Compounds for the treatment of Hepatitis C

ES 2 390 732 T3

DESCRIPTION

Compounds for the treatment of hepatitis C

Background of the Invention

Hepatitis C virus (HCV) is a major human pathogen, estimated to infect about 170 million people worldwide, approximately 5 times the number of people infected with human immunodeficiency virus type 1. A substantial fraction of these HCV-infected individuals develop severe progressive liver disease, including cirrhosis and hepatocellular carcinoma (Lauer, GM; Walker, BDN Engl. J. Med. 2001, 345, 41-52).

HCV is a positive strand RNA virus. Based on a comparison of the deduced amino acid sequence and the broad similarity in the 5'-untranslated region, HCV has been classified as a separate genus in the family Flaviviridae. All members of the Flaviviridae family have enveloped virions that contain a positive strand RNA genome that encodes all known virus-specific proteins through the translation of a single uninterrupted open reading frame.

Considerable heterogeneity is found within the nucleotide and amino acid sequence encoded by the HCV genome. At least 6 major genotypes have been characterized and more than 50 subtypes have been described. The major HCV genotypes differ in their distribution throughout the world, and the clinical significance of HCV genetic heterogeneity remains to be clarified despite numerous studies on the possible effect of genotypes on pathogenesis and therapy.

The single strand of the HCV RNA genome is approximately 9,500 nucleotides in length and has a single Open Reading Frame (ORF) encoding a single large polyprotein of approximately 3,000 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce non-structural (NS) and structural proteins. In the case of HCV, the generation of mature non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases. The former is believed to be a metalloprotease and cleaves at the junction of NS2-NS3; the second is a serine protease contained within the N-terminal region of NS3 (also called NS3 protease) and mediates all subsequent cleavages downstream of NS3, both cis, at the NS3-NS4A cleavage site, and trans, for the remaining sites NS4A-NS4B, NS4B-NS5A, NS5A-NS5B. The NS4A protein appears to play multiple roles, acting as a cofactor for the NS3 protease and possibly assisting in the membrane localization of NS3 and other components of viral replicase. Complexation of the NS3 protein with NS4A appears necessary for processing events, enhancing proteolytic efficiency at all sites. The NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities. NS5B (also called HCV polymerase) is an RNA-dependent RNA polymerase that is involved in HCV replication. The HCV NS5B protein is described in Structural Analysis of the Hepatitis C Virus RNA Polymerase in Complex with Ribonucleotides (Bressanelli; S. et al., Journal of Virology 2002, 3482-3492; and Defrancesco and Rice, Clinics in Liver Disease 2003, 7, 211-242.

Currently, the most effective HCV therapy employs a combination of interferon-alpha and ribavirin, leading to sustained efficacy in 40% of patients (Poynard, T. et al. Lancet 1998, 352, 1426-1432). Recent clinical results demonstrate that, as monotherapy, pegylated interferon-alpha is superior to unmodified interferon-alpha (Zeuzem, S. et al. N. Engl. J. Med. 2000, 343, 1666-1672). However, even with experimental regimens involving combinations of pegylated interferon-alpha and ribavirin, a substantial fraction of patients do not have a sustained reduction in viral load. Therefore, there is a clear and important need to develop effective therapies for the treatment of HCV infection.

Description of the invention

One aspect of the invention is a compound of formula I

<img file="ES2390732T3_D0001.tif" />

in which:

ES 2 390 732 T3

R¹ is CONR⁵R⁶; R² it is

<img file="ES2390732T3_D0002.tif" />

R³ is hydrogen, halo, alkyl, alkenyl, hydroxy, benzyloxy, alkoxy, or haloalkoxy;

R⁴ is cycloalkyl;

R⁵ is alkenylSO2, alkynylSO2, alkoxyalkylSO2, (cycloalkyl) alkylSO2, (alkyl) cycloalkylSO2, ((cycloalkyl) alkyl) cycloalkylSO₂, (benzyl) cycloalkylSO₂), (alkenyl) cycloalkylSO₂, (alkynyl) cycloalkylSO₂, (trialkylsilyl) cycloalkylSO₂, (CO2R⁷) cycloalkylSO2, (PhCO) cycloalkylSO2, (PhN (R⁷) CO) cycloalkylSO2, tetrahydrofuranylSO2, tetrahydropyranylSO2, (tetrahydrofuranyl) alkylSO2, (tetrahydropyranyl) alkylSO2, isoxazolidinylSO2, Ar¹SO2, (Ar¹) alkylSO2, Ar²SO2 or (CON (R⁷) (R⁷))I rent;

R⁶ is hydrogen or alkyl;

R⁷ is hydrogen or alkyl;

R⁸ is hydrogen, alkyl, cycloalkyl, (cycloalkyl) alkyl, alkylcarbonyl, cycloalkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, alkylSO2, cycloalkylSO2, haloalkylSO2, aminocarbonyl, (alkylamino) carbonyl, (dialkylamino) carbonyl, benzyl, benzyloxycarbonyl; or pyridinyl, benzyloxycarbonyl;

Ar¹ is phenyl, pyridinyl, pyrimidinyl, quinolinyl, or isoquinolinyl, and is substituted with 0-3 substituents selected from halo, alkyl, alkoxy, and cyano; Y

Ar² is furanyl, thienyl, pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl or tetrazolyl, and is substituted with 0-3 substituents selected from halo, alkyl, alkoxy and cyano;

or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I, wherein R³ it is hydrogen.

Another aspect of the invention is a compound of formula I, wherein R³ it is methoxy.

Another aspect of the invention is a compound of formula I, wherein R⁴ is cyclohexyl.

Another aspect of the invention is a compound of formula I, in which Ar¹ is phenyl, pyridinyl, quinolinyl, or isoquinolinyl, and is substituted with 0-3 substituents selected from halo, alkyl, alkoxy, and cyano.

Another aspect of the invention is a compound of formula I according to the following stereochemistry.

<img file="ES2390732T3_D0003.tif" />

Another aspect of the invention is a compound of formula I according to the following stereochemistry.

<img file="ES2390732T3_D0004.tif" />

Any scope of any variable, including R¹, R²

R³, R⁴, R⁵, R⁶, R⁷

R⁸, Ar¹ and Ar², can be used

ES 2 390 732 T3 independently with the scope of any other case of a variable.

Unless otherwise specified, these terms have the following meanings. Alkyl refers to a straight or branched alkyl group composed of 1 to 6 carbons. Alkenyl refers to a linear or branched alkyl group composed of 2 to 6 carbons with at least one double bond. Alkynyl refers to a linear or branched alkyl group composed of 2 to 6 carbons with at least one triple bond. Cycloalkyl refers to a monocyclic ring system composed of 3 to 7 carbons. Hydroxyalkyl, alkoxy, and other terms with a substituted alkyl moiety include linear and branched isomers composed of 1 to 6 carbon atoms for the alkyl moiety. Haloalkyl and haloalkoxy include all halogenated isomers of monohalo substituted alkyl to perhalo substituted alkyl. Aryl includes carbocyclic and heterocyclic aromatic substituents. Terms in parentheses or between parentheses are intended to clarify linking relationships to those skilled in the art. For example, a term, such as ((R) alkyl) refers to an alkyl substituent additionally substituted with the R substituent.

The invention includes all pharmaceutically acceptable salt forms of the compounds. Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and, as such, function as pharmacological equivalents. These salts can be prepared according to common organic techniques using commercially available reagents. Some forms of anionic salts include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucuronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinophoate. Some forms of cationic salts include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, megglumine, 4-phenylchlorine, plperazine, potassium, sodium, tromethamine, and zinc.

Some of the compounds of the invention possess asymmetric carbon atoms (see, for example, compounds below). The Invention Includes all isomeric forms, including enantlomers and dlastereomers, as well as mixtures of stereoisomers, such as racemates. Some stereoisomers can be prepared using procedures known in the art. Stereoisomeric mixtures of the related compounds and intermediates can be separated into individual isomers according to procedures commonly known in the art. The use of wedges or pads in the representations of molecular structures in the following schemes and tables is only intended to indicate relative stereochemistry and should not be construed as implying absolute stereochemical assignments.

R '

<img file="ES2390732T3_D0005.tif" />

Synthetic Procedures

The compounds can be prepared by procedures known in the art, including those described below. Some reagents and intermediates are known in the art. Other reagents and intermediates can be prepared by procedures known in the art using readily available materials. The variables (eg, numbered R substituents) used to describe the synthesis of the compounds are only intended to illustrate how they are manufactured and should not be confused with the variables used in the claims or in other sections of the specification. The abbreviations used within the schemes generally follow the conventions used in the art.

Methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate can be hydrolyzed to give 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (See Scheme 1). This compound can be condensed with a variety of sulfonyl ureas, using for example 1,1'-carbonylldimdazole together with 1,8-dlazabclo [5.4.0] undec-7-ene in anhydrous THF. The resulting acyl sulfamides can be subjected to known coupling reactions with a variety of 2-formyl boronic acids or esters, using for example Suzuki coupling conditions, to provide cyclic hemiaminal intermediates of the type depicted. These compounds can be converted to ndolobenzazepines derivatives by treatment with methyl 2- (dimethoxyphosphoryl) acrylate under the influence of cesium carbonate in DMF by consecutive Mlchael and Homer Emmons reactions.

Related fused cyclopropyl ester derivatives can be generated by procedures known in the art, including treatment of indolobenzazepine esters with trimethyl sulfoxonium iodide under strong basic conditions in DMSO. The residual aliphatic ester moiety in the resulting fused cyclopropanes can be hydrolyzed and the acids in the products can be fused with a variety of alkyl fused diamines. For example, 0- (1H-benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate and diisopropyl 1 ethyl amine

ES 2 390 732 T3 in DMSO can give alkyl-fused diaminecarboxamides.

Scheme 1.

<img file="ES2390732T3_D0006.tif" />

1. Reflux EtOh at 0 ° C

2. THF HCI 2 N ta

<img file="ES2390732T3_D0007.tif" />

OEt

<img file="ES2390732T3_D0008.tif" />

OR

<img file="ES2390732T3_D0009.tif" />

CHO

<img file="ES2390732T3_D0010.tif" />

CHO (HOhB-QR

M (PPhj). (3% in mol)

LÉCI

Na_zCO,

EtOH / toluene / hhO 70 ° C

<img file="ES2390732T3_D0011.tif" />

CS2CO3, DMF, € 0 ° C

<img file="ES2390732T3_D0012.tif" />

<img file="ES2390732T3_D0013.tif" />

N-protected dlamines can also be coupled to idolobenzazepine acids Intermediates and the resulting dlamine carboxamids can be deprotected using procedures known in the art and derived using a variety of synthetic protocols, some illustrative examples thereof are shown below (See Scheme 2 ).

ES 2 390 732 T3

Scheme 2.

<img file="ES2390732T3_D0014.tif" />

<img file="ES2390732T3_D0015.tif" />

sodium bis (diphenylphosphino) propane tert-butoxide

<img file="ES2390732T3_D0016.tif" />

Na (CN) BH] ZnCI₂, MeOH

OR

<img file="ES2390732T3_D0017.tif" />

TBTU, UIPEA

ArtJr, PdjtdbaJj

<img file="ES2390732T3_D0018.tif" />

A useful intermediate for the synthesis of some compounds of the Invention involves the preparation of the tert-butyl ester indolobenzazepine shown in Scheme 3.

ES 2 390 732 T3

Scheme 3.

<img file="ES2390732T3_D0019.tif" />

This methodology involves base-catalyzed hydrolysis of the indole methyl ester shown, followed by its reaction with thionyl chloride and potassium tertiary butoxide, or alkylation with silver carbonate and tertiary butyl bromides. The resulting compound can be transformed using chemical procedures analogous to those indicated above to provide the mixed indolebenzepine esters shown above.

These intermediates are useful in an alternative process that can be employed for the preparation of diamines fused with alkyl acylsulfamide and acylsulfonamide, as shown in Scheme 4. Cyclopropanation of a t-butyl ester indoleobenzazepine intermediate and subsequent cleavage of the t-butyl ester group it can generate the acid that can be coupled to a variety of sulfonamides and sulfonylureas. Subsequent hydrolysis provides the related aliphatic acid, which can be coupled with a variety of alkyl fused diamines. For example, O- (1H-benzotriazol-1-yl) -N, N, Ν ', Ν'-tetramethyluronium tetrafluoroborate and diisopropyl ethyl amine in DMSO can give the alkyl fused diamine carboxamides.

ES 2 390 732 T3

Scheme 4.

<img file="ES2390732T3_D0020.tif" />

Some examples exist as stereolsomeric mixtures. The invention encompasses all stereolsomers of the compounds. Procedures for fractionating stereolsomeric mixtures are well known in the art and include, but are not limited to; Chiral Preparative Supercritical Fluid Chromatography (SFC) and Chiral High Performance Liquid Chromatography (HPLC). An example of using this approach is shown in Scheme 5.

Scheme 5.

<img file="ES2390732T3_D0021.tif" />

ES 2 390 732 T3

An additional procedure for achieving such separations involves the preparation of mixtures of dlastereomers that can be separated using a variety of procedures known in the art. An example of this approach is shown below (Scheme 6).

Scheme 6.

<img file="ES2390732T3_D0022.tif" />

TBTU, DIPEA DMSO

<img file="ES2390732T3_D0023.tif" />

<img file="ES2390732T3_D0024.tif" />

<img file="ES2390732T3_D0025.tif" />

Diastereomers separated by reverse phase HPLC

Some dlastereomeric amides can be separated using Reverse phase HPLC. After hydrolysis, the resulting optically active acids can be coupled with condensed derivatives of dlamine (Scheme 6). For example, 0- (1H-benzotrazole-1-µl) -N, N, Ν ', Ν'-tetramethylluronlo and düsopropyl ethyl amine tetrafluoroborate in DMSO can be used to give the alkyl fused carboxamides. Other conventional amine acid coupling procedures can also be used to give optically active carboxamides.

<img file="ES2390732T3_D0026.tif" />

<img file="ES2390732T3_D0027.tif" />

Scheme 6.

<img file="ES2390732T3_D0028.tif" />

Biological procedures

Compounds demonstrated activity against HCV NS5B as determined in the following HCV RdRp assays.

ES 2 390 732 T3

Cloning, Expression, and Purification of HCV NS5B RdRp. The cDNA encoding the HCV NS5B protein, genotype 1b, was cloned into the expression reader pET21a. The protein was expressed with a C-terminal truncation of 18 amino acids to improve solubility. For the expression of the protein, the competent cell line BL21 (DE3) from E. coli was used. The cultures were grown at 37 ° C for ~ 4 hours until the cultures reached an optical density of 2.0 at 600 nm. The cultures were cooled to 20 ° C and induced with 1 mM ipTG. Fresh ampicillin was added to a final concentration of 50 mg / ml and the cells were grown overnight at 20 ° C.

Cell foods (3 L) were lysed for purification to yield 15-24 mg of purified NS5B. The lysis buffer consisted of 20 mM Tris-HCl, pH 7.4, 500 mM NaCl, 0.5% Triton X-100, 1 mM DTT, 1 mM EDTA, 20% glycerol, 0.5 mg / lysozyme. ml, 10 mM MgCl2, 15 pg / ml dexosirribonuclease I, and complete protease inhibitor TM tablets (Roche). After addition of the lysis buffer, frozen cell pellets were resuspended using a tissue homogenizer. To reduce the viscosity of the sample, aliquots of lysate were sonicated on ice using a micro-tip attached to Branson sonication. The sonicated lysate was centrifuged at 100,000 xg for 1 hour at 4 ° C and filtered through a 0.2 pm filter unit (Corning).

The protein was purified using two sequential chromatography steps: Heparin sepharose CL-6B and polyU sepharose 4B (Pharmacy). The chromatography buffers were identical to the lysis buffer but did not contain lysozyme, deoxyribonuclease I, MgCl2, or protease inhibitor and the NaCl concentration of the buffer was adjusted according to the requirements for loading the protein on the column. Each column was eluted with a NaCl gradient varying in length from 5-50 column volumes depending on the type of column. After the final chromatography step, the resulting purity of the enzyme is&gt; 90%, based on SDS-PAGE analysis. The enzyme was aliquoted and stored at -80 ° C.

HCV NS5B RdRp Conventional Enzyme Assay. Assays were performed with genotype 1 HCV RdRp in a final volume of 60 µl in 96-well plates (Corning 3600). The assay buffer is composed of 20 mM Hepes, pH 7.5, 2.5 mM KCl, 2.5 mM MgCl2, 1 mM DTT, 1.6 U RNAse inhibitor (Promega N2515), 0.01 mg / BSA. ml (Sigma B6917) and 2% glycerol. All compounds were serially diluted (3-fold) in DMSO and further diluted in water such that the final DMSO concentration in the assay was 2%. The RdRp enzyme from HCV genotype 1 was used at a final concentration of 28 nM. A 6 nM polyA template and a biotinylated oligo-dT12 primer were used at a final concentration of 180 nM. The template was obtained commercially (Amersham 27-4110). The biotinylated primer was prepared by Sigma Genosys. 3H-UTP was used at 0.6 pCi (0.29 pM total UTP). Reactions were started by enzyme addition, incubated at 30 ° C for 60 min. and stopped by the addition of 25 µl of 50 mM EDTA containing SPA beads (4 µg / µl, Amersham RPNQ 0007). Plates were read in Packard Top Count NXT after&gt; 1 hour incubation at room temperature.

Modified HCV NS5B RdRp Enzyme Assay. A modified enzyme assay was performed essentially as described for the standard enzyme assay except for the following: the biotinylated oligo dT12 primer was pre-captured onto streptavirin-coated SPA beads by mixing the primer and beads in assay buffer and incubating at room temperature for 1 hour. After centrifugation the unbound primer was removed. The primer bound beads were resuspended in 20 mM HEPES buffer, pH 7.5 and used in the assay at final concentrations of 20 nM primer and 0.67 pg / pl beads. The order of addition in the assay was as follows: the enzyme (1.75 nM) was added to the diluted compound followed by the addition of a template mixture (0.36 nM), 3H-UTP (0.6 pCi, 0.29 pM), and beads attached to the primer, to initiate the reaction; concentrations provided are final. Reactions were allowed to proceed for 4 hours at 30 ° C.

Cl values₅₀ for compounds they were determined using seven different [I]. Cl values₅₀ were calculated from inhibition using the formula y = A + ((BA) / (1 + ((C / x)^TOD))).

Preparation of the FRET assay. The HCV FRET screening assay was performed in 96-well cell culture plates. The FRET peptide (Anaspec, Inc.) (Taliani et al., Anal. Biochem. 1996, 240, 60-67) contains a fluorescence donor, EDANS, near one end of the peptide and an acceptor, DABCYL, near the other. extreme. Peptide fluorescence is inactivated by intermolecular resonance energy transfer (RET) between donor and acceptor, but as NS3 protease cleaves the peptide the products are released from RET quenching and donor fluorescence becomes apparent. The assay reagent was prepared as follows: 5X Luciferase Cells Cell Culture Lysis Reagent from Promega (# E153A) diluted 1X with dH2O, final 150 mM NaCl, the FRET peptide was diluted to 20 mM final a 2 mM reserve.

To prepare the plates, HCV replicon cells, with or without a Renilla Luciferase reporter gene, were digested with trypsin and seeded in a 96-well plate with the titrated test compounds added in columns 3 to 12. ; Columns 1 and 2 contained a control compound (control HCV inhibitor) and the bottom row contained cells with DMSO only. The plates were then placed in a CO2 incubator at 37 ° C.

Essays. After the addition of the test compounds described above (FRET Assay Preparation), at various times the plate was removed and Alamar blue solution (T rek Diagnostics, # 00-100) was added to measure cellular toxicity. After reading on a Cytoflour 4000 instrument (PE Biosystems), the plates were rinsed with PBS and then used for the FRET assay by adding 30 ul of the assay reagent of the

ES 2 390 732 T3 FRET peptide described above (Preparation of the FRET assay) per well. The plate was then placed on the Cytoflour 4000 instrument which had been set to 340 excitation / 490 emission, automatic mode for 20 cycles and the plate was read in a kinetic mode. Typically, the signal to noise ratio, using end point analysis after the readings, was at least three times. Alternatively, after Alamar Blue reading, the plates were rinsed with PBS, then used for the luciferase assay using the Promega Dual-Glo Luciferase Assay System or the Promega EnduRen Live Cell Substrate Assay.

Compound analysis was performed by quantification of relative HCV replicon inhibition and relative cytotoxicity values. To calculate the cytotoxicity values, the means of the Alamar blue fluorescence signals from the control wells were established as 100% non-toxic. Then, to determine the percent cytotoxicity, the individual signals in each of the test compound wells were divided by the average control signal and multiplied by 100%. To calculate HCV replicon inhibition values, an average background value was obtained from the two wells containing the highest amount of control HCV inhibitor at the end of the assay period. These numbers were similar to those obtained from untreated Huh-7 cells. Subsequently, the background numbers were subtracted from the mean signal obtained from the control wells and this number was used as 100% activity. To determine the percent activity, the individual signals in each of the test compound wells were divided by the averaged control values ​​after background subtraction and multiplied by 100%. EC50 values ​​were calculated as the concentration that caused a 50% reduction in FRET or luciferase activity. The two numbers generated for the compound plaque, percent cytotoxicity and percent activity, were used to determine the compounds of interest for further analysis.

Representative data for compounds are presented in Table 1.

Table 1.

<td>Structure</td><td>IC50</td><td>EC50</td>

<td>TO'</td><td>B</td><td>B</td>

<td>OO ° ΓΛ</td><td>B</td><td>B</td>

<td></td><td>B</td><td>B</td>

<td>. TO which, or '</td><td>B</td><td>B</td>

<td>or A- A ° s ° » UTA or</td><td>B</td><td>B</td>

ES 2 390 732 T3 (continued)

<td>Structure</td><td>IC50</td><td>EC50</td>

<td></td><td>B</td><td>B</td>

<td>Jj— 0 ^, «^ TO 0 Δ 8 ΟρΛο</td><td>B</td><td>B</td>

<td>₀ A / iY ^ cA.</td><td>B</td><td>B</td>

<td>° A?^M ILJLA^-C Ko</td><td>B</td><td>B</td>

<td>Aa V'X</td><td>B</td><td>B</td>

<td>t) -. 0; eaJ \^{s A s} ΐΛρΟ-ο</td><td>B</td><td>B</td>

<td>Α «γ · \ ° v, ° o</td><td>B</td><td>B</td>

<td>—C ^^Nme &lt;u&gt; 8 A To kXRA</td><td>B</td><td>B</td>

<td>-A ~ -&gt; TO*⁰ OR</td><td>B</td><td>B</td>

ES 2 390 732 T3 (continued)

<td>Structure</td><td>IC50</td><td>EC50</td>

<td>OR_WO ° ΓΛ OR</td><td>B</td><td>B</td>

<td>c&gt; 0 0 0</td><td>B</td><td>B</td>

<td></td><td>B</td><td>B</td>

<td>° \ z ° 8 f \</td><td>B</td><td>B</td>

<td></td><td>B</td><td>B</td>

<td>or A? ' O 0 n % * I 'i aáWo</td><td>B</td><td>B</td>

<td>already/'</td><td>B</td><td>B</td>

<td>0. .0 8 / 'λ Or to IlHk Xs ^ / ^ O</td><td>B</td><td>AND</td>

<td>ip % í "o- '3</td><td>B</td><td>B</td>

ES 2 390 732 T3 (continued)

<td>Structure</td><td>IC50</td><td>EC50</td>

<td>--Aj.</td><td>B</td><td>B</td>

<td></td><td>B</td><td>B</td>

<td></td><td>B</td><td>B</td>

<td>oo ⁰ Λλ θί? "^ΛΟΑ-θ'ο ^</td><td>B</td><td>B</td>

<td>1 Chiral or ,, «λί ''</td><td>B</td><td>B</td>

<td>he has'</td><td>B</td><td>B</td>

<td>OR_WO ° ΛΊ / 'WkSv</td><td>B</td><td>B</td>

<td>0 Λ- ' • ^ Ycc ^ v,</td><td>B</td><td>B</td>

<td>TO-</td><td>B</td><td>B</td>

ES 2 390 732 T3 (continued)

<td>Structure</td><td>IC50</td><td>EC50</td>

<td></td><td></td><td></td>

<td>0 j ¡¡XX&gt; -0k_or</td><td></td><td></td>

<td>V ° j! r \</td><td>B</td><td>B</td>

<td>or „Vi &lt;a« frYrrWv</td><td>B</td><td>B</td>

<td>or item / ' O * &lt;- ° H</td><td>B</td><td>B</td>

<td>or item too 2/1</td><td>B</td><td>B</td>

<td>«ΓΑ? '- rVSVvOv</td><td>B</td><td>B</td>

<td>Ολ, Ν-Ά ' O ° o ^ 3 t ^ W) -.,</td><td>B</td><td>B</td>

<td>° v ^^N' O O. .0 Μ Γ ^ * Λ</td><td></td><td></td>

ES 2 390 732 T3 (continued)

<td>Structure</td><td>IC50</td><td>EC50</td>

<td> ---</td><td></td><td></td>

<td colspan="3">A&gt; 0.5 pM; B 0.0042 pM - 0.5 pM; C &lt;0.02 pM but an exact value was not determined; D&gt; 0.04 pM but an exact value was not determined; E &lt;0.07 pM but an exact value was not determined; F&gt; 1.0 pM but an exact value was not determined</td>

Pharmaceutical Compositions and Treatment Procedures

The compounds show activity against HCV NS5B and may be useful in the treatment of HCV and HCV infection. Therefore, another aspect of the invention is a composition comprising a compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Another aspect of the invention is a composition further comprising a compound having anti-HCV activity.

Another aspect of the invention is a composition in which the compound having anti-HCV activity is an interferon. Another aspect of the invention is when the interferon is selected from interferon alpha 28, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastoid interferon tau.

Another aspect of the invention is a composition in which the compound having anti-HCV activity is a cyclosporin. Another aspect of the invention is when the cyclosporin is cyclosporin A.

Another aspect of the invention is a composition in which the compound having anti-HCV activity is selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a T helper-type lymphocyte response 1, RNA interference, antisense RNA, Imiquimod, ribavirin, an inosine 5'-monophosphate dehydrogenase inhibitor, amantadine, and rimantarin.

Another aspect of the invention is a composition in which the compound having anti-HCV activity is effective to inhibit the function of a selected target of HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, NS4B protein of HCV. HCV, HCV entry, HCV assembly, HCV exit, HCV NS5A protein, IMPDH, and a nucleoside analog for the treatment of HCV infection.

Another aspect of the invention is a composition comprising a compound, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, an interferon, and ribavirin.

Another aspect of the invention is a compound of the invention for use in a method of inhibiting HCV replicon function which comprises contacting the HCV replicon with a compound, or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of the invention for use in a method of inhibiting the function of the HCV NS5B protein which comprises contacting the HCV NS5B protein with a compound, or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of the invention for use in a method of treating an HCV infection in a patient which comprises administering to the patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof. In another embodiment the compound is effective to inhibit the function of the HCV replicon. In another embodiment the compound is effective in inhibiting the function of the HCV NS5B protein.

Another aspect of the invention is a compound of the invention for use in a method of treating HCV infection in a patient comprising administering to the patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, in combination with (before, after, or simultaneously) another compound that has anti-HCV activity.

Another aspect of the invention is the method in which the other compound having anti-HCV activity is an interferon.

Another aspect of the invention is the method in which the interferon is selected from interferon alpha 2B, pegylated interferon, consensus interferon, interferon alpha 2A, lymphoblastoid interferon tau.

ES 2 390 732 T3

Another aspect of the invention is the method in which the other compound having anti-HCV activity is a cyclosporine.

Another aspect of the invention is the process in which the cyclosporin is cyclosporin A.

Another aspect of the invention is the method in which the other compound having anti-HCV activity is selected from interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T lymphocyte response, RNA interference, antisense RNA, Imiquimod, ribavirin, an inosine 5'-monophosphate dehydrogenase inhibitor, amantadine, and rimantarin.

Another aspect of the invention is the method in which the other compound having anti-HCV activity is effective to inhibit the function of a target selected from the group consisting of HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase. HCV, HCV NS4B protein, HCV entry, HCV assembly, HCV exit, HCV NS5A protein, IMPDH, and a nucleoside analog for the treatment of HCV infection.

Another aspect of the invention is the method in which the other compound having anti-HCV activity is effective to inhibit the function of a target in the HCV life cycle other than the HCV NS5B protein.

Therapeutically effective "means the amount of agent necessary to provide significant benefit to the patient as understood by those of skill in the field of hepatitis and HCV infection.

Patient ”means a person infected with the HCV virus and suitable for therapy as understood by experts in the field of hepatitis and HCV infection.

HCV treatment, therapy, regimen, infection, and related terms are used as understood by those of skill in the field of hepatitis and HCV infection.

The compounds of the present invention are generally administered as pharmaceutical compositions comprising a therapeutically effective amount of a compound or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier and may contain conventional excipients. A therapeutically effective amount is one that is needed to provide significant benefit to the patient. Pharmaceutically acceptable carriers are those conventionally known carriers that have acceptable safety profiles. The compositions encompass all common solid and liquid forms including capsules, tablets, lozenges, and powders, as well as liquid suspensions, syrups, elixirs, and solutions. The compositions are prepared using common formulation techniques and conventional excipients (such as binding and wetting agents) and carriers (such as water and alcohols) are generally used for the compositions.

Solid compositions that are normally formulated in dosage units and compositions that provide from about 1 to 1000 mg of the active ingredient per dose are preferred. Some examples of dosages are 1mg, 10mg, 100mg, 250mg, 500mg, and 1000mg. Generally, other agents will be present in a unit range similar to the agents of that class used clinically. Typically this is 0.25-1000 mg / unit.

Typically liquid compositions are in unit dosage ranges. Generally, the liquid composition will be in a unit dosage range of 1-100 mg / ml. Some examples of dosages are 1 mg / ml, 10 mg / ml, 25 mg / ml, 50 mg / ml, and 100 mg / ml. Generally, other agents will be present in a unit range similar to clinically used agents of this class. Typically this is 1-100 mg / ml.

The invention encompasses all conventional modes of administration; oral and parenteral procedures being preferred. Generally, the dosage regimen will be similar to other agents used clinically. Typically the daily dose will be 1-100 mg / kg of body weight per day. Generally, more compound is required orally and less parenterally. However, the specific dosage regimen will be determined by a physician using medical judgment.

The invention also encompasses methods in which the compound is administered in combination therapy. That is, the compound can be used in conjunction with, but separately from, other agents useful in the treatment of hepatitis and HCV infection. In these combination procedures, the compound will generally be administered in a body weight daily dose of 1-100 mg / kg per day in conjunction with other agents. The other agents will generally be administered in the amounts used therapeutically. However, the specific dosage regimen will be determined by a physician using medical judgment.

Some examples of compounds suitable for the compositions and procedures are listed in Table 2.

ES 2 390 732 T3

Table 2.

<td>Brand name</td><td>Type of inhibitor or target</td><td>Company Source</td>

<td>Omega IFN</td><td>IFN-ω</td><td>Intarcia Therapeutics</td>

<td>BILN-2061</td><td>Serine protease inhibitor</td><td>Boehringer Ingelheim Phanna KG, Ingelheim, Germany</td>

<td>Summetrel</td><td>antiviral</td><td>Endo Pharmaceuticals Holdings Inc., Chadds Ford, PA</td>

<td>Roferon A</td><td>IFN-a2a</td><td>F. Hoffmann-La Roche LTD, Basel, Switzerland</td>

<td>Pegasys</td><td>PEGylated IFN-a2a</td><td>F. Hoffmann-La Roche LTD, Basel, Switzerland</td>

<td>Pegasys and Ribavirin</td><td>PEGylated IFN-a2a / ribavirin</td><td>F. Hoffmann-La Roche LTD, Basel, Switzerland</td>

<td>CellCept</td><td>HCV IgG Immunosuppressant</td><td>F. Hoffmann-La Roche LTD, Basel, Switzerland</td>

<td>Wellferon</td><td>IFN-an1 lymphoblastoid</td><td>GlaxoSmithKline plc, Uxbridge, UK</td>

<td>Albuferon - α</td><td>IFN-a2b albumin</td><td>Human Genome Sciences Inc., Rockville, MD</td>

<td>Levovirine</td><td>Ribavirin</td><td>ICN Pharmaceuticals, Costa Mesa, CA</td>

<td>IDN-6556</td><td>Caspase inhibitor</td><td>Idun Pharmaceuticals Inc., San Diego, CA</td>

<td>IP-501</td><td>Antifibrotic</td><td>Indevus Pharmaceuticals Inc., Lexington, MA</td>

<td>Actimmune</td><td>INF-γ</td><td>InterMune Inc., Brisbane, CA</td>

<td>Infer A</td><td>IFN alfacon-1</td><td>InterMune Pharmaceutical Inc., Brisbane, CA</td>

<td>ISIS 14803</td><td>Antisense</td><td>ISIS Pharmaceuticals Inc, Carlsbad, CA / Elan Phamaceuticals Inc., New York, NY</td>

<td>JTK-003</td><td>RdRp inhibitor</td><td>Japan Tobacco Inc., Tokyo, Japan</td>

<td>Pegasys and Ceplene</td><td>PEGylated IFN-a2a / immunomodulator</td><td>Maxim Pharmaceuticals Inc., San Diego, CA</td>

<td>Ceplene</td><td>Immunomodulator</td><td>Maxim Pharmaceuticals Inc., San Diego, CA</td>

<td>Civair</td><td>HCV IgG Immunosuppressant</td><td>Nabi Biopharmaceuticals Inc., Boca Raton, FL</td>

<td>Intron A and Zadaxin</td><td>IFN-a2b / a1-thymosin</td><td>RegeneRx Biopharmiceuticals Inc., Bethesda, MD / SciClone Pharmaceuticals Inc, San Mateo, CA</td>

<td>Levovirine</td><td>IMPDH inhibitor</td><td>Ribapharm Inc., Costa Mesa, CA</td>

<td>Viramidine</td><td>Ribavirin prodrug</td><td>Ribapharm Inc., Costa Mesa, CA</td>

<td>Heptazyme</td><td>ribozyme</td><td>Ribozyme Pharmaceuticals Inc., Boulder, CO</td>

<td>Intron A</td><td>IFN-a2b</td><td>Schering-Plow Corporation, Kenilworth, NJ</td>

ES 2 390 732 T3 (continued)

<td>Brand name</td><td>Type of inhibitor or target</td><td>Company Source</td>

<td>PEG-Intron</td><td>PEGylated IFN-a2b</td><td>Schering-Plow Corporation, Kenilworth, NJ</td>

<td>Rebetron</td><td>IFN-a2b / ribavirin</td><td>Schering-Plow Corporation, Kenilworth, NJ</td>

<td>Ribavirin</td><td>ribavirin</td><td>Schering-Plow Corporation, Kenilworth, NJ</td>

<td>PEG-Intron / Ribavirin</td><td>PEGylated IFN-a2b / ribavirin</td><td>Schering-Plow Corporation, Kenilworth, NJ</td>

<td>Zadazim</td><td>Immunomodulator</td><td>SciClone Pharmaceuticals Inc., San Mateo, CA</td>

<td>Rebif</td><td>IFN-e1a</td><td>Serono, Geneva, Switzerland</td>

<td>IFN-β and EMZ701</td><td>IFN-β and EMZ701</td><td>TransitionTherapeuticsInc., Ontario, Canada</td>

<td>Batabulin (T67)</td><td>Β tubulin inhibitor</td><td>Tularik Inc., South San Francisco, CA</td>

<td>Merimepodib (VX-497)</td><td>IMPDH inhibitor</td><td>Vertex Pharmaceuticals Inc., Cambridge, MA</td>

<td>Telaprevir (VX-950, LY-570310)</td><td>NS3 serine protease inhibitor</td><td>Vertex Pharmaceuticals Inc., Cambridge, MA / Eli Lilly and Co. Inc., Indianapolis, IN</td>

<td>Omniferon</td><td>Natural IFN-α</td><td>Viragen Inc., Plantation, FL</td>

<td>XTL-6865 (XTL-002)</td><td>Monoclonal antibody</td><td>XTL Biopharmaceuticals Ltd., Rehovot, Israel</td>

<td>HCV-796</td><td>NS5B Replicase Inhibitor</td><td>Wyeth / Viropharma</td>

<td>NM-283</td><td>NS5B Replicase Inhibitor</td><td>Idenix / Novartis</td>

<td>GL-59728</td><td>NS5B Replicase Inhibitor</td><td>Gene Labs / Novartis</td>

<td>GL-60667</td><td>NS5B Replicase Inhibitor</td><td>Gene Labs / Novartis</td>

<td>2'C MeA</td><td>NS5B Replicase Inhibitor</td><td>Gilead</td>

<td>PSI6130</td><td>NS5B Replicase Inhibitor</td><td>Roche</td>

<td>R1626</td><td>NS5B Replicase Inhibitor</td><td>Roche</td>

<td>SCH 503034</td><td>Serine protease inhibitor</td><td>Schering Plow</td>

<td>NIM811</td><td>Cyclophilin Inhibitor</td><td>Novartis</td>

<td>Suvus</td><td>Methylene blue</td><td>Bioenvision</td>

<td>Multiferon</td><td>Long-lasting IFN</td><td>Viragen / Valentis</td>

<td>Actilon (CPG10101)</td><td>TLR9 agonist</td><td>Coley</td>

ES 2 390 732 T3 (continued)

<td>Brand name</td><td>Type of inhibitor or target</td><td>Company Source</td>

<td>Interferon-β</td><td>Interferon-e-1a</td><td>Serono</td>

<td>Zadaxin</td><td>Immunomodulator</td><td>Sciclone</td>

<td>Pyrazolopyrimidine Compounds and Salts from WO-2005047288 May 26, 2005</td><td>HCV inhibitors</td><td>Arrow Therapeutics Ltd.</td>

<td>2'C Methyl adenosine</td><td>NS5B Replicase Inhibitor</td><td>Merck</td>

<td>GS-9132 (ACH-806)</td><td>HCV inhibitor</td><td>Achillion / Gilead</td>

Description of the specific realizations

Unless otherwise specified, analytical LCEM data in the following intermediates and examples were acquired using the following columns and conditions. Stop time: Gradient time + 1 minute; Conc. Starting: 0% B unless otherwise indicated; Eluent A: 5% CH3CN / 95% H2O with 10 mM NH4OAc (for columns A, D and E); 10% MeOH / 90% H2O with 0.1% TFA (for columns B and C); Eluent B: 95% CH3CN / 5% H2O with 10 mM NH4OAc (for columns A, D and E); 90% MeOH / 10% H2O with 0.1% TFA (for columns B and C); Column A: Phenomenex 10μ 4.6 x 50 mm C 18; Column B: Phenomenex C18 10μ 3.0 x 50 mm; Column C: Phenomenex 4.6 x 50 mm C18 10µ; Column D: Phenomenex Lina C18 5μ 3.0 x 50 mm; Column E: Phenomenex 5μ 4.6 x 50 mm C18.

As an object of graphics software, some structures have missing hydrogen atoms.

Intermediate 1

<img file="ES2390732T3_D0029.tif" />

1H-Indole-6-carboxylic acid, 2-bromo-3-cyclohexyl-, methyl ester. Freshly recrystallized pyridinium tribromide (recrystallized from hot AcOH (5 ml per 1 g) rinsed with cold AcOH and dried under high vacuum over KOH) was added portionwise (over 10 min) to a stirring solution of 3-cyclohexyl-1H Methyl indole-6-carboxylate (60 g, 233 mmol) (prepared using procedures described in WO2004 / 065367) in CHCh / THF (1: 1, 1.25 L) at 20 ° C. The reaction solution was stirred at 0-5 ° C for 2.5 h and washed with aq NaHSO3. sat. (1 L), 1 N HCl (1 L), and brine (1 L). The organic phase was dried (MgSO4) and concentrated. The resulting red oil was diluted with Et2O and concentrated. The resulting pink solid was dissolved in Et2O (200 ml), treated with hexanes (300 ml), and partially concentrated. The solids were collected by filtration and rinsed with hexanes. The mother liquor was concentrated to dryness and the procedure was repeated. The solids were combined to produce 1H-indole-6-carboxylic acid, 2-bromo-3-cyclohexyl-, methyl ester (64 g, 190 mmol, 82%) as a fluffy pink solid, which was used without further purification. NMR¹H (300 MHz, CDCh) δ 8.47 (sa, 1H), 8.03 (d, J = 1.4 Hz, 1H), 7.74 (dd, J = 1.4, 8.8 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 3.92 (s, 3H), 2.82 (tt, J = 3.7, 11.7 Hz, 1H), 1, 98-1.72 (m, 7H), 1.50-1.27 (m, 3H). 13C NMR (75 MHz, CDCl3) δ 168.2, 135.6, 130.2, 123.1, 120.8, 120.3, 118.7, 112.8, 110.7, 52.1, 37 , 0.32.2 (2), 27.0 (2), 26.1. LCMS: m / e 334 (MH)^-, ret time. 3.34 min, column A, 4 minute gradient.

ES 2 390 732 T3

Intermediate 2

<img file="ES2390732T3_D0030.tif" />

1H-indole-6-carboxylic acid, 2-bromo-3-coclohexyl-. A solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (20 g, 60 mmol) and LiOH (3.8 g, 160 mmol) in MeOH / THF / H₂O (1: 1: 1, 300 ml) was heated at 90 ° C for 2 h. The reaction mixture was cooled in an ice / H2O bath, neutralized with 1M HCl (~ 160 mL), diluted with H2O (250 mL) and stirred for 1 h at rt. The precipitates were collected by filtration, rinsed with H₂O and dried to yield 1H-indole-6-carboxylic acid, 2-bromo-3-cyclohexyl- (quant.) Which was used without further purification.

An alternative procedure that can be used to provide 1H-indole-6-carboxylic acid, 2-bromo-3-cyclohexyl is described below:

A solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (117 g, 349 mmol) and LiOH.H₂O (26.4 g, 629 mmol) in MeOH / THF / H2O (1: 1: 1, 1.8 L) was refluxed for 3 h. The reaction mixture was cooled in an ice / H2O bath to ~ 2 ° C, neutralized with 1M HCl (~ 650 ml) (added at such a rate that the temperature did not exceed 5 ° C), diluted with H2O (1 L) and stirred while warming to room temperature. The precipitates were collected by filtration, rinsed with H2O, and dried to yield the 1H-indole-6-carboxylic acid, 2-bromo-3-cyclohexyl- THF monosolvate (135.5 g, 345 mmol, 99% ) as a yellow solid, which was used without further purification. NMR¹H (300 MHz, CDCla) δ 11.01 (sa, 1H), 8.77 (s, 1H), 8.07 (d, J = 1.5 Hz, 1H), 7.82 (dd, J = 1.5, 8.8 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 3.84-3.74 (m, 4H), 2.89 (m, 1H), 1.98-1.72 (m, 11H), 1.50-1.24 (m, 3H). 13C NMR (75 MHz, CDCl3) δ 172.7, 135.5, 130.7, 122.3, 120.9 (2), 118.8, 113.3, 111.1, 67.9 (2) , 37.0, 32.2 (2), 27.0 (2), 26.1, 25.5 (2). LCMS: m / e 320 (MH)^-, ret time. 2.21 min, column A, 4 minute gradient. Intermediate 3

<img file="ES2390732T3_D0031.tif" />

1H-indole-6-carboxamide, 2-bromo-3-cyclohexyl-N - [(dimethylamino) sulfonyl] -. 1,1'-Carbonyldiimidazole (1.17 g, 7.2 mmol) was added to a stirred solution of 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (2.03 g, 6.3 mmol ) in THF (6 ml) at 22 ° C. The evolution of CO2 was instantaneous and when reduced, the solution was heated to 50 ° C for 1 h and then cooled to 22 ° C. N, N-dimethylsulfamide (0.94 g, 7.56 mmol) was added followed by the dropwise addition of a solution of DBU (1.34 g, 8.8 mmol) in THF (4 ml). Stirring was continued for 24 h. The mixture was partitioned between ethyl acetate and dilute HCl. The ethyl acetate phase was washed with water followed by brine and dried over Na2SO4. The extract was concentrated to dryness to leave the title product as a friable pale yellow foam, (2.0 g, 74%,&gt; 90% purity, estimated from NMR). NMR¹H (300 MHz, DMSO-D6) δ ppm 1.28 1.49 (m, 3H) 1.59 - 2.04 (m, 7H) 2.74 - 2.82 (m, 1H) 2 , 88 (s, 6H) 7.57 (dd, J = 8.42, 1.46 Hz, 1H) 7.74 (d, J = 8.78 Hz, 1H) 7.91 (s, 1H) 11.71 (s, 1H) 12.08 (s, 1H).

An alternative procedure for the preparation of 1H-indole-6-carboxamide,

2-Bromo-3-cyclohexyl-N - [(dimethylamino) sulfonyl] - is described below.

In a 1 L, four necked round bottom flask, equipped with a mechanical stirrer, temperature controller, N2 inlet, and condenser, under N2 atmosphere, 2-bromo-3-cyclohexyl acid was added. 1H-indole-6-carboxylic acid (102.0 g, 0.259 mol) and dry THF (300 ml). After stirring for 10 min, CDI (50.3 g, 0.31 mol) was added portionwise. The reaction mixture was then heated at 50 ° C for 2 h. After cooling to 30 ° C, N, N-dimethylaminosulfonamide (41.7 g, 0.336 mol) was added in one portion, followed by dropwise addition of DBU (54.1 ml, 0.362 mol) over a period of 1 hour. The reaction mixture was then stirred at rt for 20 h. The solvent was removed in vacuo and the residue was partitioned between EtoAc and 1N HCl (1: 1.2 L). The organic phase was separated and the aqueous phase was extracted with EtOAc (500 ml). The combined organic phases were washed with brine (1.5 L) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude product (111.0 g). The crude product was suspended in EtOAc (400 ml) at 60 ° C. Heptane (2 L) was slowly added to the suspension.

ES 2 390 732 T3

The resulting suspension was stirred and cooled to 0 ° C. Then it was leaked. The filter cake was rinsed with a small amount of heptane and air dried under house vacuum for 2 days. The product was collected as a white solid (92.0 g, 83%). NMR¹H (MeOD, 300 MHz) δ 7.89 (s, H), 7.77 (d, J = 8.4 Hz, 1H), 7.55 (dd, J = 8.4 and 1.8 Hz, 1H), 3.01 (s, 6H), 2.73-2.95 (m, 1H), 1.81-2.05 (m, 8H), 1.39-1.50 (m, 2H) ; m / z 429 (M + H) +.

Intermediate 4

<img file="ES2390732T3_D0032.tif" />

1H-indole-6-carboxamide, 3-cyclohexyl-N - [(dimethylamino) sulfonyl] -2- (2-formyl-4-methoxyphenyl) -. A mix of the

2- Bromo-3-cyclohexyl-N - [(dimethylamino) sulfonyl] -1H-indole-6-carboxamide (4.28 g, 0.01 mol), acid

4-methoxy-2-formylphenyl boronic (2.7 g, 0.015 mol), 2-dicyclohexylphosphino-2 ', 6'-dimethoxy-biphenyl (41 mg, 0.0001 mol), palladium acetate (11.2 mg) and finely ground potassium carbonate (4.24 g, 0.02 mol) in toluene (30 ml) was stirred at reflux temperature and under a nitrogen atmosphere for 30 min, at which time LC / MS analysis showed that the reaction was complete. The reaction mixture was then diluted with ethyl acetate and water, and then acidified with excess dilute HCl. The ethyl acetate phase was then collected and washed with dilute HCl, water, and brine. The organic solution was then dried (magnesium sulfate), filtered, and concentrated to give a gum. The gum was diluted with hexanes (250 ml) and ethyl acetate (25 ml), and the mixture was stirred for 20 h at 22 ° C, during which time the product turned into a bright yellow granular solid (4, 8 g) which was used directly without further purification.

An alternative procedure for the preparation of 1 H-indole-6-carboxamide,

3- cyclohexyl-N - [(dimethylamino) sulfonyl] -2- (2-formyl-4-methoxyphenyl) - is provided below:

To a suspension solution of 2-bromo-3-cyclohexyl-N - [(dimethylamino) sulfonyl] -indole-6-carboxamide (54.0 g, 126 mmol), 4-methoxy-2-formylphenylboronic acid (29.5 g, 164 mmol) and LiCl (13.3 g, 315 mmol) in EtOH / toluene (1: 1, I l) was added a solution of Na2CO₃ (40.1 g, 379 mmol) in water (380 ml). The reaction mixture was stirred for 10 min and then Pd (PPh3) 4 (11.3 g, 10.0 mmol) was added. The reaction solution was flushed with nitrogen and heated to 70 ° C (internal monitoring) overnight and then cooled to rt. The reaction was diluted with EtOAc (1 L) and EtOH (100 mL), washed carefully with 1N aqueous HCl (1 L) and brine (500 mL), dried (MgSO4), filtered, and concentrated. The residual solids were stirred with Et2O (600 mL) for 1 h and collected by filtration to yield 1H-indole-6-carboxamide, 3-cyclohexyl-N - [(dimethylamino) sulfonyl] -2- (2-formyl-4- methoxyphenyl) - (52.8 g, 109 mmol, 87%) as a yellow powder, which was used without further purification. NMR¹H (300 MHz, d6-DMSO) δ 11.66 (s, 1H), 8.17 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.59 (dd, J = 1.4, 8.4 Hz, 1H), 7.23 - 7.16 (m, 2H), 7.08 (dd, J = 2.6, 8.4 Hz, 1H), 6.54 (d, J = 8.8 Hz, 1H), 3.86 (s, 3H), 3.22-3.08 (m, 1H) , 2.91 (s, 6H), 2.00-1.74 (m, 7H), 1.60-1.38 (m, 3H). 13 C NMR (75 MHz, CDCl3) δ 165.7, 158.8, 147.2, 139.1, 134.3, 132.0, 123.4, 122.0, 119.2, 118.2, 1 14.8, 112.3, 110.4, 109.8, 79.6, 45.9, 37.2 (2), 34.7, 32.0 (2), 25.9 (2), 24 , 9. LCMS: m / e 482 (MH)^-, ret time. 2.56 min, column A, 4 minute gradient.

Intermediate 5

<img file="ES2390732T3_D0033.tif" />

6H-Isoindolo [2,1-a] indole-3-carboxamide, 11-cyclohexyl-N - [(dimethylamino) sulfonyl] -6-ethoxy-8-methoxy-. Toluene (900 ml), EtOH (900 ml), 2-bromo3- cyclohexyl-N- (N, N-dimethylsulfamoyl) -1H-indole-6-carboxamide (90 g, 0.21 mol), 2-formyl-4-methoxyphenylboronic acid (49.2 g, 0.273 mol) and LiCl (22 , 1 g, 0.525 mol). The resulting solution was bubbled with N2 for 15 min. A Na2CO solution₃ (66.8 g, 0.63 mol) in H2O (675 mL) was added and the reaction mixture was bubbled with N2 for a further (10 min). Pd (PPh₃) 4 (7.0 g, 6.3 mmol) and the reaction mixture was heated at 70 ° C for 20 h. After

ES 2 390 732 T3 cool to 35 ° C, a 1N HCl solution (1.5 L) was added slowly. The resulting mixture was transferred to a 6 L separatory funnel and extracted with EtOAc (2 x 1.5 L). The combined organic extracts were washed with brine (2 L), dried over MgSO4, filtered, and concentrated in vacuo to give a yellow solid, which was triturated with 20% EtOAc in hexane (450 mL, 50 ° C to 0 ° C) to give 3-cyclohexyl-N- (N, N-dimethylsulfamoyl) -2- (2-formyl-4-methoxyphenyl) -1H-indole-6-carboxamide (65.9 g) as a yellow solid. HPLC purity, 98%.

The mother liquor from the trituration was concentrated in vacuo. The residue was refluxed with EtOH (50 ml) for 3 h. The solution was then cooled to 0 ° C. The precipitates were filtered and washed with chilled (5 ° C) TBME (20 ml). The filter cake was air dried in house vacuum to give an additional amount of the title compound as a white solid (16.0 g). HPLC purity, 99%. NMR¹H (CDCl3, 300 MHz) δ 8.75 (s, 1H), 7.96 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.45 (dd, J = 8.4 and 1.4 Hz, 1H), 7.09 (d, J = 2.2 Hz, 1H), 6.98 (dd, J = 8.4 and 2.2 Hz, 1H), 6.50 (s, 1H), 3.86 (s, 3H), 3.05 (s, 6H), 2.92-3.13 (m , 3H), 1.85-1.93 (m, 7H), 1.40-1.42 (m, 3H), 1.05 (t, J = 7.1Hz, 3H). m / z 512 (M + H) +.

Intermediate 6

<img file="ES2390732T3_D0034.tif" />

1H-indole-6-carboxamide, 3-cyclohexyl-N - [(dimethylamino) sulfonyl] -2- (2-formyl-4-methoxyphenyl) -. Dissolved

11-cyclohexyl-N- (N, N-dimethylsulfamoyl) -6-ethoxy-8-methoxy-6H-isoindolo [2,1-a] indole-3-carboxamide in THF (75 ml). A 2N HCl solution (300 ml) was added to the solution. The mixture was vigorously stirred under N2 atmosphere at rt for 16 h. The resulting suspension was filtered and washed with chilled TBME (2 x 30 ml), the filter cake was dried in house vacuum overnight to give the title compound as a yellow solid. HPLC purity, 99%. NMR¹H (DMSO-d6, 300 MHz) δ 11.65 (s, 1H), 8.16 (s, 1H), 7.76 (d, J = 5.9 Hz, 1H), 7.73 (d, J = 5.9 Hz, 1H), 7.58 (dd, J = 8.5 and 1.5 Hz, 1H), 7.17-7.20 (m, 2H), 7.08 (dd, J = 8.5 and 1.4 Hz, 1H), 6.55 (d, J = 8.6 Hz, 1H), 3.86 (s, 3H), 3.14-3.18 (m, 1H) , 2.91 (s, 6H), 1.75-1.99 (m, 7H), 1.48-1.60 (m, 3H); m / z 484 (M + H) +.

Intermediate 7

<img file="ES2390732T3_D0035.tif" />

7H-indole [2,1-a] [2] benzazepine-6-carboxylic acid, 13-cyclohexyl-10 - [[[(dimethylamino) sulfonyl] amino] carbonyl] -3-methoxy-, methyl ester. A mixture of 3-cyclohexyl-N- (N, N-dimethylsulfamoyl) -2- (2-formyl-4-methoxyphenyl) -1Hindole-6-carboxamide (4.8 g, 0.01 mol), 2- ( Methyl dimethoxyphosphoryl) acrylate (9.7 g, 0.02 mol) and cesium carbonate (7.1 g, 0.02 mol) in DMF (28 ml) were stirred for 20 h at an oil bath temperature of 55 ° C. The mixture was poured into ice-water and acidified with HCl to precipitate the crude product. The solid was collected, dried and flash chromatographed on SiO2 (110 g) using a solution of ethyl acetate and methylene chloride (1:10) containing 2% acetic acid. The homogeneous fractions were combined and evaporated to provide the title compound as a pale yellow solid (3.9 g, 71% yield). MS: 552 (M = H +).

An alternative process for the preparation of 7H-indole [2,1-a] [2] benzazepine-6-carboxylic acid, 13-cyclohexyl-10 - [[[(dimethylamino) sulfonyl] amino] carbonyl] -3-methoxy- , methyl ester is provided below.

A solution of 11-cyclohexyl-N - [(dimethylamino) sulfonyl] -6-hydroxy-8-methoxy-6H-isoindolo [2,1-a] indole-3-carboxamide (cyclic hemiaminal) (63.0 g, 130 mmol), methyl 2- (dimethoxyphosphoryl) acrylate (60 g, 261 mmol), cesium carbonate (106 g, 326 mmol) in DMF (400 ml) heated at 60 ° C (bath temperature) for 4.5 h. Additional methyl 2- (dimethoxyphosphoryl) acrylate (15 g, 65 mmol) and cesium carbonate (21.2 g, 65 mmol) were added and the reaction was heated to 60 ° C overnight and then cooled to ta. The stirred reaction mixture was diluted with H₂O (1 L), was slowly neutralized with 1N aqueous HCl (800 mL), stirred for 3 h, and then the precipitates were collected by

ES 2 390 732 T3 filtration. The solids were triturated with Et2O (800 mL) and dried to yield methyl-7H-indole [2,1-a] [2] benzazepine-6-carboxylic acid, 13-cyclohexyl-10 - [[[(dimethylamino) sulfonyl ] amino] carbonyl] -3-methoxy-, methyl ester (70.2 g, 127 mmol, 98%) as a yellow solid that was used without further purification. NMR¹H (300 MHz, CDCl3) δ 8.67 (s, 1H), 8.09 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.80 (s, 1H) , 7.50 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.08 (dd, J = 2.6, 8.8 Hz, 1H), 6.98 (d, J = 2.6 Hz, 1H), 5.75-5.51 (m, 1H), 4.29-4.01 (m, 1H), 3.89 (s , 3H), 3.82 (s, 3H), 3.05 (s, 6H), 2.87-2.73 (m, 1H), 2.11-1.12 (m, 10H). LCMS: m / e 550 (MH)^-, ret time. 3.21 min, column A, 4 minute gradient.

Intermediate 8

<img file="ES2390732T3_D0036.tif" />

Cycloprop [d] indole [2,1-a] [2] benzazepin-1a (2H) -carboxylic acid, 8-cyclohexyl-5 - [[[(dimethylamino) sulfonyl] amino] carbonyl] -1,12b-dihydro- 11-methoxy-, methyl ester, (+/-) -. DMSO (5 ml) was added to a mixture of trimethylsulfoxonium iodide (199 mg, 0.906 mmol) and NaH (38 mg in a 60% oil dispersion, 0.953 mmol) in a round bottom flask. The reaction mixture was stirred at rt for 0.5 h. Then 7H-indole [2,1-a] [2] benzazepine-6-carboxylic acid, 13-cyclohexyl-10 - [[[(dimethylamino) sulfonyl] amino] carbonyl] -3- (methoxy) - was added, methyl ester (125 mg, 0.227 mmol) and the reaction mixture was stirred at rt. for 3 h, and then at 50 ° C for a further 3 h. The reaction was then quenched with water and acidified with a 1N HCl solution. The product then precipitated as a light yellow solid which was collected by filtration and air dried (106 mg, 83% yield). Then 6 mg of this material was purified by prep HPLC. to provide the title compound as a light yellow solid (1.8 mg). MS m / z 566 (MH +), Retention time: 3.850 min. NMR¹H (500 MHz, MeOD) δ ppm 0.28 (m, 0.36 H) 1.19 - 2.20 (m, 11.64 H) 2.70 - 3.02 (m, 2H) 3, 03 (s, 2.16H) 3.05 (s, 3.84H) 3.49 (d, J = 15.26 Hz, 0.64H) 3.54 (s, 1.92H) 3 , 83 (s, 1.08H) 3.91 (s, 3H) 4.08 (d, J = 15.26 Hz, 0.36H) 5.29 (d, J = 15.26 Hz, 0 , 36H) 5.50 (d, J = 14.95Hz, 0.64H) 6.98-7.06 (m, 1H) 7.16 (d, J = 2.44Hz, 0, 36 H) 7.23 (d, J = 2.44 Hz, 0.64 H) 7.30 (d, J = 8.55 Hz, 0.64 H) 7.34 (d, J = 8.55 Hz, 0.36 H) 7.56 (dd, J = 8.55, 1.53 Hz, 0.64 H) 7.63 (dd, J = 8.55, 1.53 Hz, 0.36 H) 7.88 (d, J = 8.55 Hz, 0.64 H) 7.91 (d, J = 8.55 Hz, 0.36 H) 8.12 (s, 0.36 H) 8.33 (d, J = 1.53 Hz, 0.64 H). An alternative procedure for the preparation of the title compounds is provided below.

Sodium hydride (95%) (3.09 g , 129.2 mmol) and dry DMF (200 ml). With vigorous stirring, trimethylsulfoxonium iodide (32.5 g, 147.3 mmol) was added portionwise, during which time the temperature was raised to 30 ° C. After stirring for 30 min, a solution of 7H-indole [2,1-a] [2] benzazepine-6-carboxylic acid, 13-cyclohexyl-10 - [[[(dimethylamino) sulfonyl] amino] carbonyl] -3 - (methoxy) -, methyl ester (33.8 g, 61.3 mmol) in dry DMF (70 mL) was added quickly. The reaction mixture was stirred below 30 ° C for 30 min and then poured portionwise into an ice cold solution of 1N HCl (130 mL) in H2O (2 L). After mechanically stirring the resulting suspension for 1 h, the precipitates were filtered and the filter cake was washed with H2O (100 ml). The filter cake was partitioned between EtOAc and 0.5N HCl (1: 1, 4 L). The organic phases were separated, washed with H2O (1 L) and brine (1 L), dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in EtOAc (150 ml) and the solution was filtered through a plug of silica gel (300 g in hexane) and rinsed with 50% EtOAc in hexane (5 L). The filtrate was concentrated in vacuo to give a slightly yellow solid which was triturated with 10% EtOAc in TBME (220 mL) at 50 ° C to 0 ° C to give cycloprop [d] indole [2,1-a] [acid]. 2] benzazepin-1a (2H) -carboxylic,

8-cyclohexyl-5 - [[[(dimethylamino) sulfonyl] amino] carbonyl] -1,12b-dihydro-11-methoxy-, methyl ester, (+/-) - as a white solid (26, 1 g, 75% yield). HPLC purity, 100%. NMR¹H (DMSO-d6, 300 MHz) δ 11.61 (s, 1H), 8.47 (s, 0.5H), 8.25 (s, 0.5H), 7.81-7.88 (m , 1H), 7.57-7.63 (m, 1H), 7.23-7.29 (m, 2H), 7.01-7.07 (m, 1H), 5.43 (d, J = 15.0 Hz, 0.5H), 5.22 (d, J = 15 Hz, 0.5H), 4.04 (dd, J = 15.4 and 6.6 Hz, 0.5H), 3 , 83 (s, 3H), 3.75 (s, 1H), 3.08-3.47 (m, 0.5H), 3.29 (s, 3H), 2.73-2.92 (m , 8H), 1.11-1.99 (m, 10.5H), 0.20 (m, 0.5H); m / z 566 (M + H) +.

ES 2 390 732 T3

Intermediate 9

<img file="ES2390732T3_D0037.tif" />

Cycloprop [d] indole [2,1-a] [2] benzazepin-1a (2H) -carboxylic acid, 8-cyclohexyl-5 - [[[(dimethylamino) sulfonylamino] carbonyl] -1,12b-dihydro-11- methoxy-, methyl ester, (-) -. A sample of (+/-) cycloprop [d] indole [2,1-a] [2] benzazepin-1a (2H) -carboxylic acid, 8-cyclohexyl-5 - [[[(dimethylamino) sulfonyl] amino] carbonyl ] 1,12b-dihydro-11-methoxy-methyl ester was dissolved in EtOH / CH3CN 1/1 + 0.5% DEA at a concentration of 50 mg / ml. [The addition of DEA ensures that the compound remains in solution during the injection procedure]. This solution was then injected into a Thar SFC-350 preparative SFC under the conditions shown below.

Preparative conditions in Thar SFC-350: Column: Chiralcel OJ-H 5 x 25 cm; mobile phase: 25% MeOH / CH3CI (1/1) in CO2; pressure (bar): 100; flow rate (ml / min): 240; solution concentration (mg / ml): 50; injection quantity (ml): · 4.5-5; Cycle time (min / iny): 6.5-7; Temperature (° C): 45; processing capacity (g / h): ~ 2; Detector wavelength (nm): 254.

From 371.4 g of racemic starting material, a total of 177.3 g of the isomer eluting second (-) containing ~ 1 Mequiv was obtained. of diethylamine. This material was purified using the following procedure. The mixture (24.7 g) dissolved in dichloromethane (800 ml)) was washed sequentially with; 0.5N HCl (1 x 400 mL, 1 x 240 mL), H2O (2 x 240 mL), and brine (2 x 240 mL). The organic phase was then dried (Anhydrous Na2SO4), filtered and evaporated to give 22.33 g of (cycloprop [d] indolo [2,1-a] [2] benzazepin-1a (2H) -carboxylic acid ,

8-cyclohexyl-5 - [[[(dimethylamino) sulfonylamino] carbonyl] -1,12b-dihydro-11-methoxy-, methyl ester, (-) - as a yellow solid (92% recovery). HPLC¹ &gt; 99% (Tr 2.3 min); LC / MS (ES +) 566.51 (M + H, 100); [a] or^25C 194.64 ° (c 1.03, MeOH). Anal. Calcd for C30H35N3O6SO3H2O: C 63.04; H, 6.29; N, 7.35; S, 5.61; H2O, 1.04. Found: C, 63.07; H, 6.01; N, 7.24; S, 5.58; H2O, 1.03. NMR shows the absence of Et2NH. The SE of this material was determined to be&gt; 99% using the following analytical HPLC procedure.

Analytical conditions for the determination of ee in an analytical SFC Thar. Analytical column: Chiralcel OJ (46 x 25 cm, 10 pl); BPR pressure: 100 bar; Temperature: 35 ° C; Flow rate: 3.0 ml / min; Mobile phase: 15% MeOH / CH3CN (1/1) in CO2; Detector wavelength: 254 nm; Retention time (min): 4, 6.5.

Intermediate 10

<img file="ES2390732T3_D0038.tif" />

8-cyclohexyl-5 - [[[(dimethylamino) sulfonyl] amino] acid solution (-)

Cycloprop [d] indolo [2,1-a] [2] benzazepin-1a (2H) -carboxylic acid, carbonyl] -1,12b-dihydro-11-methoxy-, (-) -. To a cycloprop [d] indole [2,1-a] [2] benzazepin-1a (2H) -carboxylic, 8-cyclohexyl-5 - [[[(dimethylamino) sulfonyl] amino] carbonyl] 1,12b-dihydro- 11-methoxy-, methyl ester (22.33 g, 39.5 mmol) in MeOH (300 ml) was added slowly 1N NaOH (120 ml) over 20 min, while maintaining the reaction temperature &lt;30 ° C . The mixture was stirred at rt under N2 for 18 h. HPLC indicated that the reaction was complete. 1N HCl (130 ml) was added to the reaction solution. After the addition was complete, the pH of the reaction mixture was about 2. The methanol in the reaction mixture was evaporated. Water (300 ml) was added to the mixture which was then extracted with CH2Cl2 (1 x 600 ml, 1 x 200 ml). The combined extracts were washed with H2O (2 x 300 ml) and brine (2 x 300 ml), dried (Na2SO4) and evaporated to give 20.82 g (96% yield) of the compound of the

ES 2 390 732 T3 title as a yellow solid. HPLC conditions, column: Phenomenex Synergy Polar-RP 4 um 4.6 x 50 mm; UV: 220 nm; gradient time: 4 min; flow rate: 4 ml / min, 75-100% B; Solvent A: 10% MeOH / 90% H2O with 0.2% H3PO4, Solvent B: 90% MeOH / 10% H2O with 0.2% H3PO4, HPLC&gt; 99% (Tr 1.80 min ) LC / MS (ES +) 552.25 (M + H, 100); [a] or^25C - 166.99 ° (c 1.00, MeOH). GC analysis: CH2Cl2 4.94%; Anal. Calcd for C2gH33N3O6S-0.16 H2O-0.35 CH2Ct C, 60.37; H, 5.87; N, 7.20; S, 5.49; H2O, 0.49; CH2Cl2, 5.02. Found: C, 59.95; H, 5.89; N, 7.03; S, 5.38; H2O, 0.47; CH2CU 4.94.

Intermediate 11

<img file="ES2390732T3_D0039.tif" />

Cycloprop [d] indole [2,1-a] [2] benzazepin-1a (2H) -carboxylic acid, 8-cyclohexyl-5 - [[[(dimethylamino) sulfonyl] amino] carbonyl] -1,12b-dihydro- 11-methoxy-, (+/-) -. To a solution of (+/-) cycloprop [d] indolo [2,1-a] [2] benzazepin-1a (2H) -carboxylic acid, 8-cyclohexyl-5 - [[[(dimethylamino) sulfonyl] amino] carbonyl] 1,12b-dihydro-11-methoxy-, methyl ester (100 mg, 0.177 mmol) in a mixture of THF / Methanol (2.0 ml / 2.0 ml), 2N NaOH solution ( 1.0 ml). The reaction mixture was heated to 90 ° C under microwave conditions for 5 min. Then, it was concentrated, acidified with a 1N HCl solution and extracted with ethyl acetate (2 x 20 ml). The organic phases were combined, dried (MgSO4), filtered, and concentrated. The residue was purified by preparative HPLC to provide the desired product as a light yellow solid, (59 mg, 60% yield). MS m / z 552 (MH +), Retention time: 3.850 min. NMR¹H (300 MHz, MeOD) δ ppm 0.25 (m, 0.38 H) 1.14 - 2.22 (m, 11.62 H) 2.69 - 2.98 (m, 2H) 3, 02 (s, 2.28H) 3.02 (s, 3.72H) 3.41 (d, J = 15.00 Hz, 0.62H) 3.88 (s, 3H) 4.01 (d, J = 15.00 Hz, 0.38 H) 5.26 (d, J = 15.00 Hz, 0.38 H) 5.45 (d, J = 14.64 Hz, 0.62 H ) 6.94 - 7.02 (m, 1H) 7.13 (d, J = 2.56 Hz, 0.38 H) 7.21 (d, J = 2.20 Hz, 0.62 H) 7.26 (d, J = 8.42 Hz, 0.62 H) 7.30 (d, J = 8.78 Hz, 0.38 H) 7.53 (dd, J = 8.42, 1, 46 Hz, 0.62 H) 7.61 (dd, J = 8.60, 1.65 Hz, 0.38 H) 7.85 (d, J = 8.42 Hz, 0.62 H) 7.89 (d, J = 8.42 Hz, 0.38 H) 8.10 (s, 0.38 H) 8.28 (d, J = 1.46 Hz, 0.62 H).

Intermediate 12

<img file="ES2390732T3_D0040.tif" />

Cycloprop [d] indole [2,1-a] [2] benzazepin-1a, 5 (2H) -dicarboxamide, 8-cyclohexyl-N⁵- [(dimethylamino) sulfonyl] 1,12b-dihydro-N^1st- [(2R, 3S) -3-hydroxy- 4,7,7-trimethylbicyclo [2,2,1] hep-2-yl] -11-methoxy-, (1 aR) - [partial] -. TBTU (437 mg, 1.36 mmol) and DIPEA (0.95 ml, 5.436 mmol) were added to a solution of (+/-) cycloprop [d] indole [2,1-a] [2] benzazepin- acid. 1a (2H) -carboxylic,

8-cyclohexyl-5 - [[[(dimethylamino) sulfonyl] amino] carbonyl] -1,12b-dihydro-11-methoxy- (500 mg, 0.906 mmol) in DMSO (20.0 ml). The reaction mixture was stirred at rt for 15 min. Then (2S, 3R) -3-amino1,7,7-trimethylbicyclo [2,2,1] heptan-2-ol (280 mg, 1.36 mmol) was added and the reaction mixture was stirred at rt for one night. The reaction mixture was quenched with water and acidified with a 1N HCl solution. A brown solid separated and was collected by filtration. This material was then fractionated by Preparative HPLC under the following conditions. Column: Waters Sunfire 19mm x 100mm; Solvent A: 10% CH3Cn -90% H2O-0.1% TFA; Solvent B: 90% CH3CN -10% H2O-0.1% TFA; Program: Start with 65% solvent B, initial waiting time for 5 min, then gradually increase to 90% solvent B in 30 min with a flow rate of 25 ml / min. Loading: 50-60 mg / process.

ES 2 390 732 T3

Cycloprop [d] indole [2,1-a] [2] benzazepin-1a, 5 (2H) -dicarboxamide,

8-cyclohexyl-N⁵- [(dimethylamino) sulfonyl] -1,12b-dihydro-N^1st- [(2R, 3S) -3-hydroxy-4,7,7-trimethylbicyclo [2,2,1] hept-2-yl] -11methoxy-, (1 aR) - [partial] - is eluted before Cicloprop [d] indole [2,1-a] [2] benzazepin-1a, 5 (2H) -dicarboxamide, 8-cyclohexyl-N⁵- [(dimethylamino) sulfonyl] -1,12b-dihydro-N^1st- [(2R, 3S) -3-hydroxy-4,7,7-trimethylbicyclo [2,2,1] hept-2-yl] -11methoxy-, (1aS) - [partial] - under the described HPLC conditions previously. Product obtained as a light yellow solid, 230 mg, 36% yield). MS m / 703 (MH +), Retention time: 3.936 min. NMR¹H (500 MHz, MeOD) δ ppm 0.14 - 0.24 (m, 2.64 H) 0.51 (s, 2.46 H) 0.72 - 2.21 (m, 20.9 H) 2.49 (m, 0.18H) 2.62 (m, 0.82H) 2.85 (m, 0.18H) 2.96 (m, 0.82H) 3.03 (s, 6H) 3.39 (m, 0.82H) 3.49-3.58 (m, 1.64H) 3.71-3.80 (m, 0.36H) 3.90 (s, 3 H) 4.17 (d, J = 14.65 Hz, 0.18 H) 5.06 (d, J = 14.65 Hz, 0.18 H) 5.37 (d, J = 14.95 Hz, 0.82 H) 6.73 (d, J = 5.49 Hz, 0.82 H) 6.98 - 7.05 (m, 1H) 7.08 (d, J = 4.5 Hz , 0.18 H) 7.10 (d, J = 2.44 Hz, 0.18 H) 7.21 (d, J = 2.44 Hz, 0.82 H) 7.31 (d, J = 8.55 Hz, 0.82 H) 7.34 (d, J = 8.55 Hz, 0.18 H) 7.59 - 7.64 (m, 1H) 7.87 - 7.93 ( m, 1H) 7.99 (s, 0.18H) 8.09 (d, J = 1.22Hz, 0.82H).

Intermediate 13

<img file="ES2390732T3_D0041.tif" />

Cycloprop [d] indole [2,1-a] [2] benzazepin-1a, 5 (2H) -dicarboxamide, 8-cyclohexyl-N⁵- [(dimethylamino) sulfonyl] 1,12b-dihydro-N^1st- [(2R, 3S) -3-hydroxy- 4,7,7-trimethylbicyclo [2,2,1] hept-2-yl] -11-methoxy-, (1aS) - [partial] -. TBTU (437 mg, 1.36 mmol) and DIPEA (0.95 ml, 5.436 mmol) were added to a solution of (+/-) cycloprop [d] indole [2,1-a] [2] benzazepin- acid. 1a (2H) -carboxylic, 8-cyclohexyl-5 - [[[(dimethylamino) sulfonyl] amino] carbonyl] 1,12b-dihydro-11-methoxy- (500 mg, 0.906 mmol) in DMSO (20.0 mL) . The reaction mixture was stirred at rt for 15 min. Then (2S, 3R) -3-amino-1,7,7-trimethylbicyclo [2,2,1] heptan-2-ol (280 mg, 1.36 mmol) was added and the reaction mixture was stirred at ta for one night. The reaction mixture was quenched with water and then acidified with a 1N HCl solution. S and separated brown solid, which was collected by filtration. This material was then fractionated by preparative HPLC under the following conditions. Column: Waters Sunfire 19mm x 100mm; Solvent A: 10% CH3CN -90% H2O-0.1% TFA; Solvent B: 90% CH3CN -10% H2O-0.1% TFA; Program: Start with 65% solvent B, initial rest time for 5 min, then gradually increase to 90% solvent B in 30 min with a flow rate of 25 ml / min. Loading: 50-60 mg / process.

Cycloprop [d] indole [2,1-a] [2] benzazepin-1a, 5 (2H) -dicarboxamide, 8-cyclohexyl-N⁵- [(dimethylamino) sulfonyl] 1,12b-dihydro-N^1st- [(2R, 3S) -3-hydroxy-4,7,7-trimethylbicyclo [2,2,1] hept-2-yl] -11-methoxy-, (1aS) - [partial] - is eluted after Cycloprop [d] indole [2,1-a] [2] benzazepin-1a, 5 (2H) -dicarboxamide, 8-cyclohexyl-N⁵- [(dimethylamino) sulfonyl] 1,12b-dihydro-N^1st- [(2R, 3S) -3-hydroxy-4,7,7-trimethylbicyclo [2,2,1] hept-2-yl] -11-methoxy-, (1aR) - [partial] - under the conditions of HPLC described above. Product obtained as a light yellow solid, 215 mg, 34% yield). MS m / 703 (MH +), Retention time: 4.038 min. NMR¹H (500 MHz, MeOD) δ ppm 0.20 (m, 0.38 H) 0.75 (s, 1.86 H) 0.76 (s, 1.86 H) 0.84 (s, 1, 86H) 0.85 (s, 1.14H) 0.89-2.18 (m, 18.9H) 2.52 (m, 0.38H) 2.70 (m, 0.62H ) 2.85 (m, 0.38H) 2.97 (m, 0.62H) 3.03 (s, 2.28H) 3.04 (s, 3.72H) 3.33-3 , 39 (m, 0.62H) 3.43-3.51 (m, 1.24H) 3.73 3.77 (m, 0.38H) 3.78-3.84 (m, 0 , 38H) 3.90 (s, 1.86H) 3.90 (s, 1.14H) 4.14 (d, J = 14.65 Hz, 0.38H) 5.11 (d, J = 14.65 Hz, 0.38 H) 5.44 (d, J = 15.26 Hz, 0.62 H) 6.68 (d, J = 4.88 Hz, 0.62 H) 6, 96 - 7.03 (m, 1 H) 7.07 (d, J = 5.19 Hz, 0.38 H) 7.12 (d, J = 2.44 Hz, 0.38 H) 7.23 (d, J = 2.14 Hz , 0.62 H) 7.27 (d, J = 8.54 Hz, 0.62 H) 7.33 (d, J = 8.54 Hz, 0.38 H) 7.55 (dd, J = 8.39, 1.68 Hz, 0.62 H) 7.62 (dd, J = 8.55, 1.53 Hz, 0.38 H) 7.87 (d, J = 8.54 Hz, 0 , 62H) 7.91 (d, J = 8.55Hz, 0.38H) 8.08 (d, J = 1.22Hz, 0.38H) 8.10 (d, J = 1, 22Hz, 0.62H).

ES 2 390 732 T3

Intermediate 14

<img file="ES2390732T3_D0042.tif" />

Cycl oprop [d] indole [2,1-a] benzazepin-1a (2H) -carb oxylic acid,

8-cyclohexyl-5 - [[[(dimethylamino) sulfonyl] amino] carbonyl] -1,12b-dihydro-11-methoxy-, (-) -. A 10 N solution of NaOH (2.0 ml, 20 mmol) and 4 ml of water were added to a solution of cycloprop [d] indolo [2,1-a] [2] benzazepin-1a, 5 (2H) - dicarboxamide, 8-cyclohexyl-N⁵- [(dimethylamino) sulfonyl] 1,12b-dihydro-N^1st- [(2R, 3 S) -3-hydroxy-4,7,7-trimethylbicyclo [2,2,1] hept-2-yl] -11-methoxy-, (1 aR) - [partial] - (160 mg, 0.228 mmol) in THF / MeOH (7 ml / 7 ml). The reaction mixture was heated to 120 ° C under microwave conditions for 1 hr. Then, it was concentrated, acidified with a conc. Solution. of HCl and extracted with ethyl acetate twice (2 x 30 ml). The organic phases were combined, dried (MgSO4), filtered, and concentrated in vacuo to give an orange oil. The crude product was then purified by a Prep HPLC column. to provide the product as a light yellow solid, (80 mg, 64% yield). Average specific rotation 130.85 °; MeOH solvent; Wavelength 589 nm; 50 cm cell. MS m / 552 (MH +). Retention time: 3,760 min. NMR¹H (500 MHz, MeOD) δ ppm 0.27 (m, 0.38 H) 1.14 - 2.22 (m, 11.62 H) 2.76 (m, 0.38 H) 2.80 - 2.92 (m, 1H) 2.92-3.09 (m, 6.62H) 3.45 (d, J = 14.95 Hz, 0.62H) 3.90 (s, 1, 86 H) 3.91 (s, 1.14 H) 4.04 (d, J = 15.26 Hz, 0.38 H) 5.28 (d, J = 15.26 Hz, 0.38 H) 5.47 (d, J = 15.26 Hz, 0.62 H) 6.95 - 7.05 (m, 1H) 7.15 (d, J = 2.75 Hz, 0.38 H) 7 , 23 (d, J = 1.83 Hz, 0.62 H) 7.28 (d, J = 8.55 Hz, 0.62 H) 7.33 (d, J = 8.54 Hz, 0, 38 H) 7.54 (dd, J = 8.39, 1.68 Hz, 0.62 H) 7.63 (dd, J = 8.55, 1.53 Hz, 0.38 H) 7.86 (d, J = 8.55 Hz, 0.62 H) 7.91 (d, J = 8.55 Hz, 0.38 H) 8.11 (d, J = 1 , 22Hz, 0.62H) 8.29 (d, J = 1.22Hz, 0.38H).

Intermediate 15

<img file="ES2390732T3_D0043.tif" />

Cycloprop [d] indole [2,1-a] [2] benzazepin-1a (2H) -carboxylic acid,

8-cyclohexyl-5 - [[[(dimethylamino) sulfonyl] amino] carbonyl] -1,12b-dihydro-11-methoxy-, (+) -. A 10 N solution of NaOH (1.8 ml, 18 mmol) and 4 ml of water were added to a solution of cycloprop [d] indolo [2,1-a] [2] benzazepin-1a, 5 (2H) - dicarboxamide,

8-cyclohexyl-N⁵- [(dimethylamino) sulfonyl] -1,12b-dihydro-N^1st- [(2R, 3S) -3-hydroxy-4,7,7-trimethylbicyclo [2,2,1] hept-2-yl] -11methoxy-, (1aS) - [partial] - (130 mg, 0.185 mmol ) in bTHF / MeOH (7 ml / 7 ml). The reaction mixture was heated to 120 ° C under microwave conditions for 1 hr. It was concentrated, acidified with a conc. Solution. of HCl and extracted twice with ethyl acetate (2 x 30 ml). The organic phases were combined, dried (MgSO4), filtered, and concentrated in vacuo to give an orange oil. The crude product was then purified by a Prep HPLC column. to provide the product as a light yellow solid, (68mg, 67% yield). Average specific rotation + 174.73 °; MeOH solvent; Wavelength 589 nm; 50 cm cell. MS m / 552 (MH +), Retention time: 3.773 min. NMR¹H (500 MHz, MeOD) δ ppm 0.27 (m, 0.38 H) 1.14 - 2.22 (m, 11.62 H) 2.76 (m, 0.38 H) 2.80 - 2.92 (m, 1H) 2.92-3.09 (m, 6.62H) 3.45 (d, J = 14.95 Hz, 0.62H) 3.90 (s, 1, 86 H) 3.91 (s, 1.14 H) 4.04 (d, J = 15.26 Hz, 0.38 H) 5.28 (d, J = 15.26 Hz, 0.38 H) 5.47 (d, J = 15.26 Hz, 0.62 H) 6.95 - 7.05 (m, 1H) 7.15 (d, J = 2.75 Hz, 0.38 H) 7, 23 (d, J = 1.83 Hz, 0.62 H) 7.28 (d, J = 8.55 Hz, 0.62 H) 7.33 (d, J = 8.54 Hz, 0.38 H) 7.54 (dd, J = 8.39, 1.68 Hz, 0.62 H) 7.63 (dd, J = 8.55, 1.53 Hz, 0.38 H) 7.86 (d, J = 8.55 Hz, 0.62 H) 7.91 (d, J = 8.55 Hz, 0.38 H) 8.11 (d, J = 1 , 22Hz, 0.62H) 8.29 (d, J = 1.22Hz, 0.38H).

ES 2 390 732 T3

Intermediate 16

<img file="ES2390732T3_D0044.tif" />

1H-Indole-6-carboxylic acid, 2-bromo-3-cyclohexyl-, 1,1-dimethylethyl ester. A mechanically stirred solution of 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (80 g, 0.24 m) in dry methylene dichloride (1.2 L) and THF (100 ml) was given added activated molecular sieves (4A, 80g) and silver carbonate (275g, 0.99m). The reaction mixture was cooled to 0 ° C and t-butyl bromide (142 g, 1.04 m) was added dropwise. The mixture was stirred overnight at rt and monitored by TLC (80:20 hexane-ethyl acetate, Fr (Product) = 0.7). If any bromine acid was left unconverted, an additional 10% silver carbonate was added and stirring continued for an additional 2-4 h. When complete, the reaction mixture was filtered through a short pad of celite. The filtrate was washed with methylene dichloride (500 ml). The combined filtrates were concentrated in vacuo and the crude product thus obtained was purified by chromatography on silica gel: (230-400 mesh, eluting with a gradient of ethyl acetate in pet. 0-2% ether). The homogeneous fractions were combined and evaporated under reduced pressure to give 80 g (85%) of the title compound. HPLC: 90.1% (RT = 6.56 min), Column: C18 BDS, (50 x 4.6 mm), Mobile phase: Gradient of 0.1% TFA in water: ACN (30 ^ 100 30) , Flow rate 0.8 ml / min. LCMS: 99.8% (TR = 4.44 min), Column: Geneis,

C18 50 x 4.6 mm. Mobile phase: 0.1% formic acid gradient in water: ACN (70 95 70), Flow rate: 0.8 ml / min;

M-1 = 376.5; NMR¹H (CDCla) (400 MHz) δ 1.37 -1.40 (m, 3H, Hexyl cyc.), 1.62 (s, 9H, t-Bu), 1.80 - 1.94 (two groups of m, 3H and 4H respectively, part of cyc. hexyl), 2.81 (m, 1H, CH of cyc-benzyl Hexyl), 7.70-7.75 (m, 2H, Indole-H4ys), 8, 04 (s, 1H, Indole-Hy), 8.52 (s, 1H, Indole-NH).

Intermediate 17

<img file="ES2390732T3_D0045.tif" />

1H-Indole-6-carboxylic acid, 3-cyclohexyl-2- (2-formyl-4-methoxyphenyl) -, 1,1-dimethylethyl ester. Dissolved

Tert-Butyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (72 g, 0.19 m) in a 1: 1 mixture of toluene and ethanol (720 ml) and degassed. Then LiCl (23.9 g, 0.51 m) was added, followed by sodium carbonate (720 ml, 1.0 M solution degassed separately) and Pd-tetrakis (13.1 g, 0.011 m). After stirring for 0.25 h, 2-formyl-4-methoxyphenylboronic acid (41.1 g, 0.22 m) was added and the reaction mixture was heated at 85 ° C for 4 h. The reaction was then monitored by TLC, (80:20 Hexane-Ethyl Acetate, Fr (Product) = 0.55). When complete, the reaction mixture was cooled to rt and water (1.0 L) was added, followed by ethyl acetate (1.0 L). The organic phase was washed with brine and dried and concentrated in vacuo to provide the title compound as a yellow solid. Yield 75g (74%). HPLC: 99.7% (RT = 6.30 min), Column: C 18 BDS (4.6 x 50 mm), SC-307. Mobile phase: 0.1% TFA gradient in water: ACN (30 100 30), Flow rate 0.8 ml / min. LCMS: 98.0% (RT = 5.28 min),

Column: Geneis, C18 (50 x 4.6 mm), Mobile phase: Gradient of 0.1% formic acid in water: ACN (70 95 70),

Flow rate: 0.8 ml / min; M-1 = 432.2; NMR¹H (DMSO -d₆) (400 MHz) δ 1.40-1.48 (m, 3H, Hexyl cyc.), 1.57 (s, 9H, t-Bu), 1.84-1.90 (m, 7H, part of Hexyl cyc.), 3.09 (m, 1H, CH of Hexyl cyc-benzyl), 3.84 (s, 3H, OCH3), 6.55 (d, J = 4 Hz, 1H, aryl H2), 7.06 (d, 1H, aryl H3), 7.08 (s, 1H, aryl Ha), 7.23 (d, 1H, Indole-H₅), 7.53 (d, J = 8 Hz, 1H, Indole-H4), 7.70-7.75 (m, 2H, NH + Indole-Hz), 8.06 (s, 1H, CHO).

ES 2 390 732 T3

Intermediate 18

<img file="ES2390732T3_D0046.tif" />

7H-Indolo [2,1-a] [2] benzazepine-6,10-dicarboxylic acid, 13-cyclohexyl-, 10- (1,1-dimethylethyl) 6-methyl ester. Tert-Butyl 3-cyclohexyl-2- (2-formyl-4-methoxyphenyl) -1H-indole-6-carboxylate (62.5 g, 0.144 m) was dissolved in dry DMF (1.2 L) and stirred mechanically. Then, cesium carbonate (84 g, 0.17 m) and methyl 2- (dimethoxyphosphoryl) acrylate (65-70% pure according to GC, 56.2 g, 0.18 m) were added and the reaction mixture was heated to 65 ° C for 4 h and the reaction was monitored by TLC (Hexane-Ethyl Acetate 80:20, F_r (Product) = 0.7). When complete, the mixture was cooled to rt and then quenched with water (1.0 L). A yellow solid precipitated, which was collected by filtration and air dried. This material was then suspended in methanol, filtered and dried under vacuum to give the product as a yellow powder, (70 g, 90%). HPLC: 99.1% (TR = 6.45 min), Column: C18 BDS (4.6 x 50 mm), Mobile phase: Gradient of 0.1% TFA in water: ACN (30 100 30), Flow 0.8 ml / min. LCMS: 100% (TR = 7.00 min),

Column: Geneis, CD18 (50 x 4.6 mm), Mobile phase: Gradient of 0.1% formic acid in water: ACN (70 95 70),

Flow rate: 0.8 ml / min; M + 1 = 502.2; NMR¹H (CDCls) (400 MHz) δ 1.10-1.30 (m, 3H, Hexyl cyc.), 1.64 (s, 9H, t-Bu), 1.77-2.07 (m, 7H , part of Hexyl cyc.), 2.80 (m, 1H, CH of Hexyl cyc-benzyl), 3.84 (s, 3h, OCH3), 3.93 (s, 3H, COOCH3), 4.15 and 5.65 (two a. peaks, each 1H, allyl CH2), 6.95 (s, 1H, aryl He) 7.01 (d, 1H, aryl H2), 7.53 (d, J = 8 Hz, 1H, aryl H3), 7.70 (d, J = 4 Hz, 1H, Indole-H5), 7.84 (s + d, 2H, olefinic H + Indole-H), 8.24 (s, 1H, indole-H); NMR¹³C (CDCla) (100.0 MHz) δ 166.92, 165.71, 158.96, 142.28, 136.47, 13.50, 134.61, 132.43, 132.01, 129.73 , 124.78, 124.68, 120.33, 119.39, 119.04, 115.62, 115.05, 111.27, 80.27, 55.49, 52.50, 39.09, 36 , 81.33.40, 28.38, 27.15, 26.28.

Intermediate 19

<img file="ES2390732T3_D0047.tif" />

2-propenoic acid, 2- (dimethoxyphosphinyl) -, methyl ester. Paraformaldehyde (40.5 g, 1.35 mol), MeOH (2 l) and piperidine (2 ml). The reaction mixture was refluxed under N2 for 3 h. After cooling to 50 ° C, 2- (dimethoxyphosphoryl) acetate (150 g, 0.824 mol) was added in one portion. The reaction mixture continued to reflux for 18 h. After cooling to rt, the reaction solution was concentrated in vacuo to give a clear, colorless oil. The above oil was dissolved in dry toluene (1 L) in a 3 L four necked round bottom flask equipped with a temperature controller, an N2 inlet, a magnetic stirrer and a Dean-Stark apparatus. TsOH.H was added to the solution.₂O (5.2 g). The reaction mixture was then azeotroped under reflux to remove methanol for 18 h. After cooling to rt, the solution was concentrated in vacuo to give a yellow oil which was distilled in vacuo at 150-155 ° C / 26.60 Pa (0.2 mmHg) to provide the product as an oil. colorless (135.0 g). Purity, 90% based on 1H NMR. NMR¹H (CDCl3, 300 MHz) δ 7.0 (dd, J = 42.4 and 1.5 Hz, 1H), 6.73 (dd, J = 20.5 and 1.8 Hz, 1H), 3, 80 (s, 6H), 3.76 (s, 3H).

Intermediate 20

<img file="ES2390732T3_D0048.tif" />

Cycloprop [d] indole [2,1-a] [2] benzazepin-1a, 5 (2H) -dicarboxylic acid, 8-cyclohexyl-1,12b-dihydro-11-methoxy-,

ES 2 390 732 T3

5- (1,1-dimethylethyl) 1a-methyl ester, (+/-). Sodium hydride (96 mg, 4 mmol) was added to a stirred suspension of trimethylsulfoxonium chloride (567 mg, 4.4 mmol) in anhydrous DMSO (10 ml) under a nitrogen atmosphere. The resulting mixture was stirred at rt for 30-45 min and then 7H-indole [2,1-a] [2] benzazepine-6,10-dicarboxylic acid, 13-cyclohexyl-3-methoxy-, was added in small portions. Pure 10- (1,1-dimethylethyl) 6-methyl ester (1.0.2 mmol). The suspension was diluted with DMSO (5 ml) and heated at 50 ° C for 3-4 h. The reaction mixture was allowed to cool to rt and water was added. A solid separated, which was collected by filtration, washed with water and then air dried overnight to provide 1.15 g of the crude product. This material was purified by flash column chromatography (silica gel, 3% MeOH in DCM) to provide the pure title compound (0.96 g): LC / MS: Retention time 3.816 min; m / e 516 (MH +). NMR¹H (400 MHz, CDCl3): The product was found to exist as interconvertible rotamers, as demonstrated from the compound's NMR spectrum.

The following procedure is an example of a procedure to effect resolution of cycloprop [d] indole [2,1-a] [2] benzazepin-1a, 5 (2H) -dicarboxylic acid, 8-cyclohexyl-1,12b-dihydro -11-methoxy-, 5- (1,1-dimethylethyl) 1a-methyl ester, (+/-) racemic. A sample of cycloprop [d] indole [2,1-a] [2] benzazepin-1a, 5 (2H) -dicarboxylic acid, 8-cyclohexyl-1,12b-dihydro-1-methoxy-, 5- (1, 1-dimethylethyl) 1a-methyl ester, (+/-) - was dissolved in a mixture of isopropanol and acetonitrile (8: 2) to give a final concentration of 20 mg / ml. This mixture was injected into a chiral preparative SFC chromatography system using the following conditions: Chiralcel OJ-H column, 4.6 x 250 mm, 5 pm; Mobile phase: 8% MeOH in CO2; Temp: 35 ° C; Flow rate: 2 ml / min for 16 min; Monitored by UV @ 260 nm; Injection: 5 µl of ~ 20.0 mg / ml in IPA: ACN (8: 2).

Intermediate 21

<img file="ES2390732T3_D0049.tif" />

Cycloprop [d] indolo [2,1-a] [2] benzazepin-1a, 5 (2H) -dicarboxylic acid, 8-cyclohexyl-1,12b-dihydro-11-methoxy-, 1a-methyl ester, (+ / -) -. TFA (5 ml) was added to a solution of (+/-) 8-cyclohexyl-1,1a, 2,12b-tetrahydro-11-methoxy 1a- (methoxycarbonyl) -cycloprop [d] indole [2,1-a ] [2] benzazepine-5-carboxylic, tert-butyl ester (515 mg, 1 mmol) in anhydrous DCM (10 ml). The resulting solution was stirred at rt for approximately 8 to 12 h. The reaction was then evaporated to dryness to provide the title compound (0.47 g, 100%). LC / MS: Retention time 2.245 min; m / e 460 (MH +). NMR¹H (400 MHz, CDCl3): From the NMR spectrum of the compounds, it was observed that the product existed as a mixture of interconvertible rotamers.

Intermediate 22

<img file="ES2390732T3_D0050.tif" />

Cycloprop [d] indole [2,1-a] [2] benzazepin-1a (2H) -carboxylic acid, 8-cyclohexyl-1,12b-dihydro-11-methoxy5 - [[[(methylamino) sulfonyl] amino] carbonyl ] -, methyl ester. An acid solution

8-cyclohexyl-1,1a, 2,12b-tetrahydro-11-methoxy-1a- (methoxycarbonyl) -cycloprop [d] indole [2,1-a] [2] benzazepine-5-carboxylic (140 mg, 0, 31 mmol) and CDI (64 mg, 0.40 mmol) in THF (3 ml) was stirred for 1 hr at 60 ° C. N-methylsulfamide (68 mg, 0.62 mmol) and DBU (71.6 mg, 0.47 mmol) were added and the mixture was stirred at 60 ° C overnight. The reaction was then poured into cold water, acidified with dilute hydrochloric acid, and extracted into ethyl acetate. The extracts were washed sequentially with dilute hydrochloric acid (0.1 N) and brine, and then dried (anhydrous sodium sulfate), filtered, and evaporated to provide the title compound as a brown solid. ESI-MS m / e 552 (Mh +). This material was used without further purification.

ES 2 390 732 T3

Intermediate 23

<img file="ES2390732T3_D0051.tif" />

Cycloprop [d] indole [2,1-a] [2] benzazepin-1a (2H) -carboxylic acid, 8-cyclohexyl-1,12b-dihydro-11-methoxy5 - [[[(methylamino) sulfonyl] amino] carbonyl ] -. Cycloprop [d] indole [2,1-a] [2] benzazepin-1a (2H) -carboxylic acid, 8-cyclohexyl-5 - [[[(methylamino) sulfonyl] amino] carbonyl] -1,12b- was dissolved dihydro-11-methoxy-methyl ester in THF, then a mixture of MeOH (2 ml, 2 ml), 2.5 M NaOH (aq.) (1.2 ml, 3 mmol) was added and the reaction was stirred at 22 ° C for 2 h. The solution was then neutralized with 1M HCl (aq.) (3 mL) and concentrated to remove organic solvents. The residue was suspended with H2O and the solids were collected by filtration, washed with H2O, and dried to yield the title compound (160mg, 0.30mmol). ESI-MS m / e 538 (MH +). This material was used without further purification. Intermediate 24

<img file="ES2390732T3_D0052.tif" />

Cycloprop [d] indole [2,1-a] [2] benzazepin-1a (2H) -carboxylic acid, 8-cyclohexyl-5 - [[[(benzylamino) sulfonyl] amino] carbonyl] -1,12b-dihydro- 11- (methoxy) -12- (methoxy) -, methyl ester, (+/-) -. A solution of (+/-) 8-cyclohexyl-1,1a, 2,12b-tetrahydro-11-methoxy-1a- (methoxycarbonyl) -cycloprop [d] indole [2,1-a] [2] benzazepine- 5-carboxylic acid (200mg, 0.44mmol) and CDI (92mg, 0.57mmol) in THF (5ml) were stirred for 1h at 60 ° C. Then, N-benzylsulfamide (164 mg, 0.88 mmol) and DBU (100 mg, 0.66 mmol) were added and the resulting mixture was stirred at 60 ° C overnight. The reaction was then poured into cold water, acidified with dilute hydrochloric acid, and extracted into ethyl acetate. The organic phase was washed with hydrochloric acid (0.1N) and brine, dried (sodium sulfate) and evaporated in vacuo to provide the title compound as a brown solid. ESI-MS m / e 628 (MH +).

Intermediate 25

<img file="ES2390732T3_D0053.tif" />

Cycloprop [d] indole [2,1-a] [2] benzazepin-1a (2H) -carboxylic acid, 8-cyclohexyl-1,12b-dihydro-11-methoxy-5 [[[[(phenylmethyl) amino] sulfonyl ] amino] carbonyl] -, (+ /) -. The title compound was prepared using a procedure similar to that described for cycloprop [d] indolo [2,1-a] [2] benzazepin-1a (2H) -carboxylic acid, acid

8-cyclohexyl-5 - [[[(methylamino) sulfonyl] amino] carbonyl] -1,12b-dihydro-11-methoxy-cycloprop [d] indolo [2,1-a] [2] benzazepine1a (2H) -carboxylic , starting from acid (+/-) 8-cyclohexyl-1,1a, 2,12b-tetrahydro-11-methoxy1a- (methoxycarbonyl) -cycloprop [d] indole [2,1-a] [2] benzazepin-5- carboxylic. ESI-MS m / e 613 (MH +), NMR¹H (500 MHz, MeOD) δ ppm 1.22 -2.20 (m, 13 H) 3.27 - 3.31 (m, 1H) 3.47 (d, J = 14.95 Hz, 0, 6H) 3.92 (d, J = 2.44 Hz, 3H) 4.04 (d,

ES 2 390 732 T3

0.4H) 4.31 (d, J = 2.75 Hz, 2H) 5.24 (d, 0.4H) 5.48 (d, 0.6H) 7.02 (d, 1 H) 7.17 (d, J = 2.75 Hz, 1H) 7.19 - 7.35 (m, 5H) 7.39 (t, J = 7.48 Hz, 2H) 7.45 - 7.52 (m, 1H) 7.80 (d, J = 1.53 Hz, 0.4H) 7.85 (dd, J = 8.39, 6.87 Hz, 1H) 8.22 ( d, J = 1.53 Hz, 0.6 H).

Intermediate 26

<img file="ES2390732T3_D0054.tif" />

Cycloprop [d] indole [2,1-a] [2] benzazepin-1a (2H) -carboxylic acid, 8-cyclohexyl-5 - [[(cyclopropylsulfonyl) amino] carbonyl] -1,12b-dihydro-11-methoxy -, (+ /) -. A mixture of acid (+/-) 8-cyclohexyl-1,1a, 2,12b-tetrahydro-11-methoxy1a- (methoxycarbonyl) -cycloprop [d] indolo [2,1-a] [2] benzazepin-5- carboxylic (1 equiv.) and carbonyldiimidazole (1.5 equiv.) in anhydrous THF was heated to 50 ° C for 30 min and allowed to cool to rt. Then, 1 equiv of cyclopropanesulfonamide and 1,8-diazabicyclo [5.4.0] undec-7-ene (2 equiv) were added consecutively. The resulting mixture was stirred at rt overnight. After aqueous acid work-up, the isolated crude product was purified by prep HPLC. The intermediate ester was then hydrolyzed using 1N NaOH in THF-MeOH to provide the title compound. LC / MS: Retention time: 2.030 min; m / e 549 (MH +). NMR¹H (400 MHz, CDCla): The product was found to exist as interconvertible rotamers, as demonstrated from the NMR spectrum of the compounds.

Intermediates 27-38 use the following experimental procedures until otherwise indicated. CLEM data: Stop time: Gradient time + 1 minute; Starting conc: 0% B unless otherwise indicated; Conc. Final: 100% B unless otherwise noted; Eluent A: 5% CH3CN / 95% H2O with 10 mM NH4OAc (for columns A, D and E); 10% MeOH / 90% H2O with 0.1% TFA (for columns B and C); Eluent B: 95% CH3CN / 5% H2O with 10 mM N ^ OAc (for columns A, D and E); 90% MeOH / 10% H2O with 0.1% TFA (for columns B and C); Column A: Phenomenex 10μ 4.6 x 50 mm C18; Column B: Phenomenex C18 10μ 3.0 x 50 mm; Column C: Phenomenex 4.6 x 50 mm C18 10µ; Column D: Phenomenex Lina C18 5μ 3.0 x 50 mm; Column E: Phenomenex 5µ 4.6 x 50 mm C 18; Preparative HPLC data: H2O / CH3CN conditions with 10 mM NH4OAc buffer; Gradient: Linear for 20 min unless otherwise indicated; Starting conc: 15% B unless otherwise indicated; Final conc: 100% B; Eluent A: CH₃5% CN / H₂Or 95% with NH₄10 mM OAc; Eluent B: 95% CH3CN / 5% H2O with 10 mM NH4OAc; Column: Sunfire Prep C18 OBD 5μ 30 x 100 mm; Conditions for H2O / MeOH with 0.1% TFA buffer; Gradient: Linear for 20 min unless otherwise indicated; Starting conc: B at unless otherwise indicated; Final conc: 100% B; Eluent A: 10% MeOH / 90% H2O with 0.1% TFA; Eluent B: 90% MeOH / 10% H2O with 0.1% TFA; Column: Phenomenex 21 x 100 mm C18 H2O.

Intermediate 27

<img file="ES2390732T3_D0055.tif" />

Cycloprop [d] indole [2,1-a] [2] benzazepin-1a (2H) -carboxylic acid,

8-cyclohexyl-5 - [[(cyclopropylsulfonyl) amino] carbonyl] -1,12b-dihydro-11-methoxy-, (+ /) -. A mixture of acid (+/-)

8-cyclohexyl-1,1a, 2,12b-tetrahydro-11-methoxy-1a- (methoxycarbonyl) -cycloprop [d] indole [2,] - a] [2] benzazepine-5-carboxylic (1 equiv.) And Carbonyldiimidazole (1.5 equiv.) in anhydrous THF was heated to 50 ° C for 30 min and allowed to cool to rt. Then, 1 equiv. Were added consecutively. of cyclopropanesulfonamide and 1,8-diazabicyclo [5.4.0] undec-7-ene (2 equiv.). The resulting mixture was stirred at rt overnight. After aqueous acid work-up, the isolated crude product was purified by prep HPLC. The intermediate ester was then hydrolyzed using 1N NaOH in THF-MeOH to provide the title compound. LC / MS: Retention time: 2.030 min; m / e 549 (MH +). NMR¹H (400 MHz,

ES 2 390 732 T3

CDCL): The product was found to exist as interconvertible rotamers, as demonstrated from the compound's NMR spectrum.

Intermediate 28

<img file="ES2390732T3_D0056.tif" />

13-Cyclohexyl-3-methoxy-6- (methoxycarbonyl) -7H-indole [2,1-a] [2] benzazepine-10-carboxylic acid. Trifluoroacetic acid (30 ml) was added dropwise to a stirring suspension of 6-methyl 13-cyclohexyl-3-methoxy-7H-indolo [2,1-a] [2] benzazepine-6,10-dicarboxylate of 10 -tert-butyl (10 g, 20 mmol) in dichloroethane (30 ml) under an atmosphere of N2. The clear dark green solution was stirred at rt for 2.5 h, concentrated to dryness, and stirred with EtOAc (100 mL) overnight. The solids were collected by filtration, washed with EtOAc and Et2O to yield 13-cyclohexyl-3-methoxy-6- (methoxycarbonyl) -7H-indole [2,1-a] [2] benzazepine-10-carboxylic acid (8 , 35 g, 18.8 mmol, 94%) which was as a yellow solid which was used without further purification. NMR¹H (300 MHz, CDCla) δ 1.13-2.16 (m, 10H), 2.74-2.88 (m, 1H), 3.84 (s, 3H), 3.89 (s, 3H ), 4.06 - 4.29 (m, 1H), 5.54 - 5.76 (m, 1H), 6.98 (d, J = 2.6 Hz, 1H), 7.08 (dd, J = 8.4, 2.6 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.78 (dd, J = 8.8, 1.1 Hz, 1H), 7.80 (s, 1H), 7.86 (d, J = 8.8Hz, 1H), 8.34 (d, J = 1.1Hz, 1H). LCMS: m / e 446 (M + H) +, ret. Time. 3.21 min, column B, 4 minute gradient.

Intermediate 29

<img file="ES2390732T3_D0057.tif" />

Methyl 13-Cyclohexyl-10 - ((cyclopropylsulfonyl) carbamoyl) -3-methoxy-7H-indolo [2,1-a] [2] benzazepine-6-carboxylate. 1,1'-carbonyldiimidazole (1.82 g, 11.2 mmol) was added to a slurry of acid

13-cyclohexyl-3-methoxy-6- (methoxycarbonyl) -7H indole [2,1-a] [2] benzazepine-10-carboxylic acid (3.85 g, 8.65 mmol) in THF (15 ml). The reaction mixture was heated to 60 ° C for 1.5 h, cooled to rt, treated with cyclopropanesulfonamide (1.36 g, 11.2 mmol), stirred for 10 min, then treated with dropwise addition dropwise from a solution of DBU (2.0 ml, 13 mmol) in THF (3 ml). The reaction mixture was stirred at rt overnight, diluted with EtOAc (100 mL), and washed with H2O (~ 30 mL), 1N HCl (aq.) (2 x 50 mL), and brine (~ 30 mL). ). The combined aqueous phases were extracted with EtOAc (100 ml) and the organic phase was washed with 1N HCl (aq.) (~ 50 ml). The combined organic phases were washed with brine (~ 30 mL), dried (MgSO4), filtered, and concentrated. The residue was stirred with Et2O (~ 100 mL) for 2 h and the solids were collected by filtration, rinsed with Et2O, and dried to yield 13-cyclohexyl-10 - ((cyclopropylsulfonyl) carbamoyl) -3-methoxy-7H-indole. Methyl [2,1-a] [2] benzazepine-6-carboxylate (4.24 g, 7.73 mmol, 89%) as a pale yellow solid, which was used without further purification. NMR¹H (300 MHz, CDCls) δ 1.08-2.13 (m, 14H), 2.73-2.87 (m, 1H), 3.13-3.24 (m, 1H), 3.82 (s, 3H), 3.89 (s, 3H), 4.04-4.27 (m, 1H), 5.50-5.7 (m, 1H), 6.98 (d, J = 2 , 6 Hz, 1H), 7.08 (dd, J = 8.8, 2.6 Hz, 1H), 7.44 (dd, J = 8.4, 1.1 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.80 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H), 8.11 (bs, 1H), 8.78 (brs, 1H). LCMS: m / e 549 (M + H) +, ret. 3.79 min, column B, 4 minute gradient.

ES 2 390 732 T3

Intermediate 30

OR

<img file="ES2390732T3_D0058.tif" />

Z

13-cyclohexyl-10 - ((cyclopropylsulfonyl) carbamoyl) -3-methoxy-7H-indolo [2,1-a] - [2] benzazepine-6-carboxylic acid. Methyl 13-cyclohexyl-10 - ((cyclopropylsulfonyl) carbamoyl) -3-methoxy-7H-indolo [2,1-a] [2] benzazepine-6-carboxylate (1.0 g, 1.8 mmol) was dissolved It was dissolved in MeOH // THF (1: 1, 24 ml) and treated with 1M aqueous NaOH (5 ml). The reaction mixture was stirred, heated at 60 ° C for 1.5 h, and cooled to rt. The clear solution was neutralized with 1M aqueous HCl (5 mL) and concentrated to remove organic solvents. The resulting solids were collected by filtration, washed with H₂O and dried in vacuo to yield 13-cyclohexyl-10 ((cyclopropylsulfonyl) carbamoyl) -3-methoxy-7H-indole [2,1-a] [2] benzazepine-6-carboxylic acid (1.0 g, 1 , 7 mmol, 94%) as a bright yellow solid (with 0.75 equiv THF) that was used without further purification. NMR¹H (300 MHz, CD3OD) δ 1.11-2.24 (m, 17H, THF 3H), 2.81-2.96 (m, 1H), 3.17-3.28 (m, 1H) , 3.69-3.79 (m, 3H, from THF), 3.94 (s, 3H), 4.07-4.33 (m, 1H), 5.55-5.81 (m, 1H ), 7.14-7.24 (m, 2H), 7.55-7.64 (m, 2H), 7.88-7.94 (m, 2H), 8.20 (br, 1H). LCMS: m / e 535 (M + H) +, ret time. 3.73 min, column B, 4 minute gradient.

Intermediate 31

<img file="ES2390732T3_D0059.tif" />

Methyl 8-Cyclohexyl-5 - ((cyclopropylsulfonyl) carbamoyl) -11-methoxy-1,12b-dihydrocyclopropa [d] indolo [2,1a] [2] benzazepine-1a (2H) -carboxylate. To a suspension of sodium hydride (60% dispersion in mineral oil, 370 mg, 9.2 mmol) in DMSO (8 ml) under stirring under an atmosphere of N2 was added trimethylsulfoxonium iodide (2.03 g, 9, 2 mmol). The reaction mixture was stirred for 45 min and then methyl 13-cyclohexyl-10 - ((cyclopropylsulfonyl) carbamoyl) -3-methoxy-7H-indolo [2,1-a] [2] benzazepine-6-carboxylate was added. (2.2 g, 4.0 mmol) in DMSO (5 ml) (flask rinsed with DMSO (2 x 3 ml)). The reaction mixture was stirred for 1 hr, poured into 0.25N HCl (100 ml), and extracted with EtOAc (150 ml). The organic phase was washed with brine (20 ml) and the combined aqueous phases were extracted with EtOAc (100 ml). The combined organic phases were washed with brine (~ 20 ml), dried (MgSO4), filtered and concentrated to dryness. The residue was stirred with EtOAc / Et2O (1: 3, 50 mL) and the solids were removed by filtration. The mother liquors were concentrated and dried under high vacuum to yield 8-cyclohexyl-5 - ((cyclopropylsulfonyl) carbamoyl) -11-methoxy-1,12b-dihydrocyclopropa [d] indole [2,1-a] [2] benzazepin1a Methyl (2H) -carboxylate (1.92 g, 3.4 mmol, 85%) as a yellow solid which was used without further purification. Present as a ~ 2: 1 mixture of rotamers or atropisomers. NMR¹H (300 MHz, CD3OD) δ 0.19 0.26 (m, 0.4H), 0.78-2.19 (m, 15.6H), 2.64-3.02 (m, 2H), 3.16-3.28 (m, 1H), 3.41 (d, J = 15.0Hz, 0.6H), 3.51 (s, 1.8H), 3.80 (s, 1, 2H), 3.88 (s, 3H), 4.00 (d, J = 15.0Hz, 0.4H), 5.22 (d, J = 15.0Hz, 0.4H), 5, 42 (d, J = 15.0 Hz, 0.6H), 6.93-7.01 (m, 1H), 7.12 (d, J = 2.6 Hz, 0.4H), 7.19 (d, J = 2.6 Hz, 0.6H), 7.25 (d, J = 8.8 Hz, 0.6H), 7.29 (d, J = 8.8 Hz, 0.4H) , 7.55 (dd, J = 8.8, 1.5 Hz, 0.6H), 7.63 (dd, J = 8.8, 1.5 Hz, 0.4H), 7.85 (d , J = 8.8 Hz, 0.6H), 7.88 (d, J = 8.8 Hz, 0.4H), 8.08 (d, J = 1.5 Hz, 0.4H), 8.31 (d, J = 1.5 Hz, 0 , 6H). LCMS: m / e 563 (M + H) +, ret. Time. 3.75 min, column B, 4 minute gradient.

ES 2 390 732 T3

Intermediate 32

<img file="ES2390732T3_D0060.tif" />

8-Cyclohexyl-5 - ((cyclopropylsulfonyl) carbamoyl) -11-methoxy-1,12b-dihydrocyclopropa [d] indolo [2,1-a] [2] benzazepine-1a (2H) -carboxylic acid. Methyl 8-cyclohexyl-5 - ((cyclopropylsulfonyl) carbamoyl) -11-methoxy1,12b-dihydrocyclopropa [d] indolo [2,1-a] [2] benzazepine-1a (2H) -carboxylate (1.92 g, 3.41 mmol) in MeOH // THF (1: 1.40 ml) and treated with 1M aqueous NaOH (8 ml). The reaction mixture was stirred and heated at 60 ° C for 2 h and cooled to rt. The clear solution was neutralized with 1M aqueous HCl (8 mL) and concentrated to remove organic solvents. The resulting solids were collected by filtration, washed with H2O, and dried under vacuum to yield 8-cyclohexyl-5 - ((cyclopropylsulfonyl) carbamoyl) -11-methoxy-1,12b-dihydrocyclopropa [d] indole acid [2,1 -a] [2] benzazepin-1a (2H) -carboxylic (1.66 g, 3.03 mmol, 89%) as a yellow powder that was used without further purification. Present as a 1: 1 mixture of rotamers or atropisomers. NMR¹H (300 MHz, CDCla) δ 0.32 (t, J = 6.2 Hz, 0.5H), 0.71 - 2.12 (m, 15.5H), 2.61 - 2.94 (m , 2H), 3.16-3.27 (m, 1H), 3.41 (d, J = 15.0Hz, 0.5H), 3.82 (s, 1.5H), 3.86 ( s, 1.5H), 3.99 (d, J = 15.0Hz, 0.5H), 5.28 (d, J = 15.0Hz, 0.5H), 5.49 (d, J = 15.0 Hz, 0.5H),

6.85 (dd, J = 8.4, 2.6 Hz, 0.5H), 6.91 (dd, J = 8.4, 2.6 Hz, 0.5H), 6.96 (d, J = 2.6 Hz, 0.5H), 7.08 (d, J = 2.6 Hz, 0.5H), 7.19 (d, J = 8.4 Hz, 0.5H), 7, 24 (d, J = 8.4 Hz, 0.5H), 7.61 (d, J = 8.4 Hz, 0.5H), 7.67 (d, J = 8.4 Hz, 0.5H ), 7.83 (d, J = 8.4 Hz, 0.5H), 7.85 (d, J = 8.4 Hz, 0.5H), 8.06 (s, 0.5H), 8 , 35 (s, 0.5H), 9.31-10.35 (m, 1H). LCMS: m / e 547 (MH) -, ret time. 2.06 min, column A, 4 minute gradient.

Intermediate 33

<img file="ES2390732T3_D0061.tif" />

Methyl 13-Cyclohexyl-10 - ((isopropylsulfonyl) carbamoyl) -3-methoxy-7H-indolo [2,1-a] [2] benzazepine-6-carboxylate. 1,1'-carbonyldiimidazole (262 mg, 1.62 mmol) was added to a suspension of 13-cyclohexyl-3-methoxy-6- (methoxycarbonyl) -7H-indole [2,1-a] [2] benzazepine acid -10-carboxylic (603 mg, 1.36 mmol) in THF (3 ml). The reaction mixture was heated to 60 ° C for 1.5 h, cooled to rt, treated with propane-2-sulfonamide (200 mg, 1.62 mmol), stirred for 10 min, and then treated with the dropwise addition of a solution of DBU (0.27 ml, 1.8 mmol) in THF (0.75 ml). The reaction mixture was stirred at rt overnight, diluted with EtOAc (15 mL), and washed with H2O (~ 5 mL), 1N HCl (aq.) (2 x 10 mL), and brine (~ 5 mL) ). The combined aqueous phases were extracted with EtOAc (15 ml) and the organic phase was washed with 1N HCl (aq) (~ 10 ml). The combined organic phases were washed with brine (~ 5 ml), dried (MgSO4), filtered and concentrated. The residue was stirred with Et2O (~ 15 mL) for 2 h and the solids were collected by filtration, rinsed with Et2O, and dried to yield 13-cyclohexyl-10 - ((isopropylsulfonyl) carbamoyl) -3-methoxy-7H-indole. Methyl [2,1-a] [2] benzazepine-6-carboxylate (640 mg, 1.2 mmol, 85%) as a bright yellow solid that was used without further purification. NMR¹H (300 MHz, CDCls) δ 1.12-2.13 (m, 10H), 1.47 (d, J = 7.0 Hz, 6H), 2.73-2.86 (m, 1H), 3.82 (s, 3H), 3.89 (s 3H), 4.06-4.26 (m, 1H), 4.09 1 (septuplet, J = 7.0 Hz, 1H), 5.51 -5.71 (m, 1H), 6.98 (d, J = 2.6 Hz, 1H), 7.08 (dd, J = 8.4 2.6 Hz, 1H), 7.44 (dd , J = 8.4, 1.5 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.80 (s, 1H), 7.87 (d, J = 8, 4Hz, 1H), 8.10 (d, J = 1.5Hz, 1H), 8.57 (s, 1H). LCMS: m / e 551 (M + H) +, ret. Time. 3.87 min, column B, 4 minute gradient.

ES 2 390 732 T3

Intermediate 34

<img file="ES2390732T3_D0062.tif" />

8-Cyclohexyl-5 - ((isopropylsulfonyl) carbamoyl) -11-methoxy-1,12b-dihydrocyclopropa [d] indole [2,1-a]

[2] methyl benzazepin-1a (2H) -carboxylate. To a suspension of sodium hydride (60% dispersion in mineral oil, 97 mg, 2.4 mmol) in DMSO (2 ml) under stirring under an atmosphere of N2 was added trimethylsulfoxonium iodide (530 g, 2.4 mmol ). The reaction mixture was stirred for 45 min and then methyl 13-cyclohexyl-10 - ((isopropylsulfonyl) carbamoyl) -3-methoxy-7H-indolo [2,1-a] [2] benzazepine-6-carboxylate was added. (578 g, 1.05 mmol) in DMSO (1.5 ml) (flask rinsed with DMSO (2 x 0.75 ml)). The reaction mixture was stirred for 1 hr, poured into 0.25N HCl (25 ml) and extracted with EtOAc (40 ml). The organic phase was washed with brine (10 ml) and the combined aqueous phases were extracted with EtOAc (25 ml). The combined organic phases were washed with brine (~ 10 mL), dried (MgSO4), filtered, and concentrated to dryness. The residue was stirred with EtOAc / Et2O (1: 4.10 mL) and the solids were filtered off. The mother liquors were concentrated and dried under high vacuum to yield 8-cyclohexyl-5 - ((isopropylsulfonyl) carbamoyl) -11-methoxy-1,12b-dihydrocyclopropa [d] indole [2,1-a]

[2] methyl benzazepin-1a (2H) -carboxylate (620 mg, 1.0 mmol, quant.) As a yellow solid that was used without further purification. Present as a ~ 2: 1 mixture of rotamers or atropisomers. NMR¹H (300 MHz, CDCla) δ 0.32-0.39 (m, 0.4H), 0.77-2.09 (m, 17.6H), 2.60-2.96 (m, 2H) , 3.41 (d, J = 15.0Hz, 0.6H), 3.53 (s, 1.8H), 3.79 (s, 1.2H), 3.87 (s, 3H), 4.02-4.14 (m, 1.4H), 5.14 (d, J = 15.0Hz, 0.4H), 5.39 (d, J = 15.0Hz, 0.6H) , 6.89 (dd, J = 8.4, 2.6 Hz, 0.4H), 6.91 (dd, J = 8.4, 2.6 Hz, 0.6H), 7.00 (d , J = 2.6 Hz, 0.4H), 7.11 (d, J = 2.6 Hz, 0.6H), 7.23 (d, J = 8.4 Hz, 0.6H), 7 , 25 (d, J = 8.4 Hz, 0.4H), 7.38 (dd, J = 8.4, 1.5 Hz, 0.6H), 7.43 (dd, J = 8.4 , 1.5 Hz, 0.4H), 7.83 (d, J = 8.4 z, 0.6H), 7.86 (d, J = 8.4 Hz, 0.4H), 7.96 (d, J = 1.5 Hz, 0.4H), 8, 20 (d, J = 1.5Hz, 0.6H), 8.39 (s, 0.4H), 8.43 (s, 0.6H). LCMS: m / e 563 (MH)^-, ret time. 3.00 min, column A, 4 minute gradient.

Intermediate 35

<img file="ES2390732T3_D0063.tif" />

8-Cyclohexyl-5 - ((isopropylsulfonyl) carbamoyl) -11-methoxy-1,12b-dihydrocyclopropa [d] indolo [2,1a] [2] benzazepine-1a (2H) -carboxylic acid. Methyl 8-cyclohexyl-5 - ((isopropylsulfonyl) carbamoyl) -11methoxy-1,12b-dihydrocyclopropa [d] indolo [2,1-a] [2] benzazepine-1a (2H) -carboxylate (606 mg, 1.07 mmol) in MeOH // THF (1: 1, 14 ml) and treated with 1M aqueous NaOH (2.5 ml). The reaction mixture was stirred and heated at 60 ° C for 2 h and cooled to rt. The clear solution was neutralized with 1M aqueous HCl (2.5 ml) and concentrated to remove organic solvents. The residue was stirred with H2O (10 mL) overnight and the resulting solids were collected by filtration, washed with H2O, and dried under vacuum to yield 8-cyclohexyl-5 - ((isopropylsulfonyl) carbamoyl) -1-methoxy acid. -1,12b-dihydrocyclopropa [d] indole [2,1-a] [2] benzazepine-1a (2H) carboxylic acid (530 mg, 0.96 mmol, 90%) as a bright yellow solid that is used without further purification. Present as a ~ 2: 1 mixture of rotamers or atropisomers. NMR¹H (300 MHz, CD3OD) δ 0.23 0.30 (m, 0.4H), 0.80-2.24 (m, 17.6H), 2.70-3.11 (m, 2H), 3.46 (d, J = 15.0Hz, 0.6H), 3.95 (s, 3H), 3.93-4.10 (m, 1.4H), 5.29 (d, J = 15.0 Hz, 0.4H), 5.48 (d, J = 15.0 Hz, 0.6H), 6.98- 7.05 (m, 1H), 7.16 (d, J = 2 , 6 Hz, 0.4H), 7.23 (d, J = 2.6 Hz, 0.6H), 7.29 (d, J = 8.8 Hz, 0.6H), 7.33 (d , J = 8.8 Hz, 0.4H), 7.56 (dd, J = 8.8, 1.5 Hz, 0.6H), 7.64 (dd, J = 8.4, 1.5 Hz, 0.4H), 7.87 (d, J = 8.8 Hz, 0.6H), 7.92 (d, J = 8.4 Hz, 0.4H), 8.13 (d, J = 1.5 Hz, 0.4H), 8.31 (d, J = 1.5 Hz, 0.6H). LCMS: m / e 551 (M + H) +, ret. Time. 3.74 min, column B, 4 minute gradient.

ES 2 390 732 T3

Intermediate 36

<img file="ES2390732T3_D0064.tif" />

Methyl 10 - ((Aminosulfonyl) carbamoyl) -13-coclohexyl-3-methoxy-7H-indolo [2,1-a] [2] benzazepine-6-carboxylate. 1,1'-carbonyldiimidazole (1.23 g, 7.60 mmol) was added to a slurry of acid

13-cyclohexyl-3-methoxy-6- (methoxycarbonyl) -7H-indole [2,1-a] [2] benzazepine-10-carboxylic acid (2.6 g, 5.8 mmol) in THF (11 ml). The reaction mixture was heated to 60 ° C for 1.5 h, cooled to rt, treated with sulfonamide (1.12 g, 11.7 mmol), stirred for 10 min, then worked up with the dropwise addition dropwise from a solution of DBU (1.8 ml, 11.7 mmol) in THF (3 ml). The reaction mixture was stirred at rt for 3 h, diluted with EtOAc (80 mL) and CH2Cl2 (100 mL), and concentrated to dryness. The residue was diluted with CH2Cl2 (100 mL) and washed with 1N HCl (aq.) (2 x 100 mL). The combined aqueous phases were extracted with CH2Cl2 (100 mL) and the combined organic phases were washed with semisaturated brine (~ 50 mL), dried (MgSO4), filtered, and concentrated. The residue was stirred with Et2O (~ 75 mL) for 1 h and the solids were collected by filtration, rinsed with Et2O, and dried to yield 10 - ((aminosulfonyl) carbamoyl) -13-cyclohexyl-3-methoxy-7H-indole. Methyl [2,1-a] [2] benzazepine-6-carboxylate (2.8 g, 5.3 mmol, 91%) as a bright yellow solid that was used without further purification. NMR¹H (300 MHz, CDla) δ 1.08-2.10 (m, 10H), 2.71-2.84 (m, 1H), 3.79 (s, 3H), 3.89 (s, 3H ), 4.00 - 4.18 (m, 1H), 5.50 - 5.64 (m, 1H), 5.68 (s, 2H), 6.97 (d, J = 2.6 Hz, 1H), 7.07 (dd, J = 8.8, 2.6 Hz, 1H), 7.46 (dd, J = 8.4, 1.5 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.78 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 8.10 (bs, 1H), 9.49 (s, 1H ). LCMS: m / e 524 (M + H) +, ret. Time. 3.60 min, column B, 4 minute gradient.

Intermediate 37

<img file="ES2390732T3_D0065.tif" />

10 - ((aminosulfonyl) carbamoyl) -13-cyclohexyl-3-methoxy-7H-indolo [2,1-a] [2] benzazepine-6-carboxylic acid. Methyl 10 - ((aminosulfonyl) carbamoyl) -13-cyclohexyl-3-methoxy-7H-indolo [2,1-a] [2] benzazepine-6-carboxylate (725 mg, 1.39 mmol) was dissolved in MeOH // THF (1: 1, 16 ml) and treated with 1M aqueous NaOH (3 ml). The reaction mixture was stirred and heated at 60 ° C for 0.5 h and cooled to rt. The reaction solution was diluted with MeOH / H2O (2: 1.15 mL), neutralized with 1M aqueous HCl (3 mL), and concentrated to remove organic solvents. The resulting solids were collected by filtration, washed with H2O, and dried in vacuo to yield 10 - ((aminosulfonyl) carbamoyl) -13-cyclohexyl-3-methoxy-7H-indole [2,1-a] [2] acid. Benzazepine-6-carboxylic acid (650 g, 1.3 mmol, 92%) as a bright yellow solid that was used without further purification. NMR¹H (300 MHz, CDCl3) δ 1.16-2.22 (m, 10H), 2.82 - 2.96 (m, 1H), 3.94 (s, 3H), 4.07 - 4.29 (m, 1H), 5.57-5.80 (m, 1H), 7.14-7.23 (m, 2H), 7.55-7.63 (m, 2H), 7.88-7 , 94 (m 2H), 8.18 (s, 1H). LCMS: m / e 510 (M + H) +, ret. 2.85 min, column B, 4 minute gradient.

ES 2 390 732 T3

Intermediate 38

<img file="ES2390732T3_D0066.tif" />

Methyl 5 - ((Aminosulfonyl) carbamoyl) -8-cyclohexyl-11-methoxy-1,12b-dihydrocyclopropa [d] indole [2,1-a] [2] benzazepin-1a (2H) -carboxylate. Trimethylsulfoxonium iodide (1.93 g, 8 , 8 mmol) in three portions. The reaction mixture was stirred for 0.5 h and then 10 - ((aminosulfonyl) carbamoyl) -13-cyclohexyl-3-methoxy-7H-indolo [2,1-a] [2] benzazepine-6-carboxylate was added. methyl (2.0 g, 3.8 mmol) in DMSO (8 ml) (flask rinsed with DMSO (2 x 2 ml)). The reaction mixture was stirred for 1 hr, poured into 0.25N HCl (100 mL), and diluted with CH2Cl2 (100 mL). The solution was filtered to collect the solids and the organic phase of the mother liquors was separated and concentrated to dryness. The residue was dissolved in EtOAc (~ 150 mL), washed with H2O (~ 50 mL) and brine (~ 50 mL), dried (MgSO4), filtered, and concentrated to dryness. The residue was stirred with EtOAc / Et2O (4: 1, 50 mL) and the solids were collected by filtration and washed with EtOAc. These solids were combined with the initially collected solids to produce

Methyl 5 - ((aminosulfonyl) carbamoyl) -8-cyclohexyl-11-methoxy-1,12b-dihydrocyclopropa [d] indolo [2,1-a] [2] benzazepine-1a (2H) carboxylate (1.39 g , 2.6 mmol, 68%) as a tan solid that was used without further purification. Present as a 1: 1 mixture of rotamers or atropisomers. NMR¹H (300 MHz, DMSO-d₆) δ 0.13

- 0.21 (m, 0.5H), 1.06-2.12 (m, 11.5H), 2.64-2.94 (m, 2H), 3.46 (s, 1.5H) , 3.49 (d, J = 15.0Hz, 0.5H), 3.75 (s, 1.5H),

3.85 (s, 3H), 4.02 (d, J = 15.0Hz, 0.5H), 5.21 (d, J = 15.0Hz, 0.5H), 5.42 (d , J = 15.0 Hz, 0.5H), 6.99-7.09 (m, 1H), 7.17

- 7.31 (m, 1H), 7.41 (s, 0.5H), 7.43 (s, 0.5H), 7.66-7.56 (m, 1H), 7.82 (d , J = 8.4 Hz, 0.5H), 7.87 (d, J = 8.8 Hz, 0.5H), 8.25 (s, 0.5H), 8.47 (s, 0, 5H), 11.62 (s, 0.5H), 11.69 (s, 0.5H). LCMS: m / e 538 (M + H) +, ret time. 3.56 min, column B, 4 minute gradient.

Intermediate 39

<img file="ES2390732T3_D0067.tif" />

5 - ((aminosulfonyl) carbamoyl) -8-cyclohexyl-11-methoxy-1,12b-dihydrocyclopropa [d] indolo [2,1-a] [2] benzazepine-1a (2H) -carboxylic acid. Methyl 5 - ((aminosulfonyl) carbamoyl) -8-cyclohexyl-11-methoxyI, 12b-dihydrocyclopropa [d] indolo [2,1-a] [2] benzazepin-1a (2H) -carboxylate (1,1 mg, 2.0 mmol) in MeOH // THF (1: 1.24 mL) and treated with 1M aqueous NaOH (5 mL). The reaction mixture was stirred and heated at 60 ° C for 2 h and cooled to rt. The clear solution was neutralized with 1M aqueous HCl (5 mL) and concentrated to remove organic solvents. The residue was stirred with H2O (10 mL) for 1 hr and the resulting solids were collected by filtration, washed with H2O, and dried in vacuo to yield acid.

5 - ((aminosulfonyl) carbamoyl) -8-cyclohexyl-11-methoxy-1,12b-dihydrocyclopropa [d] indolo- [2,1-a] [2] benzazepine-1a (2H) carboxylic (1.05 mg, 2.0 mmol, 98%) as a light yellow solid that was used without further purification. Present as a 1: 1 mixture of rotamers or atropisomers. NMR¹H (300 MHz, DMSO-d6) δ 0.08-0.17 (m, 0.5H), 0.79-2.13 (m, 11.5H), 2.65-2.94 (m, 2H), 3.44 (d, J = 14.6 Hz, 0.5H), 3.85 (s, 3H), 3.96 (d, J = 14.6 Hz, 0.5H), 5, 20 (d, J = 14.6 Hz, 0.5H), 5.40 (d, J = 14.6 Hz, 0.5H), 6.98-7.08 (m, 1H), 7.17 - 7.46 (m, 4H), 7.58 (d, J = 8.1 Hz, 0.5H). 7.62 (d, J = 8.1 Hz, 0.5H), 7.81 (d, J = 8.8 Hz, 0.5H), 7.87 (d, J = 8.8 Hz, 0 , 5H), 8.25 (s, 0.5H), 8.44 (s 0.5H),

II, 48-13.19 (m, 2H). LCMS: m / e 524 (M + H) +, ret. Time. 3.51 min, column B, 4 minute gradient.

Intermediates 40-44 use the following experimental procedures until indicated.

ES 2 390 732 T3

Intermediate 40

<img file="ES2390732T3_D0068.tif" />

Dry NaH (96 mg, 4 mmol) was added to a stirred suspension of trimethylsulfoxonium chloride (567 mg, 4.4 mmol) in anh DMSO. (10 ml) under a nitrogen atmosphere. The resulting mixture was stirred at rt for 30-45 min and then pure olefin (1.0.2 mmol) was added in small portions. The suspension was diluted with DMSO (5 ml) and heated at 50 ° C for 3-4 h. The reaction mixture was allowed to cool to rt and water was added. The precipitated solid was filtered and washed with water, and then air dried overnight to provide 1.15 g of crude product which was purified by flash column chromatography (silica gel, 3% MeOH in DCM) , to provide the pure desired cyclopropyl compound (0.96 g), as an off-white solid: LC / MS: Retention time 3.816 min; m / e 516 (MH +). NMR¹H (400 MHz, CDl₃): The product was found to exist as interconvertible rotamers.

Intermediate 41

<img file="ES2390732T3_D0069.tif" />

The tert-butyl ester (515 mg, 1 mmol) and TFA (5 ml) in DCM anh. (10 ml) was stirred at rt until hydrolysis was complete (8-12 hr). Excess TFA and DCM were evaporated to dryness to provide the desired acid (0.47 g,

100%) in the form of a light beige solid. LC / MS: Retention time 2.245 min; m / e 460 (MH⁺). NMR¹H (400 MHz, CDCl3): The product was found to exist as interconvertible rotamers.

Intermediate 42

<img file="ES2390732T3_D0070.tif" />

General procedure. A mixture of acid (1 equiv.) And carbonyldiimidazole (1.5 equiv.) In anh. heated to 50 ° C for 30 min and allowed to cool to rt. Then, 1 equiv of sulfonamide (R = NR2) or sulfonamide (R = alkyl or aryl) and DBU (2 equiv) were added consecutively. The resulting mixture was stirred at rt overnight. After aqueous acid work-up, the isolated crude product was purified by prep HPLC. to provide the product.

ES 2 390 732 T3

Intermediate 43

<img file="ES2390732T3_D0071.tif" />

The methyl ester moiety was hydrolyzed using 1N NaOH in THF-MeOH to provide the corresponding acids.

Intermediate 44

<img file="ES2390732T3_D0072.tif" />

Acid derivatives (1 equiv.) Were combined with corresponding amine (RRNH, 1.2 equiv.), Triethylamine (2-3 equiv.) And TBTU (1.3 equiv.) In DMF anh. and stirred at rt for 1-2 hrs until amide coupling was complete. Isolated crude products were purified by prep HPLC. to provide the desired amides.

Intermediates 45-49 described below were analyzed by the following LC / MS procedure: Analysis conditions: Column: PHENOMENNEX-LUNA 3.0 x 50 mm S10; Mobile phase: (A) 10:90 methanol-water; (B)

90:10 methanol-water; Buffer: 0.1% TFA; Gradient range: 0-100% B; Gradient Time: 2 min; Flow rate: 4 ml / min; Analysis time: 3 min; Detection: Detector 1: UV at 220 nm; Detector 2: MS (ESI +) /.

Intermediate 45

<img file="ES2390732T3_D0073.tif" />

Acid (+/-) - 8- cyclohexyl- 1,1a, 2,12b- tetrahydro-11-methoxy-1a- (methoxycarbonyl) -cycloprop [d] indole [2,1- a] [2] benzazepin- 5- carboxylic, tert-butyl ester. LC / MS: Retention time 3.816 min; m / e 516 (MH +). NMR¹H (400 MHz, CDCl3): The product was found to exist as interconvertible rotamers.

ES 2 390 732 T3

Intermediate 46

<img file="ES2390732T3_D0074.tif" />

Acid (+/-) - 8- cyclohexyl- 1,1a, 2,12b- tetrahydro-11-methoxy-1a- (methoxycarbonyl) -cycloprop [d] indole [2,1- a] [2] benzazepin- 5- carboxylic. Retention time 2,245 min; m / e 460 (MH +). NMR¹H (400 MHz, CDCl3). The product was found to exist as interconvertible rotamers.

Intermediate 47

<img file="ES2390732T3_D0075.tif" />

(+/-) - 8- cyclohexyl- 5- (morpholinosulfonylcarbamoyl) -1,1a, 2,12b-tetrahydro-11-methoxy cycloprop [d] indole [2,1-a] [2] benzazepine-1a-carboxylic acids . The product was purified by prep HPLC. and was isolated as a beige solid. LC / MS: Retention time: 1,968 min; m / e 460 (MH +). NMR¹H (400 MHz, CDCh). The product was found to exist as interconvertible rotamers.

Intermediate 48

<img file="ES2390732T3_D0076.tif" />

Acid (+/-) - 8-cyclohexyl- 5- (4-methylpiperazin-1-ylsulfonylcarbamoyl) -1,1a, 2,12b-tetrahydro-11-methoxy-cycloprop [d] indole 15 [2,1- a] [2] benzazepine-1α-carboxylic. The product was purified by prep HPLC. and was isolated as a TFA mono salt, as a beige solid. cL / MS: Retention time: 1.687 min; m / e 607 (MH +). NMR¹H (400 MHz,

CD13). The product was found to exist in the form of interconvertible rotamers.

ES 2 390 732 T3

Intermediate 49

<img file="ES2390732T3_D0077.tif" />

Acid (+/-) - 8- cyclohexyl- 5- (cyclopropylsulfonylcarbamoyl) -1,1a, 2,12b- tetrahydro-11-methoxycycloprop [d] indole [2,1-a] [2] benzazepin- 1a- carboxylic. Cl / eM: Retention time: 2,030 min; m / e 549 (MH +). NMR¹H (400 MHz, CDCL): The product was found to exist as interconvertible rotamers.

Intermediates 50-60 were analyzed by the following LC / MS procedure: Start% B: 0; Final% B: 100; Gradient time: 3 min; Stop time: 4 min; Flow rate: 4 ml / min; Wavelength: 220; Solvent A: 10% MeOH / 90% H2Ü / 0.1% Trifluoroacetic Acid; Solvent B: 10% H2O / 90% MeOH / 0.1% Trifluoroacetic Acid; Column: XBridge 4.6 x 50 mm S5.,

Intermediate 50

<img file="ES2390732T3_D0078.tif" />

A mixture of the acid (1.3 g, 2.83 mmol) and CDI (0.64 g, 3.97 mmol) in THF (20 ml) was heated at 50 ° C for 0.5 h, cooled and added methylsulfonamide (0.4 g, 4.2 mmol) and DBU (0.264 ml, 1.77 mmol). The mixture was stirred for 20 h and diluted with EtOAc, washed with cold 1N HCl (2x) and brine, dried (MgSO4), the solvent was removed and purified by flash (40M Biotage) to provide the compound 1-2 (1.28 g, 85%) as a pale yellow solid. LC-MS retention time: 3.51; MS m / z 537 (M + H). Compound 1-2 was found to exist as interconvertible rotamers. The main isomer: p NMR¹H (400 MHz, CHLOROFORM-D) δ ppm 1.11 -2.17 (m, 12 H), 2.84-2.98 (m, 2 H), 3.43 (d, J = 14.86 Hz, 1H), 3.49 (s, 3H), 3.55 (s, 3H), 3.89 (s, 3H), 5.40 (d, J = 15.11 Hz, 1 H), 6.91-6.96 (m, 1H), 7.13 (d, J = 2.52 Hz, 1H), 7.22-7.27 (m, 1H), 7, 39 (dd, J = 8.31, 1.51 Hz, 1H),

7.85 (d, J = 8.81Hz, 1H), 8.23 ​​(d, J = 1.26Hz, 1H), 8.75 (s, 1H).

Intermediate 51

<img file="ES2390732T3_D0079.tif" />

To a solution of the ester (1.28 g, 2.4 mmol) in THF (5 ml) and MeOH (5 ml) was added NaOH (1 N, 12 ml, 12 mmol). After stirring at room temperature for 3 h, the mixture was diluted with EtOAc, washed with cold 1N HCl and brine, dried (MgSO4), and the solvent was removed in vacuo to provide the acid as a solid. beige in color (1.20 g, 96%). LC-MS retention time: 3.46; MS m / z 523 (M + H). The acid was found to exist as interconvertible rotamers (~ 1/1) NMR ¹H (400 MHz, CHLOROFORM-D).

ES 2 390 732 T3

Intermediate 52

<img file="ES2390732T3_D0080.tif" />

Typical general procedure for amine coupling: To a mixture of the acid (0.060 g, 0.11 mmol) and a secondary / tertiary amine containing hydrochloric bis acid salt of diamine (0.034 g, 0.17 mmol) in DMC (1, 5 ml) Et3N (0.096 ml, 0.69 mmol) and HBTU (0.065 g, 0.17 mmol) were added. The mixture was stirred at room temperature for 0.5 h, diluted with MeOH, the solvent was removed. The residue was dissolved in methanol, filtered and purified by prep HPLC. to provide a TFA salt of an amide 1 (0.0378 g, 82%) as a TFA salt which was characterized by LC-MS and ¹H NMR.

Intermediate 53

<img file="ES2390732T3_D0081.tif" />

The product was prepared from the acid (0.47 g, 44%). LCMS retention time: 3.54; MS m / z 551 (M + H).

Intermediate 54

<img file="ES2390732T3_D0082.tif" />

The product was prepared (0.43 g, 94%). LC-MS retention time: 3.49; MS m / z 537 (M + H).

Intermediate 55

<img file="ES2390732T3_D0083.tif" />

The product was prepared from the acid (0.96 g, 59%). LC-MS retention time: 3.58; MS m / z 578 (M + H). The compound was found to exist as interconvertible rotamers (3/4). The main isomer: NMR¹H (400

ES 2 390 732 T3

MHz, CHLOROFORM-D) δ ppm 1.16-1.59 (m, 4H), 1.72 (dd, J = 9.44.4.15 Hz, 3H), 1.88-2.12 (m, 4H), 2.24-2.36 (m, 2H), 2.752.97 (m, 2H), 3.44 (d, J = 14.86 Hz, 1H), 3, 56 (s, 3H), 3.89 (s, 3H), 4.09 (d, 1H), 4.24-4.37 (m, 4H), 5.41 (d, J = 14.86 Hz, 1H), 6.92-6.96 (m, 1H), 7.13 (d, J = 2.01 Hz, 1H), 7.24-7.30 (m, 1 H), 7.39 (dd, J = 8.31, 1.51 Hz, 1 H), 7.84-7.88 (m, 1 H), 8.24 (d, J = 1.51 Hz , 1 HOUR).

Intermediate 56

<img file="ES2390732T3_D0084.tif" />

The product was prepared (0.93 g, 100%). LC-MS retention time: 3.51; MS m / z 564 (M + H). The compound was found to exist as interconvertible rotamers (~ 3/4). The main isomer: NMR¹H (400 MHz) ppm 0.34 0.42 (m, 1H), 1.15-2.10 (m, 11H), 2.22-2.38 (m, 2H), 2.65 - 2.78 (m, 1H), 2.84-294 (m, J = 3.02Hz, 1H), 3.84 (s,

3 H), 4.03 (d, J = 15.11 Hz, 1H), 4.21 -4.43 (m, 4H), 5.34 (d, J = 14.86 Hz, 1H) , 6.87 (dd, J = 8.56, 2.77 Hz, 1H), 6.98 (d, J = 2.52 Hz, 1H), 7.21 (d, J = 8.31 Hz, 1H), 7.69-7.75 (m, 1H), 7.86-7.90 (m, 1H), 8.13 (s, 1H).

Intermediate 57

<img file="ES2390732T3_D0085.tif" />

The product was prepared from the acid (0.109 g, 67%). LCMS retention time: 3.60; MS m / z 580 (M + H). The compound was found to exist as interconvertible rotamers (~ 5/4). The main isomer: NMR¹H (400

MHz) ppm 1.16-2.09 (m, 14H), 2.73-2.93 (m, 2H), 3.07 (s, 3H), 3.31-3.52 (m , 3H), 3.76 (s, 3H), 3.88 (s, 3H), 4.05-4.10 (m, 1H), 5.40 (d, J = 15.11 Hz , 1H), 6.88-6.93 (m, 1H), 7.13 (d, J = 2.27Hz, 1H), 7.22-7.29 (m, 1H), 7.33 7.42 (m, 1H), 7.82-7.86 (m, 1H), 8.19 (d, J = 1.51 Hz, 1H).

Intermediate 58

<img file="ES2390732T3_D0086.tif" />

The product was prepared (0.108 g, 100%). LC-MS retention time: 3.55; MS m / z 566 (M + H).

ES 2 390 732 T3

Intermediate 59

<img file="ES2390732T3_D0087.tif" />

The product was prepared from the acid (0.127 g, 67%). LC-MS retention time: 3.64; MS m / z 594 (M + H). The compound was found to exist as interconvertible rotamers: NMR¹H (400 MHz) ppm 1.11 - 2.13 (m, 18

H), 2.64 (dd, J = 10.07, 6.80 Hz, 1H), 2.84-2.96 (m, 1H), 3.34-3.67 (m, 4H ), 3.75 (s, 3H), 3.88 (s, 3H), 4.03-4.10 (m,

H), 5.40 (d, J = 15.36 Hz, 1H), 6.90-6.95 (m, 1H), 7.13 (d, J = 2.01 Hz, 1H) , 7.21-7.29 (m, 1H), 7.33-7.39 (m, 1H), 7.83 (d, J = 8.06Hz, 1H), 8.20 ( d, J = 1.26 Hz, 1H).

Intermediate 60

<img file="ES2390732T3_D0088.tif" />

The product was prepared (0.126 g, 100%). LCMS retention time: 3.57; MS m / z 580 (M + H).

<img file="ES2390732T3_D0089.tif" />

8-Cyclohexyl-11-methoxy-N - ((1-methylcyclopropyl) sulfonyl) -1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -1, 1a, 2,12b-tetrahydrocyclopropa [d] indolo [2,1-a] [2] benzazepine-5-carboxamide. CDI (26.4 mg, 0.163 mmol) was added to a stirring solution of 8-cyclohexyl-11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3.2.1] oct-8 -yl) carbonyl) 1,1a, 2,12b-tetrahydrocyclopropa [d] indole [2,1-a] [2] benzazepine-5-carboxylic acid, TFA (60 mg, 0.092 mmol) in THF (1 mL) and The reaction was stirred at 60 ° C for 1 hr and allowed to cool to rt. Then 1-methylcyclopropane-1-sulfonamide (22mg, 0.16mmol) and DBU (0.03ml, 0.2mmol) were added, and the reaction mixture was stirred overnight at rt. The reaction mixture was diluted with MeOH and purified by preparative HPLC (H2O / CH3CN with 10 mM NH4OAc buffer) to yield 8-cyclohexyl-11-methoxy-N - ((1-methylcyclopropyl) sulfonyl) 20 1a - (( 3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -1,1a, 2,12b-tetrahydrocyclopropa [d] indolo [2,1 -a] [2] benzazepine- 5-carboxamide (15.8 mg, 0.024 mmol, 26% yield) as an off-white solid. The compound was isolated as a mixture of enantiomers and presented as a 1: 3 mixture of rotamers or atropisomers. NMR¹H (300 MHz, CD3OD) δ ppm 8.15 (s, 0.25H), 8.03 (s, 0.75H), 7.90 (d, J = 8.8 Hz, 1H), 7.72 - 7.59 (m, 1H), 7.38-7.30 (m, 1H), 7.22 (s, 0.75H), 7.16 (s, 0.25H), 7.07-6 , 97 (m, 1H), 5.17 (d, J = 15.0Hz, 0.75H), 4.23 4.13 (m, 0.25H), 3.91 (s, 3H), 3.66 (d, J = 15.0Hz, 1H), 3.33-3.20 (m, 2H), 3.12-0.87 (m, 31.75H), 0.26-0, 08 (m,

0.25H). LCMS: m / e = 671 (M + H) +, retention time = 2.33 min (Column = (3) Phenomenex 10u C18 4.6 x 30 mm Solvent A = 5% CH3CN - 95% H2O - Ammonium Acetate 10 mm. Solvent B = 95% CH3CN - 5% H2O Ammonium Acetate 10 mM, Initial% B = 0, Final% B = 100, Gradient Time = 4 min, Stop Time = 1 min, Flow rate = 4 ml / min).

ES 2 390 732 T3

<img file="ES2390732T3_D0090.tif" />

8-Cyclohexyl-N- (isopropenylsulfonyl) -11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) 1,1a, 2,12b- tetrahydrocyclopropa [d] indole [2,1-a] [2] benzazepine-5-carboxamide. CDI (26.4 mg, 0.163 mmol) was added to a stirring solution of acid

8-cyclohexyl-11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -1,1a, 2,12b-tetrahydrocyclopropa [d] indole [2,1-a] [2] benzazepine-5-carboxylic, TFA (60 mg, 0.092 mmol) in THF (1 mL) and the reaction was stirred at 60 ° C for 1 hr and allowed to cool to rt. Then prop-1-ene-2-sulfonamide (20 mg, 0.16 mmol) and DBU (0.03 ml, 0.2 mmol) were added and the reaction mixture was stirred overnight at rt. The reaction mixture was diluted with MeOH and purified by preparative HPLC (H2O / CH3CN with 10 mM NH4OAc buffer) to yield 8-cyclohexyl-N- (isopropenylsulfonyl) -11-methoxy-1a - ((3-methyl-3 , 8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -1,1a, 2,12b-tetrahydrocyclopropa [d] indole [2,1-a] [2] benzazepine-5-carboxamide (16 , 0 mg, 0.024 mmol, 26% yield) as a white solid. The compound was isolated as a mixture of enantiomers and is presented as a 1: 3 mixture of rotamers or atropisomers. NMR¹H (300 MHz, CD3OD) δ ppm 8.20 (s, 0.25H), 8.07 (s, 0.75H), 7.84-7.70 (m, 2H), 7.35-7, 27 (m, 1H), 7.23-7.18 (m, 0.75H), 7.17-7.13 (m, 0.25H), 7.05-6.95 (m, 1H), 6.00 (s, 1H), 5.54 (s, 1H), 5.24 4.81 (m, 1H), 4.54-3.30 (m, 1H), 3.91 (s, 0 , 75H) 3.90 (s, 2.25H), 3.09-0.98 (m, 29.75H), 0.28-0.18 (m, 0.25H). LCMS: m / e = 657 (M + H) +, retention time = 2.05 min (Column = (3) Phenomenex 10u C18 4.6 x 30 mm, Solvent A = 5% CH3CN - 95% H2O - Ammonium Acetate 10 mm. Solvent B = 95% CH3CN - 5% H2O - 10 mM Ammonium Acetate, Initial% B = 0, Final% B = 100, Gradient Time = 4 min, Stop Time = 1 min, Flow Rate = 4 ml / min).

<img file="ES2390732T3_D0091.tif" />

13-Cyclohexyl-3-methoxy-6 - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -7H-indolo [2,1-a] [2] tert-butyl benzazepine-10 carboxylate. HATU (680 mg, 1.8 mmol) was added to a stirring solution of 10- (tert-butoxycarbonyl) -13-cyclohexyl-3-methoxy-7H-indole [2,1-a] [2] benzazepine acid- 6-carboxylic acid (670 mg, 1.37 mmol) and 3-methyl-3,8-di-azabicyclo [3.2.1] octane di HCl salt (560 mg, 2.81 mmol) in DMF (6 ml) and tEa (1.2 ml, 8.2 mmol), and the reaction was stirred for 30 min (complete by LCMS). The reaction mixture was diluted with water (~ 35 ml) (a precipitate formed) and stirred overnight. The precipitate was collected by filtration, rinsed with water, and dried under high vacuum at 55 ° C to yield 13-cyclohexyl-3-methoxy-6 - ((3-methyl-3,8-diazabicyclo [3,2,1 ] oct8-yl) carbonyl) -7H-indolo [2,1-a] [2] tert-butyl benzazepine-10-carboxylate (775 mg, 1.30 mmol, 95% yield) as a solid of light yellow color. The material was used without further purification. NMR¹H (300 MHz, CDCl3) δ ppm 1.14-3.95 (m, 24H), 1.59 (s, 9H), 3.86 (s, 3H), 4.21-5.26 (m, 2H), 6.82 (s, 1H), 6.88 (d, J = 2.6 Hz, 1H), 7.01 (dd, J = RR, 2.6 Hz, 1H), 7.47 ( d, J = 8.8 Hz, 1H), 7.66 (dd, J = 8.4, 1.1 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 8, 02 (brs, 1H). LC-MS retention time: 3.72 min; m / z 596 (MH +). LC data were recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0 x 50mm column, using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM . Elution conditions employed a flow rate of 5 ml / min, a gradient from 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 4 min, a 1 min waiting time and 5 min analysis time where solvent A was 10% MeOH / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / MeOH 90% / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

<img file="ES2390732T3_D0092.tif" />

ES 2 390 732 T3

g. 13-Cyclohexyl-3-methoxy-6 - ((3-methyl-3,8-diazabicyclo [3.2.1] oct-8-yl) carbonyl) -7H-indolo [2.1 -a] was dissolved

[2] tert-butyl benzazepine-10-carboxylate (300 mg, 0.504 mmol) in DCE (5 mL) and then TFA (700 gl, 9.09 mmol) was added (reaction turned green in color) and the Reaction was stirred at rt for 1h (~ 70% conversion by LCMS). More TFA (700 gl, 9.09 mmol) was added and the reaction was stirred for 1h (complete by LCMS). The reaction mixture was concentrated on a rotary evaporator, diluted with diethyl ether, and concentrated again twice to yield 13-cyclohexyl-3-methoxy-6 - ((3-methyl-3,8-diazabicyclo [3, 2,1] oct-8-yl) carbonyl) -7H-indolo [2,1-a] [2] benzazepine-10-carboxylic acid (362 mg, 0.55 mmol, quant.) As a colored solid dark yellow. It was used without further purification. NMR¹H (300 MHz, DMSO-d6) δ ppm 1.06-2.13 (m, 21H), 2.68-2.86 (m, 1H), 3.36-3.50 (m, 2H), 3.90 (s, 3H), 4.11-5.35 (m, 2H), 7.14 (s, 1H), 7.18 7.28 (m, 2H), 7.53 (d, J = 8.4 Hz, 1H), 7.61 (dd, J = 8.4, 1.1 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 8.21 (sa , 1H), 9.55 (brs, 1H). LC-MS retention time: 3.72 min; m / z 596 (MH +). Cl-MS retention time: 2.50 min; 538 m / z (MH^-). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6 x 50mm column, using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM . Elution conditions employed a flow rate of 5 ml / min, a gradient from 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 4 min, a 1 min waiting time and 5 min analysis time, where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was H₂Or 5% / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

<img file="ES2390732T3_D0093.tif" />

13-Cyclohexyl-N - ((1- (cyclopropylmethyl) cyclopnopol) sulfonyl) -3-methoxy-6 - ((3-metol-3,8-diazabicyclo

[3.2.1] oct-8-yl) carbonyl) -7H-indolo [2,1-a] [2] benzazepine-10-carboxamide. CDI (27 mg, 0.17 mmol) was added to a stirring solution of acid trifluoroacetate

13-cyclohexyl-3-methoxy-6 - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -7H-indolo [2,1-a] [2] benzazepine-10-carboxylic acid (70 mg, 0.130 mmol)) in THF (0.5 ml) and the reaction mixture was heated at 60 ° C for 1.5 h. The reaction was cooled to rt and then 1- (cyclopropylmethyl) cyclopropane-1-sulfonamide (29.6 mg, 0.169 mmol) was added. The reaction was stirred for 5 min and then DBU (0.029 mL, 0.195 mmol) was added. The reaction was stirred at rt for 1 hr, more dBu (0.029 mL, 0.195 mmol) was added and stirred at rt overnight (~ 75% LCMS conversion). The reaction was diluted with EtOAc (~ 2 mL) and washed with aq. HCl. 1 M (2 x 2 ml). The organic phase was concentrated under a stream of nitrogen, dissolved in MeOH (~ 3 ml) and purified by preparative HPLC (Column: Xterra Prep MSC18 5u 30 x 100 mm, Eluent A: 5% acetonitrile / water with ammonium acetate 10 mM, Eluent B: 95% acetonitrile / water with 10 mM ammonium acetate, Flow rate: 42 ml / min, linear gradient from 15% Eluent B to 100% Eluent B over 20 min) to yield 13-cyclohexyl-N - ((1- (cyclopropylmethyl) cyclopropyl) sulfonyl) -3-methoxy-6 - (( 3-methyl-3,8-diazabicyclo

[3.2.1] oct-8-yl) carbonyl) -7H-indolo [2,1-a] [2] benzazepine-10-carboxamide (32 mg, 0.046 mmol, 35% yield) as a solid of yellow color. NMR¹H (300 MHz, CDCla) δ ppm 0.02 - 0.09 (m, 2H), 0.38 - 0.47 (m, 2H), 0.61 0.74 (m, 1H), 1.14 - 2.95 (m, 31H), 3.89 (s, 3H), 4.20-4.42 (m, 1H), 5.11-5.32 (m, 1H), 6.82 (s , 1H), 6.86-6.90 (m, 2H), 7.05 (dd, J = 8.8, 2.6 Hz, 1H), 7.49 (d, J = 8.8 Hz , 1H), 7.49-7.54 (m, 1H), 7.86 (d, J = 8.4Hz, 1H), 8.10 (brs, 1H). LC-MS retention time: 3.46 min; m / z 697 (MH +). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0 x 50 mm column, using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. Elution conditions employed a flow rate of 5 ml / min, a gradient from 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 4 min, a 1 min waiting time and 5 min analysis time where solvent A was 10% MeOH / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / MeOH 90% / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

<img file="ES2390732T3_D0094.tif" />

8-Cyclohexyl-11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -1,1a, 2,12b-tetrahydrocyclopropa [d] indole Tert-Butyl [2,1-a] [2] benzazepine-5-carboxylate. Trimethylsulfoxonium iodide (375 mg, 1.69 mmol) was added in three portions to a stirred suspension of a dispersion of 60% NaH (68 mg, 1.7 mmol) in DMSO (1.5 ml) (foaming appeared ). The reaction mixture was stirred for 20 min and then a solution of

ES 2 390 732 T3

13-cyclohexyl-3-methoxy-6 - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -7H-indolo [2,1-a] [2] tert-Butyl benzazepine-10-carboxylate (438 mg, 0.735 mmol) in DMSo (2.5 mL) and the reaction was stirred for 1h (no product desired by LCMS). The reaction mixture was heated at 90 ° C for 3 h (complete by LCMS), cooled to rt, quenched with aq. HCl. 0.25 M (20 ml) and extracted with EtOAc (2 x 20 ml). The combined organic phases were washed with brine (20 ml), dried (MgSO4), filtered and concentrated to give 72009-057 as an orange oil. The oil was used without further purification as the starting material in the preparation of 8-cyclohexyl-11-methoxy-la - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8- yl) carbonyl) -1,11a, 2,12btetrahydrocyclopropa [d] indolo [2,1-a] [2] benzazepine-5-carboxylic. The compound was isolated as a mixture of enantiomers. LC-MS retention time: 3.68 min; m / z 610 (Mh +). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0 x 50 mm column, using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. Elution conditions employed a flow rate of 5 ml / min, a gradient from 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 4 min, a 1 min waiting time and 5 min analysis time where solvent A was 10% MeOH / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / MeOH 90% / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

<img file="ES2390732T3_D0095.tif" />

8-Cyclohexyl-11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) 1,1a, 2,12b-tetrahydrocyclopropa [d ] indole [2,1-a] [2] benzazepine-5-carboxylic acid. The acid (448mg, 0.735mmol) was dissolved in DCE (6ml) and then TFA (1.5ml, 19mmol) was added (reaction turned dark red) and the reaction was stirred at rt for 2 h (complete according to CLEM). The reaction was concentrated on a rotary evaporator, diluted twice with diethyl ether, and concentrated again to give an orange oil. The residue was suspended with diethyl ether and the solids (360 mg of yellow solid) were collected by filtration and rinsed with hexanes. The solids from the addition (52 mg of a yellow solid) were collected from the filtrate rinsed with hexanes. The combined solids were found to be 8-cyclohexyl-11-methoxy-acid trifluoroacetate - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -1,1a, 2 , 12b-tetrahydrocyclopropa [d] indole [2,1-a] [2] benzazepine-5-carboxylic acid (412 mg, 0.62 mmol, 84%). The compound was isolated as a mixture of enantiomers and presented as a 1: 5 mixture of rotamers or atropisomers. For the main isomer: NMR¹H (300 MHz, CDCl3) δ ppm 0.81-1.01 (m, 2H), 1.13-2.65 (m, 18H), 2.62 (s, 3H) 2.69-3.70 (m, 2H), 3.60 (d, J = 15.4 Hz, 1H), 3.87 (s, 3H), 4.36 5.30 (m, 3H), 6.95 (dd, J = 8.8, 2.2 Hz, 1H), 7.09 (d, J = 2.2 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 7.75 (d , J = 8.4 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 8.08 (s, 1H). CL-Em retention time: 3.24 min; 554 m / z (Mh +). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0 x 50 mm column, using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. Elution conditions employed a flow rate of 5 ml / min, a gradient from 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 4 min, a 1 min waiting time and 5 min analysis time where solvent A was 10% MeOH / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / MeOH 90% / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

<img file="ES2390732T3_D0096.tif" />

8-Cyclohexyl-N - ((1-ethylcyclopropyl) sulfonyl) -11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -1, 1a, 2,12b-tetrahydrocyclopropa [d] indolo [2,1-a] [2] benzazepine-5-ccarboxamide. CDI (21 mg, 0.13 mmol) was added to a stirring solution of 8-cyclohexyl-11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3.2.1] oct -8-yl) carbonyl) -1,1a, 2,12b-tetrahydrocyclopropa [d] indole [2,1-a] [2] benzazepine-5-carboxylic acid (56 mg, 0.10 mmol) in THF (0, 5 ml) and the reaction mixture was heated at 60 ° C for 1.5 h. The reaction was cooled to rt and 1-ethylcyclopropane-1-sulfonamide (20mg, 0.13mmol) and then DBU (0.025ml, 0.15mmol as a 20% solution in THF) were added. The reaction was stirred at rt for 1 hr, more DBU (~ 0.025 mL) was added and stirring was continued for 2 hr. The reaction was heated at 60 ° C for 1 hr and then stirred overnight at rt (~ 25% conversion). Even more amounts of DBU were added

ES 2 390 732 T3 (0.025 ml) and 1-ethylcyclopropane-1-sulfonamide (20 mg, 0.13 mmol) and the reaction was allowed to stir at rt for 3 days. The reaction solution was diluted with EtOAc (2 ml) and washed with 1M HCl (2 ml). The organic phase was concentrated to dryness with a stream of nitrogen, dissolved in MeOH (1.5 L), filtered and purified by preparative HPLC (CH3CN / H2O with 10 mM NH4OAc), yielding

8-cyclohexyl-N - ((1-ethylcyclopropyl) sulfonyl) -11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -1, 1a, 2.12btetrahydrocyclopropa [d] indole [2,1-a] [2] benzazepine-5-carboxamide (5.3 mg, 7.7 mmol, 8% yield) as a yellow solid. The compound was isolated as a mixture of enantiomers and presented as a 1: 2 mixture of rotamers or atropisomers. NMR¹H (500 MHz, CDCl3) δ ppm -0.27-0.12 (m, 0.33H), 0.27 - 0.32 (m, 0.33H), 0.94 - 2.84 (m, 32.33H), 2.91-3.00 (m, 1H), 3.29-3.50 (m, 1H), 3.59 (d, J = 15.3 Hz, 1H), 3, 89 (s, 2H), 3.90 (s, 1H), 4.14 (d, J = 14.7 Hz, 0.33H), 4.35 - 4.51 (m, 0.67H), 4 , 76 (d, J = 14.7 Hz, 0.33H), 5.18 (d, J = 14.7 Hz, 0.67H), 6.92 (dd, J = 8.2, 2.6 Hz, 0.33H), 6.96 (dd, J = 8.6, 2.6 Hz, 0.67H), 7.01 (d, J = 2.6 Hz, 0.33H), 7.12 (d, J = 2.6 Hz, 0.67H), 7.29 (d, J = 8.6 Hz, 0.67H), 7.29 (d, J = 8.2 Hz, 0.33H) , 7.49 (d, J = 8.2 Hz, 0.33H), 7.54 - 7.61 (m, 0.67H), 7.87 (d, J = 8.6 Hz, 0.67H), 7.88 (d , J = 8.2 Hz, 0.33H), 7.98 (s, 1H). LC-MS retention time: 3.23 min; 685 m / z (MH +). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0 x 50 mm column, using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. Elution conditions employed a flow rate of 5 ml / min, a gradient from 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 4 min, a 1 min waiting time and 5 min analysis time where solvent A was 10% MeOH / 90% H2O / 0.1% trifluoroacetic acid and solvent B was H₂Or 10% / 90% MeOH / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

<img file="ES2390732T3_D0097.tif" />

8-Cyclohexyl-N - ((1- (cyclopropylmethyl) cyclopropyl) sulfonyl) -11-methoxy-1a - ((3- methyl- 3,8-diazabicyclo

[3,2,1] oct-8-yl) carbomyl) -1,1a, 2,12b-tetrahydrocyclopropa [d] indolo [2,1-a] [2] benzazepine-5-carboxamide. CDI (24 mg, 0.15 mmol) was added to a stirring solution of acid trifluoroacetate

8-cyclohexyl-1-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -1,1a, 2,12b-tetrahydrocyclopropa [d] indole [2.1a] [2] benzazepine-5-carboxylic (64 mg, 0.12 mmol) in THF (0.5 ml), the reaction mixture was heated at 60 ° C for 1.5 h. The reaction was cooled to rt, 1- (cyclopropylmethyl) cyclopropane-1-sulfonamide (33mg, 0.19mmol) and then DBU (0.09ml, 0.6mmol) were added and the reaction stirred at rt for one night (~ 50% conversion according to CLEM). The reaction mixture was quenched with 1M HCl (aq.), Concentrated, dissolved in MeOH (1.5 mL), filtered, and purified by preparative HPLC (CH3CN / H2O with 10 mM NH4OAc) to yield

8-cyclohexyl-N - ((1- (cyclopropylmethyl) cyclopropyl) sulfonyl) -11-methoxy-1a - ((3-methyl-3,8-diazabi-cyclo [3,2,1] oct-8-yl) carbonyl) 1,11a, 2,12b-tetrahydrocyclopropa [d] indole [2,1-a] [2] benzazepine-5-carboxamide (14.2 mg, 0.020 mmol, 17% yield) as a solid of light yellow color. The compound was isolated as a mixture of enantiomers and is presented as a 1: 3 mixture of rotamers or atropisomers. NMR¹H (300 MHz, CDCl3) δ ppm -0.33 - - 0.14 (m, 0.25H), 0.01-0.11 (m, 2H), 0.20 - 0.29 (m, 0 , 25H), 0.38-0.47 (m, 2H), 0.61-3.44 (m, 32.5H), 3.56 (d, J = 14.6 Hz, 0.75H), 3.87 (s, 2.25H), 3.88 (s, 0.75H), 4.10 (d, J = 14.3 Hz, 0.25H), 4.24 - 4.54 (m, 1H), 4.73 (d, J = 14.3 Hz, 0.25H), 5.16 (d, J = 14.6 Hz, 0.75H), 6.87-6.97 (m, 1H ), 6.99 (d, J = 2.6 Hz, 0.25H), 7.10 (d, J = 2.2 Hz, 0.75H), 7.27 (d, J = 8.8 Hz , 0.75H), 7.28 (d, J = 8.4 Hz, 0.25H), 7.48 (dd, J = 8.8, 1.1 Hz, 0.25H), 7.59 ( gives, J = 8.4 Hz, 0.75H), 7.85 (d, J = 8.4 Hz, 0.75H), 7.85 (d, J = 8.8 Hz, 0.25H), 7, 95 (s, 0.75H), 7.97 (s, 0.25H). LC-MS retention time: 3.04 min; m / z 309 (MH^-). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6 x 50 mm column, using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. Elution conditions employed a flow rate of 5 ml / min, a gradient from 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 4 min, a 1 min waiting time and 5 min analysis time, where solvent A was 5% acetonitrile / 95% H2O / a 10 mM ammonium ketate and solvent B was% H2O / 95% acetonitrile % / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

<img file="ES2390732T3_D0098.tif" />

13-Cyclohexyl-N - ((1-ethylcyclopropyl) sulfonyl) -3-methoxy-6 - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) car50

ES 2 390 732 T3 bonyl) -7H-indolo [2,1-a] [2] benzazepine-10-carboxamide. CDI (80 mg, 0.49 mmol) was added to a solution of 13-cyclohexyl-3-methoxy-6 - ((3-methyl-3,8-diazabicyclo [3.2.1] oct-8-yl) tert-Butyl carbonyl) -7H-indole [2,1-a] [2] benzazepine-10-carboxylate TFA (200 mg, 0.30 mmol) in THF (1.5 mL) and the reaction mixture was heated to 60 ° C for 2 h. The reaction was cooled to rt and then 1/3 (~ 0.55 ml) of the reaction solution was added to a stirring solution of 1-ethylcyclopropane-1-sulfonamide (40 mg, 0.27 mmol) in DBU ( 0.20 ml, 1.3 mmol) and THF (0.20 ml). The reaction was stirred at rt overnight (~ 75% LCMS conversion), concentrated to an oil, quenched with 1N HCl (~ 1 mL) (formed prec.), And extracted with EtOAc (2 x 1 ml) and DCM (2 x 1 ml). The combined organic extracts were concentrated to dryness, dissolved in MeOH (1.5 mL), and purified by preparative HPLC (CH3CN / H2O with 10 mM NH4OAc) to yield 13-cyclohexyl-N - ((1-ethylcyclopropyl) sulfonyl) -3-methoxy-6 - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -7H-indolo [2,1-a] [2] benzazepine-10carboxamide (30.9 mg, 0.046 mmol, 45% yield) as a yellow solid. NMR¹H (300 MHz, CD3OD) δ ppm 0.97-2.35 (m, 29H), 2.56-2.73 (m, 1H), 2.80-2.94 (m, 1H), 3, 38-3.58 (m, 1H), 3.94 (s, 3H), 4.29-4.64 (m, 2H), 5.14-5.31 (m, 1H), 7.05 ( s, 1H), 7.09-7.20 (m, 2H), 7.57 (d, J = 8.4 Hz, 1H), 7.65 (dd, J = 8.4, 1.5 Hz , 1H), 7.92 (d, J = 8.4Hz, 1H), 8.16 (brs, 1h). LCMS retention time: 2.91 min; m / z 669 (MH-). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6 x 50 mm column, using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. Elution conditions employed a flow rate of 5 ml / min, a gradient from 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 4 min, a 1 min waiting time and 5 min analysis time, where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile % / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

<img file="ES2390732T3_D0099.tif" />

13-cyclohexyl-N- (isopropylsulfonyl) -3-methoxy-6 - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -7Hindolo [2,1-a ] [2] benzazepine-10-carboxamide. CDI (80 mg, 0.49 mmol) was added to a solution of 13-cyclohexyl-3-methoxy-6 - ((3-methyl-3,8-diazabicyclo [3.2.1] oct-8-yl) carbonyl) -7H-indole [2,1-a] [2] benzazepine-10-carboxylate of tert-butyl TFA (200 mg, 0.30 mmol) in THF (1.5 ml) and the reaction mixture was heated at 60 ° C for 2 h. The reaction was cooled to rt and then 1/3 (~ 0.55 ml) of the reaction solution was added to a stirring solution of propane-2-sulfonamide (40 mg, 0.33 mmol) in DBU (0, 20 ml, 1.3 mmol) and THF (0.20 ml). The reaction was stirred at rt overnight (complete by LCMS), concentrated to an oil, quenched with 1N HCl (~ 1 mL) (formed prec.), And extracted with EtOAc (2 x 1 mL). The combined organic extracts were concentrated to dryness, dissolved in MeOH (1.5 mL), and purified by preparative HPLC (CH3CN / H2O with 10 mM NH4OAc) to yield 13-cyclohexyl-N- (isopropylsulfonyl) -3-methoxy- 6 - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -7H-indolo [2,1-a] [2] benza zepine-10-carboxamide (28 , 5 mg, 0.044 mmol, 43% yield) as a yellow solid. NMR¹H (300 MHz, CD3OD) δ ppm 1.13-2.77 (m, 28H), 2.80-2.93 (m, 1H), 3.93 (s, 3H), 3.90-4, 02 (m, 1H), 4.27-4.65 (m, 2H), 5.11-5.31 (m, 1H), 7.04 (s, 1H), 7.11 (d, J = 2.6 Hz, 1H), 7.16 (dd, J = 8.4, 2.6 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.67 (dd , J = 8.4, 1.5 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 8.18 (brs, 1H). LC-MS retention time: 2.55 min; m / z 643 (MH-). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6 x 50 mm column, using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. Elution conditions employed a flow rate of 5 ml / min, a gradient from 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 4 min, a waiting time of 1 min and analysis time of 5 min, where solvent A was 5% acetonitrile / H₂95% O / 10mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

<img file="ES2390732T3_D0100.tif" />

13-Cyclohexyl-3-methoxy-6 - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -N - ((1-methyl-1H-imidazol4-yl ) sulfonyl) -7H-indole [2,1-a] [2] benzazepine-10-carboxamide. 13-cyclohexyl-3-methoxy-6 - ((3-methyl-3,8diazabicyclo [3.2.1] oct-8-yl) carbonyl) -7H-indolo [2,1-a] [2] was dissolved tert-Butyl benzazepine-10-carboxylate TFA (200 mg, 0.30

ES 2 390 732 T3 mmol) in THF (1.5 ml) and stirred under a nitrogen atmosphere. CDI (80 mg, 0.49 mmol) was added and the reaction mixture was heated at 60 ° C for 2 h. The reaction was cooled to rt and then 1/3 (~ 0.55 ml) of the reaction solution was added to a stirring solution of 1-methyl-1H-imidazole-4-sulfonamide (60.0 mg, 0, 37 mmol) in DBU (0.20 ml, 1.3 mmol) and THF (0.20 ml). The reaction was stirred at rt overnight (~ 75% conv. according to LCMS), concentrated to an oil, quenched with 1N HCl (~ 1 mL) (formed prec.) and extracted with EtOAc (2 x 1 mL) and DCM (2 x 1 mL). The combined organic extracts were concentrated, dissolved in MeOH (1.5 ml), and purified by preparative HPLC (CH₃CN / H₂Or with NH₄10 mM OAc) to yield 13-cyclohexyl-3-methoxy-6 ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -N - ((1-methyl- 1H-imidazol-4-yl) sulfonyl) -7H-indolo [2,1-a] [2] benzazepine-10-carboxamide (15.6 mg, 0.023 mmol, 22% yield) as a yellow solid. NMR¹H (300 MHz, CD3OD) δ ppm 1.08-2.77 (m, 22H), 2.78-2.92 (m, 1H), 3.81 (s, 1H), 3.93 (s, 3H), 4.26-4.65 (m, 2H), 5.08-5.3 (m, 1H), 7.01 (s, 1H), 7.10 (d, J = 2.6 Hz, 1H), 7.15 (dd, J = 8.4, 2.6 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 8 , 4Hz, 1H), 7.67 (s, 1H), 7.81 (s, 1H), 7.83 (d, J = 8.4Hz, 1H), 8.17 (s, 1H). LC-MS retention time: 2.15 min; m / z 681 (MH-). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6 x 50 mm column, using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. Elution conditions employed a flow rate of 5 ml / min, a gradient from 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 4 min, a 1 min waiting time and 5 min analysis time, where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile % / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

<img file="ES2390732T3_D0101.tif" />

8-Cyclohexyl-N - ((3,5-dimethyl-4-isoxazolyl) sulfonyl) -11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct8-yl) carbonyl ) -1,1a, 2,12b-tetrahydrocyclopropa [d] indole [2,1-a] [2] benzazepine-5-carboxamide. 8-Cyclohexyl-11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -1,1a, 2,12b-tetrahydrocyclopropa [acid was dissolved. d] indole [2,1-a] [2] benzazepine-5-carboxylic acid, TFA (400mg, 0.61mmol) in THF (4ml) and stirred under a nitrogen atmosphere. CDI (160 mg, 0.98 mmol) was added and the reaction mixture was heated at 60 ° C for 2 h. The reaction was cooled to rt and then 1/8 (~ 0.50 mL) of the reaction solution was added to a stirring solution of 3,5-dimethylisoxazole-4-sulfonamide (30 mg, 0.17 mmol) in DBU (100 gl, 0.66 mmol) and THF (0.100 ml). The reaction was stirred at rt for 2 d. (complete by LCMS) quenched with 1M HCl (aq.) (0.75 mL) (slight exotherm), diluted with MeOH and concentrated. The residue was dissolved in MeOH and purified in an injection using preparative HPLC (CH₃CN / H₂Or with NH₄10 mM OAc) to yield 8-cyclohexyl-N - ((3,5-dimethyl-4-isoxazolyl) sulfonyl) -11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct -8-yl) carbon-yl) -1,1a, 2,12btetrahydrocyclopropa [d] indolo [2,1-a] [2] benzazepine-5-carboxamide (33.7 mg, 0.047 mmol, 63% yield) in the form of a yellow solid. The compound was isolated as a mixture of enantiomers and presented as a 1: 4 mixture of rotamers or atropisomers. NMR¹H (300 MHz, CDCl₃) δ ppm 0.10 - 0.17 (m, 0.2H), 0.71 - 0.92 (m, 0.8H), 1.00 - 2.14 (m, 17H), 2.25 - 2.39 (m, 2H), 2.45 (s, 2.4H), 2.46 (s, 0.6H), 2.78 (s, 3H), 2.85-3.47 (m, 6H), 3.54 (d, J = 15.4 Hz, 1H), 3.87 (s, 2.4H), 3.88 (s, 0.6H), 4.04 (d, J = 15.0 Hz, 0.2H), 4.29 - 4.56 (m, 0.8H), 4.69 (d, J = 15.0 Hz, 0.2H), 5.08 - 5.24 (m, 0.8H), 6.91 (dd, J = 8.8, 2.6 Hz, 0.2H), 6.94 (dd, J = 8.8, 2.6 Hz, 0.8H ), 7.04 (d, J = 2.6 Hz, 0.8H), 7.21 - 7.26 (m, 0.2H), 7.26 (d, J = 8.8 Hz, 0, 8H), 7.29 (d, J = 8.8 Hz, 0.2H), 7.50 (dd, J = 8.4, 1.5 Hz, 0.2H), 7.80 (dd, J = 8.4, 1.1 Hz, 0.8H), 7 , 81 (d, J = 8.4 Hz, 0.8H), 7.82 (d, J = 8.4 Hz, 0.2H), 7.89 (bs, 0.8H), 7.93 ( bs, 0.2H). LC-MS retention time: 2.22 min; m / z710 (MH-). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM . Elution conditions employed a flow rate of 5 ml / min, a gradient from 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 4 min, a waiting time of 1 min and analysis time of 5 min, where solvent A was 5% acetonitrile / H₂95% O / 10 mM ammonium acetate and solvent B was H₂Or 5% / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

<img file="ES2390732T3_D0102.tif" />

ES 2 390 732 T3

8-Cyclohexyl-11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -N - ((1-methyl-1H-imide-zole -4-yl) sulfonyl) -1,1a, 2,12b-tetrahydrocyclopropa [d] indolo [2,1-a] [2] benzazepine-5-carboxamide. Acid dissolved

8-cyclohexyl-11-methoxy-1a - ((- 3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -1,1a, 2,12b-tetrahydrocyclopropa [d] indole [2,1-a] [2] benzazepine-5-carboxylic acid, TFA (400mg, 0.61mmol) in THF (4ml) and stirred under a nitrogen atmosphere. CDI (160 mg, 0.98 mmol) was added and the reaction mixture was heated at 60 ° C for 2 h. The reaction was cooled to rt and then 1/8 (~ 0.50 ml) of the reaction solution was added to a stirring solution of 1-methyl-1H-imidazole-4-sulfonamide (30 mg, 0.19 mmol ) in DBU (100 gl, 0.66 mmol) and THF (0.100 ml). The reaction was stirred at rt for 2 d. (~ 60% conv. By LCMS) was quenched with 1M HCl (aq.) (0.75 mL) (slight exotherm), diluted with MeOH, and concentrated. The residue was dissolved in MeOH (1.5 ml), filtered and purified in an injection using preparative HPLC (CH3CN / H2O with 10 mM NH4OAc) to yield 8-cyclohexyl-1-methoxy-1a - ((3-methyl-3 , 8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -N - ((1-methyl-1H-imidazol-4-yl) sulfonyl) -1,1a, 2,12btetrahydrocyclopropa [d] indole [2,1-a] [2] benzazepine-5-carboxamide (21.8 mg, 0.031 mmol, 42% yield) as a yellow solid. The compound was isolated as a mixture of enantiomers and presented as a 1: 2 mixture of rotamers or atropisomers. NMR¹H (300 MHz, CDCh) δ ppm -0.39 - -0.56 (m, 0.33H), 0.12 - 0.21 (m, 0.33H), 0.74 - 3.68 (m , 25.33H), 3.65 (s, 3H), 3.85 (s, 2H), 3.86 (s, 1H), 4.02 (d, J = 14.6 Hz, 0.33H ), 4.18 - 4.59 (m, 0.67H), 4.72 (d, J = 14.6 Hz, 0.33H), 5.11 (d, J = 14.6 Hz, 0, 67H), 5.96 - 6.21 (m, 1H), 6.87 (dd, J = 8.8, 2.6 Hz, 0.33H), 6.91 (dd, J = 8.8, 2.6 Hz, 0.67H), 6.95 (d, J = 2.6 Hz, 0.33H), 7.06 (d, J = 2.6 Hz, 0.67H), 7.19 - 7.27 (m, 1H), 7.41 (s, 1H), 7.56 (d, J = 8.8 Hz, 0.33H), 7.61 (d, J = 8.8 Hz, 0 , 67H), 7.68-7.78 (m, 2H), 7.96 (brs, 0.67H), 7.99 (brs, 0.33H). LC-MS retention time: 2.09 min; m / z 695 (MH-). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6 x 50 mm column, using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. Elution conditions employed a flow rate of 5 ml / min, a gradient from 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 4 min, a 1 min waiting time and 5 min analysis time, where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile % / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

<img file="ES2390732T3_D0103.tif" />

8-Cyclohexyl-11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -N - ((5-methyl-2-pyridinyl) sulfonyl ) 1,1a, 2,12b-tetrahydrocyclopropa [d] indolo [2,1-a] [2] benzazepine-5-carboxamide. 8-Cyclohexyl-11-methoxy1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -1,1a, 2,12b-tetrahydrocyclopropa [d] acid was dissolved indole [2,1-a] [2] benzazepine-5-carboxylic acid, TFA (400mg, 0.61mmol) in THF (4ml) and stirred under a nitrogen atmosphere. CDI (160 mg, 0.98 mmol) was added and the reaction mixture was heated at 60 ° C for 2 h. The reaction was cooled to rt and then 1/8 (~ 0.50 mL) of the reaction solution was added to a stirring solution of 5-methylpyridine-2-sulfonamide (30 mg, 0.17 mmol) in DBU ( 100 gl, 0.66 mmol) and THF (0.100 ml). The reaction was stirred for 3 h (complete by LCMS), quenched with 1 M HCl (aq.) (0.75 mL) (slight exotherm noted), and concentrated under a stream of nitrogen for 2 d. The residue was dissolved in MeOH (~ 1 mL) and purified in an injection by preparative HPLC (CH3CN / H2O with 10 mM NH4OAc) to yield 8-cyclohexyl-11-methoxy-1a - ((3-methyl-3.8 -diazabicyclo [3,2,1] oct-8-yl) carbonyl) -N ((5-methyl-2-pyridinyl) sulfonyl) -1,1a, 2,12b-tetrahydrocyclopropa [d] indole [2,1- a] [2] benzazepine-5-carboxamide (35.9 mg, 0.051 mmol, 68% yield) as a yellow solid. The compound was isolated as a mixture of enantiomers and presented as a 1: 2 mixture of rotamers or atropisomers. NMR¹H (300 MHz, CDCls) δ ppm 0.19-0.27 (m, 0.33H), 0.95-3.11 (m, 24.67H), 2.45 (s, 3H), 3, 59 (d, J = 14.6 Hz, 1H), 3.90 (s, 2H), 3.91 (s, 1H), 4.02 (d, J = 14.6 Hz, 0.33H), 4.15 (d, J = 14.6 Hz, 0.33H), 4.64 - 4.26 (m, 1.67H), 5.12 (d, J = 14.6 Hz, 0.67H) , 6.95-7.03 (m, 1H) 7.15 (d, J = 2.6Hz, 0.33H), 7.19 (d, J = 2.6Hz, 0.67H), 7 , 30 (d, J = 8.4Hz, 0.67H), 7.31 (d, J = 8.8Hz, 0.33H), 7.66-7.84 (m, 3H). 8.03-8.10 (m, 1.67H), 8.22 (s, 0.33H), 8.44 (s, 1H). LC-MS retention time: 2.19 min; m / z 706 (MH-). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6 x 50 mm column, using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. Elution conditions employed a flow rate of 5 ml / min, a gradient from 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 4 min, a 1 min waiting time and 5 min analysis time, where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile % / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

ES 2 390 732 T3

<img file="ES2390732T3_D0104.tif" />

8-Cyclohexyl-11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -N- (phenylsulfonyl) -1,1a, 2,12btetrahydrocyclopropa [d] indole [2,1-a] [2] benzazepine-5-carboxamide. Acid dissolved

8-cyclohexyl-11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -1,1a, 2,12b-tetrahydrocyclopropa [d] indole [2,1 -a] [2] benzazepine-5-carboxylic acid, TFA (400mg, 0.61mmol) in THF (4ml) and stirred under nitrogen. CDI (160 mg, 0.98 mmol) was added and the reaction mixture was heated at 60 ° C for 2 h. The reaction was cooled to rt and then 1/8 (~ 0.50 mL) of the reaction solution was added to a stirring solution of benzenesulfonamide (30 mg, 0.19 mmol) in DBU (100 µL, 0.66 mmol) and THF (0.100 ml). The reaction was stirred at rt for 2 d. (complete by LCMS), quenched with 1M HCl (aq.) (0.75 mL) (slight exotherm), diluted with MeOH and concentrated to dryness. The residue was dissolved in MeOH (1.5 ml) and purified in an injection using preparative HPLC (CH3CN / H2O with NH₄10 mM OAc) to yield 8-cyclohexyl-11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -N (phenylsulfonyl) -1, 1a, 2,12b-tetrahydrocyclopropa [d] indole [2,1-a] [2] benzazepine-5-carboxamide (27.6 mg, 0.040 mmol, 53% yield) as a light yellow solid. The compound was isolated as a mixture of enantiomers and is presented as a 1: 3 mixture of rotamers or atropisomers. NMR¹H (300 MHz, CDCl3) δ ppm 0.14 - 0.22 (m, 0.25H), 0.93 - 2.97 (m, 24.75H), 3.39 - 3.38 (m, 1 , 25H), 3.55 (d, J = 15.0Hz, 0.75H), 3.87 (s, 3H), 3.99-4.11 (m, 0.25H), 4.20- 4.11 (m, 1H), 5.13 (d, J = 15.0Hz, 0.75H), 6.87-6.98 (m, 1.25H), 7.09 (d, J = 2.2 Hz, 0.75H), 7.23 - 7.29 (m, 1H), 7.44 - 7.63 (m, 4H), 7.80 (d, J = 8.4 Hz, 1H ), 7.90 (s, 1H), 8.11-8.19 (m, 2H). LC-MS retention time: 2.32 min; m / z 691 (MH-). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6 x 50 mm column, using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. Elution conditions employed a flow rate of 5 ml / min, a gradient from 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 4 min, a waiting time of 1 min and analysis time of 5 min, where solvent A was 5% acetonitrile / H₂95% O / 10 mM ammonium acetate and solvent B was H₂Or 5% / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

<img file="ES2390732T3_D0105.tif" />

N - ((4-Chloro-3-pyridinyl) sulfonyl) -8-cyclohexyl-11-methoxy-1a - ((3-methyl-3,8-diazabiclyclo [3,2,1] oct-8-yl) carbonyl ) 1,1a, 2,12b-tetrahydrocyclopropa [d] indolo [2,1-a] [2] benzazepine-5-carboxamide. 8-Cyclohexyl-11-methoxy1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -1,1a, 2,12b-tetrahydrocyclopropa [d] acid was dissolved indole [2,1-a] [2] benzazepine 5-carboxylic acid, TFA (400 mg, 0.61 mmol) in THF (4 ml) and stirred under a nitrogen atmosphere. CDI (160 mg, 0.98 mmol) was added and the reaction mixture was heated at 60 ° C for 2 h. The reaction was cooled to rt and then 1/8 (~ 0.50 mL) of the reaction solution was added to a stirring solution of 4-chloropyridine-3-sulfonamide (40 mg, 0.21 mmol) in DBU ( 100 µl, 0.66 mmol) and THF (0.100 ml). The reaction was stirred for 3 h (complete by LCMS) quenched with 1 M HCl (aq) (0.75 mL) (slight exotherm noted) and concentrated under a stream of nitrogen for 2 d. The residue was dissolved in MeOH (~ 1 mL) and purified by preparative HPLC (CH3CN / H2O with 10 mM NH4OAc) to yield N - ((4-chloro-3-pyridinyl) sulfonyl) -8-cyclohexyl-11-methoxy -1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8yl) carbonyl) -1,1a, 2,12b-tetrahydrocyclopropa [d] indole [2,1-a] [2 ] benzazepine-5-carboxamide (28.6 mg, 0.039 mmol, 52% yield) as a bright yellow solid. The compound was isolated as a mixture of enantiomers and was presented as atropisomers or rotamers. NMR¹Partial H (300 MHz, CD3OD) δ 3.86 (s, 3H), 6.93 (d, J = 8.8, 2.2 Hz, 1H), 7.08 (s, 1H), 7.20 -7.28 (m, 1H), 7.35 (d, J = 5.1 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.98 (s, 1H), 8.58 (d, J = 5.1 Hz, 1H), 9.87 (s, 1H). LC-MS retention time: 2.18 min; m / z 726 (MH-). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6 x 50 mm column, using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. Elution conditions employed a flow rate of 5 ml / min, a gradient from 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 4 min, a 1 min waiting time and 5 min analysis time, where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile % / 10 mM ammonium acetate. EM data is

ES 2 390 732 T3 determined using a Micromass Platform for CL in electrospray mode.

<img file="ES2390732T3_D0106.tif" />

8-Cyclohexyl-11-methoxy-N - ((2-methoxy-4-methylphenyl) sulfonyl) -1a - ((3-methyl-3,8-diazabicoclo [3,2,1] oct-8-ol) carbonyl ) 1,1a, 2,12b-tetrahydrocyclopropa [d] indolo [2,1-a] [2] benzazepine-5-carboxamide. Acid dissolved

8-cyclohexyl-11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -1,1a, 2,12b-tetrahydrocyclopropa [d] indole [2,1 -a] [2] benzazepine-5-carboxylic acid, TFA (100mg, 0.15mmol) in THF (1ml) and stirred under a nitrogen atmosphere. CDI (40 mg, 0.25 mmol) was added and the reaction mixture was heated at 60 ° C for 2 h. The reaction was cooled to rt and then 1/2 (~ 0.50 mL) of the reaction solution was added to a stirring solution of 2-methoxy-4-methylbenzenesulfonamide (35 mg, 0.17 mmol) in DBU ( 100 µl, 0.66 mmol) and THF (0.100 ml). The reaction was stirred at rt for 1 d. (complete by LCMS), quenched with 1M HCl (aq.) (0.75 mL) (slight exotherm), diluted with MeOH and concentrated. The residue was diluted with MeOH (1.3 ml) and DMF (0.2 ml) and purified in an injection using preparative HPLC (H2O / CH3CN, 10 mM NH4OAc) to yield 8-cyclohexyl-11-methoxyN - (( 2-methoxy-4-methylphenyl) sulfonyl) -1 a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -1,1a, 2,12b-tetrahydrocyclopropa [d] indole [2,1-a] [2] benzazepine-5-carboxamide (14.6 mg, 0.020 mmol, 27% yield) as an off-white solid. The compound was isolated as a mixture of enantiomers and presented as a 1: 4 mixture of rotamers or atropisomers. NMR¹H (300 MHz, CD3OD) δ ppm 0.14-0.20 (m, 0.2H), 0.89-3.12 (m, 22.8H), 3.88 (s, 2H), 2, 44 (s, 3H), 3.37 (s, 3H), 3.64 (d, J = 15.0Hz, 0.8H), 3.87-3.94 (m, 6H), 4.17 (d, J = 15.4 Hz, 0.2H), 4.25-4.35 (m, 0.8H), 4.51-4.56 (m, 0.2H), 4.87-4 , 97 (m, 0.2H), 5.13 (d, J = 15.4 Hz, 0.8H), 6.93-7.06 (m, 3H), 7.14-7.18 (m , 0.2H), 7.19-7.23 (m, 0.8H), 7.29-7.37 (m, 1H), 7.53-7.61 (m, 1H), 7.83 - 7.99 (m, 2.8H), 8.10 (s, 0.2H). LC-MS retention time: 2.90 min; m / z 735 (MH-). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6 x 50 mm column, using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. Elution conditions employed a flow rate of 5 ml / min, a gradient from 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 4 min, a waiting time of 1 min and analysis time of 5 min, where solvent A was 5% acetonitrile / H₂95% O / 10 mM ammonium acetate and solvent B was H₂Or 5% / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

<img file="ES2390732T3_D0107.tif" />

4-tert-Butylthiazole-2-sulfonamide. Sodium hypochlorite (15 ml, 28 mmol) (Reagent grade) (internally ice-cooled (~ 15 g)) was added dropwise to a vigorously stirred solution of 4-tert-butylthiazole-2-thiol (800 mg, 4.62 mmol) in DCM (25 ml) and aq. HCl. 1 M (25 ml, 25 mmol) chilled in an ice bath. The reaction was stirred at 5 ° C for 10 min. and the phases separated. The organic phase was cooled in a flask with a dry ice acetone bath and ammonia was bubbled into the solution for 5 minutes. The cold bath was removed and the reaction was allowed to reach rt. The crude reaction was concentrated, dissolved in MeOH, and filtered to remove solids. The solution was concentrated to yield 4-tert-butylthiazole-2-sulfonamide as a waxy solid which was used without further purification. LC-MS retention time: 1.85 min; m / z 219 (MH-). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6 x 50 mm column, using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. Elution conditions employed a flow rate of 5 ml / min, a gradient from 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 4 min, a 1 min waiting time and 5 min analysis time, where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

ES 2 390 732 T3

<img file="ES2390732T3_D0108.tif" />

N - ((4-tert-Butyl-1,3-thiazol-2-yl) sulfonyl) -8-cyclohexyl-11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1 ] oct-8-yl) carbonyl) -1,1a, 2,12b-tetrahydrocyclopropa [d] indolo [2,1-a] [2] benzazepine-5-carboxamide. Acid dissolved

8-cyclohexyl-11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -1,1a, 2,12b-tetrahydrocyclopropa [d] indole [2,1 -a] [2] benzazepine-5-carboxylic acid, TFA (100mg, 0.15mmol) in THF (1ml) and stirred under a nitrogen atmosphere. CDI (40 mg, 0.25 mmol) was added and the reaction mixture was heated at 60 ° C for 2 h. The reaction was cooled to rt and then 1/2 (~ 0.50 mL) of the reaction solution was added to a stirring solution of 4-tert-butylthiazole-2-sulfonamide (35 mg, 0.16 mmol) in DBU (100 µl, 0.66 mmol) and THF (0.100 ml). The reaction was stirred at rt for 1 d. (complete by LCMS), quenched with 1M HCl (aq.) (0.75 mL) (slight exotherm), diluted with MeOH and concentrated. The residue was diluted with MeOH (1.3 ml) and DMF (0.2 ml), and purified in an injection using preparative HPLC (H₂O / CH₃CN, NH₄10 mM OAc) to produce

N - ((4-tert-Butyl-1,3-thiazol-2-yl) sulfonyl) -8-cyclohexyl-11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1 ] oct-8-yl) carbonyl) -1,1a, 2,12b-tetrahydrocyclopropa [d] indole [2,1-a] [2] benzazepine-5-carboxamide (9.0 mg, 0.012 mmol, 15% yield) as an off-white solid. LC-MS retention time: 2.59 min; m / z 754 (MH-). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6 x 50 mm column, using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. Elution conditions employed a flow rate of 5 ml / min, a gradient from 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 4 min, a waiting time of 1 min and analysis time of 5 min, where solvent A was 5% acetonitrile / H₂95% O / 10mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

<img file="ES2390732T3_D0109.tif" />

Quinolin-8-sulfonamide. Quinoline-8-sulfonyl chloride (1.0 g, 4.39 mmol) was suspended in DCM (20 ml) and cooled to -60 ° C. Then, ammonia (~ 5 g, 294 mmol) was bubbled into the reaction for 5 min (volume increased to ~ 5 ml). The reaction was stirred and allowed to come to rt overnight. The residue was partitioned between water (50 ml) and EtOAc (50 ml) and the organic phase was washed with brine (20 ml) and diluted with hexanes (~ 50 ml). The solution was stirred for 20 min and the solids were collected by filtration to yield quinoline-8-sulfonamide (432 mg, 2.07 mmol, 47% yield) as a light yellow solid. NMR¹H (500 MHz, DMSO-d₆) δ ppm 7.25 (s, 2H), 7.73 (dd, J = 8.3, 4.3 Hz, 1H), 7.76 (dd, J = 8.6, 7.3 Hz, 1H ), 8.28 (d, J = 8.3 Hz, 1H), 8.31 (d, J = 7.3 Hz, 1H), 8.56 (da, J = 8.6 Hz, 1H), 9.08 (dd, J = 4.3, 0.9 Hz, 1H). LC-MS retention time: 1.27 min; m / z 209 (MH +). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6 x 50 mm column, using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. Elution conditions employed a flow rate of 5 ml / min, a gradient from 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 4 min, a waiting time of 1 min and analysis time of 5 min, where solvent A was 5% acetonitrile / H₂95% O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

<img file="ES2390732T3_D0110.tif" />

8-Cyclohexyl-11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -N- (8-quinolinylsulfonyl) 1,1a, 2, 12b-tetrahydrocyclopropa [d] indole [2,1-a] [2] benzazepine-5-carboxamide. Acid dissolved

8-cyclohexyl-11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -1,1a, 2,12b-tetrahydrocyclopropa [d] indole [2,1-a] [2] benzazepine-5-carboxylic acid, TFA (104 mg, 0.16 mmol) and CDI (40 mg, 0.25 mmol) in THF (1.0 ml), were stirred in a nitrogen atmosphere and then heated at 60 ° C for 2 h. The reaction was cooled to rt then 1/2

ES 2 390 732 T3 (~ 0.50 ml) of the reaction solution was added to a stirring solution of quinoline-8-sulfonamide (40 mg, 0.19 mmol) in DBU (0.10 ml) and THF ( 0.10 ml). The reaction was stirred at rt for 1 d, quenched with aq. HCl. 1 M (0.7 ml), diluted with MeOH and DMSO (0.2 ml), and concentrated. The crude oil was diluted with MeOH (1 mL), filtered and purified by preparative HPLC (H2O / CH3CN, 10 mM NH4OAc) in a single injection to yield 8-cyclohexyl-11-methoxy-1a - ((3- methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -N- (8-quinolinylsulfonyl) -1,1a, 2,12btetrahydrocyclopropa [d] indole [2,1- a] [ 2] benzazepine-5-carboxamide (11.2 mg, 0.015 mmol, 20% yield) as a yellow solid. The compound was isolated as a mixture of enantiomers and presented as a 1: 2 mixture of rotamers or atropisomers. NMR¹H (500 MHz, CDCL) δ ppm 0.19 - 0.27 (m, 0.33H), 0.67 - 3.61 (m, 26.67H), 3.88 (s, 2H), 3, 89 (s, 1H), 4.00-4.32 (m, 1H), 4.62-4.72 (m, 0.33H), 5.02-5.16 (m, 0.67H), 6.90 (dd, J = 8.5, 2.4 Hz, 0.33H), 6.94 (dd, J = 8.6, 2.5 Hz, 0.67H), 7.00 (sa, 0.33H), 7.10 (bs, 0.67H), 7.19-7.27 (m, 1H), 7.39-7.55 (m, 2H), 7.66-7.83 ( m, 2H), 7.90 (s, 1H), 8.01-8.11 (m, 1H), 8.15- 8.27 (m, 1H), 8.71-8.77 (m, 1H), 8.93-9.09 (m, 1H). LC-MS retention time: 2.57 min; m / z 742 (MH-). LC data were recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C 18 4.6 x 50 mm column, using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. Elution conditions employed a flow rate of 5 ml / min, a gradient from 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 4 min, a 1 min waiting time and 5 min analysis time, where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile % / 10 mM ammonium acetate. EM data was determined using a Micromass Platform

<img file="ES2390732T3_D0111.tif" />

8-Cyclohexyl-11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -N - ((2-pyridinylmethyl) sulfonyl) 11a, 2 , 12b-tetrahydrocyclopropa [d] indolo [2,1-a] [2] benzazepine-5-carboxamide. 8-Cyclohexyl-11-methoxy-1a ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -1,1a, 2,12b-tetrahydrocyclopropa acid trifruoroacetate were suspended

[d] indole [2,1-a] [2] benzazepine-5-carboxylic acid (40 mg, 0.060 mmol), pyridin-2-ylmethanesulfonamide (25 mg, 0.15 mmol) and DMAF (7 mg, 0.060 mmol) in DCM (0.5 ml) then EDC (20 mg, 0.10 mmol) was added. The vial was flushed with nitrogen, sealed and the reaction stirred at rt overnight (complete by LCMS). The reaction mixture was diluted with MeOH and purified by preparative HPLC (CH3CN / H2O w / 10 mM NH4OAc) in a single injection to yield 8-cyclohexyl-11-methoxy-1a - ((3-methyl-3,8- diazabicyclo [3,2,1] oct-8-yl) carbonyl) -N - ((2-pyridinylmethyl) sulfonyl) -1,1a, 2,12b-tetrahydrocyclopropa [d] indolo [2,1-a] [2] benzazepine -5-carboxamide (15.8 mg, 0.022 mmol, 37% yield) as a yellow solid. The compound was isolated as a mixture of enantiomers and presented as a ~ 1: 1 mixture of rotamers or atropisomers. NMR¹H (300 MHz, CDCL) δ ppm 0.19 - 0.26 (m, 0.5H), 0.34 - 3.66 (m, 26.5H), 3.88 (s, 3H), 3, 98-4.58 (m, 1.5H), 4.7: (d, J = 14.3 Hz, 0.5H), 4.87-4.99 (m, 1.5H), 5.09 (d, J = 14.6 Hz, 0.5H), 6.86-7.01 (m, 1.5H), 7.06-7.13 (m, 1H), 7.1 (-7, 30 (m, 1.5H), 7.46-7.52 (m, 1H), 7.59- 7.75 (m, 2H), 7.78-8.13 (m, 2H), 8, 53 (d, J = 5.1 Hz, 1H) Retention time LC-MS: 2.19 min, m / z 706 (MH-). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C 184.6 x 50 mm column, using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions a flow rate of 5 ml / min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 4 min, a time waiting time of 1 min and an analysis time of 5 min, in which solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

<img file="ES2390732T3_D0112.tif" />

2,4-Dimethylthiazole-5-sulfonamide. Liquid ammonia was added dropwise via a CO2 / acetone condenser to a solution of 2,4-dimethylthiazole-5-sulfonyl chloride (260 mg, 1.228 mmol) in THF (3 mL) at -78 ° C until the volume had approximately doubled (~ 10 min). The reaction was stirred at -78 ° C for 1 h and then allowed to slowly warm to rt. The reaction was concentrated to dryness and the residue was diluted with CH2Cl2. The suspension was filtered to remove solids and the solution was concentrated to yield 2,4-dimethylthiazole-5-sulfonamide (230 mg, 1.2 mmol, 97% yield) as a light yellow solid. LC-MS retention time, 0.43 min; m / z 191 (MH-). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0 x 50 mm column, using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. Elution conditions employed a flow rate of 5 ml / min, a gradient of solvent A to

ES 2 390 732 T3

100% / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 3 min, a waiting time of 1 min and an analysis time of 4 min, in which the Solvent A was 5% acetonitrile / 95% H2O / 10mM ammonium acetate and solvent B was H₂Or 5% / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

<img file="ES2390732T3_D0113.tif" />

8-cyclohexyl-N - ((2,4-dimethyl-1,3-thiazol-5-yl) sulfonyl) -11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1 ] oct-8-yl) carbonyl) -1,1a, 2,12b-tetrahydrocyclopropa [d] indole [2,1-a] [2] benzazepine-5-carboxamide. 8-Cyclohexyl-11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -1,1a, 2,12b-tetrahydrocyclopropa [acid] were suspended. d] indole [2,1-a] [2] benzazepine-5-carboxylic (40 mg, 0.072 mmol), 2,4-dimethylthiazole-5-sulfonamide (26 mg, 0.14 mmol) and DMAP (10 mg, 0.082 mmol) in CH₂Cl₂ (0.5 ml) and then treated with EDC (20 mg, 0.10 mmol). The reaction was stirred at rt overnight. The reaction was concentrated under a stream of nitrogen, dissolved in MeOH, filtered, and purified by prep HPLC. (CH3CN / H2O, w / 10 mM NH4OAc, 15-100% over 20 min) to yield 8-cyclohexyl-N - ((2,4-dimethyl-1,3-thiazol-5-yl) sulfonyl) -11- methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -1,1a, 2, 12b-tetrahydrocyclopropa [d] indole [2,1-a ] [2] benzazepine-5-carboxamide (25.4 mg, 0.035 mmol, 48% yield) as a yellow solid. LC-MS retention time 3.14 min; m / z 728 (MH +). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0 x 50 mm column, using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. Elution conditions employed a flow rate of 5 ml / min, a gradient from 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 4 min, a 1 min waiting time and 5 min analysis time where solvent A was 10% MeOH / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / MeOH 90% / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

<img file="ES2390732T3_D0114.tif" />

1H-1,2,4-Triazole-3-sulfonamide. Liquid ammonia was added dropwise via a CO2 / acetone condenser to a solution of 1H-1,2,4-triazole-3-sulfonyl chloride (500 mg, 2.98 mmol) in THF (5 mL) at - 78 ° C until the volume had approximately doubled (~ 15 min). The reaction was stirred at -78 ° C for 1 hr and then allowed to slowly warm to rt. The reaction was concentrated to dryness and the residue was diluted with DCM. The suspension was filtered to remove solids and the solution was concentrated to yield 1H-1,2,4-triazole-3-sulfonamide (240 mg, 1,620 mmol, 54.3% yield) as a colored solid. whitish. NMR¹H (300 MHz, CD₃OD) δ ppm 8.60 (bs, 1H). LC-MS retention time 0.19 min; m / z 147 (MH-). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0 x 50 mm column, using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. Elution conditions employed a flow rate of 5 ml / min, a gradient from 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 3 min, a 1 min waiting time and 4 min analysis time, where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile % / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

<img file="ES2390732T3_D0115.tif" />

8-Cyclohexyl-11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -N- (1H-1,2,4-triazole- 3-yl-sulfonyl) 1,1a, 2,12b-tetrahydrocyclopropa [d] indolo [2,1-a] [2] benzazepine-5-carboxamide. 8-Cyclohexyl-11methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -1,1a, 2,12b-tetrahydrocyclopropa [d] were suspended indole [2,1-a] [2] benzazepine-5-carboxylic acid (39 mg, 0.070 mmol), 1H-1,2,4-triazole-3-sulfonamide (25 mg, 0.17 mmol) and dMAp (10 mg,

ES 2 390 732 T3

0.082 mmol) in CH2CL (0.5 ml) and then treated with EDC (20 mg, 0.104 mmol). The reaction was stirred at rt overnight. The reaction was concentrated under a stream of nitrogen, dissolved in MeOH, filtered, and purified by Prep HPLC (CH₃CN / H₂O, w / NH₄10 mM OAc, 15-100% over 20 min) to yield 8-cyclohexyl-11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) - N- (1H-12,4-triazol-3-ylsulfonyl) -11a, 2,12btetrahydrocyclopropa [d] indole [2,1- a] [2] benzazepine-5-carboxamide (5.4 mg, 6.3 pmol , 9% yield) as a yellow solid. LC-MS retention time 2.88 min; m / z 684 (MH +). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0 x 50 mm column using an SPD-10AV UV-Vis detector detecting a detector wavelength of 220 nM . Elution conditions employed a flow rate of 5 ml / min, a gradient from 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 4 min, a 1 min waiting time and 5 min analysis time where solvent A was 10% MeOH / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / MeOH 90% / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

<img file="ES2390732T3_D0116.tif" />

Ethenosulfonamide. A solution of TEA (7.67 mL, 55.0 mmol) in Et₂O (50 ml) was added to a solution of 2-chloroethanesulfonyl chloride (5.22 ml, 50 mmol) in Et2O (100 ml) at -24 ° C (CCl4-dry ice bath) and the mixture was stirred and allowed to warm to rt over 2 h. The reaction mixture was filtered to remove a white precipitate and the filtrate was concentrated (~ 20 mL volume). NH3 was bubbled into the solution of ethenesulfonyl chloride (1.266 g, 10.00 mmol) in Et₂O (20 ml) for 10 min and the white precipitate was filtered off. The filtrate was concentrated to give ethenesulfonamide (180 mg, 1,680 mmol, 16.80% yield) as a colorless gel that was used without further purification. NMR¹H (300 MHz, CD3OD) δ ppm 6.80 (dd, J = 16.5, 9.9 Hz, 1H), 6.16 (d, J = 16.5 Hz, 1H), 5.87 (dd , J = 9.9 Hz, 1H). LC-eM retention time 0.17 min; m / z 108 (MH +). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6 x 50 mm column, using an SPD-10AV UV-Vis detector, at a detector wavelength of 220 nM. Elution conditions employed a flow rate of 5 ml / min, a gradient from 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 2 min, a 1 min retention time and 5 min analysis time, where solvent A was 10% MeOH / H₂90% O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / 90% MeOH / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

<img file="ES2390732T3_D0117.tif" />

8-Cyclohexyl-11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -N- (vinylsulfonyl) -1,1a, 2,12btetrahydrocyclopropa [d] indole [2,1-a] [2] benzazepine-5-carboxamide. Ethenosulfonamide (14.5 mg, 0.135 mmol) and DBU (0.03 ml, 0.2 mmol) were added to a stirring solution of acid

8-cyclohexyl-11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -1,1a, 2,12b-tetrahydrocyclopropa [d] indole [2,1-a] [2] benzazepine-5-carboxylic acid (50 mg, 0.090 mmol) and CDI (22 mg, 0.14 mmol) in THF (1 ml). The reaction mixture was stirred at 60 ° C for 1 hr and then at rt for 16 hr. The reaction was diluted with MeOH, filtered, and purified by prep HPLC. (H₂O-MeOH with 0.1% TFA buffer) to yield the product 8-cyclohexyl-11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl ) carbonyl) -N- (vinylsulfonyl) -1,1a, 2,12btetrahydrocyclopropa [d] indole [2,1-a] [2] benzazepine-5-carboxamide (35.2 mg, 0.055 mmol, 61% yield) as an off-white solid. The compound was isolated as a mixture of enantiomers and presented as a 1: 4 mixture of rotamers or atropisomers. NMR¹H (300 MHz, CD₃OD) δ ppm 8.07 (s, 0.2H), 8.00 (s, 0.8H), 7.93 (d, J = 8.4 Hz, 0.2H), 7.92 (d, J = 8.4 Hz, 0.8H), 7.61 (d, J = 8.4 Hz, 0.2H), 7.57 (d, J = 8.4 Hz, 0.8H), 7, 35 (d, J = 8.8 Hz, 0.2H), 7.34 (d, J = 8.4 Hz, 0.8H), 7.25-7.00 (m 3H), 6.49 ( d, J = 16.8 Hz, 1H), 6.23 (d, J = 9.9 Hz, 1H), 5.16 (d, J = 15.4 Hz, 0.8H), 4.96 ( d, J = 15.0 Hz, 0.2H), 4.74-4.63 (m, 1H), 4.37-4.26 (m, 0.8H), 4.21 (d, J = 15.0 Hz, 0.2H), 4.01-3.86 (m, 3H), 3.73-1.15 (m, 25.8H), 0.24-0.16 (m, 0, 2H). LC-MS retention time 1.72 min; m / z 641 (MH-). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6 x 50 mm column, using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. Elution conditions employed a flow rate of 5 ml / min, a gradient from 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 3 min, a 1 min waiting time and 4 min analysis time, where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile % / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

ES 2 390 732 T3

<img file="ES2390732T3_D0118.tif" />

2-Methylprop-1-ene-1-sulfonamide. T-Butyllithium (13 ml, 22.00 mmol) was added to a stirring solution of 1-bromo-2-methylprop-1-ene (2.0 ml, 20 mmol) in Et2O (100 ml) at -70 ° C. The reaction mixture was stirred at -70 ° C under an atmosphere of N₂ over 1 h and then added dropwise to a stirring solution of sulfur dichloride (3.2 ml, 40 mmol) in Et2O (100 ml) at 0 ° C, (a white precipitate formed). The reaction mixture was allowed to slowly warm to rt and stirred under N2 for 16 h. The reaction mixture was filtered and the filtrate (still cloudy) was concentrated. The residue was dissolved in THF (100 ml) to form a clear yellow solution. NH3 was bubbled into this stirring solution of 2-methylprop-1-ene-1-sulfonyl chloride (3.09 g, 20 mmol) in THF (100 ml) in a 250 ml 3-neck flask fitted with a cold finger (-70 ° C) for a period of 10 minutes (a white precipitate formed and a reflux of NH3 was observed). After 1 hr, the cold finger was removed and the reaction was stirred at rt for 16 hr. The reaction mixture was filtered to remove the white precipitate, rinsed with EtOAc, and concentrated in vacuo to yield 2-methylprop-1-ene-1-sulfonamide (2.59 g, 19.2 mmol, 96% of yield) as a clear yellow oil. LC-MS retention time 0.41 min; m / z 136 (MH +). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6 x 50 mm column, using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. Elution conditions employed a flow rate of 5 ml / min, a gradient from 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 2 min, a 1 min waiting time and 5 min analysis time where solvent A was 10% MeOH / 90% H2O / 0.1% trifluoroacetic acid and solvent B was H₂Or 10% / 90% MeOH / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

<img file="ES2390732T3_D0119.tif" />

8-Cyclohexyl-11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -N - ((2-methyl-1-propen-1 -yl) sulfonyl) 1,1a, 2,12b-tetrahydrocyclopropa [d] indole [2,1-a] [2] benzazepine-5-carboxamide. 2-Methylprop-1 -ene-1 sulfonamide (18.3 mg, 0.135 mmol) and DBU (0.03 ml, 0.2 mmol) were added to a stirring solution of 8-cyclohexyl-11methoxy-1a- acid ( (3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -1,1a, 2,12b-tetrahydrocyclopropa [d] indolo [2,1-a] [2] benzazepin -5-carboxylic (50mg, 0.090mmol) and CDI (22mg, 0.14mmol) in THF (1ml). The reaction mixture was stirred at rt for 16 h. The reaction was diluted with MeOH, filtered, and purified by prep HPLC. (H₂O-MeOH with 0.1% TFA buffer) to yield 8-cyclohexyl-11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl ) -N - ((2-methyl-1-propen-1-yl) sulfonyl) -1,1a, 2,12b-tetrahydrocyclopropa [d] indole [2,1-a] [2] benzazepine-5-carboxamide (13, 8 mg, 0.020 mmol, 22% yield) as a white solid. The compound was isolated as a mixture of enantiomers and presented as a 1: 4 mixture of rotamers or atropisomers. NMR¹H (300 MHz, CD2OD) δ ppm 8.07 (s, 0.2H), 8.00 (s, 0.8H), 7.92 (d, J = 8.4 Hz, 1H), 7.65 - 7.54 (m, 1H), 7.39-7.31 (m, 1H), 7.24-7.17 (m, 1H), 7.09-7.01 (m, 1H), 6 , 47 (s, 1H), 5.18 (d, J = 15.4 Hz, 0.8H), 5.01-4.63 (m, 1.2H), 4.34-4.18 (m , 1H), 3.91 (s, 3H), 3.73-1.16 (m, 25.8H), 2.25 (s, 3H), 2.02 (s, 3H), 0.24 - 0.18 (m, 0.2H). LC-MS retention time 3.37 min; m / z 671 (MH +). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6 x 50 mm column, using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. Elution conditions employed a flow rate of 5 ml / min, a gradient from 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 4 min, a 1 min waiting time and 5 min analysis time where solvent A was 10% MeOH / 90% H2O / 0.1% trifluoroacetic acid and solvent B was H₂Or 10% / 90% MeOH / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

<img file="ES2390732T3_D0120.tif" />

Pyrimidine-2-sulfonamide. Sodium hypochlorite (30.9 mL, 60.0 mmol) was added dropwise with rapid stirring to a solution of 2-mercaptopyrimidine (1122 mg, 10 mmol) in CH2Cl2 (60 mL) and 1N HCl (55.0 mL). , 55.0 mmol) at 0 ° C. After the addition was complete, the mixture was stirred for 15 min at 0 ° C and then the phases were separated. The organic phase was transferred to a 250 ml 3 necked flask which was then cooled in an ice bath and fitted with a cold finger (-70 ° C). NH3 was bubbled through the reaction mixture for 15 min and then the reaction was allowed to slowly warm to rt and stir for 16 h. The resulting white precipitate was separated by

ES 2 390 732 T3 was filtered and the filtrate was concentrated in vacuo to yield pyrimidine-2-sulfonamide (350 mg, 1.98 mmol, 20% yield) as a light yellow solid. Additional product could be obtained from the precipitate. NMR¹H (300 MHz, acetone-d6) δ ppm 9.00 (d, J = 4.9 Hz, 2H), 7.73 (t, J = 4.9 Hz, 1H), 6.77 (sa, 2H ). LC-MS retention time 0.17 min; m / z 160 (MH +). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6 x 50 mm column, using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. Elution conditions employed a flow rate of 5 ml / min, a gradient from 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 2 min, a 1 min waiting time and 3 min analysis time where solvent A was 10% MeOH / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / MeOH 90% / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

<img file="ES2390732T3_D0121.tif" />

8-Cyclohexyl-11-methoxy-1a - ((3-methyl-3,8-di azabicyclo [3,2,1] oct-8-yl) carbonyl) -N- (2-pyri midinylsulfonyl) -1,1a , 2,12btetrahydrocyclopropa [d] indole [2,1-a] [2] benzazepine-5-carboxamide. EDC (26.0 mg, 0.135 mmol) and DMAP (11 mg, 0.090 mmol) were added to a stirring solution of 8-cyclohexyl-11-methoxy-1a - ((3-methyl-3,8-diazabicyclo acid

[3,2,1] oct-8-yl) carbonyl) -1,1a, 2,12b-tetrahydrocyclopropa [d] indolo [2,1-a] [2] benzazepine-5-carboxylic (50 mg, 0.090 mmol ) and pyrimidine-2-sulfonamide (21.6 mg, 0.135 mmol) in CH2Cl2 (1.5 mL) and the reaction mixture was stirred at rt for 16 h. The reaction was diluted with MeOH, filtered, and purified by prep HPLC. (H₂O-CH₃CN with NH buffer₄10 mM OAc) to yield 8-cyclohexyl-11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl) carbonyl) -N- (2-pyrimidinylsulfonyl) 1,1a, 2,12b-tetrahydrocyclopropa [d] indole [2,1-a] [2] benzazepine-5-carboxamide (29.7 mg, 0.041 mmol, 45.0% yield) as a solid of light yellow color. LC-MS retention time 1.71 min; m / z 693 (MH-). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C 18 4.6 x 50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. Elution conditions employed a flow rate of 5 ml / min, a gradient from 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 3 min, a 1 min waiting time and 4 min analysis time, where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile % / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

<img file="ES2390732T3_D0122.tif" />

4,6-Dimethylpyrimidine-2-sulfonamide. Sodium hypochlorite (30.9 ml, 60.0 mmol) was added dropwise with rapid stirring to a solution of 4,6-dimethylpyrimidin-2-thiol (1.40 g, 10.00 mmol) and CaCl2 (14 g ) in CH2Cl2 (60 mL) and 1N HCl (55.0 mL, 55.0 mmol) at -23 ° C. After the addition was complete, the mixture was stirred for 15 min at -23 ° C and the phases were separated. The organic phase was transferred to a 250 ml 3 necked flask which was then cooled to -23 ° C and fitted with a cold finger (-70 ° C). NH3 was bubbled through the reaction mixture for 15 min and then the reaction was allowed to slowly warm to rt and stir for 16 h. The resulting white precipitate was filtered off and the filtrate was concentrated in vacuo to yield 4,6-dimethylpyrimidine-2-sulfonamide (1.003 g, 5.36 mmol, 53.6% yield) as a solid of White color. NMR¹H (300 MHz, acetone-d6) δ ppm 7.43 (s, 1H), 6.63 (bs, 2H), 2.53 (s, 6H). LC-MS retention time 0.39 min; m / z 188 (MH +). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6 x 50 mm column, using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. Elution conditions employed a flow rate of 5 ml / min, a gradient from 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 2 min, a 1 min waiting time and 3 min analysis time where solvent A was 10% MeOH / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / MeOH 90% / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

ES 2 390 732 T3

<img file="ES2390732T3_D0123.tif" />

8-Cyclohexyl-N - ((4,6-dimethyl-2-pyrimidinyl) sulfonyl) -11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8yl) carbonyl ) -1,1a, 2,12b-tetrahydrocyclopropa [d] indole [2,1-a] [2] benzazepine-5-carboxamide. EDC (26.0 mg, 0.135 mmol) and DMAP (11 mg, 0.090 mmol) were added to a stirring solution of 8-cyclohexyl-11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [ 3,2,1] oct-8-yl) carbonyl) -1,1a, 2,12b-tetrahydrocyclopropa [d] indolo [2,1 -a] [2] benzazepine-5-carboxylic (50 mg, 0.090 mmol) and 4,6-dimethylpyrimidine-2-sulfonamide (25.4 mg, 0.135 mmol) in C ^ Cl2 (1.5 ml) and the reaction mixture was stirred at rt for 16 h. The reaction was diluted with MeOH and purified by prep HPLC. (H2O-CH3CN with 10 mM NH4OAc buffer) to produce

8-cyclohexyl-N - ((4,6-dimethyl-2-pyrimidinyl) sulfonyl) -11-methoxy-1a - ((3-methyl-3,8-diazabicyclo [3,2,1] oct-8-yl ) carbonyl) -1,1a, 2, 12b-tetrahydrocyclopropa [d] indole [2,1-a] [2] benzazepine-5-carboxamide (24.3 mg, 0.032 mmol, 35.0% yield) as light yellow solid. LC-MS retention time 1.25 min; m / z 721 (MH-). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6 x 50 mm column, using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. Elution conditions employed a flow rate of 5 ml / min, a gradient from 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, at a gradient time of 2 min, a 1 min waiting time and 3 min analysis time, where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was H₂Or 5% / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

Compounds in the following procedures were analyzed using the following LC / MS procedure until indicated: Analysis conditions: Column: PHENOMENNEX-LUNA 3.0 x 50 mm S10; Mobile phase: (A) 10:90 methanol-water; (B) 90:10 methanol-water; Buffer: 0.1% TFA; Gradient range: 0-100% B; Gradient Time: 2 min; Flow rate: 4 ml / min; Analysis time: 3 min; Detection: Detector 1: UV at 220 nm; Detector 2: MS (ESI +).

General procedure for the preparation of acylsulfonamide derivatives. A mixture of acid (1 equiv.) And carbonyldiimidazole (1.5 equiv.) In anh. heated to 50 ° C for 30 min and allowed to cool to rt. Then, 1 equiv of sulfonamide (R = alkyl or aryl) and DBU (2 equiv) were added consecutively. The resulting mixture was stirred at rt overnight. After aqueous acid treatment, the isolated product was purified by prep HPLC. to provide acylsulfonamide derivatives.

<img file="ES2390732T3_D0124.tif" />

(+/-) - 8-cyclohexyl-N- (1-benzylcyclopropane-1-sulfonyl) -1,1a, 2,12b-tetrahydro-11-methoxo-1a- (3-methyl-3,8-diazabicyclo [3,2 , 1] octane-8-carbonyl) cycloprop [d] indolo [2,1-a] [2] benzazepine-5-carboxamide. The product was purified by prep HPLC. and was isolated as a TFA salt. LC-MS retention time: 3.365 min; MS m / z (M + H) 747. The product was found to exist as interconvertible rotamers. NMR¹H (400 MHz, CHLOROFORM-d) δ ppm 1.57 (25 H, m), 2.74 (4 H, m), 3.36 (3 H, m), 3.64 (1H, d, J = 15.11 Hz), 3.88 (3H, m), 4.41 (1H, bs), 5.16 (1H, m), 6.97 (1H, m), 7.11 ( 1H, m), 7.20 (6H, m), 7.30 (1H, m), 7.83 (2H, m).

ES 2 390 732 T3

<img file="ES2390732T3_D0125.tif" />

(+/-) - 8-cyclohexyl-N- (1- (pent-2-ynyl) cyclopropane-1-sulfonyl) -1,1a, 12b-tetrahydro-11-methoxy-1a- (3-methyl-3, 8-diazabicyclo [3,2,1] octane-8-carbonyl) cycloprop [d] indole [2,1-a] [2] benzazepine-5-carboxamide. The product was purified by prep HPLC. and was isolated as a TFA salt. LCMS retention time: 3.334 min; MS m / z (M + H) 723. The product was found to exist as interconvertible rotamers. NMR¹H (400 MHz, CHLOROFORM-d) δ ppm

3.62 (· H, d), 3.89 (3H, s), 4.46 (1H, m), 5.16 (1H, m), 6.98 (1H, dd, J = 8.56, 2.52 Hz), 7.11 (1 H, d, J = 2.52 Hz), 7.30 (1 1H d, J = 8.81 Hz), 7.55 (1H , m), 7.88 (1H, d, J = 8.31Hz), 8.03 (1H, s).

<img file="ES2390732T3_D0126.tif" />

(+/-) - 8-cyclohexyl-N- (1- (trimethylsilyl) cyclopropane-1-sulfonyl) -1,1a, 2,12b-tetrahydro-11-methoxy-1a- (3-methyl-3,810 diazabicoclo [3 , 2,1] octane-8-carbonyl) cycloprop [d] indolo [2,1-a] [2] benzazepine-5-carboxamide. The product was purified by prep HPLC. and was isolated as a TFA salt. LCMS retention time: 3.383 min; MS m / z (M + H) 729. The product was found to exist as interconvertible rotamers. NMR¹H (400 MHz, CHLOROFORM-d) δ ppm 0.15 (9 H, s), 1.09 (2 H, m), 1.41 (7 H, m), 1.80 (5 H, m) , 2.01 (7H, m), 2.49 (5H, m), 2.96 (2H, m), 3.61 (2H, d, J = 15.11 Hz), 3, 89 (3H, s), 4.48 (2H, m), 5.16 (1H, m), 6.98 (1H, dd, J = 8.44, 2.64 Hz), 7 , 11 (1H, d, J = 2.52Hz), 7.28 (1H, d, J = 8.81Hz), 7.49 (1H, m), 7.90 (1H, d, J = 8.31 Hz), 7.99 (1H, s).

<img file="ES2390732T3_D0127.tif" />

(+/-) - 8-cyclohexyl-N- (1-benzoylcyclopropane-1-sulfonyl) -1,1a, 2,12b-tetrahydro-11-methoxy-1a- (3-methyl-3,8-diazabicyclo [3,2 , 1] octane-8-carbonyl) cycloprop [d] indolo [2,1-a] [2] benzazepine-5-carboxamide. The product was purified by prep HPLC. and was isolated as a tFa salt. LC-MS retention time: 3.256 min; MS m / z (M + H) 761.

ES 2 390 732 T3

<img file="ES2390732T3_D0128.tif" />

(+/-) - 8-cyclohexyl-N- (2-cyanobenzenesulfonyl) -1,1a, 2,12b-tetrahydro-11-methoxy-1a- (3-methyl-3,8-diazabicyclo

[3,2,1] octane-8-carbonyl) cycloprop [d] indolo [2,1-a] [2] benzazepine-5-carboxamide. The product was purified by prep HPLC. and was isolated as a TFA salt. LCMS retention time: 3,320 min; eM m / z (M + H) 733.

<img file="ES2390732T3_D0129.tif" />

(+/-) - 8-cyclohexyl-N- (cyclobutylmethanesulfonyl) -1,1a, 2,12b-tetrahydro-11-methoxy-1a- (3-methyl-3,8-diazabicyclo

[3,2,1] octane-8-carbonyl) cycloprop [d] indolo [2,1-a] [2] benzazepine-5-carboxamide. The product was purified by prep HPLC. and was isolated as a TFA salt. LC-MS retention time: 3.263 min; MS m / z (M + H) 685. The product was found to exist as interconvertible rotamers. NMR¹H (400 MHz, CHLOROFORM-d) δ ppm 1.36 (5H, m), 1.99 (20H, m), 2.80 (5H, m), 3.64 (5H, m) , 3.90 (3H, s), 4.40 (2H, m), 5.23 (1H, m), 6.97 (1H, m), 7.12 (1H, d, J = 2.52 Hz), 7.27 (1H, m), 7.51 (1H, m), 7.90 (1H, m), 8.04 (1H, m).

<img file="ES2390732T3_D0130.tif" />

(+/-) - 8-cyclohexyl-N- (cyclopropylmethanesulfonyl) -1,1a, 2,12b-tetrahydro-11-methoxy-1a- (3-methyl-3,8-diazabicyclo

[3,2,1] octane-8-carbonyl) cycloprop [d] indolo [2,1-a] [2] benzazepine-5-carboxamide. The product was purified by prep HPLC. and was isolated as a TFA salt. LC-MS retention time: 3.170 min; MS m / z (M + H) .671. Compound 22m was found to exist as interconvertible rotamers. NMR¹H (400 MHz, CHLOROFORM-d) δ ppm 0.39 (2 H, m), 0.67 (2 H, m), 1.32 (6 H, m), 1.65-3.22 (18 H, m), 3.56 (5H, m), 3.89 (3H, s), 4.34 (2H, m), 5.20 (1H, m), 6.98 (1 H, m), 7.11 (1H, d, J = 2.27Hz), 7.30 (1H, m), 7.66 (1H, m), 7.90 (1H, m ), 8.10 (1H, m).

ES 2 390 732 T3

<img file="ES2390732T3_D0131.tif" />

(+/-) - 8-cyclohexyl-N- (2-methoxyethanesulfonyl) -1,1a, 2,12b-tetrahydro-11-methoxy-1a- (3-methyl-3,8-diazabicyclo [3,2,1 ] octane-8-carbonyl) cycloprop [d] indole [2,1-a] [2] benzazepine-5-carboxamide. The product was purified by prep HPLC. and was isolated as a TFa salt. LC-MS retention time: 3.070 min; MS m / z (M + H) 675. The compound was found to exist as interconvertible rotamers. NMR¹H (400 MHz, CHLOROFORM-d) δ ppm 1.58 (16H, m), 2.56 (2H, sa), 2.95 (3H, sa), 3.30 (3H, s) , 3.59 (3H, m), 3.85 (8H, m), 4.43 (2H, m), 5.18 (2H, bs), 6.97 (1H, m) , 7.11 (1H, d, J = 2.52Hz), 7.30 (1H, m), 7.53 (1H, m), 7.91 (1H, m), 8, 03 (1H, sa).

<img file="ES2390732T3_D0132.tif" />

(+/-) - 8-cyclohexyl-N- (phenylcarbamoyl) cyclopropylsulfonyl) -1,1a, 2,12b-tetrahydro-11-methoxy-1a- (3-methyl-3,810 diazabicyclo [3,2,1] octane- 8-carbonyl) cycloprop [d] indole [2,1-a] [2] benzazepine-5-carboxamide. The product was purified by

HPLC prep. and was isolated as a TFA salt. LCMS retention time: 3.303 min; MS m / z (M + H) 776.

<img file="ES2390732T3_D0133.tif" />

(+/-) - 8-cyclohexyl-N- (1-allylcyclopropane-1-sulfonyl) -1,1a, 2,12b-tetrahydro-11-methoxy-1a- (3-methyl-3,8-diazabicoclo

[3,2,1] octane-8-carbonyl) cycloprop [d] indolo [2,1-a] [2] benzazepine-5-carboxamide. The product was purified by prep HPLC.

and was isolated as a TFA salt. LC-E M retention time : 3.235 min; MS m / z (M + H) 697. The product was found to exist as interconvertible rotamers. NMR¹H (400 MHz, CHLOROFORM-d) δ ppm 1.26 (6H, m), 1.98 (17H, m), 2.70 (6H, m), 3.10 (3H, m) , 3.63 (1H, d, J = 15.11Hz), 3.89 (3H, s), 4.36 (2H, m), 5.11 (2H, m), 5, 73 (1H, m), 6.99 (1H, m), 7.11 (1H, d, J = 2.27Hz), 7.29 (1H, d, J = 8.56Hz ), 7.53 (1H, m), 7.89 (1H, m), 8.01 (1H, s).

ES 2 390 732 T3

<img file="ES2390732T3_D0134.tif" />

(+/-) - 8-cyclohexyl-N- (phenylmethanesulfonyl) -1,1a, 2,12b-tetrahydro-11-methoxy-1a- (3-methyl-3,8-diazabicyclo [3,2,1] octane -8-carbonyl) cycloprop [d] indole [2,1-a] [2] benzazepine-5-carboxamide. The product was purified by prep HPLC. and was isolated as a TFA salt. LCMS Procedure 1 (72007-001): LCMS Retention Time: 3.253 min;

MS m / z (M + H) 707. The product was found to exist as interconvertible rotamers. NMR¹H (400 MHz, CHLOROFORM- d) δ ppm 1.35 (6H, m), 1.96 (8H, m), 2.76 (12H, m), 3.32 (1H, sa) , 3.60 (1H, d, J = 15.11 Hz), 3.90 (3H, s), 4.21 (1H, m), 4.79 (1H, m), 4, 88 (1H, m), 5.10 (0H, m), 6.97 (1H, dd, J = 8.56, 2.52 Hz), 7.10 (1H, d, J = 2.52Hz), 7.32 (7H, m), 7.66 (1H, d, J = 8.06Hz), 7.92 (1H, d, J = 8.56Hz).

<img file="ES2390732T3_D0135.tif" />

(+/-) - 8-cyclohexyl-N - ((3,5-dichlorophenyl) methanesulfonyl) -1,1a, 2,12b-tetrahydro-11-methoxy-1a- (3-methyl-3,8diazabicyclo [3, 2,1] octane-8-carbonyl) cycloprop [d] indolo [2,1-a] [2] benzazepine-5-carboxamide. The product was purified by prep HPLC. and was isolated as a TFa salt. LC-MS retention time: 3.405 min; MS m / z (M + H) 775.

<img file="ES2390732T3_D0136.tif" />

(+/-) - 8-cyclohexyl-N - ((3-chlorophenyl) methanesulfonyl) -1,1a, 2,12b-tetrahydro-11-methoxy-1a- (3-methyl-3,8-diazabicyclo 15 [3 , 2,1] octane-8-carbonyl) cycloprop [d] indolo [2,1-a] [2] benzazepine-5-carboxamide. The product was purified by prep HPLC.

and was isolated as a TFA salt. LCMS retention time: 3.3301 min; Em m / z (M + H) 741.

ES 2 390 732 T3

<img file="ES2390732T3_D0137.tif" />

(+/-) - 8-cyclohexyl-N - ((methoxycarbonyl) (cyclopropylsulfonyl) -1,1a, 2,12b-tetrahydro-11-methoxy-1a- (3-methyl-3,8diazabicyclo [3,2,1 ] octane-8-carbonyl) cycloprop [d] indole [2,1-a] [2] benzazepine-5-carboxamide The product was purified by prep HPLC and isolated as a TEA salt Retention time LC-MS: 3.090 min, MS m / z (M + H) 715.

<img file="ES2390732T3_D0138.tif" />

8-cyclohexyl-N- (2-methoxyethanesulfonyl) -1,1a, 2,12b-tetrahydro-11-methoxy-1a- (3-methyl-3,8-diazabicyclo

[3,2,1] octane-8-carbonyl) cycloprop [d] indolo [2,1-a] [2] benzazepine-5-carboxamide. Step 1: To a solution of t-butyl ester-ethyl ester (0.4 g, 0.776 mmol) in THF (8 ml) was added 1N NaOH (3.10 ml, 3.10 mmol) and MeOH (~ 5 ml ) (2:20 PM). The white mixture was stirred at room temperature for 2 h, diluted with EtOAc, washed with brine, dried (MgSO4), and the solvent was removed in vacuo to provide acid-ester as a white solid ( 0.38 g, 100%). LC-MS retention time: 3.913 min; MS m / z (M + H) 502. Step 2: To a mixture of ester-acid (0.38 g, 0.758 mmol) and 3-methyl-3,8-diazabicyclo [3.2.1] octane (0.181 g, 0.909 mmol) in DCM (3 ml) were added TEA (0.5 ml, 3.59 mmol) and HBTU (0.345 g, 0.909 mmol). The mixture was stirred at room temperature for 2 h, diluted with EtOAc and washed with 1N NaOH and brine, dried (MgSO4), and purified by a Biotage 25M column to provide ester-amide as a foamy solid. white (0.398 g, 86%). CL-eM retention time: 3.493 min; MS m / z (M + H) 610, Step 3: Ester-amide (0.398 g, 0.653 mmol) was dissolved in DCM (2 mL) and TFA (2 mL, 26.0 mmol) was added in a cold bath with ice. The reaction mixture was stirred for 1.5 h at rt, the solvent was removed in vacuo to provide acid amide as a brown solid (0.36 g, 100%). LC-MS retention time: 3.186; eM m / z (M + H) 554, Step 4: Amide-amide was purified and isolated as the TFA salt. LCMS retention time: 3.078 min; MS m / z (M + H) 675, and was found to exist as interconvertible rotamers. NMR¹H (400 MHz, CHLOROFORM-d) δ ppm 1.28 (7 H, m), 2.15 (22 H, m), 3.28 (3 H, s), 3.47 (1 H, m) , 3.86 (3H, m), 4.06 (2H, bs), 5.24 (1H, m), 6.96 (1H, m), 7.11 (1H, d, J = 2.52 Hz), 7.29 (1H, m), 7.60 (1H, bs), 7.90 (1H, m), 8.10 (1H, m).

All samples for the following procedures were analyzed by CLEM Procedure 1 described below:

LCMS procedure 1:% Initial B: 0,% Final B: 100; Gradient time: 3 min; Stop time: 4 min; Flow rate: 4 ml / min; Wavelength: 220; Solvent A: 10% MeOH / 90% H2O / 0.1% Trifluoroacetic Acid; Solvent B: 10% H2O / 90% MeOH / 0.1% Trifluoroacetic Acid; Column: Xbridge 4.6 x 50mm S5.

ES 2 390 732 T3

<img file="ES2390732T3_D0139.tif" />

(+/-) - 8-cyclohexyl-N - [(2-fluorophenyl) methanesulfonyl] -1,1a, 2,12b-tetrahydro-11-methoxy-1a- (3-methyl-3,8-di-azabicoclo [ 3,2,1] octane-8-carbonyl) cycloprop [d] indole [2,1-a] [2] benzazepine-5-carboxamide (YT4)

Step 1: Preparation of acylsulfonamide YT2

To a solution of compound YT1 (60 mg, 0.105 mmol), (2-fluorophenyl) methanesulfonamide (39.6 mg, 0.209 mmol) and DMAP (55 mg, 0.450 mmol) in DCM (1 ml) was added eDcI (40 mg, 0.209 mmol). The mixture was stirred at rt for three days. The reaction mixture was purified by prep HPLC. and purified again by 12M Biotage (0-10% MeOH / DCM) to provide YT2 as a colorless crystal (66mg, 100%). LC-MS retention time: 3.55 min; MS m / z (M + H) 631.

Stage 2: Hydrolysis of methyl ester YT2 to acid YT3

To a solution of compound YT2 (66 mg, 0.102 mmol) in THF (3 ml) and MeOH (1 ml) was added NaOH (1 ml, 1,000 mmol). The mixture was stirred at room temperature for 2 h and then diluted with EtOAc, washed with cold HCl (1N) and brine, dried (MgSO4). Evaporation of the solvents in vacuo provided YT3 as a yellow solid (63 mg, 100%). LC-MS retention time: 3.501 min; MS m / z (M + H) 617.

Stage 3: Amide Coupling

To a mixture of compound YT3 (63 mg, 0.102 mmol) and 3-methyl-3,8-diazabicyclo [3.2.1] octane, 2HCl (20.34 mg, 0.102 mmol) in DCM (1.5 ml) TEA (0.05 ml, 0.359 mmol) and HBTU (54.2 mg, 0.143 mmol) were added. The mixture was stirred at room temperature for 2 h. The reaction was quenched with MeOH (1 ml), evaporated to dryness and the residue was dissolved in MeOH, filtered and purified by prep HPLC. to provide YT4 as a beige solid as the mono TFA salt (30.8 mg, 35.9%). NMR ¹H (400 MHz, CHLOROFORM-d) δ ppm 7.88 - 7.97 (1H, m), 7.63 (1H, sa), 7.34-7.45 (1H, m), 7 , 20-7.32 (4H, m), 7.05-7.18 (2H, m), 6.96 (1H, dd, J = 8.94, 2.64 Hz), 5, 14 (1H, d, J = 16.12 Hz), 4.95-5.04 (1H, m), 4.83-4.90 (1H, m), 3.88 (3H, s), 3.67-4.62 (2H, m), 3.63 (1H, d, J = 14.86Hz), 3.30-3.42 (1H, m), 2, 13-3.08 (10H, m), 1.62-2.16 (8H, m), 0.95-1.52 (6H, m). LC-MS retention time: 3.171 min; MS m / z (M + H) 725.

<img file="ES2390732T3_D0140.tif" />

(+/-) - 8-cyclohexyl-N- [1- (methoxycarbonyl) cyclopropanesulfonyl] -1,1a, 2,12b-tetrahydro-11-methoxy-1a- (3-methyl-3,8-diazabicyclo [3,2, 1] octane-8-carbonyl) cycloprop [d] indole [2,1-a] [2] benzazepine-5-carboxamide (YT6). To compound YT5 (240mg, 0.359mmol) and CDI (146mg, 0.899mmol) was added THF (1ml). The mixture was stirred at 50 ° C for 0.5 h and cooled. Methyl 1-sulfamoylcyclopropanecarboxylate (160mg, 0.893mmol) and DBU (0.217ml, 1.438mmol) were added. The mixture was stirred for 3 days and diluted with EtOAc, washed with sat. NaH2PO4. and brine, dried (MgSO4) and purified on a Biotage 25S column (MeOH / DCM: 0 to 25%) to provide YT6 as a white solid (160 mg, 27%). LC-MS retention time: 3.171 min; eM m / z (M + H) 725.