l-(2-trimethylsilylethoxycarbonyl)-4-piperidyl]indole-l-carboxylate. Light yellow oil, MS: 560.3 [M+H]+.Intermediate 24

[1634] tert-Butyl 2-(l,l-dioxothian-2-yl)-3-[(2S)-3-methoxy-2-(methylamino)-3-oxo-propyl]indole-1-carboxylate

[1635] °y,o

[1636] „N

[1637] o^y

[1638] H

[1639] N o

[1640] o

[1641] 1: Methyl (2S)-2-(tert-butoxvcarbonylamino)-3-r2-(3,4-dihvdro-2H-thi

[1642]

[1643] -6-vD-lH-

[1644]

[1645] indol-3-

[1646] The title compound was produced in analogy to intermediate 20, step 1, replacing 3 -bromo- 1-methyl-pyridin-2-one by 3,4-dihydro-2H-thiopyran-6-yl trifluoromethanesulfonate. Yellow solid, MS: 361.1 [M-C4H8+H]+.

[1647] 2: Methyl (2S)-2-(tert-butoxvcarbonvlamino)-3-r2-(l, l-dioxo-3,4-dihydro-2H-thiopyran-6-

[1648]

[1649] yl)-lH-indol-3-

[1650] To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[2-(3,4-dihydro-2H-thiopyran-6-yl)-lH-indol-3-yl]propanoate (960 mg, 2.3 mmol) in dichloromethane (20 mL) was added 3-chloroperoxybenzoic acid (796 mg, 4.61 mmol) at 25°C, then after 3 h another portion of 3-chloroperoxybenzoic acid (398 mg, 2.3 mmol) was added and stirring was continued for another 2 h. The suspension was then filtered, and the filtrate was concentrated to give a residue, which was purified by chromatography (petroleum ether / ethyl acetate 5:2) to produce the title compound (750 mg, 64%). Yellow solid, MS: 349.1 [M-Boc+H]+.

[1651] Step 3: Methyl (2S)-2-(tert-butoxycarbonylamino)-3-r2-(l,l-dioxothian-2-yl)-lH-indol-3->

[1652] To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[2-(l,l-dioxo-3,4-dihydro-2H-thiopyran-6-yl)-lH-indol-3-yl]propanoate (750 mg, 1.67 mmol,) in methanol (30 mL) was added palladium (10% on activated charcoal, 750 mg), and the mixture was stirred at atmospheric pressure under a hydrogen atmosphere. After 4 h the reaction mixture was filtered throughdiatomaceous earth, and the filtrate was concentrated to produce the title compound (690 mg, 87%). Yellow solid, MS: 351.1 [M-Boc+H]+.

[1653] 4: Methyl (2S)-2-amino-3-r2-(l,l-dioxothian-2-yl)-lH-indol-3-

[1654]

[1655] hydrochloride

[1656] The title compound was produced in analogy to intermediate 11, step 2, from methyl (2S)-2-(tert-butoxycarbonylamino)-3-[2-(l, l-dioxothian-2-yl)-lH-indol-3-yl]propanoate. Yellow solid, MS: 351.1 [M+H]+.

[1657] 5: Methyl (2S)-3-r2-(l,l-dioxothian-2-yl)-lH-indol-3-yl]-2-

[1658]

[1659] The title compound was produced in analogy to intermediate 4, step 4, from methyl (2S)-2-amino-3-[2-(l,l-dioxothian-2-yl)-lH-indol-3-yl]propanoate; hydrochloride. Yellow solid, MS: 536.1[M+H]+.

[1660] 6: Methyl (2S)-3-r2-(l,l-dioxothian-2-yl)-lH-indol-3-yl]-2- -(2-i

[1661]

[1662] The title compound was produced in analogy to intermediate 11, step 4, from methyl (2S)-3-[2-(l,l-dioxothian-2-yl)-lH-indol-3-yl]-2-[(2 -nitrophenyl) sulfonylamino]propanoate. Light brown solid, MS: 550.1[M+H]+.

[1663] 7: tert-Butyl 2-(l,l-dioxothian-2-yl)-3-r(2S)-3-methoxy-2-|

[1664]

[1665] -(2-ni

[1666]

[1667] -3 -oxo-i:-l -carboxylate

[1668] The title compound was produced in analogy to intermediate 4, step 5, from methyl (2S)-3-[2-(l,l-dioxothian-2-yl)-lH-indol-3-yl]-2-[methyl-(2-nitro phenyl)sulfonyl-amino]propanoate. Yellow solid, MS: 550.1 [M-Boc+H]+.

[1669] 8: tert-Butyl 2-(l,l-dioxothian-2-yl)-3-[(2S)-3-methoxy-2-(methylamino)-3-oxo-

[1670]

[1671] -I -carboxylate

[1672] The title compound was produced in analogy to intermediate 4, step 8, from tert-butyl 2-(l, 1-dioxothian-2-yl)-3-[(2S)-3-methoxy-2-[methyl-(2 -nitro phenyl)sulfonyl-amino]-3-oxo-propyl]indole-l -carboxylate. Yellow oil, MS: 465.1 [M+H]+.Intermediate 25

[1673] tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo-propyl]-2-[(2-oxopyrrolidin-l-yl)methyl]indole-l-carboxylate

[1674]

[1675] Step 1: 4-Chloro-N-(lH-indol-2-ylmethyl)butanamide

[1676] To a solution of 2-(aminomethyl)indole (6.00 g, 41.0 mmol) and triethylamine (17.2 mL, 123 mmol) in dichloromethane (120 mL) was added dropwise 4-chlorobutyryl chloride (5.51 mL, 49.3 mmol) at 0°C, and the solution was stirred at 25°C for 1 h, then partitioned between water (100 mL) and dichloromethane (100 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to produce the title compound (13.0 g, 90%), which was used directly in the next step. Orange oil, MS: 251.0 [M+H]+.

[1677] Step 2: l-(lH-Indol-2-ylmethyl)pyrrolidin-2-one

[1678] To a solution of 4-chloro-N-(lH-indol-2-ylmethyl)butanamide (13.0 g, 51.9 mmol) in tetrahydrofuran (200 mL) was added sodium hydride (60% dispersion in mineral oil, 4.15 g, 104 mmol) in portions at 0°C. Then the suspension was warmed to 25°C and stirred for 1 h. The reaction mixture was partitioned between water (200 mL) and ethyl acetate (200 mL). The organic layer was washed with brine (200 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by chromatography (SiO2;petroleum ether / ethyl acetate 2: 1) to produce the title compound (6.70 g, 56%). Light yellow solid, MS: 215.1 [M+H]+.

[1679] Step 3: tert-butyl 2-l(2-oxopyrrolidin-l-yl)methyl1indole-l-carboxylate

[1680] To a solution of l-(lH-indol-2-ylmethyl)pyrrolidin-2-one (6.20 g, 28.9 mmol) and 4-(dimethylamino)pyridine (1.77 g, 14.5 mmol) in dichloromethane (130 mL) were added triethylamine (8.0 mL, 57.9 mmol) and di-tert-butyl-dicarbonate (7.58 g, 34.7 mmol) at 25°C. After 16 h the solution was washed between water (50 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate and concentrated. Chromatography of the residue (SiCL, petroleum ether / ethyl acetate 2: 1) produced the title compound (9.3 g, 99%). Yellow oil, MS: 315.1 [M+H]+, ESL

[1681]

[1682] 4: tert-Butyl 3-bromo-2- in-1-;-l -carboxylate

[1683] To a solution of tert-butyl 2-[(2-oxopyrrolidin-l-yl)methyl]indole-l -carboxylate (9.0 g, 28.6 mmol) in dichloromethane (100 mL) was added N-bromosuccinimide (6.62 g, 37.2 mmol) in portions at 0°C, then after 2 h the reaction mixture was treated with water (50 mL). The organic layer was washed with brine (40 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography (SiO2; petroleum ether / ethyl acetate 3:1) to produce the title compound (8.5 g, 71%). Orange oil, MS: 393.0 [M+H]+.

[1684] 5: tert-Butyl 3-r(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methoxy-3-oxo-

[1685]

[1686] 2-F (2-oxopyrrolidin- 1 -

[1687]

[1688] ;-l -carboxylate

[1689] To a suspension of tert-butyl 3 -bromo-2-[(2-oxopyrrolidin-l-yl)methyl]indole-l -carboxylate (2.2 g, 5.59 mmol) and methyl (2R)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-iodo-propanoate (CAS-RN 156017-42-4; 3.28 g, 7.27 mmol) in dimethoxy ethane (40 mL) were added [Ir(dtbbpy)[dF(CF3)ppy]2]PF6(CAS-RN 870987-63-6; 62.8 mg, 0.06 mmol), dichloro(4,4'-di-tert-butyl-2,2'-bipyridine)nickel (CAS-RN 1034901-50-2; 11.1 mg, 0.03 mmol), tris(trimethylsilyl)silane (1.39 g, 5.59 mmol) and sodium carbonate (1.19 g, 11.2 mmol) in turn at 25°C under a nitrogen atmosphere. The mixture was purged with nitrogen, then irradiated with a 455 nm blue light-emitting diode at 25°C while stirring. After 16 h insoluble material was removed by filtration, and the filtrate was concentrated. The residue was purified by chromatography (SiO₂; petroleum ether / ethyl acetate 2: 1) to produce the title compound (1.30 g, 29%). Yellow solid, MS: 638.5 [M+H]+.

[1690] 6: tert-Butyl 3 -r(2S)-2-amino-3-m ethoxy-3 -oxo-i

[1691]

[1692] idin-1-

[1693]

[1694] -I -carboxylate

[1695] To a light yellow solution of tert-butyl 3-[(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methoxy-3-oxo-propyl]-2-[(2-oxopyrrolidin-l-yl)methyl]indole-l-carboxylate (1.30 g, 2.04mmol) in acetonitrile (26 mL) was added diethylamine (2.32 mL, 22.5 mmol) at 25°C, then after 3 h the reaction mixture was evaporated. The residue was purified by flash chromatography (SiO2; dichloromethane / methanol 9:1) to produce the title compound (800 mg, 85%). Yellow solid, MS: 416.3 [M+H]+.

[1696] 7: tert-Butyl 3-l(2S)-3-methoxy-2-| -3-oxo- 1-2-

[1697]

[1698] -I--;-l -carboxylate

[1699] The title compound was produced in analogy to intermediate 4, step 4, from tert-butyl 3-[(2S)-2-amino-3-methoxy-3-oxo-propyl]-2-[(2-oxopyrrolidin-l-yl)methyl]indole-l -carboxylate. Yellow solid, MS: 601.2 [M+H]+.

[1700]

[1701] 8: tert-Butyl 3-l(2S)-3-methoxy-2-| -(2-ni 1-3 -oxo-i 2-1 (2-oxonyrrolidin- 1 -

[1702]

[1703] ;-l -carboxylate

[1704] The title compound was produced in analogy to intermediate 11, step 4, from tert-butyl 3-[(2S)-3-methoxy-2-[(2-nitrophenyl)sulfonylamino]-3-oxo-propyl]-2-[(2-oxopyrrolidin-l-yl)methyl]indole-l -carboxylate. Yellow solid, MS: 615.3 [M+H]+.

[1705]

[1706] 9: (2S)-3- -tert-butoxycarbonyl-2-l(2-. idin-1 -■

[1707]

[1708] -3-yl]-2-lmethyl-(2-

[1709]

[1710] acid

[1711] The title compound was produced in analogy to intermediate 4, step 6, from tert-butyl 3-[(2S)-3-methoxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]-2-[(2-oxopyrrolidin-l-yl)methyl]indole-l -carboxylate. Yellow solid, MS: 601.3 [M+H]+.

[1712]

[1713] -3-oxo- 2-1 (2-oxonyrrolidin- 1 -

[1714]

[1715] :-l -carboxylate

[1716] The title compound was produced in analogy to intermediate 4, step 7, from (2S)-3-[l-tert-butoxycarbonyl-2-[(2-oxopyrrolidin-l-yl)methyl]indol-3-yl]-2-[methyl-(2-nitrophenyl)sulfonyl-amino]propanoic acid. Yellow solid, MS: 641.2 [M+H]+.

[1717] 11: tert-Butyl 3- i-3 -allyloxy -2-(methylamino)-3 -oxo-i

[1718]

[1719] -2-1(2-. idin-1-

[1720]

[1721] ;-l -carboxylate

[1722] The title compound was produced in analogy to intermediate 4, step 8, from tert-butyl 3-[(2S)-3-allyloxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]-2-[(2-oxopyrrolidin-l-yl)methyl]indole-l -carboxylate. Yellow oil, MS: 456.4 [M+H]+.

[1723] Intermediate 26

[1724] tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo-propyl]-2-[(l,l-dioxo-l.,2-thiazolidin-2-yl)methyl]indole-l-carboxylate

[1725]

[1726] The title compound was produced in analogy to intermediate 25, replacing 4-chlorobutyryl chloride in step 1 by 3 -chloropropanesulfonyl chloride. Colourless oil, MS: 492.2 [M+H]+.

[1727] Intermediate 27

[1728] tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo-propyl]-2-[2-(dimethylamino)-2-oxo-ethyl]indole-l-carboxylate

[1729]

[1730] Step 1: tert-Butyl 3 -bromo-2-(2-tert-butoxy-2-oxo-ethyl)indole-l -carboxylate

[1731] The title compound was produced in analogy to intermediate 25, step 4, replacing tert-butyl 2-[(2-oxopyrrolidin-l-yl)methyl]indole-l -carboxylate by tert-butyl 2-(2-tert-butoxy-2-oxo-ethyl)indole-l -carboxylate (CAS-RN 2242452-80-6). Off-white solid, MS: 432.1 [M+Na]+.

[1732] Step 2: tert-Butyl 2-(2-tert-butoxy-2-oxo-ethyl)-3-l(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3 -m ethoxy-3 -oxo-propyllindole-1 -carboxylateThe title compound was produced in analogy to intermediate 25, step 5, from tert-butyl 3-bromo-2-(2-tert-butoxy-2-oxo-ethyl)indole-l -carboxylate. Light yellow solid, MS: 677.3 [M+Na]+.

[1733] Step 3: tert-Butyl 3-[(2S)-2-amino-3-methoxy-3-oxo-propyl]-2-(2-tert-butoxy-2-oxo-ethyl)indole- 1 -carboxylate

[1734] The title compound was produced in analogy to intermediate 25, step 6, from tert-butyl 2-(2-tert-butoxy-2-oxo-ethyl)-3-[(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methoxy-3-oxo-propyl]indole-l -carboxylate. Light yellow oil, MS: 433.3[M+H]+.

[1735] 4: tert-Butyl 2-(2-tert-butoxy-2-oxo-ethyl)-3-F(2S)-3-methoxy-2-

[1736]

[1737]

[1738] -3 -oxo-i:-l -carboxylate

[1739] The title compound was produced in analogy to intermediate 4, step 4, from tert-butyl 3-[(2S)-2-amino-3-methoxy-3-oxo-propyl]-2-(2-tert-butoxy-2-oxo-ethyl)indole-l-carboxylate. Light yellow solid, MS: 640.1 [M+Na]+.

[1740] 5: tert-Butyl 2-(2-tert-butoxy-2-oxo-ethyl)-3-|Y2S)-3-methoxy-2-

[1741]

[1742]

[1743] -3 -oxo-i:-l -carboxylate

[1744] The title compound was produced in analogy to intermediate 11, step 4, from tert-butyl 2-(2-tert-butoxy-2-oxo-ethyl)-3-[(2S)-3-methoxy-2-[(2-nitrophenyl) sulfonylamino]-3-oxo-propyl]indole-1 -carboxylate. Light yellow oil, MS: 654.3 [M+Na]+.

[1745] 6: tert-Butyl 2-(2-tert-butoxy-2-oxo-ethyl)-3-|Y2S)-3-methoxy-2-

[1746]

[1747] -(2-nitro-

[1748]

[1749] 1-3 -oxo-i

[1750]

[1751] -I -carboxylate

[1752] A solution of tert-butyl 2-(2-tert-butoxy-2-oxo-ethyl)-3-[(2S)-3-methoxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]indole-l-carboxylate (320 mg, 0.51 mmol) and trifluoroacetic acid (1.0 mL, 13 mmol) in dichloromethane (10 mL) was stirred at 25°C for 2 h, then the solution was concentrated to produce the title compound (240 mg, 95%). Yellow solid, MS: 476.2 [M+Na]+.

[1753] Step 7: 2-[3-[(2S)-3-Methoxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]-lH-indol-2-yllacetic acid

[1754] To a solution of 2-[3-[(2S)-3-methoxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]-lH-indol-2-yl]acetic acid (480 mg, 1.01 mmol) and dimethylamine hydrochloride (123 mg, 1.51mmol) in N, N-dimethylformamide (8 mL) were added diisopropylethylamine (0.7 mL, 4.0 mmol) and O-(7-azabenzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (768 mg, 2.02 mmol) at 25°C, then after 16 the reaction mixture was partitioned between dichloromethane (20 mL) and water (10 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, and concentrated. The residue was purified by chromatography (SiO₂; petroleum ether / ethyl acetate 5:4) to produce the title compound (500 mg, 88%). Yellow oil, MS: 503.2 [M+H]+.

[1755] 8: Methyl (2S)-3-r2-r2-(dimethylamino)-2-oxo-ethyl]-lH-indol-3-yl]-2-rmethyl-(2-

[1756]

[1757] The title compound was produced in analogy to intermediate 4, step 5, from methyl (2S)-3-[2-[2-(dimethylamino)-2-oxo-ethyl]-lH-indol-3-yl]-2-[methyl-(2-nitrophenyl)sulfonyl-amino]propanoate. Yellow oil, MS: 603.3 [M+H]+.

[1758] 9: tert-Butyl 2-r2-(dimethylamino)-2-oxo-i

[1759]

[1760] -3-r(2S)-3-methoxy-2-|

[1761]

[1762] -(2-

[1763]

[1764] -3-oxo-

[1765]

[1766] ;-l -carboxylate

[1767] The title compound was produced in analogy to intermediate 4, step 6, from tert-butyl 2-[2-(dimethylamino)-2-oxo-ethyl]-3-[(2S)-3-methoxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]indole-l -carboxylate. Yellow solid, MS: 589.2 [M+H]+.

[1768] 10: (2S)-3-ri-tert-Butoxycarbonyl-2-r2-(dimethylamino)-2-oxo-ethyl]indol-3-yl]-2-

[1769]

[1770] -(2-: ic acid

[1771] The title compound was produced in analogy to intermediate 4, step 7, from (2S)-3-[ 1 -tertbutoxy carbonyl-2-[2-(dimethylamino)-2-oxo-ethyl]indol-3-yl]-2-[methyl-(2-nitrophenyl)sulfonyl-amino]propanoic acid. Yellow oil, MS: 629.2 [M+H]+.

[1772] Step 11: tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo-propyl]-2-[2-(dimethylamino)-2-oxo-ethy 11 indol e- 1 -carb oxy 1 ate

[1773] The title compound was produced in analogy to intermediate 4, step 8, from tert-butyl 3-[(2S)-3-allyloxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]-2-[2-(dimethylamino)-2-oxo-ethyl]indole-l -carboxylate. Yellow oil, MS: 444.2 [M+H]+.Intermediate 28

[1774] tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo-propyl]-2-(2-ethoxy-2-oxo-ethyl)indole-l-carboxylate

[1775] O 7 -N x-o H o ' N

[1776]

[1777] 1: Methyl (2S)-3-r2-(2-ethoxy-2-oxo-ethyl)-lH-indol-3-yll-2-| -(2-ni sulfonyl-:

[1778]

[1779] A suspension of methyl (2S)-3-(lH-indol-3-yl)-2-[methyl-(2-nitrophenyl)sulfonyl-amino]propanoate (CAS-RN 856865-77-5; 30.0 g, 71.9 mmol), ethyl bromoacetate (23.9 mL, 216 mmol), norbornene (13.5 g, 143 mmol), potassium carbonate (24.8 g, 180 mmol) and palladium(II) chloride (2.55 g, 14.4 mmol) in N, N-dimethylformamide (300 mL) and water (30 mL) was stirred at 60°C for 2.5 h. After cooling the reaction mixture was poured into brine (3 L) and extracted with ethyl acetate (5 x 300 ml). The organic layers were combined, washed with 5% aq. lithium chloride solution (1 L), and evaporated. The residue was purified by chromatography (SiO2; dichloromethane / ethyl acetate 95:5) to produce the title compound (33.1 g, 89%). Light brown foam, MS: 504.1 [M+H]+.

[1780] Step 2: tert-Butyl 2-(2-ethoxy-2-oxo-ethyl)-3-[(2S)-3-methoxy-2-[methyl-(2-nitrophenyl)-sulfonyl-amino]-3-oxo-propvl]indole-l-carboxylate)

[1781] To the solution of methyl (2S)-3-[2-(2-ethoxy-2-oxo-ethyl)-lH-indol-3-yl]-2-[methyl-(2-nitrophenyl)sulfonyl-amino]propanoate (33.1 g, 65.8 mmol) in dichloromethane (350 mL) was added di-tert-butyldicarbonate (15.1 g, 69.1 mmol) and 4-dimethylaminopyridine (804 mg, 6.58 mmol) and the resulting mixture was stirred at 30°C for 45 min, then the reaction mixture was washed with saturated aq. sodium hydrogen carbonate solution (3 x 300 mL) and saturated aq. ammonium chloride solution (2 x 300 mL). The organic layer was evaporated in vacuo, and the residue was purified by chromatography (SiO2; ethyl acetate / cyclohexane 1:1) to produce thetitle compound (36.2 g, 75%). White solid, MS: 602.2 [M-H].

[1782] 3: (2S)-3-ri-tert-Butoxycarbonyl-2-(2-ethoxy-2-oxo-ethyl)indol-3-yl]-2-rmethyl-(2-

[1783]

[1784] acid):

[1785] To a solution of tert-butyl 2-(2-ethoxy-2-oxo-ethyl)-3-[(2S)-3-methoxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]indole-l-carboxylate (36.2 g, 60.04 mmol) and triethylamine (58.6 mL, 420 mmol) in acetonitrile (700 mL) and water (70 mL) lithium bromide (36.5 g, 0.42 mol) was added at room temperature, and the the resulting mixture was stirred at 50°C for 72 h. After cooling the reaction mixture was diluted with water (500 mL) and the pH of the reaction mixture was adjusted to ~4 using 6 M aq. hydrochloric acid solution. The aqueous layer was extracted with ethyl acetate (3 x 500 mL), the combined organic layers were washed with brine and evaporated. Chromatograhy (SiO₂; ethyl acetate / cyclohexane / acetic acid 10: 10:0.02) produced the title compound (24.5 g, 61%). Light yellow foam, MS: 588.1 [M-H].

[1786] Step 4: tert-Butyl 3-[(2S)-3-allyloxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]-2-(2-ethoxy-2-oxo-ethyl)indole- 1 -carboxylate)

[1787] To a solution of (2S)-3-[l-tert-butoxycarbonyl-2-(2-ethoxy-2-oxo-ethyl)indol-3-yl]-2-[methyl-(2-nitrophenyl)sulfonyl-amino]propanoic acid (24.9 g, 42.2 mmol) in dry N, N-dimethylformamide (650 mL), were added triethylamine (29.4 mL, 211 mmol) and allyl bromide (18.2 mL, 211 mmol) at room temperature. The reaction mixture was stirred at 50°C for 1 h, then cooled to room temperature, diluted with brine (6 L) and extracted with ethyl acetate (3 x 800 mL). The combined organic layers were washed with 5% aq. lithium chloride solution (500 mL) and evaporated under reduced pressure to produce the title compound (27.8 g, 92%), which was directly used in the next step. Light brown oil, MS: 574.1 [M-isobutene+H]+.

[1788] Step 5: tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo-propyl]-2-(2-ethoxy-2-oxo-ethyl)indole- 1 -carboxylate)

[1789] A solution of tert-butyl 3-[(2S)-3-allyloxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]-2-(2-ethoxy-2-oxo-ethyl)indole-l -carboxylate (27.8 g, 44.1 mmol) inN, N-dimethylformamide was cooled to 0°C, then sodium thiophenolate (6.99 g, 52.9 mmol) was added in five portions over 15 min, then after 4 h the reaction mixture was partitioned between brine (3 L) and ethyl acetate (1 L). The organic layer was washed with 5% aq. lithium chloridesolution and evaporated. Chromatography (SiO₂; dichloromethane / methanol 19:1) produced the title compound (15.6 g, 72%). Light yellow oil, MS: 445.20 [M+H]+.

[1790] Alternative synthesis o f tert-butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo-propyll-2-(2-ethoxy-2-oxo-ethyl)indole-l -carboxylate (intermediate 28):

[1791] The title compound was produced in analogy to intermediate 25, steps 4-9, replacing tert-butyl 2-[(2-oxopyrrolidin-l-yl)methyl]indole-l -carboxylate in step 4 by tert-butyl 2-(2-ethoxy-2-oxo-ethyl)indole-l -carboxylate (CAS-RN 172226-77-6). Yellow oil, MS: 445.3 [M+H]+.

[1792] Intermediate 29

[1793] tert-Butyl 4-[4-chloro-2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]-3-[(3-formyl-2-pyridyl)sulfanyl] phenyl] benzoate

[1794]

[1795] To a solution of 9H-fluoren-9-ylmethyl N-[[6-bromo-3-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate (CAS-RN 2097290-48-5; 3.00 g, 5.17 mmol) and 4-(tert-butoxycarbonyl)phenylboronic acid (1.21 g, 5.43 mmol) in toluene (30 mL) and water (3 mL) was added potassium phosphate (1.65 g, 7.76 mmol) and bis(tri-tert-butylphosphine)palladium(0) (132 mg, 0.26 mmol), then the mixture was heated at 80°C for 5 h-After cooling the reaction mixture was partitioned between water (40 mL) and ethyl acetate (50 mL). The organic layer was dried over sodium sulfate and evaporated to produce the title compound (2.90 g, 77%). Yellow solid, MS: 677.1 [M+H]+.

[1796] The following intermediates were produced in analogy to intermediate 29, replacing 9H-fluoren-9-ylmethyl N-[[6-bromo-3-chloro-2-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate by the appropriate starting material.Int. Name Starting material MS (m / z) 30 tert-Butyl 4-[4-(difluoromethyl)-2- 9H-Fluoren-9-ylmethyl N- [ [6-bromo- 693.2 [(9H-fluoren-9-ylmethoxycarbonyl- 3 -(difluoromethyl)-2- [(3 -formyl-2- [M+H]+amino)methyl] -3 - [(3 -formyl-2- py ri dy 1)- sulfanyl ] phenyl ] methyl ] - pyridyl)sulfanyl]phenyl]benzoate carbamate (intermediate 1)

[1797] O

[1798] rys.

[1799] c> O V'

[1800] Y ° \

[1801] « HN L

[1802] \ T II J

[1803] F

[1804] 31 tert-Butyl 4-[2-[(9H-fluoren-9- 9H-Fluoren-9-ylmethyl N- [ [6-bromo- 657.2 ylmethoxycarbonylamino)methyl]-3- 2-[(3-formyl-2-pyridyl)sulfanyl]-3- [M+H]+[(3-formyl-2-pyridyl)sulfanyl]-4- methy 1 -phenyl ] methyl ] carb amate

[1805] methy 1 -phenyl ]b enzoate (CAS-RN 2377676-63-4)

[1806] 0

[1807] ° O V'

[1808] ° \

[1809]

[1810] Int. Name Starting material MS (m / z)

[1811] 32 tert-Butyl 4-[2-[(9H-fluoren-9- 9H-Fluoren-9-ylmethyl N- [ [6-bromo- 661.1 ylmethoxycarbonylamino)methyl]-4- 3 -fluoro-2-[(3 -formyl-2-pyridyl)- [M+H]+fluoro-3 -[(3 -formyl-2-pyridyl)- sulfanyl]phenyl]methyl]carbamate sulfanyl]phenyl]benzoate (CAS-RN 2377676-62-3)

[1812] o

[1813] 'sss / o^o V

[1814] Y0\

[1815] 33 tert-Butyl 4-[2-[(9H-fluoren-9- 9H-Fluoren-9-ylmethyl N- [ [2-bromo- 643.2 ylmethoxycarbonylamino)methyl]-3- 6-[(3-formyl-2-pyridyl)sulfanyl]- [M+H]+[(3-formyl-2-pyridyl)sulfanyl]- phenyl]methyl]carbamate (CAS-RN phenyl]benzoate 2377676-61-2)

[1816] O

[1817] >=ss / O O

[1818] Y0\

[1819]

[1820] The following intermediates (Int.) were produced in analogy to intermediate 2, replacing 4-pyridinecarboxaldehyde in step 1 by the appropriate aldehyde.Int. Name Aldehyde MS (m / z) 34 tert-Butyl 3-[(2S)-3-methoxy-2-(methylamino)-3-oxo- Pyridine-3- 424.2 propyl]-2-(3-pyridylmethyl)indole-l-carboxylate carbaldehyde [M+H]+

[1821] 0

[1822] y '_"oZ"

[1823] CXX

[1824] oXo

[1825] \

[1826] 35 tert-Butyl 3-[(2S)-3-methoxy-2-(methylamino)-3-oxo- 1 -Methyl-imidazole-2- 427.2 propyl]-2-[( 1 -methylimidazol-2-yl)methyl]indole- 1 - carbaldehyde. [M+H]+carboxylate

[1827] On->

[1828] \

[1829] 36 tert-Butyl 3-[(2S)-3-methoxy-2-(methylamino)-3-oxo- 3-Methylpyridine-4- 438.2 propyl]-2-[(3-methyl-4-pyridyl)methyl]indole-l- carbaldehyde [M+H]+carboxylate

[1830] o

[1831] ■y_o

[1832] LXK /

[1833] H> 4 ^

[1834] 0^°

[1835] \

[1836]

[1837] Int. Name Aldehyde MS (m / z) 37 tert-Butyl 3-[(2S)-3-methoxy-2-(methylamino)-3-oxo- 4-Methyl-l,2,5- 429.1 propyl]-2-[(4-methyl-l,2,5-oxadiazol-3- oxadiazole-3- [M+H]+y l)methy 1 ] indol e- 1 -carb oxy 1 ate carbaldehyde (CAS- RN 90507-35-0) y / "

[1838] Ohv

[1839] NO'N

[1840] 0^°

[1841] \

[1842] 38 tert-Butyl 3-[(2S)-3-methoxy-2-(methylamino)-3-oxo- Pyridine-2- 424.2 propyl]-2-(2-pyridylmethyl)indole-l -carboxylate carbaldehyde. [M+H]+

[1843] y / - UL / A

[1844] H?

[1845] \ _ /

[1846] ' O^°

[1847] \

[1848]

[1849] The following intermediates (Int.) were produced in analogy to intermediate 4, replacing 3-thiophenecarboxaldehyde in step 1 by the appropriate aldehyde.Int. Name Aldehyde MS (m / z) 39 tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo- l-[[2- 569.4 propyl]-2-[[l-(2-trimethylsilylethoxymethyl)pyrazol-4- (Trimethylsilyl)ethoxy [M+H]+yl]methyl]indole-l -carboxylate ]methyl]-lH-pyrazole- 4-carboxaldehyde

[1850] O

[1851] ■K-O

[1852] (CAS-RN 869558-91- CCK, 8).

[1853] V°

[1854] — Si—

[1855] 1

[1856] 40 tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo- 1 -Methyl- 1,2,3 - 454.3 propyl]-2-[(l -methyltri azol -4-yl)methyl]indole- 1- triazole-4- [M+H]+carboxylate carbaldehyde.

[1857] oR

[1858] H > N. N

[1859] 41 tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo- 1 -Methyl-imidazole-4- 453.3 propyl]-2-[( 1 -methylimidazol-4-yl)methyl]indole- 1 - carbaldehyde. [M+H]+carboxylate

[1860] o

[1861] ^-o

[1862]

[1863] Int. Name Aldehyde MS (m / z) 42 tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo- 1 -Methyl -py razol e-3 - 453.3 propyl]-2-[(l-methylpyrazol-3-yl)methyl]indole-l- carbaldehyde. [M+H]+carboxylate

[1864] y / "

[1865] >-o

[1866] 43 tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo- 2 -Methyl- 1,2,4- 454.2 propyl]-2-[(2-methyl-l,2,4-triazol-3-yl)methyl]indole- triazole-3- [M+H]+1 -carboxylate carbaldehyde.

[1867] O 'V'''

[1868] izbrV

[1869] H 1 hl N

[1870] f-O

[1871]

[1872] Intermediate 44

[1873] tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo-propyl]-2-[(l-tert-butoxycarbonylpyrrol-3-yl)methyl]indole-l-carboxylate

[1874]

[1875] Step 1: Methyl (3S)-l-ri-(p-tolylsulfonyl)pyrrol-3-yl]-2 A9-tetrahydro-lH-pyridol3,4-3 -carboxylate

[1876] To a solution of L-tryptophan methyl ester hydrochloride (17.5 g, 68.7 mmol) in dichloroethane (250 mL) was added l-(p-tolylsulfonyl)pyrrole-3-carbaldehyde (CAS-RN 117954-70-8; 18.8 g, 75.6 mmol). The reaction mixture was heated at 80°C for 5 h, then concentrated under reduced pressure to produce the title compound (34.0 g), which was used directly in the next step.

[1877] Yellow solid, MS: 450.2 [M+H]+.

[1878]

[1879] Step 2: Methyl (3S)-2-methyl-1-[1-(p-tolylsulfonyl)pyrrol-3-yl]-1,3,4,9-tetrahydropyrido[3,4-b]indole-3-carboxylate

[1880] The title compound was produced in analogy to intermediate 2, step 2, from methyl (3S)-l-[l-(p-tolylsulfonyl)pyrrol-3-yl]-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indole-3-carboxylate. Light yellow solid, MS: 464.1 [M+H]+.

[1881]

[1882] Step 3: Methyl (3S)-2-methyl-1-(1H-pyrrol-3-yl)-1,3,4,9-tetrahydropyrido[3,4-b]indole-3-carboxylate

[1883] To a solution of methyl (3S)-2-methyl-l-[l-(p-tolylsulfonyl)pyrrol-3-yl]-l, 3,4,9-tetrahydropyrido[3,4-b]indole-3 -carboxylate (3.0 g, 6.47 mmol) in methanol (60 mL) was added ammonium chloride (1.8 g, 34 mmol) and magnesium (0.8 g, 34 mmol) in six portions in 20-25 min intervals. After each addition of these reagents the temperature rose to 40-45°C, and came back to 35°C within 20-25 min. After completion of this procedure the reaction mixture was diluted with ethyl acetate (150 mL) and treated with 1 M aq. hydrochloric acid solution until everything had dissolved. The mixture was washed with water (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to produce a residue, which was purified by chromatography (SiO2; petroleum ether / ethyl acetate 5:3) to produce the title compound 1.10 g, 52%). Light yellow solid, MS: 310.2 [M+H]+.

[1884] Step 4: Methyl (2S)-2-(methylamino)-3-[2-(1H-pyrrol-3-ylmethyl)-1H-indol-3-yl]propanoate

[1885] The title compound was produced in analogy to intermediate 2, step 3, from methyl (3S)-2-methyl-l-(lH-pyrrol-3-yl)-l,3,4,9-tetrahydropyrido[3,4-b]indole-3-carboxylate. Light yellow solid, MS: 312.2 [M+H]+.

[1886]

[1887] Step 5: Methyl (2S)-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-[2-(1H-pyrrol-3-ylmethyl)-1H-indol-3-The title compound was produced in analogy to intermediate 4, step 4, from methyl (2S)-2-(methylamino)-3-[2-(lH-pyrrol-3-ylmethyl)-lH-indol-3-yl]propanoate. Yellow solid, MS: 497.2 [M+H]+.

[1888] Step 6: tert-Butyl 2-[(1-tert-butoxycarbonylpyrrol-3-yl)methyl]-3-[(2S)-3-methoxy-2-[methyl-(2-

[1889]

[1890] -3-oxo-propyl]indole-1-carboxylate

[1891] To a solution of methyl (2S)-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-[2-(lH-pyrrol-3-ylmethyl)-lH-indol-3-yl]propanoate (1.40 g, 2.82 mmol) in ethyl acetate (28 mL) was added 4-dimethylaminopyridine (138 mg, 1.13 mmol) and di-tert-butyldicarbonate (1.35 g, 6.2 mmol) at 25°C, then after 2 h the reaction mixture was washed with water (15 mL) and brine (15 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue (SiO₂; petroleum ether; petroleum ether / ethyl acetate 7:3) produced the title compound (1.90 g, 96%). Yellow solid, MS: 697.3 [M+H]+..

[1892] Step 7: (2S)-3-[1-tert-Butoxycarbonyl-2-[(1-tert-butoxycarbonylpyrrol-3-yl)methyl]indol-3-yl]-

[1893]

[1894] -2-[methyl-(2-nitrophenyl)sulfonyl-amino]propanoic acid

[1895] The title compound was produced in analogy to intermediate 4, step 6, from tert-butyl 2-[(l -tert-butoxycarbonylpyrrol-3-yl)methyl]-3-[(2S)-3-methoxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]indole-l-carboxylate. Light yellow solid, MS: 683.3 [M+H]+.

[1896]

[1897]

[1898] -butoxycarbonylpyrrol-3-yl)methyl]indole-1-carboxylate

[1899] The title compound was produced in analogy to intermediate 4, step 7, from of (2S)-3-[l-tert-butoxycarbonyl-2-[(l-tert-butoxycarbonylpyrrol-3-yl)methyl]indol-3-yl]-2-[methyl-(2-nitrophenyl)sulfonyl-amino]propanoic acid. Light yellow solid, MS: 723.3 [M+H]+.

[1900] Step 9: tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo-

[1901]

[1902] -2-[(1-tert-

[1903]

[1904] -3-yl)methyl]indole-1-carboxylate

[1905] The title compound was produced in analogy to intermediate 4, step 8, from tert-butyl 3-[(2S)-3-allyloxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]-2-[(l-tert-butoxycarbonylpyrrol-3-yl)methyl]indole-l -carboxylate. Light yellow oil, MS: 538.3 [M+H]+.Intermediate 45

[1906] tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo-propyl]-2-(2-methoxy-3-pyridyl)indole-l-carboxylate

[1907]

[1908] The title compound was produced in analogy to intermediate 12, replacing 2-bromo-1-methoxy-3-methyl-benzene in step 1 by 3-iodo-2-methoxypyridine. Yellow oil, MS: 466.3 [M+H]+.

[1909] Intermediate 46

[1910] tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo-propyl]-2-(4-tert-butoxycarbonylphenyl)indole-l-carboxylate

[1911]

[1912] The title compound was produced in analogy to intermediate 11, replacing 2-methoxyphenylboronic acid in step 1 by 4-(tert-butoxycarbonyl)phenylboronic acid. Yellow oil, MS: 535.4 [M+H]+.

[1913] Intermediate 47

[1914] tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo-propyl]-2-cyclopropyl-indole-l-carboxylate

[1915]

[1916] Step 1: Methyl (2S)-2-(benzyloxycarbonylamino)-3-(2-cyclopropyl-lH-indol-3-yl)propanoate

[1917] To a solution of 2-cyclopropyl-lH-indole (CAS-RN 40478-44-5; 2.00 g, 12.7 mmol) in DCM (15 mL) to give a light yellow suspension, which was added (S)-N-[(benzyloxy)carbonyl]aziridine-2-carboxylic acid methyl ester (CAS-RN 104597-98-0; 2.26 mL, 11.5 mmol), scandium trifluoromethanesulfonate (1.25 g, 2.54 mmol) at 25°C, then after 5 h another portion of (S)-N-[(benzyloxy)carbonyl]aziridine-2-carboxylic acid methyl ester (2.26 mL, 11.5 mmol) and scandium trifluoromethanesulfonate (1.25 g, 2.54 mmol) was added. After another 20 h the reaction mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated.

[1918] Chromatography of the residue (SiO₂; petroleum ether - ethyl acetate gradient) produced the title compound (2.80 g, 45%), which contained the inseparable side product, methyl (2R)-3-(benzyloxycarbonylamino)-2-(2-cyclopropyl-lH-indol-3-yl)propanoate: Light brown oil, MS: 393.3, [M+H]+.

[1919] Step 2: Methyl (2S)-2-amino-3-(2-cyclopropyl-lH-indol-3-yl)propanoate

[1920] To a solution of methyl (2S)-2-(benzyloxycarbonylamino)-3-(2-cyclopropyl-lH-indol-3-yl)propanoate (3.0 g, 7.64 mmol) in methanol (30 mL) was added palladium (10% on activated charcoal, 500 mg). The reaction mixture was stirred at 25°C, then insoluble material was removed by filtration, and the filtrate was evaporated to produce the title compound (2.0 g, 69%). Lightyellow oil, MS: 259.1 [M+H]+.

[1921] Step 3: Methyl (2S)-3-(2-cyclopropyl-1H-indol-3-yl)-2-[(2-nitrophenyl)sulfonylamino]propanoate

[1922] The title compound was produced in analogy to intermediate 4, step 4, from methyl (2S)-2-amino-3-(2-cyclopropyl-lH-indol-3-yl)propanoate. Light yellow oil, MS: 444.3 [M+H]+.4: Methyl (2R)-2-(2-< -lH-indol-3-yl)-3- -(2-ni

[1923]

[1924] The title compound was produced in analogy to intermediate 11, step 4, from methyl (2S)-3-(2-cyclopropyl-lH-indol-3-yl)-2-[(2-nitrophenyl)sulfonylamino]propanoate. Light yellow oil, MS: 458.1 [M+H]+.

[1925] 5: tert-Butyl 2-< -3-r(2S)-3-methoxy-2-rmethyl-(2-ni

[1926]

[1927]

[1928] 3-oxo-;-l -carboxylate

[1929] The title compound was produced in analogy to intermediate 3, step 4, from methyl (2S)-3-(2-cyclopropyl-lH-indol-3-yl)-2-[methyl-(2-nitrophenyl)sulfonyl-amino]propanoate. Colourless oil, MS: 580.3 [M+Na]+.

[1930]

[1931] 6: (2S)-3-(T -tert-Butoxy carbonyl-2-^ -indol-3-yl)-2-rmethyl-(2-

[1932]

[1933] ic acid

[1934] The title compound was produced in analogy to intermediate 4, step 6, from tert-butyl 2-cyclopropyl-3-[(2S)-3-methoxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]indole-1 -carboxylate. Light yellow oil, MS: 444.3 [M+H]+.

[1935]

[1936] 7: tert-Butyl 3-|Y2S)-3-aHvloxy-2- -(2-ni -3-oxo- 1-2- -indole- 1 -carboxylate

[1937] The title compound was produced in analogy to intermediate 4, step 7, from (2S)-3-(l-tert-butoxycarbonyl-2-cyclopropyl-indol-3-yl)-2-[methyl-(2-nitrophenyl)sulfonyl-amino]propanoic acid. Light yellow oil, MS: 580.2 [M+H]+.

[1938]

[1939] 8: tert-Butyl 3- i-3 -allyloxy-2-(methylamino)-3 -oxo-i

[1940]

[1941] -2-i -indole- 1-carboxylate

[1942] The title compound was produced in analogy to intermediate 4, step 8, from tert-butyl 3-[(2S)-3-allyloxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]-2-cyclopropyl-indole-l-carboxylate. Colourless oil, MS: 399.2 [M+H]+.

[1943] Intermediate 48

[1944] tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo-propyl]-2-tetrahydropyran-4-yl-indole-l-carboxylate

[1945]

[1946] Step 1: Methyl (2S)-2-(tert-butoxycarbonylamino)-3-r2-(3,6-dihydro-2H-pyran-4-yl)-l H-indol-3-yl]propanoate

[1947] The title compound was produced in analogy to intermediate 20, step 1, replacing 3 -bromo- 1-methyl-pyridin-2-one by 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (CAS-RN 188975-30-6). Light yellow solid, MS: 401.2 [M+H]+.

[1948] Step 2: Methyl (2S)-2-(tert-butoxycarbonylamino)-3-(2-tetrahydropyran-4-yl-lH-indol-3-yDpropanoate

[1949] To a mixture of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[2-(3,6-dihydro-2H-pyran-4-yl)-lH-indol-3-yl]propanoate (830.0 mg, 2.07 mmol, 1.0 eq) in methanol (7 mL) was added palladium (10% on activated charcoal, 1.0 g) at 25°C, and the mixture was stirred under a hydrogen atmosphere for 16 h, then the catalyst was removed by filtration and the filtrate was concentrated to produce the title compound (600 mg, 65%). Light yellow solid, MS: 403.3 [M+H]+.

[1950] Step 3: Methyl (2S)-2-amino-3-(2-tetrahydropyran-4-yl-lH-indol-3-yl)propanoate;hydrochloride

[1951] The title compound was produced in analogy to intermediate 11, step 2, from methyl (2S)-2-(tert-butoxycarbonylamino)-3-(2-tetrahydropyran-4-yl-lH-indol-3-yl)propanoate. Light yellow solid, MS: 303.2 [M+H]+.

[1952] Step 4: Methyl (2S)-2-r(2-nitrophenyl)sulfonylamino]-3-(2-tetrahydropyran-4-yl-lH-indol-3-yDpropanoate

[1953] The title compound was produced in analogy to intermediate 4, step 4, from methyl (2S)-2-amino-3-(2-tetrahydropyran-4-yl-lH-indol-3-yl)propanoate;hydrochloride. Light yellow solid,MS: 488.2 [M+H]+.

[1954] 5: Methyl (2S)-2- -(2-ni -3 -(2-1 -4-yl-lH-

[1955]

[1956] indol-3-

[1957] The title compound was produced in analogy to intermediate 11, step 4, from methyl (2S)-2-[(2-nitrophenyl)sulfonylamino]-3-(2-tetrahydropyran-4-yl-lH-indol-3-yl)propanoate. Light yellow solid, MS: 502.1 [M+H]+.

[1958]

[1959] 6: tert-Butyl 3-r(2S)-3-methoxy-2-| -(2-ni 1-3 -oxo-1 2-tetrahydropyran-4-yl-indole-l -carboxylate

[1960] The title compound was produced in analogy to intermediate 4, step 5, from methyl (2S)-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-(2-tetrahydropyran-4-yl-lH-indol-3-yl)propanoate. Light yellow solid, MS: 602.1 [M+H]+.

[1961]

[1962] 7: (2S)-3-(l-tert-Butoxycarbonyl-2- -4-yl-indol-3-yl)-2-rmethyl-(2-

[1963]

[1964] ic acid

[1965] The title compound was produced in analogy to intermediate 4, step 6, from methyl tert-butyl 3-[(2S)-3-methoxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]-2-tetrahydropyran-4-yl-indole-1 -carboxylate. Light yellow solid, MS: 488.1 [M+H]+.

[1966]

[1967] -3-oxo- 1-2-

[1968]

[1969] -4-yl-indole-l -carboxylate

[1970] The title compound was produced in analogy to intermediate 4, step 7, from (2S)-3-(l-tert-butoxycarbonyl-2-tetrahydropyran-4-yl-indol-3-yl)-2-[methyl-(2-nitrophenyl)sulfonyl-amino]propanoic acid. Light yellow oil, MS: 628.1 [M+H]+.

[1971]

[1972] 9: tert-Butyl 3- i-3 -allyloxy-2-(methylamino)-3 -oxo-1

[1973]

[1974] -2- -4-yl-indole- 1 -carboxylate

[1975] The title compound was produced in analogy to intermediate 4, step 8, from tert-butyl 3-[(2S)-3-allyloxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]-2-tetrahydropyran-4-yl-indole-1 -carboxylate. Light yellow oil, MS: 443.2 [M+H]+.Intermediate 49

[1976] 9H-Fluoren-9-ylmethyl (5R)-9-oxa-2,6-diazaspiro [4.5] decane-6-carboxylate; hydrochloride

[1977]

[1978] Step 1: tert-Butyl (5R)-9-oxa-2-aza-6-azoniaspirol4.51decane-2-carboxylate;(2R)-2-hydroxy-2-phenyl-acetate

[1979] tert-Butyl 9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate (CAS-RN 1251003-79-8; 2.4 g, 9.9 mmol) was dissolved in a mixture of toluene (19.2 mL) and 2-propanol (4.8 mL). (R)-(-)-mandelic acid (2.4 g, 15.8 mmol) was added. The reaction mixture was heated to 75°C and then allowed to reach 0°C over 3 h. The precipitate was collected by filtration, washed subsequently with cold toluene / 2-propanol 9:2 (15 mL) and heptane, and dried to produce the title compound (1.67 g, 41%). White solid, MS: 187 [M+H-isobutene]+. A chiral HPLC analysis (Chiralpak IA, H2O / MeOH / 25% aq. ammonia solution 95:5:0.1) confirmed that a single stereoisomer had formed.

[1980] Step 2: tert-Butyl (5R)-9-oxa-2,6-diazaspirol4.51decane-2-carboxylate

[1981]

[1982] tert-Butyl (5R)-9-oxa-2-aza-6-azoniaspiro[4.5]decane-2-carboxylate;(2R)-2-cyclohexyl-2-hydroxy-acetate (1.69 g, 3.54 mmol) was dissolved in dichloromethane (90 mL) and saturated saturated aq. sodium hydrogen carbonate solution (90 ml) was added. The resulting mixture was stirred at 25°C for 2 h, then the aqueous layer was removed, and the organic phase was washed with saturated aq. sodium hydrogen carbonate solution, separated and concentrated to produce the title compound (1.3 g, 89%). Colourless oil, MS: 243.3 [M+H]+.

[1983] Step 3: O2-tert-Butyl O6-(9H-fluoren-9-ylmethyl) (5R)-9-oxa-2,6-diazaspirol4.51decane-2,6-dicarboxylate

[1984] To an ice cooled solution of tert-butyl (5R)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate (1.3 g, 5.36 mmol) and sodium hydrogen carbonate (1.35 g, 16.1 mmol) in 1,4-dioxane (50 mL) and water (7.5 mL), was added a solution of 9-fluorenylmethyl chloroformate (1.53 g, 5.9 mmol) in 1,4-dioxane (25 mL) at 25°C, ten after 90 min the reaction mixture was partition...

Claims

Claims1. A compound of formula (I)or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:Y is CH or N;A is selected from the group consisting of phenyl, pyridyl, and thienyl;B and C are each independently selected from the group consisting of:(i) 5- to 14-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon;(ii) Ce-io-aryl;(iii) 3- to 14-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon; and(iv) C3-10-cycloalkyl;m is an integer selected from the group consisting of 1, 2, and 3;n is an integer selected from the group consisting of 1, 2, and 3;p is an integer selected from the group consisting of 0, 1, and 2;L is selected from the group consisting of a covalent bond, –CH2–, –(CH2)2– and –C1-6-alkyl-CO–*; wherein the asterisk indicates the point of attachment of L to ring B;L1is selected from the group consisting of a covalent bond, –CH2–, –(CH2)2– and –COO–(CH2)p–*; wherein the asterisk indicates the point of attachment of L1to ring C;R1is selected from the group consisting of hydrogen, halogen, Ci-6-alkyl, amino-C1-6-alkyl, Ci-6-alkoxy, halo-Ci-6-alkyl, halo-Ci-6-alkoxy, Cs-io-cycloalkyl, Ci-6-alkyl-O- CH2-, and C3-io-cycloalkyl-0-CH2-;RR2is halogen or a groupR3is selected from the group consisting of halogen, Ci-6-alkyl-COR9, C2-6-alkenyl-BJ_- / ^Ri8COR10, C1-6-alkyl-NR13R14, -CO-CO-NR15R16, and a groupR4is selected from the group consisting of hydrogen, halogen, NH2, COOH, SO2OH, and lH-tetrazol-5-yl;R5is selected from the group consisting of hydrogen, halogen, and Ci-6-alkyl;R6is selected from the group consisting of hydrogen, halogen, Ci-6-alkyl, Ci-6-alkoxy, amino-Ci-6-alkyl, hydroxy-Ci-6-alkyl, halo-Ci-6-alkyl, Ci-6-alkoxy-Ci-6-alkyl, NH2,OH, oxo, COOR17, -CO-NH2, -CO-NH-Ci-6-alkyl, and a groupR7is selected from the group consisting of hydrogen, NH2, halogen, and Ci-6-alkyl; R8is selected from the group consisting of hydrogen and cyano;R9and R10are selected from the group consisting of OH2NR11R12, and Ci-6-alkoxy;R11and R12are each independently selected from the group consisting of hydrogen, C1-6- alkyl, hydroxy-Ci-6-alkyl, and amino-Ci-6-alkyl;R13and R14are each independently selected from the group consisting of hydrogen, C1-6- alkyl, and halo-Ci-6-alkyl;R15and R16are each independently selected from the group consisting of hydrogen and Ci- 6-alkyl; andR17is selected from the group consisting of hydrogen and Ci-6-alkyl.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Y is N.

3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1is selected from the group consisting of hydrogen, halogen, Ci-6-alkyl, and halo-Ci-6-alkyl.

4. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1is selected from the group consisting of halogen and Ci-6-alkyl.

5. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1is selected from the group consisting of chloro and methyl.

6. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:A is selected from the group consisting of phenyl and pyridyl;R1R2is halogen or a groupR4is selected from the group consisting of hydrogen, halogen, NH2, and COOH; and R5is hydrogen.

7. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:A is phenyl;Ris a groupR4is COOH; andR5is hydrogen.

8. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:0JQI0HR2is a group9. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:B is selected from the group consisting of:(i) 5- to 14-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon;(ii) Ce-io-aryl;(iii) 3- to 10-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon; and(iv) C3-10-cycloalkyl;C is selected from the group consisting of:(i) 5- to 14-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon;(ii) 3- to 14-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, the remaining atoms being carbon; and(iii) C3-10-cycloalkyl;P is 2;L is selected from the group consisting of a covalent bond, -CH2-, and -Ci-6-alkyl- CO-*; wherein the asterisk indicates the point of attachment of L to ring B;L1is selected from the group consisting of a covalent bond, -CH2-, -(CH2)2- and -COO-(CH2)p-*; wherein the asterisk indicates the point of attachment of L1to ring C;R3is selected from the group consisting of halogen, Ci-6-alkyl-COR9, C2-6-alkenyl- R6COR10, C1-6-alkyl-NR13R14, -CO-CO-NR15R16, and a group; R6is selected from the group consisting of hydrogen, halogen, Ci-6-alkyl, Ci-6-alkoxy, amino-Ci-6-alkyl, hydroxy-Ci-6-alkyl, halo-Ci-6-alkyl, Ci-6-alkoxy-Ci-6-alkyl, NH2,OH, oxo, COOR17, -CO-NH2, -CO-NH-Ci-6-alkyl, and a groupR7is selected from the group consisting of hydrogen, NH2, halogen, and Ci-6-alkyl; R8is selected from the group consisting of hydrogen and cyano;R9is selected from the group consisting of OH2NR11R12, and Ci-6-alkoxy;R10is selected from the group consisting of OH2NR11R12, and Ci-6-alkoxy;R11is selected from the group consisting of Ci-6-alkyl and hydroxy-Ci-6-alkyl;R12is selected from the group consisting of Ci-6-alkyl and amino-Ci-6-alkyl;R13is selected from the group consisting of hydrogen, Ci-6-alkyl, and halo-Ci-6-alkyl; R14is selected from the group consisting of hydrogen and Ci-6-alkyl;R15is Ci-6-alkyl;R16is Ci-6-alkyl; andR17is selected from the group consisting of hydrogen and Ci-6-alkyl.

10. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:B is selected from the group consisting of:(i) 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, the remaining atoms being carbon; and(ii) 3- to 10-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, the remaining atoms being carbon;L is selected from the group consisting of a covalent bond, -CH2-, and-CH2-CO-*; wherein the asterisk indicates the point of attachment of L to ring B;R3is selected from the group consisting of Ci-6-alkyl-COR9and a groupR6is selected from the group consisting of hydrogen, oxo, Ci-6-alkyl, and halo-Ci-6- alkyl;R7is hydrogen;R8is hydrogen;R9is NR11R12;R11is Ci-6-alkyl; andR12is Ci-6-alkyl.

11. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:B is selected from the group consisting of pyrrolidinyl, oxopyrrolidinyl, piperidyl, pyridyl, pyrazolyl, 2,3,4,4a,5,6,7,7a-octahydropyrrolo[3,4-b][1,4]oxazinyl, 1,7- diazaspiro[4.4]nonanyl, and 9-oxa-2,6-diazaspiro[4.5]decanyl;L is selected from the group consisting of a covalent bond, -CH2-, and-CH2-CO-*; wherein the asterisk indicates the point of attachment of L to ring B;R3is selected from the group consisting of-CH2-COR9and a groupR6is selected from the group consisting of hydrogen, oxo, methyl, and 2,2- difluoroethyl;R7is hydrogen;R8is hydrogen;R9is NR11R12;R11is methyl; andR12is methyl.

12. The compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m is 2 and n is 3.

13. The compound of formula (I) according to claim 1, selected from the group consisting of:4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-chloro-16-methyl-12,15,18- trioxo-17-[[2-[(2-oxopyrrolidin-l-yl)methyl]-lH-indol-3-yl]methyl]-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18- trioxo-17-[[2-[(2-oxopyrrolidin-l-yl)methyl]-lH-indol-3-yl]methyl]-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-[(l- methylpyrazol-3-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-[(l- methylpyrazol-4-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17- f[2-(2-oxo-3-piperidyl)-lH-indol-3-yl]methyl]-2-thia-4,10,13,16,19- pentazatri cyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17- [[2-(3-oxo-lH-isobenzofuran-4-yl)-lH-indol-3-yl]methyl]-2-thia-4,10,13,16,19- pentazatri cyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17- [ [2-(3 -oxoindan-4-yl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatri cyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17- f[2-(3-thienylmethyl)-lH-indol-3-yl]methyl]-2-thia-4,10,13,16,19- pentazatri cyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17-[[2-(thiazol-5-ylmethyl)-1H-indol-3-yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17-[[2-[(2-oxopyrrolidin-1-yl)methyl]-1H-indol-3-yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-17-[[2-[(l- methylpyrazol-4-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-17-[(2-benzyl-1H-indol-3-yl)methyl]-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-(l,l-dioxo-2,3- dihy drobenzothi ophen-7-yl)-lH-indol-3-yl]methyl]-l 6-methyl-12, 15, 18-tri oxo-2 -thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-17-[[2-(1H-imidazol-2-ylmethyl)-1H-indol-3-yl]methyl]-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-17-[[2-(1H-imidazol-4-ylmethyl)-1H-indol-3-yl]methyl]-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-17-[[2-(2-methoxy-6-methyl-phenyl)-1H-indol-3-yl]methyl]-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-17-[[2-(2-methoxyphenyl)-1H-indol-3-yl]methyl]-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-(5-cyano-3-fluoro-2- methoxy-phenyl)-lH-indol-3-yl]methyl]-16-methyl- 12, 15, 18-tri oxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[(l,l-dioxo-l,2- thiazolidin-2-yl)methyl]-lH-indol-3-yl]methyl]-16-methyl-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;44-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-17-[[2-[2-(dimethylamino)-2-oxo-ethyl]-1H-indol-3-yl]methyl]-16,25-dimethyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 44-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-17-[[2-[2-(dimethylamino)-2-oxo-ethyl]-1H-indol-3-yl]methyl]-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-(dimethylamino)-2- oxo-ethyl]-lH-indol-3-yl]methyl]-25-fluoro-16-methyl-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4- [( 11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25-(difluorom ethyl)- 16-methyl- 12,15,18-trioxo-17-[[2-[(2-oxopyrrolidin-l-yl)methyl]-lH-indol-3-yl]methyl]-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4- [( 11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25-(difluorom ethyl)- 16-methyl- 17-[[2-[(l-methylpyrazol-3-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4- [( 11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25-(difluorom ethyl)- 16-methyl- 17-[[2-[(l-methylpyrazol-4-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-(difluoromethyl)-17-[[2-[2- (dimethylamino)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16-methyl-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-chloro-16-methyl-17-[[2-[(l- methylpyrazol-3-yl)methyl]- lH-indol-3-yl]methyl]- 12, 15,18-tri oxo-2 -thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-25-chloro-16-methyl-17-[[2-[(1-methylpyrazol-4-yl)methyl]-1H-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-chloro-17-[[2-[2-(dimethylamino)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16-methyl-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-fluoro-16-methyl-12,15,18-trioxo-17-[[2-[(2-oxopyrrolidin-l-yl)methyl]-lH-indol-3-yl]methyl]-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-fluoro-16-methyl-17-[[2-[(l-methylpyrazol-3-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-fluoro-16-methyl-17-[[2-[(l-methylpyrazol-4-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16,25-dimethyl-12,15,18- trioxo- 17-[[2-(4-pyridylmethyl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16,25-dimethyl-12,15,18- trioxo- 17- [ [2-(4-piperi dy 1)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17- [[2-(l,2,5-thiadiazol-3-ylmethyl)-lH-indol-3-yl]methyl]-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17- [[2-(2-oxohexahydropyrimidin-5-yl)-lH-indol-3-yl]methyl]-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17- [ [2-(4-piperi dy 1)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17- [[2-(4-pyridylmethyl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16-methyl-17-[[2-(l-methyl-2- oxo-3 -piperidyl)- lH-indol-3 -yl]methyl]- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16-methyl-17-[[2-(2-methyl-3- oxo-isoindolin-4-yl)- lH-indol-3 -yl]methyl]- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-(l,l-dioxothian-2-yl)- lH-indol-3 -yl]methyl]- 16-m ethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[( 11 S, 14 S, 17 S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 17- [ [2 - (3 -methoxypyridazin-4- yl)- lH-indol-3 -yl]methyl]- 16-m ethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4- [( 11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25-(difluorom ethyl)- 16-methyl- 12.15.18-trioxo- 17- [ [2-(4-piperi dy 1)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4- [( 11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25-(difluorom ethyl)- 16-methyl- 12.15.18-trioxo- 17-[[2-(4-pyridylmethyl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-chloro-16-methyl-12,15,18- trioxo- 17- [ [2-(4-piperi dy 1)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-chloro-16-methyl-12,15,18- trioxo- 17-[[2-(4-pyridylmethyl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;-[(l l S, I4S,17S)-l4-(4- Aminobutyl )-l l -(3-aminopropyl)-25-fluoro-l 6-methyl-l 2,15, 18- tri oxo- 17- [ [2-(4-piperi dy 1)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-fluoro-l 6-methyl- 12, 15, 18- trioxo- 17-[[2-(4-pyridylmethyl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[3 -[[(11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-22-bromo-25-chloro- 16- methyl-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa- l(25),3(8),4,6,21,23-hexaen-17-yl]methyl]-lH-indol-2-yl]acetic acid;-[3-[[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-chloro-16-methyl- 12,15,18-trioxo-22-(3 -pyridyl)-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-17-yl]methyl]-lH- indol-2-yl]acetic acid;-[3 -[[(11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-22-(6-amino-3 -pyridyl)-25- chloro- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-17-yl]methyl]-lH- indol-2-yl]acetic acid;-[3-[[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-chloro-22-(2-fluoro-4- pyridyl)- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-17-yl]methyl]-lH- indol-2-yl]acetic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[(E)-3-(dimethylamino)-3-oxo-prop-l-enyl]-lH-indol-3-yl]methyl]-l 6-methyl-12, 15, 18-tri oxo-2 -thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;-[(l lS,14S,17S)-14-(4-Aminobutyl)-l 1 -(3-aminopropyl)- 16-methyl-12, 15, 18-trioxo- 17- [[2-(2-oxo-2-piperazin- 1 -yl-ethyl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; trihydrochloride;-[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 11 -(3-aminopropyl)- 16,25-dimethyl- 12, 15, 18- trioxo-17-[[2-(2-oxo-2-piperazin-l-yl-ethyl)-lH-indol-3-yl]methyl]-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-[2-(4- methylpiperazin-l-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-17-[[2-[2-[4- (methylcarbamoyl)-l-piperidyl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2- thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen- 22-yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-(l,7- diazaspiro[4.4]nonan-7-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16-methyl-12,15,18- trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;4-[( 11 S, 14S, 17 S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 17-[[2-[2-(2,2- dimethylpiperazin-l-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16-methyl-12,15,18- trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-[(3R)-3- aminopyrrolidin- 1 -yl]-2-oxo-ethyl]- lH-indol-3 -yl]methyl]- 16-methyl- 12,15,18-trioxo- 2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen- 22-yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-[3-aminopropyl(2- hydroxyethyl)amino]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16-methyl-12,15,18-tri oxo-2- thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen- 22-yl]benzoic acid;4- [( 11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25-(difluorom ethyl)- 16-methyl- 12,15,18-trioxo-17-[[2-(2-oxo-2-piperazin-l-yl-ethyl)-lH-indol-3-yl]methyl]-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4- [( 11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25-(difluorom ethyl)- 16-methyl- 17-[[2-[2-(4-methylpiperazin-l-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18- trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-chloro-16-methyl-12,15,18-trioxo-17-[[2-(2-oxo-2-piperazin-l-yl-ethyl)-lH-indol-3-yl]methyl]-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-chloro-16-methyl-17-[[2-[2-(4-methylpiperazin-l-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-fluoro-16-methyl-12,15,18-trioxo-17-[[2-(2-oxo-2-piperazin-l-yl-ethyl)-lH-indol-3-yl]methyl]-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-fluoro-16-methyl-17-[[2-[2-(4-methylpiperazin-l-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-17-[[2-[2-(4-amino-l-piperidyl)-2-oxo-ethyl]-lH-indol-3 -yl]methyl]- 11 -(3 -aminopropyl)- 16-m ethyl- 12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-17-[[2-[2-[4-(aminomethyl)-l-piperidyl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-ll-(3-aminopropyl)-16-methyl-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4-[(llS,14S,17S)-17-[[2-[2-[(4aR,7aR)-l,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridin-6-yl]-2-oxo-ethyl]- lH-indol-3 -yl]methyl]- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 16-methyl-12, 15,18-trioxo-2-thia-4,l 0,13, 16,19-pentazatricy clo[l 9.4.0.03,8]pentacosa-1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;4-[(llS,14S,17S)-17-[[2-[2-[(4aS,7aS)-l,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridin-6-yl]-2-oxo-ethyl]- lH-indol-3 -yl]methyl]- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 16-methyl-12, 15,18-trioxo-2-thia-4,l 0,13, 16,19-pentazatricy clo[l 9.4.0.03,8]pentacosa-1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-(3,6- diazabicyclo[3.1.1 ]heptan-6-yl)-2-oxo-ethyl]- lH-indol-3 -yl]methyl]- 16-methyl- 12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;-[( 11 S, 14S, 17 S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 17-[[2-[2-(4,7- diazaspiro[2.5]octan-4-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16-methyl-12,15,18- trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-17-[[2-[2-[(7R)-7-amino-5-azaspiro[2.4]heptan-5-yl]-2-oxo-ethyl]-lH- indol-3 -yl]methyl]- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 16-m ethyl- 12,15,18-trioxo- 2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen- 22-yl]benzoic acid;-[( 11 S, 14S, 17 S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 17-[[2-[2-(5- azaspiro[2.4]heptan-5-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16-methyl-12,15,18- trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;-[( 11 S, 14S, 17 S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 17-[[2-[2-(3’8- diazabicyclo[3.2.1]octan-8-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16-methyl-12,15,18- trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-(4-methoxy carbonyl-1-piperidyl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16-methyl-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-[(3S)-3- aminopyrrolidin- 1 -yl]-2-oxo-ethyl]- lH-indol-3 -yl]methyl]- 16-methyl- 12,15,18-trioxo- 2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen- 22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[(E)-2-carboxyvinyl]- lH-indol-3 -yl]methyl]- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[(E)-3-ethoxy-3-oxo- prop-l-enyl]-lH-indol-3-yl]methyl]-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-(2-ethoxy-2-oxo-ethyl)- lH-indol-3 -yl]methyl]- 16-m ethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17- [[2-(2 -pyridylmethyl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17-[[2-(3-pyridylmethyl)-1H-indol-3-yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-17-[[2-[(l- methylimidazol-2-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-17-[[2-[(3-methyl-4- pyridyl)methyl]- lH-indol-3 -yl]methyl]- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-17-[[2-[(4-methyl- l,2,5-oxadiazol-3-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17- [(2-tetrahydropyran-4-yl- lH-indol-3 -yl)methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17- [[2-(lH-pyrazol-4-ylmethyl)-lH-indol-3-yl]methyl]-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17- [[2-(lH-pyrrol-3-ylmethyl)-lH-indol-3-yl]methyl]-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; dihydrochloride;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-17-[[2-[(l- methylimidazol-4-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-17-[[2-[(l- methylpyrazol-3-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-17-[[2-[(l- methyltriazol-4-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-17-[[2-[(2-methyl- l,2,4-triazol-3-yl)methyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[(2-cyclopropyl-lH-indol-3- yl)methyl]- 16-m ethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-(2-methoxy-3-pyridyl)- lH-indol-3 -yl]methyl]- 16-m ethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-(4-carboxyphenyl)-lH- indol-3 -yl]methyl]- 16-m ethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16-methyl-12,15,18-trioxo-17- [[2-(2-oxo- IH-pyri din-3 -yl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[( 11 S, 14 S, 17 S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 17 - [ [2 - (2 -hy droxyphenyl)- 1 H- indol-3 -yl]methyl]- 16-m ethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4- [( 11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 17-[[2-(2-hydroxy-6-methyl- phenyl)-lH-indol-3-yl]methyl]-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-[2-[(5R)- 9-oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18- trioxo-2-thia-4, 10, 13, 16,19-pentazatri cyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-[2-[(5S)- 9-oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18- trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-16-methyl-17-[[2-[2-[(5R)-9-oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-1H-indol-3-yl]methyl]-12,15,18-trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-aminobutyl)-ll-(3-aminopropyl)-16-methyl-17-[[2-[2-[(5S)-9- oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18- trioxo-2-thia-4, 10, 13, 16,19-pentazatri cyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-aminobutyl)-ll-(3-aminopropyl)-25-(difluoromethyl)-16-methyl- 17-[[2-[2-[(5R)-9-oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-lH-indol-3- yl]methyl]- 12, 15,18-tri oxo-2-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-aminobutyl)-ll-(3-aminopropyl)-25-(difluoromethyl)-16-methyl- 17-[[2-[2-[(5S)-9-oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-lH-indol-3- yl]methyl]- 12, 15,18-tri oxo-2 -thia-4,10,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;-[(l IS, 14S,17S)- 14-(4-aminobutyl)-l 1 -(3-aminopropyl)-25-chl oro-16-methyl-l 7-[[2-[2- f(5R)-9-oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]- 12, 15,18-tri oxo-2-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;-[(l IS, 14S,17S)- 14-(4-aminobutyl)-l 1 -(3-aminopropyl)-25-chl oro-16-methyl-l 7-[[2-[2- f(5S)-9-oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]- 12, 15,18-tri oxo-2-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18- trioxo-17-[[2-[2-oxo-2-(8-oxo-2,6,9-triazaspiro[4.5]decan-2-yl)ethyl]-lH-indol-3- yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-[2-(9- methyl-8-oxo-2,6,9-triazaspiro[4.5]decan-2-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]- 12, 15, 18-trioxo-2-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18- trioxo-17-[[2-[2-oxo-2-[(5R)-l,7-diazaspiro[4.4]nonan-7-yl]ethyl]-lH-indol-3- yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18- trioxo-17-[[2-[2-oxo-2-[(5S)-l,7-diazaspiro[4.4]nonan-7-yl]ethyl]-lH-indol-3- yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18- trioxo-17-[[2-[2-oxo-2-[2-(trifluoromethyl)piperazin-l-yl]ethyl]-lH-indol-3-yl]methyl]- 2-thia-4, 10, 13, 16,19-pentazatri cyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen- 22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18- trioxo-17-[[2-[2-oxo-2-[3-(trifluoromethyl)piperazin-l-yl]ethyl]-lH-indol-3-yl]methyl]- 2-thia-4, 10, 13, 16,19-pentazatri cyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen- 22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-[2-(4- oxa-l,8-diazaspiro[5.5]undecan-8-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18- trioxo-2-thia-4, 10, 13, 16,19-pentazatri cyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16,25-dimethyl-17-[[2-[2-(4- oxa- 1,9-diazaspiro[5.5]undecan-9-yl)-2-oxo-ethyl]- lH-indol-3 -yl]methyl]- 12,15,18- trioxo-2-thia-4, 10, 13, 16,19-pentazatri cyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-[2-(8- oxa-2,5-diazaspiro[3.5]nonan-2-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18- trioxo-2-thia-4, 10, 13, 16,19-pentazatri cyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-[2-[(5R)- 6-methyl-9-oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]- 12, 15, 18-trioxo-2-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-[2-[(5S)- 6-methyl-9-oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]- 12, 15, 18-trioxo-2-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16-methyl-17-[[2-[2-[(5R)-6- methyl-9-oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]- 12, 15,18-trioxo-2-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16-methyl-17-[[2-[2-[(5S)-6- methyl-9-oxa-2,6-diazaspiro[4.5]decan-2-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]- 12, 15,18-trioxo-2-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-(3- carbamoylpiperazin-l-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16,25-dimethyl- 12, 15,18-trioxo-2-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;-[( 11 S, 14S, 17 S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 17- [ [2- [2-(4,7- diazaspiro[2.5]octan-7-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16,25-dimethyl- 12, 15,18-trioxo-2-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-[(3R)-3- (methoxymethyl)piperazin-l-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16,25-dimethyl- 12, 15,18-trioxo-2-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-[(3S)-3- (hydroxymethyl)piperazin-l-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16,25-dimethyl- 12, 15, 18-trioxo-2-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-[(3S)-3- (methoxymethyl)piperazin-l-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16,25-dimethyl- 12, 15, 18-trioxo-2-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-[3- (fluoromethyl)piperazin-l-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16,25-dimethyl- 12, 15,18-trioxo-2-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-[3-aminopropyl(2- hydroxyethyl)amino]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16,25-dimethyl-12,15,18- trioxo-2-thia-4, 10, 13, 16,19-pentazatri cyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-chloro-16-methyl-17-[[2-[2- (4-oxa-l,9-diazaspiro[5.5]undecan-9-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18- trioxo-2-thia-4, 10, 13, 16,19-pentazatri cyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-chloro-16-methyl-17-[[2-[2- (8-oxa-2,5-diazaspiro[3.5]nonan-2-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-12,15,18- trioxo-2-thia-4, 10, 13, 16,19-pentazatri cyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-17-[[2-[2-[(3S,4R)-3-amino-4-fluoro-pyrrolidin-l- yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18- trioxo-2-thia-4, 10, 13, 16,19-pentazatri cyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-17-[[2-[2-[(3S,4R)-3-amino-4-hydroxy-pyrrolidin-l- yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18- trioxo-2-thia-4, 10, 13, 16,19-pentazatri cyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-17-[[2-[2-[(3S,4S)-3-amino-4-fluoro-pyrrolidin-l- yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18- trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-17-[[2-[2-[(3S,4S)-3-amino-4-hydroxy-pyrrolidin-l- yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18- trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-17-[[2-[2-[2-aminoethyl(2-hydroxyethyl)amino]-2- oxo-ethyl]-lH-indol-3-yl]methyl]-l l-(3-aminopropyl)-16,25-dimethyl-12,15,18-trioxo- 2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen- 22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-17-[[2-[2-[4-amino-4-(hydroxymethyl)-l-piperidyl]- 2-oxo-ethyl]-lH-indol-3-yl]methyl]-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18- trioxo-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23- hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-17-[[2-[2-[(4aR,7aR)-3,4,4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4- b][l,4]oxazin-6-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-14-(4-aminobutyl)-ll-(3- aminopropyl)- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-17-[[2-[2-[(4aR,7aR)-3,4,4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4- b][l,4]oxazin-6-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-14-(4-aminobutyl)-l l-(3- aminopropyl)- 16-m ethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-17-[[2-[2-[(4aR,7aR)-3,4,4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4- b][l,4]oxazin-6-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-14-(4-aminobutyl)-l l-(3- aminopropyl)-25-(difluorom ethyl)- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-17-[[2-[2-[(4aR,7aR)-3,4,4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4- b][l,4]oxazin-6-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-14-(4-aminobutyl)-l l-(3- aminopropyl)-25-chloro- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-17-[[2-[2-[(4aS,7aS)-3,4,4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4- b][l,4]oxazin-6-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-14-(4-aminobutyl)-ll-(3- aminopropyl)- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-17-[[2-[2-[(4aS,7aS)-3,4,4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4- b][l,4]oxazin-6-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-14-(4-aminobutyl)-l l-(3- aminopropyl)- 16-m ethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-17-[[2-[2-[(4aS,7aS)-3,4,4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4- b][l,4]oxazin-6-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-14-(4-aminobutyl)-l l-(3- aminopropyl)-25-(difluorom ethyl)- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-17-[[2-[2-[(4aS,7aS)-3,4,4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4- b][l,4]oxazin-6-yl]-2-oxo-ethyl]-lH-indol-3-yl]methyl]-14-(4-aminobutyl)-l l-(3- aminopropyl)-25-chloro- 16-methyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-17-[[cis-2-[2-(3,4,4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4-b][l,4]oxazin-6- yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-14-(4-aminobutyl)-ll-(3-aminopropyl)-16,25- dimethyl-12, 15,18-tri oxo-2 -thia-4,10,13, 16,19-pentazatricy clo[l 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;-[( 11 S, 14S, 17 S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 17-[[2-[2-(9,9-difluoro-2,6- diazaspiro[4.5]decan-2-yl)-2-oxo-ethyl]-lH-indol-3-yl]methyl]-16,25-dimethyl- 12, 15,18-tri oxo-2-thia-4,l 0,13, 16,19-pentazatricy clo[l 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;-[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 1 l-(3-aminopropyl)-l 6,25-dimethyl- 12, 15, 18- trioxo- 17-[[2-[2-oxo-2-[(3R)-3-(hydroxymethyl)piperazin-l-yl]ethyl]-lH-indol-3- yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[2-(dimethylamino)-2- oxo-acetyl]-lH-indol-3-yl]methyl]- 16,25-dimethyl- 12, 15,18-tri oxo-2 -thia- 4,10,13, 16,19-pentazatricy clo[l 9.4.0.03,8]pentacosa- 1(25), 3(8), 4, 6, 21, 23-hexaen-22- yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18- trioxo-17-[[2-[(3-oxo-2,8-diazaspiro[4.5]decan-2-yl)methyl]-lH-indol-3-yl]methyl]-2- thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen- 22-yl]benzoic acid;-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-l 6,25-dimethyl- 12, 15, 18- trioxo- 17-[[2-(piperazin- 1 -ylmethyl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[( 11 S, 14S, 17 S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 17-[[2- [(dimethylamino)methyl]-lH-indol-3-yl]methyl]-16,25-dimethyl-12,15,18-trioxo-2- thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen- 22-yl]benzoic acid;-[(l lS,14S,17S)-14-(4-Aminobutyl)-17-[[2-(aminomethyl)-lH-indol-3-yl]methyl]-l l-(3- aminopropyl)- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-(3-aminopropyl)-lH- indol-3 -yl]methyl]- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(l lS,14S,17S)-14-(4-Aminobutyl)-17-[[2-(4-Aminobutyl)-lH-indol-3-yl]methyl]-l 1- (3 -aminopropyl)- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(l lS,14S,17S)-14-(4-Aminobutyl)-17-[[2-(2-aminoethyl)-lH-indol-3-yl]methyl]-l l-(3- aminopropyl)- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(l IS, 14S,17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 16,25-dimethyl- 12, 15,18- trioxo- 17-[[2-(4-piperidylmethyl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-(azetidin-3-ylmethyl)- lH-indol-3 -yl]methyl]- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(l IS, 14S,17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 16,25-dimethyl- 12, 15,18- trioxo- 17-[[2-(pyrrolidin-3 -ylmethyl)- lH-indol-3 -yl]methyl]-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18- trioxo-17-[[2-(l,2,3,6-tetrahydropyridin-5-yl)-lH-indol-3-yl]methyl]-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-(2,5-dihydro-lH-pyrrol- 3-yl)- lH-indol-3-yl]methyl]-l 6,25-dimethyl- 12, 15,18-trioxo-2-thia-4,l 0,13, 16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(l IS, 14S,17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)- 17-[(2 -bromo- lH-indol-3- yl)methyl]- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-(l- methyl-4-piperidyl)- lH-indol-3 -yl]methyl]- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 1 l-(3-aminopropyl)-l 6,25-dimethyl- 12, 15, 18- trioxo-17-[[2-[l-(2,2,2-trifluoroethyl)-4-piperidyl]-lH-indol-3-yl]methyl]-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;-[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 1 l-(3-aminopropyl)-l 6,25-dimethyl- 12, 15, 18- trioxo-17-[[2-(l,2,3,6-tetrahydropyridin-4-yl)-lH-indol-3-yl]methyl]-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;-[(l IS, 14S, 17 S)-14-(4- Aminobutyl)- 1 l-(3-aminopropyl)-17-[[2-[l-(2 -hydroxy ethyl)-4- piperi dy 1 ] - lH-indol-3 -yl]methyl]- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(l IS, 14S, 17 S)-14-(4- Aminobutyl)- 1 l-(3-aminopropyl)-17-[[2-[l-(2 -methoxy ethyl)-4- piperi dy 1 ] - lH-indol-3 -yl]methyl]- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; -[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[l-(2-imidazol-l- ylethoxycarbonyl)-4-piperidyl]-lH-indol-3-yl]methyl]-16,25-dimethyl-12,15,18-trioxo- 2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen- 22-yl]benzoic acid;-[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 1 l-(3-aminopropyl)-l 6,25-dimethyl- 12, 15, 18- trioxo-17-[[2-[l-(3,3,3-trifluoropropyl)-4-piperidyl]-lH-indol-3-yl]methyl]-2-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[l-(2,2-difluoroethyl)-4- piperi dy 1 ] - lH-indol-3 -yl]methyl]- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[l-(2-fluoroethyl)-4- piperi dy 1 ] - lH-indol-3 -yl]methyl]- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-17-[[2-[l- (oxetan-3-ylmethyl)-4-piperidyl]-lH-indol-3-yl]methyl]-12,15,18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-[l-(2-imidazol-l- ylethyl)-4-piperidyl]-lH-indol-3-yl]methyl]-l 6,25-dimethyl- 12, 15, 18-trioxo-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-[[2-(l-cyclopropyl-4- piperidyl)- lH-indol-3 -yl]methyl]- 16,25-dimethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21,23 -hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-16,25-dimethyl-12,15,18- trioxo-17-[[2-[(2,2,2-trifluoroethylamino)methyl]-lH-indol-3-yl]methyl]-2-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzoic acidor a pharmaceutically acceptable salt or stereoisomer thereof.

14. A pharmaceutical composition comprising a compound according to any of claims 1 to 13, or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more pharmaceutically acceptable excipients.

15. A compound according to any of claims 1 to 13, or a pharmaceutically acceptable salt or stereoisomer thereof, for use as therapeutically active substance.

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