WO2012059568A1

WO2012059568A1 - Novel water-soluble indolobenzazepine molecules demonstrating antimitotic, antivascular, and antitumor activities in vivo

Info

Publication number: WO2012059568A1
Application number: PCT/EP2011/069385
Authority: WO
Inventors: Robert Dodd; Joanna Bakala; Jianmiao Liu; Jérôme BIGNON; Valérie PONS; Stéphane Beaumont
Original assignee: Centre National De La Recherche Scientifique (Cnrs)
Priority date: 2010-11-05
Filing date: 2011-11-04
Publication date: 2012-05-10
Also published as: FR2967159A1

Abstract

The present patent application relates to indolobenzazepine derivatives having an antitumor activity, to the synthesis thereof, and to the use thereof. In particular, the present patent application relates to the stereocontrolled synthesis of C5-substituted indolobenzazepinones enabling only one of the two possible C5 isomers to be obtained, as well as water-soluble analogs making it possible to demonstrate the very high effectiveness of said molecules in reducing the size of tumors in vivo.

Description

NEW INDOLOBENZAZEPINE MOLECULES

HYDROSOLUBLES DEMONSTRATING ANTIMITOTIC ACTIVITIES,

ANTIVASCULAR AND ANTITUMORAL IN VIVO

The subject of the present patent application relates to indolobenzazepine derivatives with anti-tumor activity.

In 25 years, the number of cancer cases in France has almost doubled, from 170,000 in 1980 to 320,000 in 2005 and representing the second leading cause of death after cardiovascular disease. Cancers correspond to the anarchic multiplication of certain cells of the organism that escape the normal mechanisms of differentiation and regulation of their multiplication. In addition, these cells are able to invade the surrounding normal tissue, destroying it, and then migrate remotely to form metastases. To treat various cancers, the means employed are constantly evolving. It is a first step to eliminate the tumor developed on the affected organ, but also and especially to limit its extension to other healthy organs. For this, the prescribed treatments are mainly surgery, radiotherapy, hormone therapy and chemotherapy, used alone or most often in combination. In the field of chemotherapy, the majority of anticancer molecules can be classified into different families according to their biological target. These include alkylating agents or electrophiles (which form covalent bonds with the nucleic acid, e.g., cisplatines and cyclophosphamide), antimetabolites ¹ (which inhibit synthesis of nucleic acids, e.g., methotrexate and 5-fluorouracil), poisons of topoisomerases I and II (which cause irreversible cleavage of DNA strands, for example, camptothecin, doxorubicin and epipodophyllotoxin), ² antihormonal drugs (which inhibit pro-cancer activity certain hormones, eg tamoxifen), ³ inhibitors of de-regulated cell signaling pathways (eg, Gleevec, tyrosine kinase inhibitor) ⁴ and spindle poisons (or antimitotic). ⁵ They have the ability to interact with tubulin, a protein that plays an essential role in many cellular mechanism. The polymerization of α and β tubulins is at the origin of the formation of microtubules, essential components of the cytoskeleton and which participate, inter alia, in cell division. Its properties are managed by the balance that exists between the polymerization and the depolymerization of these microtubules. Deregulation of this balance can have dramatic consequences for cell division. This is why a molecule with the ability to modify this dynamic proves to be potentially interesting in the treatment of cancers. Indeed, antimitotic compounds are generally classified into two major groups: inhibitors of tubulin assembly (colchicine 1 and vinca alkaloids such as vinblastine 2 and vincristine 3) and inhibitors of tubulin disassembly ( taxanes such as taxol 4 and taxotere 5, epothilones 6). ^{July 6} For the former, a sub-classification can be made depending on the site of action of molecules of tubulin. Thus, the compounds interacting with the colchicine site are distinguished from those interacting with the vinca alkaloid site.

Colchicine and its close analogues are not used clinically as anticancer agents due to excessive toxicity. ⁸ Other compounds binding to the same binding site as colchicine included stégnanes (e.g., (-) - steganacin 7), allocochinoids (e.g., N-acetylcolchinol (NAC, 8) and its phosphate form ZD 6126 (9), combretastatin A-4 (CA4, 10) and its phosphated analogue CA4P (11) and podophyllotoxin (12). ¹⁰ All these molecules have proven to be powerful tools in chemotherapy. However, they have significant drawbacks, including side effects associated with toxicity resulting from the lack of selectivity between healthy tissue and cancerous tissue, but also in terms of the resistance of certain tumors to different compounds.In addition, these products protect little against metastatic phenomena.

8: W-Acetylcolchinol (NAC): R = H

7: (-) - Steganicin 9: ZD 6126: R = P (= O) OH ₂

12: Podophyllotoxin

All these problems prompted researchers to move towards other strategies, one of them directly targeting the vascularization of tumors. Two main lines of research have been developed:

- The anti-angiogenic approach, aimed at the discovery of compounds that can generally prevent the formation of new vessels during growth and tumor development. Deprived of their nutritive supply, the tumor cells are asphyxiated and, without blood supply, they die. - the anti-vascular approach, the aim of which is to obtain products capable of causing the rapid and selective collapse of tumor vessels and a rapid decrease in tumor blood flow. Unlike anti-angiogenic agents that inhibit the birth of new vessels, anti-vascular agents (AAVs) target already established tumor vessels.

This second anti-vascular strategy against cancer is a recent concept designed to asphyxiate, wean and isolate the tumor so as to hinder its development by causing a rapid and complete destruction of tumor blood vessels. This strategy has many advantages over conventional therapies. So,

- the same blood vessel provides nutrients and oxygen and allows waste disposal of the metabolism of thousands of tumor cells; damaging one of these vessels can block the blood flow essential for tumor development and lead to the accumulation of toxic waste,

the endothelial cells (constituting the wall of the blood vessels) are adjacent to the blood flow, ensuring a good delivery of the active principle,

- a complete destruction of the endothelial cells is not obligatory, a change of morphology or a local initiation of coagulation are sufficient, - finally, these targets are normal diploid cells which are not likely to acquire genetic mutations thus a risk Treatment resistance acquisition is lower.

Morphological and functional changes in endothelial cells treated with anti-vascular products are associated with cytoskeletal remodeling: changes in cell shape, actin stress fiber formation, intercellular junction rupture, and increased permeability for macromolecules . The leakage of plasma proteins reduces the differential of oncotic pressure which is at least partially responsible for the reduction of the caliber of the vessels. Subsequently, various events related to the closure of the vascular network may contribute to anti-tumor effects: blood thickening, platelet activation, coagulation .... Some small molecules exploit the differences between normal and tumor vessels, allowing selective occlusion of the tumor vessels. These differences with healthy endothelial cells are notably at the level of permeability and rapid anarchic proliferation. They produce a characteristic effect of deep necrosis at the center of the tumor, which can extend to 95% of tumor cells. Among these small molecules, colchicine was the first to interact with tubulin whose anti-vascular activity has been described. As with many tubulin-binding agents such as vincristine and vinblastine, stopping of tumor vascularization is actually observed but at doses close to their maximum tolerated dose (MTD). ¹²

A second generation of small antimitotic molecules has since been developed, with the same anti-vascular effect but well below DMT. The two leaders of these agents are the phosphoric ester of N-acetylcolchinol (ZD6126), active at 1/30 of the DMT ^{13 14} and the disodium phosphate of the combretastatin A-4 (CA4P), active at 1/10 DMT. ¹⁵ The latter two molecules are in fact water soluble prodrugs respectively combretastatin A-4 and N-acetylcolchinol. Under the action of blood phosphatases, these prodrugs release their active principle. The activity and selectivity of these two compounds are the consequence of the architectural, cellular and biochemical differences that exist between tumor vessels and normal vessels. ¹⁶

The laboratory has recently described novel C5-alkylated indolobenzazepinones of general formula 13 demonstrating submicromolar cytotoxicity (IC ₅₀ ) in a variety of cancer cell strains. ¹⁷ For example, 5-ethyl compound 14 has an IC ₅₀ of 37 nM in the type of cancer cells KB (cervical carcinoma), a value comparable to that of colchicine (20 nM) and N-acetylcolchinol (75 nM) in the same cells. It has also been observed that these 5-alkylindolobenzazepinones inhibit the polymerization of tubulin and that this activity can be correlated with their cytotoxic effects. Thus, compound 14 inhibits the polymerization of tubulin with a IC ₅₀ of 1.8 μΜ similar to the activity of colchicine (IC ₅₀ = 2.2 μΜ).

The action of compound 14 on the development of glioblastoma, the most common and aggressive primary brain tumor, was evaluated using a embryonic embryo model. In fact, the growth of glioblastoma cells grafted onto the chorioallantoic membrane of the chicken embryo (CAM) reproduces the characteristics of the human disease. Local treatment of glioblastoma for 4 days with compound 14 (10 μl) showed a very pronounced arrest of tumor development. Thus, the volume of the tumor treated decreased by 76% while the volume of the so-called control tumor increased by 20%. In comparison, treatments with colchicine (10 μΜ) and NAC (100 μΜ) induce a reduction in tumor volume of only 50 and 42%, respectively.

Although these 5-alkylindolobenzazepinones have been found to be very active in these preliminary assays, their solubility in aqueous media is very low thus limiting their in vivo use as antitumor agents.

A second problem is that our synthetic method produces a racemic mixture at the level of C5 carbon, except in the case of 5-methyl and 5-ethyl derivatives since the corresponding aminobenzyl starting materials are commercially available in optically form pure. This allowed us to confirm, for example, that the (R) -5-methyl derivative is much less cytotoxic than its (S) -enantiomer (340 nM vs 80 nM, respectively).

13

5-alk

yl indolobenzazepinones

These two obstacles have been solved by the development, claimed in this patent application, of a stereocontrolled synthesis of C5 substituted indolobenzazepinones making it possible to obtain only one or the other of the two possible C 5 isomers as well as water-soluble analogues. to demonstrate the very high efficiency of these molecules to reduce in vivo the size of grafted tumors in mice.

Summary of the invention

The subject of the present invention relates to water-soluble indole derivatives corresponding to the general formula A):

(AT)

in which:

RI represents a hydroxyl group, phosphate, organophosphate, sulfate, organo sulfate, nitro, carboxylic acid, carboxylate, amino, ammonium, alkyl amine to C ₆ linear or branched, ammonium alkyl linear C ₆ or branched acid amine, a peptide chain of 2 to 10 amino acids, a group of formula (B) linked by the bond *:

(B)

in which : R6 R7 independently represents an alkyl to C ₆ linear or branched, or an alkyloxy group, to C ₆ linear or branched,

R7 is alkyl to C ₆ linear or branched, or an alkyloxy group, to C ₆ linear or branched,

R2 represents a hydrogen atom, an alkyl group at C _4,

R3 is alkyl to C ₄ alkenyl, C ₂ -C _4, an arylalkyl group to C ₆ substituted or unsubstituted heteroarylalkyl or to C ₆ substituted or unsubstituted,

R4 represents a hydrogen atom, halogen, hydroxyl, nitro, carboxylic acid, carboxylate, amino, ammonium, alkyl amine to C ₆ linear or branched, alkyl ammonium to C ₆ linear or branched alkoxy in linear or branched Ci-C ₆ , an amino acid,

R5 represents a hydrogen atom, halogen, hydroxyl, nitro, carboxylic acid, carboxylate, amino, ammonium, alkyl amine to C ₆ linear or branched, alkyl ammonium to C ₆ linear or branched alkoxy in linear or branched Ci-C ₆ , an amino acid,

in all proportions of one and / or the other of the enantiomers, in particular as a racemic mixture, as an enriched mixture of the S or R enantiomer, as only the S enantiomer or only R enantiomer, or optionally a salt thereof.

Another subject of the present invention relates to a process for obtaining salts of compound (A) described above, characterized in that the compound of formula

in which: RI represents a hydroxyl group,

R2 represents a hydrogen atom, a C1-C4 alkyl group,

R3 is alkyl to C ₄ alkenyl, C ₂ -C _4, an arylalkyl group to C ₆ substituted or unsubstituted,

R4 represents a hydrogen atom, halogen, hydroxyl, nitro, carboxylic acid, carboxylate, amino, ammonium, alkyl amine to C ₆ linear or branched, alkyl ammonium to C ₆ linear or branched alkoxy in

Ci to C ₆ linear or branched, an amino acid,

R5 represents a hydrogen atom, halogen, hydroxyl, nitro, carboxylic acid, carboxylate, amino, ammonium, alkyl amine to C ₆ linear or branched, alkyl ammonium to C ₆ linear or branched alkoxy in

Ci to C ₆ linear or branched, an amino acid,

in all proportions of one and / or the other of the enantiomers, in particular as a racemic mixture, as an enriched mixture of the S or R enantiomer, as only the S enantiomer or only R enantiomer is subjected to 3 successive steps of:

1 - reaction phosphitylation or sulfonation of the RI group,

Optionally, hydrolysis of the organophosphate formed in phosphate or of the sulfate organosulfate,

3 - salt formation.

Another object of the present invention is a compound (A) described above for use as a medicament. Another object of the present invention is a compound (A) described above for use as an anticancer agent.

Another object of the present invention is a compound (A) described above for use in targeting the tumor vasculature.

Another object of the present invention is an injectable composition comprising a compound (A) described above. Definitions

C₁-C _n alkyl

In the present invention, the term "C₁-C _n" wherein n is a positive integer, comprises linear or branched saturated hydrocarbon moieties having from one to n carbon atoms. Thus, by "C ₁ -C ₆ alkyl group" is meant a linear or branched, saturated hydrocarbon-based chain containing from 1 to 6 carbon atoms, for example a methyl, ethyl, isopropyl, tert-butyl or pentyl group, etc.

"TBu" refers to tert-butyl.

aryl

By "aryl" group is meant an aromatic group, preferably comprising from 5 to 10 carbon atoms, comprising one or more rings, for example a phenyl, naphthalene group, etc.

heteroaryl

By "heteroaryl" group is meant an aromatic group, preferably containing from 4 to 10 carbon atoms, comprising one or more rings and comprising one or more heteroatoms, in particular oxygen, nitrogen or sulfur, as for example a furan, indole or pyridine group.

C 1 -C 6 arylalkyl

By "C ₁ -C ₆ arylalkyl" group is meant in the sense of the present invention, an aryl group, as defined above, linked to the molecule through a C ₁ -C ₆ alkyl group. By way of example, mention may be made of benzyl, phenylethyl or phenylpropyl groups. C 1 -C 6 heteroarylalkyl

For the purpose of the present invention, the term "heteroaryl-C ₁ -C ₆ alkyl group" means a heteroaryl group as defined above, linked to the molecule by via an alkyl to C _6. By way of example, mention may be made of indol-methyl or else pyridin-ethyl.

Alkyloxy group in linear or branched Ce

By "linear or branched C ₁ -C ₆ alkyloxy" group is meant, in the sense of the present invention, a linear or branched C ₁ -C ₆ alkyl group, as defined above, linked to the molecule by the intermediate of an oxygen atom. By way of example, mention may be made of methoxy, ethoxy, propoxy, isopropoxy, butoxy or even tert-butoxy groups.

Alkenyl group in C? at C ₄

By "C ₂ -C ₄ alkenyl" group is meant in the sense of the present invention, a linear or branched, mono- or poly-unsaturated aliphatic group comprising from 2 to 4 carbon atoms. An alkenyl group according to the invention preferably comprises 1 or 2 ethylenic unsaturations. By way of example, mention may be made of ethylene, propylene, propyl-2-ene or propyl-3-ene, butylene, etc. groups.

Linear or branched alkyl amine group.

Amine alkyl to C ₆ linear or branched, it is within the scope of the present invention an amine substituted by at least one alkyl group to C ₆ linear or branched.

Alkyl ammonium group in linear or branched Ce.

By linear or branched C ₁ -C ₆ alkylamino group, it is within the scope of the present invention an ammonium substituted with at least one linear or branched C ₁ -C ₆ alkyl group.

peptide

The term "peptide" should be understood as a polymer of amino acids linked together by a peptide bond (also called amide). A peptide generally contains between 2 and 80 to 100 amino acids, the upper limit not being clearly defined. In the context of the present invention, the peptides contain between 2 and 10 amino acids.

Natural amino acids

The term "natural amino acid" represents, inter alia, the following amino acids: glycine (Gly), alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), serine (Ser) threonine (Thr), phenylalanine (Phe), tyrosine (Tyr), tryptophan (Trp), cysteine (Cys), methionine (Met), proline (Pro), hydroxyproline (Hpr), aspartic acid (Asp), asparagine (Asn), glutamine (Gin), glutamic acid (Glu), histidine (His), arginine (Arg), ornithine, and lysine (Lys). The functional groups of the side chain of each amino acid may be protected by one or more protective groups or not.

Side chain of an amino acid

The term "side chain of an amino acid" represents the moiety carried by the α-carbon of an amino acid. For example, side chains of naturally occurring amino acids such as glycine, valine, alanine and aspartic acid correspond to hydrogen, isopropyl, methyl and CH ₂ COOH respectively.

The side chains of other amino acids may be included in the definition, such as those of the following amino acids: 4-amino-tetrahydropyran-4-carboxylic acid, allylglycine, diamino-butyric acid, diamino-propionic acid, aminoserine, aminobutyric acid, amino-butylglycine phenylglycine, 4-chloro-phenylalanine, 4-nitrophenylalanine, citrulline, cyclohexylalanine, thienylalanine, and the like. The side chains of the amino acids may be protected by protecting groups (P) and more particularly N-protecting, O-protecting or S-protecting groups when these chains contain the corresponding heteroatoms. Advantageously in the context of the present invention, the side chains of the amino acids or peptides are not protected. The protection of some of the reactive functions of the peptides is mandatory during the synthesis of said peptides. In fact, peptide synthesis is conventionally done by activating the carboxylic acid function of an amino acid, or an amino acid chain, by the use of a coupling agent. This activated acid is placed in the presence of an amino acid, or a amino acid chain, whose terminal amine is not protected, thus resulting in the formation of an amide bond, also called peptide bond. The coupling conditions as well as the coupling agents used are very well known to those skilled in the art.

Protecting groups (P) are also groups known to those skilled in the art. These protective groups and their use are described in books such as, for example Greene, "Protective Groups in Organic Synthesis", Wiley, New York, 2007 ^4th edition; Harrison et al. "Compendium of Synthetic Organic Methods", Vol. 1-8 (J. Wiley & sons, 1971 to 1996); Paul Lloyd-Williams, Fernando Albericio, Ernest Giralt, "Chemical Approaches to the Synthesis of Peptides and Proteins", CRC Press, 1997 or Houben-Weyl, "Methods of Organic Chemistry, Synthesis of Peptides and Peptidomimetics", Vol E 22a, Vol. E 22b, Vol E 22c, Vol E 22d., M. Goodmann Ed., Georg Thieme Verlag, 2002. Depending on whether the protective groups are borne by a nitrogen atom, they will be designated as N-protective groups. It is the same for groups S -protecteurs, O-protectors, etc. For example, a hydroxy may be protected with a trityl group, or a carboxylic acid may be protected as a tert-butyl ester. In the case of a solid support synthesis, it is the resin which serves as a protective group for the C-terminal carboxylic function. Protection of the amino group of the amino acid may be effected for example by a tert-butyloxycarbonyl group (hereinafter referred to as Boc-) or a fluorenylmethyloxycarbonyl group (hereinafter referred to as Fmoc) represented by the formula:

The protection is performed according to the known methods of the prior art. For example, protection by the Boc-group can be obtained by reacting the amino acid with di-tert-butylpyrocarbonate (Boc ₂ 0).

detailed description An object of the present invention relates to water-soluble indole derivatives of the general formula (A):

in which:

RI represents a hydroxyl group, phosphate, organophosphate, sulfate, organo sulfate, nitro, carboxylic acid, carboxylate, amine, ammonium, alkyl amine to C ₆ linear or branched, ammonium alkyl linear C ₆ or branched acid amine, a peptide chain of 2 to 10 amino acids, a group of formula (B) linked by the bond *:

(B)

in which :

R6 R7 independently represents an alkyl to C ₆ linear or branched, or an alkyloxy group, to C ₆ linear or branched,

R5 is alkyl to C ₆ linear or branched, or an alkyloxy group, to C ₆ linear or branched,

R2 represents a hydrogen atom, an alkyl group at C _4,

R3 is alkyl to C ₄ alkenyl, C ₂ -C _4, an arylalkyl group to C ₆ substituted or unsubstituted heteroaryl or

To C ₆ substituted or unsubstituted,

R4 represents a hydrogen atom, halogen, hydroxyl, nitro, carboxylic acid, carboxylate, amine, ammonium, alkyl amine to C ₆ linear or branched, alkyl ammonium to C ₆ linear or branched alkoxy in

Ci to C ₆ linear or branched, an amino acid, R5 represents a hydrogen atom, halogen, hydroxyl, nitro, carboxylic acid, carboxylate, amino, ammonium, alkyl amine to C ₆ linear or branched, alkyl ammonium to C ₆ linear or branched alkoxy in linear or branched Ci-C ₆ , an amino acid,

in all proportions of one and / or the other of the enantiomers, in particular as a racemic mixture, as an enriched mixture of the S or R enantiomer, as only the S enantiomer or only R enantiomer, or optionally a salt thereof. An object of the present invention relates to a compound (A) as defined above, characterized in that RI represents a hydroxyl, phosphate, organophosphate, sulfate, organo sulfate, amine, ammonium, linear C ₁ -C ₆ alkyl amine group. or branched alkyl ammonium to C ₆ linear or branched, an amino acid. An object of the present invention relates to a compound (A) as defined above, characterized in that RI represents a hydroxyl group, phosphate, organophosphate, sulfate, organo sulfate, ammonium, an amino acid.

An object of the present invention relates to a compound (A) as defined above, characterized in that RI represents a hydroxyl group, phosphate, organophosphate, sulfate, organo sulfate.

An object of the present invention relates to a compound (A) as defined above, characterized in that RI represents a hydroxyl group.

An object of the present invention relates to a compound (A) as defined above, characterized in that RI represents a phosphate group.

An object of the present invention relates to a compound (A) as defined above, characterized in that RI represents an organophosphate group. An object of the present invention relates to a compound (A) as defined above, characterized in that RI represents a sulfate group.

An object of the present invention relates to a compound (A) as defined above, characterized in that RI represents an organo sulfate group.

An object of the present invention relates to a compound (A) as defined above, characterized in that:

RI is a phosphate or organophosphate group of formula (D) or a sulphate or organosulfate group of formula (E) linked by the bond *:

0

I 0

- 0-P = 0 _* I l

I - O-S-O-R10

0 ^ I l

R9 0

(D) (E)

wherein,

R8 and R9 independently of one another are hydrogen, alkyl to C ₆ linear or branched, an alkenyl group

C ₂ to C ₆ , a potassium ion, a sodium ion or a cesium ion;

RIO represents a hydrogen atom, alkyl to C ₆ linear or branched, an alkenyl group, C ₂ -C _6, a potassium ion or a sodium ion.

Advantageously, R1 is a phosphate group of formula (D) described above.

More preferably, R 1 is a phosphate group of formula (D) described above in which R 8 and / or R 9 represent, independently of one another, a linear or branched C ₁ -C ₆ alkyl group, such as methyl or ethyl isopropyl, tert-butyl, pentyl, preferably tert-butyl.

More preferably, R 1 is a phosphate group of formula (D) described above in which R 8 and / or R 9 independently of one another represent a hydrogen atom. More preferably, R 1 is a phosphate group of formula (D) described above in which R 8 and / or R 9 represent, independently of one another, a sodium ion.

Advantageously, RI is a sulfate group of formula (E) described above. More preferably, R 1 is a sulphate group of formula (E) described above in which R 10 represents a linear or branched C ₁ -C ₆ alkyl group, such as methyl, ethyl, isopropyl, tert-butyl or pentyl, preferably tertiary. butyl.

More preferably, R1 is a sulphate group of formula (E) described above wherein R10 represents a hydrogen atom.

More preferably, R1 is a sulfate group of formula (E) described above wherein R10 is a sodium ion.

Advantageously, the group R2 represents a hydrogen group.

Advantageously, the group R 3 represents a linear or branched C ₁ -C ₄ alkyl group or a substituted or unsubstituted C ₁ -C ₆ arylalkyl group.

Advantageously, the group R 3 represents a linear or branched C ₁ -C ₄ alkyl group.

Advantageously, the group R 3 represents a C ₂ alkenyl group at

C ₄ .

Advantageously, the group R 3 represents an ethylene group.

Advantageously, the group R 3 represents a propyl-2-ene group.

Advantageously, the R 3 group represents an arylalkyl group to C ₆ substituted or unsubstituted.

Advantageously, the group R 3 represents a benzyl group.

Advantageously, the group R4 represents a hydrogen atom.

Advantageously, the group R4 represents a halogen atom.

Advantageously, the group R4 represents a hydroxyl group. Advantageously, the R4 group is an alkoxy group to C ₆ linear or branched.

Advantageously, the group R4 represents a methoxy group. Advantageously, the group R5 represents a hydrogen atom.

Advantageously, the group R5 represents a halogen atom.

Advantageously, the group R5 represents a hydroxyl group.

Advantageously, the group R5 represents an alkoxy group to C ₆ linear or branched.

Advantageously, the group R5 represents a methoxy group.

An object of the present invention relates to a compound (A), characterized in that:

R 1 represents a phosphate group (D) in which R 8 and R 9 are sodium ions,

R2 represents a hydrogen atom,

- R3 is alkyl to C ₄ linear or branched;

R4 represents a hydrogen atom,

R5 represents a hydrogen atom,

Advantageously, the group R 3 represents a methyl, ethyl, isopropyl, tert-butyl or pentyl group, preferably tert-butyl.

- RI represents a hydroxyl group,

R2 represents a hydrogen atom,

- R3 is alkyl to C ₄ linear or branched;

R4 represents a hydrogen atom,

R5 represents a hydrogen atom,

Advantageously, the group R 3 represents a methyl, ethyl, isopropyl, tert-butyl or pentyl group, preferably tert-butyl. An object of the present invention relates to a compound (A), characterized in that the carbon (5) is of configuration R only, named "compound (A-5-R)". Another object of the present invention relates to a compound (A), characterized in that the carbon (5) is of S configuration only, named "compound (A-5-S)".

Yet another object of the present invention is a mixture in all proportions of the compound (A-5-R) with the compound (A-5-S).

In the context of the present application "mixture in all proportions of the compound (A-5-R) with the compound (A-5-S)" means a mixture of enantiomers of the compound (A-5-R) and the compound (A-5-S), wherein the mass ratio between the compound (A-5-R) and the compound (A-5-S) is 1: 1, i.e., racemic.

The mass ratio between the compound (A-5-S) and the compound (A-5-R), that is to say

"(A-5-R): (A-5-S)", may be greater than or equal to 55:45, more preferably greater than or equal to 60:40, still more preferably greater than or equal to 70:30, still more preferably greater than or equal to 80:20, still more preferably greater than or equal to 90:10, still more preferably greater than or equal to 95: 5, still more preferably greater than or equal to 98: 2, still more preferably greater than or equal to 99: 1, still more preferably greater than or equal to 99.5: 0.5, still more preferably 100: 0.

The mass ratio between the compound (A-5-R) and the compound (A-5-S), that is to say "(A-5-R): (A-5-S)", can be greater than or equal to 55:45, more preferably greater than or equal to 60:40, still more preferably greater than or equal to 70:30, still more preferably greater than or equal to 80:20, still more preferably greater than or equal to 90: 10, still more preferably greater than or equal to 95: 5, still more preferably greater than or equal to 98: 2, still more preferably greater than or equal to 99: 1, still more preferably greater than or equal to 99.5: 0.5, still more preferably equal at 100: 0.

R 1 represents a phosphate group (D) in which R 8 and R 9 are sodium ions,

R2 represents a hydrogen atom,

- R3 is alkyl to C ₄ linear or branched;

R4 represents a hydrogen atom, R5 represents a hydrogen atom,

the carbon (5) is of configuration R only.

- RI represents a hydroxyl group,

R2 represents a hydrogen atom,

- R3 is alkyl to C ₄ linear or branched;

R4 represents a hydrogen atom,

R5 represents a hydrogen atom,

the carbon (5) is of configuration R only.

R2 represents a hydrogen atom;

and the carbon (5) is of configuration R only.

- R3 represents a benzyl group;

and the carbon (5) is of configuration R only.

An object of the present invention relates to a compound (A) characterized in that:

R 3 represents an ethylene, or a propyl-2-ene,

and the carbon (5) is of configuration R only.

Advantageously, the group R 3 represents an ethylene group when the carbon (5) is of configuration R only.

Advantageously, the group R 3 represents a propyl-2-ene group when the carbon (5) is of configuration R only.

An object of the present invention relates to a compound (A) characterized in that - R4 represents a hydrogen atom, halogen, hydroxyl, nitro, carboxylic acid, carboxylate, amino, ammonium, alkoxy C ₆ linear or branched,

and the carbon (5) is of configuration R only.

Advantageously, the group R4 represents a hydrogen atom when the carbon (5) is of configuration R only.

Advantageously, the group R4 represents a halogen atom when the carbon (5) is of configuration R only.

Advantageously, the group R4 represents a hydroxyl group when the carbon (5) is of configuration R only.

Advantageously, the R4 group is an alkoxy group to C ₆ linear or branched when carbon (5) is of R configuration only.

Advantageously, the group R4 represents a methoxy group when the carbon (5) is of configuration R only.

R 5 represents a hydrogen atom, a halogen atom, a hydroxyl, nitro, carboxylic acid, carboxylate, amine, ammonium or linear or branched C ₁ -C ₆ alkoxy group;

and the carbon (5) is of configuration R only.

Advantageously, the group R5 represents a hydrogen atom when the carbon (5) is of configuration R only.

Advantageously, the group R5 represents a halogen atom when the carbon (5) is of configuration R only.

Advantageously, the group R5 represents a hydroxyl group when the carbon (5) is of configuration R only.

Advantageously, the group R5 represents an alkoxy group to C ₆ linear or branched when carbon (5) is of R configuration only.

Advantageously, the group R5 represents a methoxy group when the carbon (5) is of configuration R only.

An object of the present invention relates to a method, characterized in that: step 1 is made from phosphoramidite, optionally followed by oxidation.

In the context of the present invention, a phosphoramidite is a molecule of formula (F) below:

R1 1 0-R14

N-P

R12 0-R13

(F)

wherein RI 1, RI 2, RI 3, RI 4 independently of each other hydrogen, alkyl to C ₆ linear or branched, an alkenyl group of C ₂ to C _6, an aryl -C ₁ -C ₄ alkyl, substituted or unsubstituted aryl, mono- or polycyclic group, or substituted or unsubstituted mono- or polycyclic (C ₃ -C ₇ ) cycloalkyl, R 11 and R 12 may form with the nitrogen atom which they are attached a ring alkyl-amine to C ₆ substituted or not, or an alkenyl-amine cycle C ₂ -C ₆ substituted or unsubstituted and R13 and R14 may form with the oxygen atoms and the phosphorus carries a cycle.

Without being over-exemplified, the phosphoramidites that can be used in the context of the present invention are well known to the synthetic chemist.

By oxidation, the synthetic chemist understands that the use of any known oxidizing agent such as KMnO ₄ , O ₃ , O ₂ , IBX, mCPBA, hyperacids, Swern reagents, oxygenated water, electrolysis process. oxidation reduction, etc.

An object of the present invention relates to a method, characterized in that:

step 2 is carried out in an acidic condition, preferably with TFA.

By acidic conditions, those skilled in the art include any mineral or organic acid in the gaseous or liquid state, pure or in solution in an organic or inorganic solvent. The usable acids can be HCl, H ₂ SO ₄ , H ₃ PO ₄ , carboxylic acid, hyperacid, TFA, IFF, FIBr, and any other known acid.

An object of the present invention relates to a method, characterized in that: Step 3 salt formation is with a resin exchange preferably DOWEX® Na type. The principle of ion exchangers consists of exchanging the central cation of one complex to form another, the stability of which depends on the operating conditions (concentration, atomic number of the element). Ion exchange resins, like zeolite, are often synthetic. A polymer is modified in such a way that ionic groups are present on its chains. If the resin is cation exchange, the polymer attracts the positive ions by the presence of negatively charged groups. There are also electrolytic ion exchange processes employing semipermeable membranes that could be used in the context of the present invention.

An object of the present invention is an injectable composition further comprising a pharmaceutical carrier.

The pharmaceutical compositions according to the invention may be formulated in conventional ways well known to those skilled in the art using one or more physiologically acceptable carriers comprising excipients, adjuvants and auxiliaries such as, for example, preservatives of stabilizers of wetting or emulsification. The chosen formulation method depends on the desired route of administration.

In the case of administration by injection, for example subcutaneous, intradermal, intramuscular, intraocular, or intra-articular, an aqueous solution is advantageously used, in particular a physiologically acceptable buffer solution, such as a solution of Hank, a Ringer's solution or physiological saline buffer solution. In the case of transdermal or mucosal administration, penetrants suitable for the mucosa to be traversed are advantageously used. Such penetrants are well known to those skilled in the art.

The term "pharmaceutical vehicle" is understood to mean a composition whose function is to transport at least one active agent according to the present invention to a site of interest, controlling the rate of access, the release, of the active agent by sequestration or other means, and facilitating the administration of said active ingredient (s). Other features, objects and advantages of the invention will emerge from the examples which follow. In addition, the numbering of the molecules presented is specific to the examples and independent of the rest of the description above. The invention is not limited to the particular examples mentioned for illustrative purposes only and which must be read with reference to the following figures:

Legends of the Figures Figure 1: Effect of a racemic mixture of compounds (R) and (S) on the morphology of HUVEC cells.

Figure 2: Inhibitory effect of a racemic mixture of compounds (R) and (S) on the in vitro formation of vascular tubes on Matrigel.

Figure 3: Anti-vascular effect of compound 28 (R) on a human glioblastoma grafted on the chorioallantoic membrane of the chicken embryo (CAM).

Figure 4: Images of histological sections of 28 (R) -treated glioblastoma demonstrating haemorrhages produced by the anti-vascular effect of the test compound. Figure 5: Inhibition of the growth of subcutaneous grafted ETM6 breast tumors in mice after 4 days of treatment with compound 28 (R).

Examples

Examples 1 and 2 show reaction sequences to obtain molecules covered by the present application.

Example 3 relates to the technical characteristics of the equipment used and certain so-called general procedures which have been used in the context of the present invention.

Examples 4 to 38 are protocols and product characterizations obtained in the context of the present invention. In Examples 4 to 38, when reference is made to a general procedure, such as the protection of indoles, for example, reference should be made to Example 3.

Examples 39 to 43 relate to in vitro or in vivo biological tests carried out in the context of the present invention.

Example 44 relates to docking tests done in silico. Example 1: General scheme of enantioselective synthesis of indolobenzazepinones according to the present invention.

Diagram 1: synthesis of a starting material 17

15 16 17

Scheme 2: synthesis of indolobenzazepinones according to the present invention

17 (1 equiv) 18 (2 equiv) 19

20 (S) 21 (SR)

Example 2: General scheme of the synthesis of a water-soluble indolobenzazepinone derivative

25 (R) 26 (R)

Example 3: General procedures and technical characteristics

instruments

Melting points (m.p.) were measured in capillary tubes on a Biichi B-540 device and are uncorrected. Even if the compounds have not crystallized, the melting points have nonetheless been measured, that is to say when the compound in question is solid.

Infrared spectra (I.R.) were recorded on a Perkin Elmer Spectrum BX FT-IR spectrometer.

- The proton (1H) and carbon ( ¹³ C) NMR spectra were recorded on Bruker spectrometers: 300 MHz advance (QNP-C13, P31, F19 probe or dual C13 probe) and 500 MHz Avance (ΒΒ0 probe - ATM or BBI-ATM probe). Carbon NMR ( ¹³ C) spectra were recorded at 125 or 75 MHz, using a broadband decoupled, the multiplicities having been obtained by means of a JMOD or DEPT sequence. NMR experiments were carried out in deuterated chloroform (CDCl ₃ ), (d) methanol (CD ₃ OD) and dimethyl sulfoxide (DMSO). The chemical offsets (δ) are reported in parts per million (ppm) by reference to CDCl 3 (1H: 7.26, ¹³ C: 77.00), CD ₃ OD (1H: 3.31, ¹³ C: 49, 00) and DMSO-D ₆ (1H: 2.50, ¹³ C: 39.50). For the spectral multiplicities of the proton, the following abbreviations are used: s: singlet, d: doublet, t: triplet, q: quartuplet, m: multiplet, br: large. The coupling constants (J) are reported in Hertz (Hz). Values in italics refer to the minor diastereomer / atropoisomer, if applicable.

- Mass spectra (MS) were obtained either with an LCT instrument (Micromass) using electrospray ionization (ES), or from a flight time analyzer (ESI-MS) for high mass spectra resolution (HRMS).

- Elemental analyzes (Anal.) Were performed on a Perkin Elmer CHN 2400 analyzer with catharometry detection.

chromatography

Thin layer chromatography was carried out on silica gel 60 F254 aluminum plates (Merck) and visualized under a UVP Mineralight UVLS-28 lamp (254 nm) with ninhydrin and acid. phosphomolybdic in ethanol.

Flash chromatography was performed on Merck silica gel 60 (40-63 μιη) under average pressure (300 mbar) or on CombiFlash (Serlabo Technologies).

Solvents and reagents

All reagents were obtained from commercial suppliers such as 2-formylphenylboronic acid, unless otherwise indicated. Where necessary, the organic solvents were dried and / or distilled in a customary manner before use, and stored on argon sieves.

The organic extracts were dried over (MgSO ₄ ).

General procedure for iodization of indoles

80.2 mmol (3.8 eq) of potassium hydroxide are added portionwise to solution of 21.1 mmol (1 eq) of indole-2-carboxylic acid ethyl ester in 12 ml of DMF. The reaction mixture was stirred at room temperature for 15 minutes and a solution of 21.1 mmol (1 eq) iodine in 12 ml of DMF was added. This mixture is stirred at room temperature for a further 45 minutes and poured into a mixture of 8 ml of 25% aqueous NaHSO _{3 solution} , 16 ml of 33% aqueous H ₄ OH solution and 320 ml of water. 'water. The precipitate is filtered and dried in vacuo to give a solid which is dissolved in 60 ml of EtOH and concentrated in vacuo to give the desired product. Typical procedure for the protection of indoles

A solution of 6.3 mmol (1 eq) of unprotected iodide in 30 ml of TFIF at 0 ° C was added to a suspension of 9.5 mmol (1.5 eq. the oil) of sodium hydride in 30 ml of dry TFIF under Ar. The reaction mixture is stirred for 45 minutes and 12.6 mmol (2 eq) of phenylsulfonyl chloride are added. The reaction mixture is warmed to room temperature and stirred overnight. The solvent is removed in vacuo and the residue is dissolved in 50 ml of CH ₂ Cl ₂ and then washed with 10 ml of water. The aqueous phase is extracted in 3 × 20 ml of CH ₂ Cl ₂ . The combined organic extracts are washed with 20 ml of water and 2 x 10 ml of a 1M aqueous solution of NaHCO ₃ , dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting solid is purified by flash column chromatography on silica gel (heptane / CH ₂ Cl ₂ , 2/1) to give the desired sulfonamide.

General procedure for Suzuki-Miyaura cross coupling

To a solution of 13.3 mmol (2 eq) of 2-formylphenylboronic acid in 64 ml of dry degassed dioxane was added 26.7 mmol (4 eq) of previously melted CsF under vacuum. In a second round-bottomed flask, 6.67 mmol (1 eq) of ethyl iodoindole-2-carboxylate, 0.2 mmol of Pd (OAc) ₂ and 0.3 mmol of toluene are introduced under argon. dppf in 128 ml of dry dioxane. This second reaction mixture is stirred at room temperature for 30 minutes and then added by cannula to the solution containing boronic acid. The solution is heated to 80 ° C until complete conversion of the starting material. After cooling, the resulting mixture was filtered through Celite and washed with CH ₂ Cl ₂ . The solvent is removed in vacuo and the residue in 200 ml of CH ₂ Cl ₂ and then washed with 100 ml of water. The aqueous phase is extracted with 3 x 100 ml of CH ₂ Cl ₂ . The combined organic extracts are washed with 100 ml of water, dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting crude product is purified by flash chromatography on silica gel (heptane / AcOEt 95/5 to 75/25) to give the desired compounds as a mixture of atropoisomers.

General procedure for the preparation of tert-butylsulfinimines

To the solution of 5.56 mmol (1 eq) of (-2-methyl-2-propanesulphinamide and 11.12 mmol (2 eq. ) Ti (OEt) ₄ in 14 ml of CH ₂ Cl _2. the mixture was stirred at room temperature for 2 days. the solution was diluted with water, diluted with AcOEt and filtered The aqueous phase is extracted with 4 x 100 ml of AcOEt and the organic phases are washed with 3 x 100 ml of water, dried over MgSO ₄ , filtered and concentrated in vacuo. resulting crude product by flash chromatography on silica gel (heptane / AcOEt 9/1 to 8/2) to give the desired product as a mixture of atropoisomers.

General procedure for the addition of Grignard reagents to tert-butylsulfinimines

To a solution of 9.42 mmol (1 eq) of the sulfonimine in 45 ml of CH ₂ Cl ₂ is added 28.3 ml (28.3 mmol, 3 eq) of a magnesium halide solution. at -50 ° C. The mixture is stirred at -50 ° C for 2 hours and then allowed to warm to room temperature. The reaction mixture is diluted with 20 ml of saturated H ₄ Cl solution, the aqueous phase is extracted with 3 x 100 ml of AcOEt and the organic phases are washed with 2 × 100 ml of water and dried over MgSO 4. ₄ , filtered and concentrated in vacuo. The resulting crude product is purified by flash chromatography on silica gel (heptane / AcOEt 9/1 to 1/1) to give the desired product as a mixture of 2 atropoisomers. General procedure for the deprotection of tert-butylsulfinimines

9.42 mmol (1 eq) of tert-butylsulfinimine are diluted in 128 ml of MeOH, 31.4 ml of 6N HCl are added and the mixture is stirred for 3 hours at room temperature. room. Then a solution of 6 M NaOH is added until the pH of the mixture is 7. The aqueous phase is extracted with 3 x 100 ml of AcOEt and the organic phases are washed with 50 ml of water. dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting crude product is purified by flash chromatography on silica gel (CH ₂ Cl ₂ / MeOH 10/0 to 9/1) to give the desired product as a mixture of 2 atropoisomers.

General procedure for the preparation of lactams B

0.32 mmol (1 eq) of the amine is dissolved in 2.4 ml of absolute ethanol and a solution of NaOEt prepared by adding 2.6 mmol (8 eq) of Na in 2.4 is added. ml of absolute ethanol. The reaction mixture is stirred under reflux for 10 hours. The mixture is diluted in CH ₂ Cl ₂ and a 10% solution of HCl is added to a pH of 1. The aqueous phase is extracted with 3 × 25 ml of CH ₂ Cl ₂ . The combined organic extracts are washed with 100 ml of water, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue obtained is purified by flash chromatography on silica gel (CH ₂ Cl ₂ / MeOH, 10/0 to 90/10) to give the desired lactams.

Example 4 ¹⁸ : 5-Benzyloxy-1H-3-iodoindole-2-carboxylic acid ethyl ester; 16

Prepared according to the general procedure for iodization of indoles.

The desired product is obtained in the form of a pale yellow solid with a yield of 92%.

Ethyl 5-benzyloxy-1H-2-carboxylate (8.0 g, 27.1 mmol) was dissolved in 15 ml of DMF and 5.76 g (103.0 mmol) of sodium hydroxide were added in portions. potassium. The reaction mixture is stirred at room temperature for 20 minutes and a solution of 6.88 g (27.1 mmol) of iodine in 15 ml of DMF is added. This mixture is stirred room temperature for another 45 minutes and poured into a mixture of 10.5 ml of aqueous 25% NaHSO _{3 solution} , 20 ml of aqueous solution of 33% H ₄ OH and 410 ml of water. The resulting precipitate is filtered and dried in vacuo to give the desired product as a pale yellow solid with a yield of

92%.

Characteristics :

m.p. 155-158 ° C (EtOH)

R _f 0.53 (heptane / CH2Cl2 1/1)

LR. (without solvent, cm ^-1 ) v 3294, 1673, 1505, 1166

1 H-NMR (500 MHz, CDCl ₃ ) δ 9.11 (bs, 1H), 7.50 (d, J = 7.0 Hz, 2H), 7.41 (t, J = 7.0 Hz, 2H), 7.34 (t, J = 7.0 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7, 11 (d, J = 8.5 Hz, 1H). , 7.04 (s, 1H), 5, 13 (s, 2H), 4.45 (q, J = 7.0 Hz, 2H), 1.46 (t, J = 7.0 Hz, 3H).

¹³ C NMR (75 MHz, CDCl ₃ ) δ 160.8 (C), 154.7 (C), 137.0 (C), 131.9 (C), 131.4 (C), 128.6. (2CH), 128.0 (CH), 127.8 (2CH), 127.4 (C), 118.9 (CH), 113, 1 (CH), 104.8 (CH), 70.7 (CH), CH ₂ ), 65.3 (Cl), 61.4 (CH ₂ ), 14.4 (CH ₃ )

MS m / z 444 [(M + Na) ⁺ ], 460 [(M + K) ⁺ ]

HRMS m / z [(M + K) ^+] calcd for Ci ₈ Hi ₆ N0 ₃ IK 459.9812 459.9824 found.

Example 5: N- (benzenesulfonyl) -5-benzyloxy-1H-3-iodoindole-2-carboxylic acid ethyl ester; 17

Prepared according to the general procedure for the protection of indoles.

The desired product is obtained in the form of a pale yellow solid with a yield of 94%. A solution of 10.3 g (24.4 mmol) of ethyl 5-benzyloxy-1H-3-iodoindole-2-carboxylate 16 in 40 ml of THF, at 0 ° C under argon, is added to a suspension of 1.45 g (36.6 mmol, 60% in oil) of sodium hydride in 40 ml of dry THF. The reaction mixture is stirred for 45 minutes at 0 ° C and benzene sulfonyl chloride (3.8 ml, 29.3 mmol) is slowly added. The reaction mixture is brought to room temperature overnight. The solvent is removed in vacuo and the residue is dissolved with 60 ml of CH ₂ Cl ₂ and 30 ml of water. The aqueous phase is extracted with 3 x 60 ml of CH ₂ Cl ₂ . The combined organic extracts are washed with 30 ml of water and 2 x 30 ml of 1M aqueous NaHCO _{3 solution} , dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting solid is purified by flash chromatography on silica gel (heptane / CH ₂ Cl ₂ 2/1) to give the desired product as a pale yellow solid with a yield of 94%.

Characteristics :

mp 221-222 ° C (hexane / Et ₂ O)

R _f 0.16 (heptane / CH ₂ C1 ₂ 1/1)

LR. (without solvent, cm ^"1 ) v 1716, 1185

1 H NMR (500 MHz, CDC) δ 7.95-7.88 (m, 3H), 7.55 (t, J = 7.6 Hz, 1H), 7.47-7.42 (m, 4H), 7.39 (t, J = 7.0 Hz, 2H), 7.34 (t, J = 7.0 Hz, 1H), 7, 11 (dd, J = 9.2 Hz, = 2.7 Hz, 1H), 6.90 (d, J = 2.7 Hz, 1H), 5.08 (s, 2H), 4.52 (q, J = 7.0 Hz, 2H), 1.47 (t, J = 7.0 Hz, 3H)

¹³ C NMR (75 MHz, CDCl ₃ ) δ 161.7 (C), 156.7 (C), 137.2 (C), 136.5 (C), 134.2 (CH), 134, 1 (C), 132.7 (C), 130.2 (C), 129, 1 (2CH), 128.6 (2CH), 128.2 (CH), 127.7 (2CH), 127.3 ( 2CH), 117.6 (CH), 116, 1 (CH), 106.3 (CH), 74.0 (Cl), 70.6 (CH ₂ ), 62.8 (CH ₂ ), 14, 1 (CH ₃ )

MS m / z 584 [(M + Na)]

HRMS m / z [(M + Na) ⁺ ] calcd for C ₂₄ H ₂ ONO ₅ NaSI 584,0005 found 583.9983

Anal Calcd (%) for C ₂₄ H ₂₀ INO ₅ S: C, 51.35; H, 3.59; N, 2.50; found C, 50.99; H, 3.52; N, 2.37 Example 6: N- (Benzenesulfonyl) -5-benzyloxy-3- (2-formylphenyl) -1H-indole-2-carboxylate ethyl; 19

Prepared according to the general cross-coupling procedure of Suzuki-Miyaura B. 17 (6.35 g, 11.3 mmol, 1 eq.)

The resulting crude product is purified by flash chromatography on silica gel (heptane / AcOEt 95/5 to 75/25) to give the desired product as an off-white foam in 92% yield. Characteristics :

R _f 0.63 (heptane / ethyl acetate 1/1)

LR. (without solvent, cm- ¹ ) v 1724, 1695, 1371, 1176

1H NMR (500 MHz, CDCl ₃ ) δ 9.63 (s, 1H), 8.06 (d, J = 7.6 Hz, 1H), 8.04 (d, J = 7.6 Hz, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.63 (t, J = 7.6 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H) , 7.56 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 8.0 Hz, 2H), 7.34-7.26 (m, 6H), 7, 13 ( dd, J = 9.1 Hz, J '= 2.2 Hz, 1H), 6.63 (d, J = 2.2 Hz, 1H), 4.90 (s, 2H), 4.21 (g). , J = 7.3 Hz, 2H), 1.10 (t, J = 7.3 Hz, 3H)

¹³ C NMR (75 MHz, CDCl ₃ ) δ 191.2 (CO), 161.5 (CO), 156.9 (C), 137.4 (C), 136.6 (C), 135.1 (C), 134.5 (C), 134.4 (CH), 133.9 (CH), 131.6 (C), 131.4 (CH), 131.2 (C), 130.7 ( C), 129.4 (CH), 129.3 (2CH), 128.7 (2CH), 128.3 (CH), 127.8 (2CH), 127.7 (CH), 127.5 (2CH); ), 124.7 (C), 117.7 (CH), 116.8 (CH), 104.3 (CH), 70.4 (CH ₂ ), 62.6 (CH ₂ ), 13.8 (CH ₂ ), CH ₃ )

MS m / z 562 [(M + Na)]

HRMS m / z [(M + Na) ^+] calcd for C ₃ iH ₂₅ N0 ₆ NaS 562, 1301 Found 562, 1283 Example 7: Ethyl N- (benzenesulfonyl) -5-benzyloxy-3- (2 - ((tert-butylsulfinylimino) methyl) phenyl) -1H-indole-2-carboxylate; 20 (S)

Prepared according to the general procedure for the preparation of tert-butylsulfinimines (4.00 g, 7.41 mmol, 1.1 equiv).

The resulting crude product is purified by flash chromatography on silica gel

(heptane / AcOEt 9/1 to 8/2) to give the desired product as a mixture of 2 atropoisomers (1/1) and as a pale yellow foam with a yield of 92% . Characteristics :

R _f 0.63 (heptane / ethyl acetate 1/1)

LR. (without solvent, cm ^-1 ) v 1722, 1370, 1186

1 H NMR (300 MHz, CDCl ₃ ) δ 8.45 (s, 1H), 8.43 (s, 1H), 8.15-8.09 (m, 1H), 8.15-8.09 (m, 1H), 8.06-7.98 (m, 2H), 8.06-7.98 (m, 2H), 7.95 (d, J = 2.6 Hz, 1H), 1, 92 (d, J = 2.6Hz, 1H), 7.59-7.49 (m, 5H), 7.59-7.49 (m, 5H), 7.36-7.23 (m, 6H), 7.36-7.23 (m, 6H), 7, 11-7.05 (m, 1H), 7, 11-7.05 (m, 1H), 6.64 (d, J = 2.4 Hz, 1H), 6.57 (d, J = 2.4 Hz, 1H), 4.92 (s, 1H), 4.92 (s, 1H), 4.88-4.86 ( m, 1H), 4.88-4.86 (m, 1H), 4.24-4, 1 1 (m, 2H), 4.24-4, 11 (m, 2H), 1, 13 (s, m.p. , 9H), 1, 09 (s, 9H), 1, 11-1.03 (m, 3H), 1, 11-1, 03 (m, 3H) The carbon peaks were difficult to identify; therefore, attribution was only made where possible.

¹³ C NMR (75 MHz, CDCl ₃ ) δ 161.5 (CO), 161.4 (CO), 161.4 (C), 161.3 (C), 156.5 (C), 156.3 (C), 137.8 (C), 137.7 (C), 136.6 (C), 136.5 (C), 134.0 (CH), 134.0 (CH), 133.5 ( C), 133.5 (C), 132.8 (C), 132.7 (C), 131.8 (CH), 131.7 (CH), 131.7 (CH), 131.6 (CH), 131.1 (CH), 131.0 (CH), 130.9 (C), 130.8 (C), 130.1 (C), 130.0 (C), 129.4 (CH), 2CH), 129.3 (2CH), 129.3 (CH), 129.2 (CH), 129, 1 (CH), 129.0 (CH), 128.5 (2CH), 128.5 (2CH); ), 128.0 (CH), 128.0 (CH), 127.6 (2CH), 127.6 (2CH), 127.4 (2CH), 127.3 (2CH), 125.9 (C) , 125.2 (C), 117, 1 (CH), 116.8 (CH), 1 16.2 (CH), 1 16.0 (CH), 104.7 (CH), 104.3 (CH), ), 70.7 (CH ₂ ), 70.6 (CH ₂ ), 62, 1 (CH ₂ ), 61.9 (CH ₂ ), 57.6 (C), 57.6 (C), 22, 6 (3CH ₃ ), 22.5 (3CH ₃ ), 13.7 (CH ₃ ), 13.6 (CH ₃ )

MS m / z 665 [(M + Na)]

HRMS m / z [(M + Na) ^+] calcd for C ₃₅ H ₃ 4 N ₂ 0 ₆ NaS ₂ 665, found 665 1756 1760 E xample 8: N- (benzenesulfonyl) -5-benzyloxy-3- (2- ethyl ((tert-butylsulfinylimino) methyl) phenyl) -1H-indole-2-carboxylate; 20 (R)

Prepared according to the general procedure for the preparation of tert-butylsulfinimines with (R ⁾ -2-methyl-2-propanesulfinamide 29 (R) (3.30 g, 6.12 mmol, 1.1 eq.).

The crude product is purified by flash chromatography on silica gel (heptane / AcOEt 9/1 to 8/2) to give the desired product as a mixture of 2 atropoisomers (1/1) and in the form of pale yellow foam with a yield of 90%.

Characteristics :

R _f 0.63 (heptane / ethyl acetate 1/1)

LR. (without solvent, cm ^-1 ) v 1722, 1370, 1186

1 H NMR (300 MHz, CDCl ₃ ) δ 8.45 (s, 1H), 8.43 (s, 1H), 8.15-8.09 (m, 1H), 8.15-8.09 (m, 1H), 8.06-7.98 (m, 2H), 8.06-7.98 (m, 2H), 7.95 (d, J = 2.6 Hz, 1H), 1, 92 (d, J = 2, 6 Hz, 1H), 7.59-7.49 (m, 5H), 7.59-7.49 (m, 5H), 7.36-7.23 (m, 6H), 7.36-7, 23 (m, 6H), 7, 11-7.05 (m, 1H), 7, 11-7.05 (m, 1H), 6.64 (d, J = 2.4 Hz, 1H), 6 , 57 (d, J = 2.4 Hz, 1H), 4.92 (s, 1H), 4.92 (s, 1H), 4.88-4.86 (m, 1H), 4.86 (m, 1H), 4.24-4, 11 (m, 2H), 4.24-4, 11 (m, 2H), 1.13 (s, 9H), 1.09 (s). , 9H), 1, 11-1.03 (m, 3H), 1, 11-1, 03 (m, 3H) The carbon peaks were difficult to identify; therefore, attribution was only made where possible.

¹³ C NMR (75 MHz, CDCl ₃ ) δ 161.5 (CO), 161.4 (CO), 161.4 (C), 161.3 (C), 156.5 (C), 156.3 (C), 137.8 (C), 137.7 (C), 136.6 (C), 136.5 (C), 134.0 (CH), 134.0 (CH), 133.5 ( C), 133.5 (C), 132.8 (C), 132.7 (C), 131.8 (CH), 131.7 (CH), 131.7 (CH), 131.6 (CH), ), 131.1 (CH), 131.0 (CH), 130.9 (C), 130.8 (C), 130.1 (C), 130.0 (C), 129.4 (2CH) 129.3 (2CH), 129.3 (CH), 129.2 (CH), 129.1 (CH), 129.0 (CH), 128.5 (2CH), 128.5 (2CH), 128.0 (CH), 128.0 (CH), 127.6 (2CH), 127.6 (2CH), 127.4 (2CH), 127.3 (2CH), 125.9 (C), 125 , 2 (C), 117, 1 (CH), 116.8 (CH), 116.2 (CH), 116.0 (CH), 104.7 (CH), 104.3 (CH), 70, 7 (CH ₂ ), 70.6 (CH ₂ ), 62, 1 (CH ₂ ), 61.9 (CH ₂ ), 57.6 (C), 57.6 (C), 22.6 (3CH ₃₎ ), 22.5 (3CH ₃ ), 13.7 (CH ₃ ), 13.6 (CH ₃ )

MS m / z 665 [(M + Na)]

HRMS m / z [(M + Na) ^+] calcd for C ₃₅ H ₃ 4 N ₂ 0 ₆ NaS ₂ 665, found 665 1756, 1729

Example 9 5- (Benzyloxy) -3- (2 - ((1R) -1- (1,1-dimethylethylsulphinamido) propyl) phenyl) -1- (phenylsulfonyl) -1H-indole-2-carboxylate ethyl; 30 (SR)

Prepared according to the general procedure for the addition of Grignard reagents to tert-butylsulfinimines (S) (3.9 g, 5.8 mmol, 1 eq).

The resulting crude product is purified by flash chromatography on silica gel (heptane / AcOEt 8/2 to 6/4) to give the desired product as a mixture. of 2 atropoisomers (1/1) and in the form of a pale yellow foam with a yield of 83%.

Characteristics :

R _f 0.32 atropisomer atropisomer 1 2 0.20 (heptane / ethyl acetate 1/1)

LR. (without solvent, cm ^-1 ) v 1725, 1369, 1184

1 H NMR (300 MHz, CDCl ₃ ) δ 8, 10-8.04 (m, 1H), 8.04-7.96 (m, 3H), 7.96-7.88 (m, 2H) , 7.95 (d, J = 7.7 Hz, 1H), 7.65-7.25 (m, 11H), 7.60-7.42 (m, 4H), 7.39-7.27 (m, 6H), 7, 19-7, 10 (m, 2H), 7, 14 (dd, J = 9.2 Hz, J '= 2.8 Hz, 1H), 7.06 (d, J = 7.7 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H), 6.50 (d, J = 2.4 Hz, 1H), 5.24 (d, J = 10). , 9 Hz, 1H), 4.93 (d, J = 11.5 Hz, 1H), 4.91 (d, J = 10.9 Hz, 1H), 4.85 (d, J = 11.5 Hz, 1H), 4.39-4.22 (m, 2H), 4.33-4.21 (m, 3H), 4.20-4, 12 (m, 1H), 4.09-4, Δ (m, 1H), 3.31-3.24 (m, 1H), 1.78-1.54 (m, 2H), 1.78-1.54 (m, 2H), 1.28 (m, 1H), s, 9H), 1, 19 (s, 9H), 1, 17 (t, J = 7.2 Hz, 3H), 1, 15 (t, J = 7.2 Hz, 3H), 0.74 ( t, J = 7.2 Hz, 3H), 0.39 (t, J = 7.2 Hz, 3H)

Carbon peaks were difficult to identify; therefore, attribution was only made where possible.

¹³ C NMR (75 MHz, CDCl ₃ ) δ 161.9 (CO), 161.7 (CO), 156.9 (C), 156.5 (C), 142.8 (C), 142.8 (C), 137.5 (C), 137.0 (C), 136.8 (C), 136.5 (C), 134.0 (CH), 134.0 (CH), 132.3 ( C), 131.4 (C), 131.0 (CH), 130.6 (C), 130.3 (C), 130, 129.6 (C), 129.4 (C), 129.2 (CH), 129, 1, 128.8, 128.7, 128.5 (2CH), 128.4 (2CH), 128, 1 (CH), 127.9 (2CH), 127.8 (CH) 127.5 (2CH), 127.3, 127.2 (CH), 127.1 (CH), 127.0 (CH), 126.9 (CH), 17.8 (CH), 117, 2 (CH), 116.9 (CH), 116, 1 (CH), 104.5 (CH), 104.4 (CH), 70.5 (CH ₂ ), 70.2 (CH ₂ ), 62 , 2 (CH ₂ ), 62.0 (CH ₂ ), 58.0 (CH), 56.6 (CH), 55.9 (C), 55.7 (C), 30.7 (CH ₂ ) , 29.4 (CH ₂ ), 22.8 (3CH ₃ ), 22.6 (3CH ₃ ), 13.8 (CH ₃ ), 13.8 (CH ₃ ), 10.5 (CH ₃ ), 9 , 92 (CH ₃ ) MS m / z 695 [(M + Na) ⁺ ]

HRMS m / z [(M + Na) ⁺ ] calcd. For C ₃₇ H ₄ ON ₂ 0 ₆ NaS ₂ 695.2226 found 695.2220 Example 1 0: 5- (Benzyloxy) -3- (2 - ((1S) -1- (1,1-dimethylethylsulfinamido) -propyl) phenyl) -1- (phenylsulfonyl) -1H-indole-2-carboxylate d ethyl; 30 (RS)

Prepared according to the general procedure for addition of Grignard reagents to tert-butylsulfinimines (R) (2.0 g, 3.11 mmol, 1.1 eq.).

The resulting crude product is purified by flash chromatography on silica gel (heptane / AcOEt 8/2 to 6/4) to give the desired product as a mixture of 2 (1: 1) atropoisomers and form of a pale yellow foam with a yield of 85%.

Characteristics :

R _f atropoisomer 1 0.32, atropoisomer 2 0.20 (heptane / ethyl acetate 1/1)

LR. (without solvent, cm ^-1 ) v 1725, 1369, 1184

¹³ C NMR (75 MHz, CDCl ₃ ) δ 161.9 (CO), 161.7 (CO), 156.9 (C), 156.5 (C), 142.8 (C), 142.8 (C), 137.5 (C), 137.0 (C), 136.8 (C), 136.5 (C), 134.0 (CH), 134.0 (CH), 132.3 (C), 131.4 (C), 131.0 (CH), 130.6 (C), 130.3 (C), 130, 129.6 (C), 129.4 (C) , 129.2 (CH), 129, 1, 128.8, 128.7, 128.5 (2CH), 128.4 (2CH), 128, 1 (CH), 127.9 (2CH), 127, 8 (CH), 127.5 (2CH), 127.3, 127.2 (CH), 127.1 (CH), 127.0 (CH), 126.9 (CH), 17.8 (CH), ), 117.2 (CH), 116.9 (CH), 116, 1 (CH), 104.5 (CH), 104.4 (CH), 70.5 (CH ₂ ), 70.2 (CH), ₂ ), 62.2 (CH ₂ ), 62.0 (CH ₂ ), 58.0 (CH), 56.6 (CH), 55.9 (C), 55.7 (C), 30.7 (CH ₂ ), 29.4 (CH ₂ ), 22.8 (3CH ₃ ), 22.6 (3CH ₃ ), 13.8 (CH ₃ ), 13.8 (CH ₃ ), 10.5 (CH ₃ ), ₃ ), 9.92 (CH ₃ ) MS m / z 695 [(M + Na) ⁺ ]

HRMS m / z [(M + Na) ⁺ ] calculated for C ₃₇ H ₄ O N ₂ 0 ₆ NaS ₂ 695.2226 found 695.2220 E xample 1 1: 5- (benzyloxy) -3- (2 - ((1R ethyl 1- (1,1-dimethylethylsulfinamido) allyl) phenyl) -1- (phenylsulfonyl) -1H-indole-2-carboxylate; 21 (SR)

Prepared according to the general procedure for the addition of Grignard reagents to tert-butylsulfinimines, (S) (0.40 g, 0.62 mmol).

The resulting crude product is purified by flash chromatography on silica gel (heptane / AcOEt 8/2 to 6/4) to give the desired product as a mixture of 2 (1: 1) atropoisomers and form of a pale yellow foam with a yield of 81%.

Characteristics :

LR. (without solvent, cm ^-1 ) v 1724, 1448, 1370, 1187, 1020, 724

1 H-NMR (300 MHz, CDCl ₃ ) δ 8.00-7.80 (m, 6H), 7.56-7.33 (m, 1H), 7.31-7.16 (m, 13H) , 7, 12-6.98 (m, 4H), 6.75-6.71 (m, 1H), 6.38-6.32 (1H), 5.58-5.65 (m, 2H) , 4.86-4.68 (m, 7H), 4.33-4.03 (m, 5H), 3.53-3.23 (m, 2H), 1, 14 (s, 9H), 1 , 07-0.96 (m, 15H) Carbon peaks were difficult to identify; therefore, the allocation was made only where possible.

¹³ C NMR (75 MHz, CDCl ₃ ) δ 161.6 (C), 161.4 (C), 156.8 (C), 156.2 (C), 140.8 (C) -140.1 (C), 138.6, 137.5, 137.0, 136.9, 136.5, 134.0, 134.0, 131.6, 131.2, 131.2, 130.9, 130, 6, 130.5, 130.4, 130.2, 130.0, 129.8, 129.2, 129.2, 129, 1, 128.5, 128.4, 128.0, 127.9, 127.8, 127.5, 127.5, 127.5, 127.4, 127.3, 127.3, 17.7, 17.5, 17.2, 16.6, 116, 3, 116.2, 105.0, 104.4, 70.4 (CH ₂ ), 70.3 (CH ₂ ), 62.0 (CH ₂ ), 61.9 (CH ₂ ), 58.9 ( CH), 58.0 (CH), 56.0 (C), 55.9 (C), 22.6 (3CH ₃ ), 22.5 (3CH ₃ ), 13.8 (CH ₃ ), 13, 7 (CH ₃ )

MS m / z 693 [(M + Na) ⁺ ]

HRMS m / z [(M + Na) ^+] calcd for C ₃₇ H ₃₈ N ₂ 0 ₆ NaS ₂ 693.2096 found 693.2064

Example 12: Ethyl 3- (2 - ((R) -1-aminopropyl) phenyl) -5- (benzyloxy) -1- (phenylsulfonyl) -1H-indole-2-carboxylate; 31 (R)

Prepared according to the general procedure for the deprotection of tert-butylsulfinimines (SR) (3.2 g, 4.75 mmol, 1 eq.)

The resulting crude product is purified by flash chromatography on silica gel (CH ₂ Cl ₂ / MeOH 10/0 to 9/1) to give the desired product as a mixture of atropoisomers and in the form of a yellow oil with a quantitative yield.

Characteristics :

Major Atropoisomer

R _f 0.23 (CH ₂ Cl ₂ / MeOH 97/3)

LR. (without solvent, cm- ¹ ) v 1723, 1606, 1447, 1370, 1187, 1175, 727 1 H-NMR (500 MHz, CDCl ₃ ) δ 8.05 (d, J = 9.2 Hz, 1H), 8.00 (d, J = 7.3 Hz, 2H), 7.59 (t, J). = 7.3 Hz, 2H), 7.51-7.44 (m, 3H), 7.38-7.26 (m, 6H), 7, 17-7, 12 (m, 2H), 6, 66 (d, J = 2.1 Hz, 1H), 4.95 (d, J = 11.6 Hz, 1H), 4.93 (d, J = 11.6Hz, 1H), 4.25 ( q, J = 7.0 Hz, 2H), 3.54 (t, J = 6.7 Hz, 1H), 1.61-1.44 (m, 2H), 1.25 (bs, 2H) , 1, 14 (t, J = 7.0 Hz, 3H), 0.68 (t, J = 7.3 Hz, 3H)

¹³ C NMR (75 MHz, CDCl ₃ ) δ 161.8 (CO), 156.5 (C), 145.7 (C), 137.4 (C), 136.6 (C), 134.0 (CH), 131.4 (C), 130.7 (C), 130.5 (CH), 130.1 (C), 129.3 (C), 129.2 (CH), 129.0 (CH), 2CH), 128.6 (2CH), 128.0 (CH), 127.4 (2CH), 127.3 (2CH), 126.6 (CH), 125.7 (CH), 116.9 (CH), ), 116.5 (CH), 104, 1 (CH), 70.4 (CH), 62.0 (CH ₂ ), 53.5 (CH ₂ ), 32.0 (CH ₂ ), 13.8 (CH ₃ ), 10.7 (CH ₃ )

MS m / z 569 [(M + H) ⁺ ]

HRMS m / z [(M + H) ⁺ ] calcd for C ₃₃ H ₃₃ N ₂ O ₅ S 569.2110 found 569.2119

Example 13: Ethyl 3- (2 - ((S) -1-aminopropyl) phenyl) -5- (benzyloxy) -1- (phenylsulfonyl) -1H-indole-2-carboxylate; 31 (S)

Prepared according to the general procedure for the deprotection of tert-butylsulfinimines (RS) (0.70 g, 1.04 mmol, 1 eq.).

The resulting crude product is purified by flash chromatography on silica gel (CH ₂ Cl ₂ / MeOH 10/0 to 9/1) to give the desired product as a mixture of 2 atropoisomers and in the form of a yellow oil with a quantitative yield.

Characteristics :

Major Atropoisomer R _f 0.23 (CH ₂ Cl ₂ / MeOH 97/3)

LR. (without solvent, cm- ¹ ) v 1723, 1606, 1447, 1370, 1187, 1175, 727

1 H-NMR (500 MHz, CDCl ₃ ) δ 8.05 (d, J = 9.2 Hz, 1H), 8.00 (d, J = 7.3 Hz, 2H), 7.59 (t, J). = 7.3 Hz, 2H), 7.51-7.44 (m, 3H), 7.38-7.26 (m, 6H), 7, 17-7, 12 (m, 2H), 6, 66 (d, J = 2.1 Hz, 1H), 4.95 (d, J = 11.6 Hz, 1H), 4.93 (d, J = 11.6Hz, 1H), 4.25 ( q, J = 7.0 Hz, 2H), 3.54 (t, J = 6.7 Hz, 1H), 1.61-1.44 (m, 2H), 1.25 (bs, 2H) , 1, 14 (t, J = 7.0 Hz, 3H), 0.68 (t, J = 7.3 Hz, 3H)

MS m / z 569 [(M + H) ⁺ ]

HRMS m / z [(M + H) ⁺ ] calcd for C ₃₃ H ₃₃ N ₂ O ₅ S 569.2110 found 569.2111

Example 14: Ethyl 3- (2 - ((R) -1-aminoallyl) phenyl) -5- (benzyloxy) -1- (phenylsulfonyl) -1H-indole-2-carboxylate; 22 (R)

Prepared according to the general procedure for the deprotection of tert-butylsulfinimines, 21 (SR) (0.30 g, 0.45 mmol).

The resulting crude product is purified by flash chromatography on silica gel (CH ₂ Cl ₂ / MeOH 10/0 to 9/1) to give the desired product as a mixture of 2 atropoisomers and in the form of a pale yellow foam with a yield of 86%. Characteristics :

R _f 0.23 (CH ₂ Cl ₂ / MeOH 97/3)

LR. (without solvent, cm- ¹ ) v 1722, 1606, 1447, 1369, 1174, 1138, 723, 684

1 H-NMR (300 MHz, CDCl ₃ ) δ 8, 11-7.96 (m, 3H), 7.64-7.22 (m, 11H), 7.20-7.06 (m, 2H), 6.71-6.54 (m, 1H), 6.02-5.77 (m, 1H), 5.09-4.77 (m, 4H), 4.38-4, 16 (m, 3H). ), 1.63 (bs, 2H), 1.20-1.06 (m, 3H)

¹³ C NMR (75 MHz, CDCl ₃ ) δ 161.9 (C), 161.6 (C), 156.6 (C), 156.5 (C), 144.6 (C), 144.1 (C), 141.5 (CH), 140, 1 (CH), 137.3 (C), 137.2 (C), 136.6 (C), 136.5 (C), 134, 1 ( CH), 134.0 (CH), 131.9 (C), 131.5 (C), 131.1 (C), 131.0 (C), 130.5 (CH), 130.2 (C), ), 130.0 (CH), 129.8 (C), 129.5 (CH), 129.3 (CH), 129.3, 129.0, 128.6, 128.5, 128.5, 128.5, 128, 1, 128.0, 127.5, 127.4, 127.3, 127, 1 (CH), 127.0 (CH), 126.9 (CH), 126.6 (CH). ), 117.3 (CH), 117, 1 (CH), 116.7 (CH), 116.6 (CH), 113.9 (CH ₂ ), 112.9 (CH ₂ ), 104.5 (CH ₂ ), CH), 104, 1 (CH), 70.5 (2CH ₂ ), 62.2 (CH ₂ ), 61.9 (CH ₂ ), 54.5 (CH), 54, 1 (CH), 13, 8 (CH ₃ ), 13.7 (CH ₃ )

MS m / z 589 [(M + Na) ⁺ ]

HRMS m / z [(M + Na) ⁺ ] calcd for C ₃₃ H ₃₀ N ₂ O ₅ S 589, 1773 found 589, 1786,

(R) -5-Ethyl-11-benzyloxy-5,8-dihydroindolo [2,3-d] [2] benzazepin-one; 32 (R)

Prepared according to the general procedure for the preparation of lactams B 31 (R) (2.70 g, 4.75 mmol, 1 eq.).

The residue obtained is purified by flash column chromatography on silica gel (CH ₂ Cl ₂ / MeOH 10/0 to 9/1) to give the desired lactams in a yield of 90%. E 1 (6) (S) -5-ethyl-11-benzyloxy-5,8-dihydroindolo [2,3-d] [2] benzazepin-7 (6H) -one; 32 (S)

Prepared according to the general procedure for the preparation of lactams B 31 (S) (0.42 g, 0.74 mmol, 1 eq.).

The residue obtained is purified by flash column chromatography on silica gel (CH ₂ Cl ₂ / MeOH 10/0 to 9/1) to give the desired lactams in the form of a pale orange solid with a yield of 89%. %.

Characteristics :

m.p. 131 ° C

R _f 0.39 (CH ₂ Cl ₂ / MeOH 97/3)

LR. (without solvent, cm ^"1 ) v 3159, 1618, 1501

1 H-NMR (500 MHz, CDCl ₃ ) δ 10.51 (brs, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.53 (brs, 1H), 7.49 -7.29 (m, 9H), 7.05 (dd, J = 8.9 Hz, J '= 2.3 Hz, 1H), 6.73 (brs, 1H),

5, 13 (d, = 11.6 Hz, AB system, 1H), 5, 10 (d, J = 11.6 Hz, AB system, 1H), 4.09 (bs, 1H), 2.39 -2.05 (m, 2H), 1.22-1.03 (m, 3H)

¹³ C NMR (75 MHz, CDCl ₃ ) δ 165.0 (CO), 154.3 (C), 138.5 (C), 137.6 (CH), 134, 1

(C), 132.8 (CH), 129.5 (C), 128.7 (2CH), 128.1 (C), 128.0 (CH), 128.0 (C), 127.8

(2CH), 127.0 (CH), 125.5 (CH), 124, 1 (C), 118.9 (C), 117.0 (CH), 113.9 (CH), 104.5

(CH), 71, 1 (CH ₂ ), 55, 1 (CH), 24.3 (CH ₂ ), 11.8 (CH ₃ )

MS m / z 405 [(M + Na) ⁺ ]

HRMS m / z [(M + Na) ⁺ ] calcd for C ₂₅ H ₂₂ N ₂ O ₆ Na 405, 1579 found 405, 1586

[α] _D = - 45.9 (acetone, c = 0.76) Anal. Calcd (%) for C ₂₅ H ₂₂ N ₂ O ₂ 0.4H ₂ O: C, 77.06; H, 5.90; N, 7, 19; found C, 77, 15; H, 5.80; N, 7.07,

Example 17: (R) -5-Vinyl-11-benzyloxy-5,8-dihydroindolo [2,3-d] [2] benzazin-7 (6H) -one; 23 (R)

Prepared according to the general procedure for the preparation of lactams B, 22 (R) (0.20 g, 0.35 mmol).

The residue obtained is purified by flash column chromatography on silica gel (CH ₂ Cl ₂ / MeOH 10/0 to 9/1) to give the desired lactams in the form of an off-white foam with a yield of 37%. %. Characteristics :

R _f 0.55 (CH ₂ Cl ₂ / MeOH 9/1)

IR (neat, cm ^-1 ) v 3250, 1619, 1468, 1447, 1261, 1158, 728

1 H-NMR (500 MHz, MeOD) δ 7.84 (d, J = 7.6 Hz, 1H), 7.51-7.27 (m, 10H), 7, 13-7.06 (m, 1H) ), 6.70-5.64 (m, 1H), 5.60-5.31 (m, 1H), 5, 11 (s, 2H), 4.98-4.70 (m, 2H)

¹³ C NMR (75 MHz, DMSO-D _6? 90 ° C)? 162.7 (CO), 153.7 (C), 139.1 (C), 137.8 (C), 136.4 (? CH), 132.7 (C), 132.3 (C), 130.9 (C), 128.2 (CH), 127.8 (CH), 127.5 (3CH),

127.4 (2CH), 127.3 (CH), 126.2 (CH), 124.9 (C), 116.5 (CH ₂ ), 115.8 (CH), 115.7 (C),

113.5 (CH), 104.7 (CH), 70.7 (CH ₂ ), 57.3 (CH)

MS w / 381 [(M + H) ⁺ ]

HRMS m / z [(M + H) ⁺ ] calcd for C ₂₅ H ₂ iN ₂ O ₂ 381, 1603 found 381, 1611

[OC] D = -2.0 (acetone, c = 0.51) Example 18: (R) -5-ethyl-11-hydroxy-5,8-dihydroindolo [2,3-d] [2] benzazepin-7 (6H) -one; 25 (R)

To a solution of 180 mg (0.47 mmol, 1.0 eq) of indolobenzazepinone 32 (R) in 4 ml of AcOEt, 12 mg of 10% Pd / C is added. The mixture is vigorously stirred under atmospheric pressure of H ₂ and monitored by TLC. The catalyst was removed by filtration over Celite with AcOEt. Then the solvent is evaporated and the resulting solid is purified by flash chromatography on silica gel (CH ₂ Cl ₂ / MeOH, 95/5) to give the desired product as a pale pink solid with a yield of 100%. Characteristics :

m.p. 179 ° C

R _f 0.30 (CH ₂ Cl ₂ / MeOH 97/3)

LR. (without solvent, cm ^-1 ) v 3188, 1611, 1478

1 H NMR (500 MHz, MeOD) δ 7.95 (d, J = 7.4 Hz, 1H), 7.52-7.21 (m, 5H), 6.94 (d, J = 8, 7 Hz, 1H), 4.01-3.90 (m, 1H), 1.83-1.49 (m, 2H), 1.23-1.01 (m, 3H)

¹³ C NMR (75 MHz, MeOD) δ 166, 1 (CO), 153.3 (C), 140.2 (C), 135.3 (C), 133.6 (C), 128.9 ( CH), 128.6 (C), 127.9 (CH), 127.0 (CH), 125.0 (CH), 123.6 (C), 116.8 (C), 117.0 (CH). ), 114.4 (CH), 105.7 (CH), 56.3 (CH), 24.9 (CH ₂ ), 12.1 (CH ₃ )

MS w / 315 [(M + Na) ⁺ ]

HRMS m / z [(M + Na) ^+] calcd for Ci ₈ Hi ₆ N ₂ 0 ₂ Na 315, found 315 1109, 1107

[a] _D = +49.3 (acetone, c = 0, 15)

HPLC, chiral IC, 4.6 * 250, 5 μιη, heptane / EtOH: 75/25, 0.7 ml / min, t (R) = 12.74 min, t (S) = 10.39 min, purity 95%, ee = 99%. (S) -5-ethyl-ll-hydroxy-5,8-dihydroindolo [2,3-d] [2] benzazepin-7 (6H) -

To a solution of 405 mg (1.06 mmol, 1.0 eq) of indolobenzazepinone 32 (S) in 8 ml of AcOEt is added 27 mg of 10% Pd / C. The mixture is vigorously stirred under atmospheric pressure of H ₂ and the reaction is monitored by TLC. The catalyst was removed by filtration over Celite with AcOEt. Then the solvent is evaporated and the resulting solid is purified by flash chromatography on silica gel (CH ₂ Cl ₂ / MeOH, 95/5) to give the desired product as a pale pink solid with a yield of 100%.

Characteristics :

m.p. 179 ° C

R _f 0.30 (CH ₂ Cl ₂ / MeOH 97/3)

LR. (without solvent, cm- ¹ ) v 3182, 1629, 1479

1 H-NMR (500 MHz, MeOD) δ 7.95 (d, J = 7.4 Hz, 1H), 7.52-7.21 (m, 5H), 6.94 (d, J = 8.7 Hz, 1H), 4.01-3.90 (m, 1H), 1.83-1.49 (m, 2H), 1.23-1.01 (m, 3H)

¹³ C NMR (75 MHz, MeOD) δ 166, 1 (CO), 153.3 (C), 140.2 (C), 135.3 (C), 133.6 (C), 128.9 ( CH), 128.6 (C), 127.9 (CH), 127.0 (CH), 125.0 (CH), 123.6 (C), 116.8 (C), 117.0 (CH). ), 114.4 (CH), 105.7 (CH), 56.3 (CH), 24.9 (CH ₂ ), 12, 1 (CH ₃ )

MS w / 315 [(M + Na) ⁺ ]

HRMS m / z [(M + Na) ^+] calcd for Ci ₈ Hi ₆ N ₂ 0 ₂ Na 315, found 315 1109, 1115

[α] _D = -49.7 (acetone, c = 0.26)

HPLC, chiral IC, 4.6 * 250, 5 μιη, heptane / EtOH: 75/25, 0.8 ml / min, t (S) = 8.82 min, t (R) = 10.80 min, purity 99%, ee = 99%. Example 20: di (5R) -5-ethyl-7-oxo-5,6,7,8-tetrahydrobenzo [5,6] azepino [3,4-b] indol-11-yl) phosphate -butyl; 26 (R)

0.30 g (1.03 mmol) of (R) was dissolved in 2.7 ml of anhydrous THF and stirred under argon at room temperature together with 0.34 ml (1.23 mmol) of diethylphosphoramidite. of di-tert-butyl and 0, 187 g (2.67 mmol) of 1H-tetrazole. After 2 hours, the solution is cooled to -40 ° C., and a solution of 0.33 g (1.33 mmol) of 3-chloroperoxybenzoic acid in 3.7 ml of CH ₂ Cl _{2 is added.} that the temperature remains below -20 ° C. The solution is warmed to 0-4 ° C. and 15 ml of saturated Na ₂ CO ₃ solution are added, and the aqueous phase is extracted with 3 × 20 ml of CH ₂ Cl ₂ . The combined organic extracts are washed with 15 ml of saturated Na ₂ CO _{3 solution} , dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting oil was purified by flash chromatography on silica gel (CH ₂ Cl ₂ / MeOH, 98/2) to give the desired product as a pink-white foam in 67% yield.

Characteristics :

R _f 0.50 (CH ₂ Cl ₂ / MeOH 94/6)

LR. (neat, cm ^-1 ) v 3189, 2977, 1632, 1529, 1502, 1462, 1252, 1148, 1039, 974, 915, 762

1 H-NMR (300 MHz, DMSO-D ₆ ) δ 12, 11 (broad, 1H), 8.72-8, 15 (m, 1H), 7.92-7.72 (m, 2H), 7.60-7.27 (m, 4H), 7.22-7.06 (m, 1H), 4.29-3.79 (m, 1H), 2.29-1.96 (m, 2H). ), 1.46 (s, 18H), 1, 17-0.94 (m, 3H)

¹³ C NMR (125 MHz, DMSO-D ₆ -90 ° C) δ 162.6 (CO), 146.3 (C), 139.5 (C), 133.6 (C), 132.7 ( C), 131.4 (C), 127.4-127.3 (CH), 126.4 (CH), 124.6 (C), 118.3 (CH), 118, 1 (CH), 115 , 8 (C), 113.2-113, 1 (CH), 111.0 (CH), 110.7 (CH), 110.5 (2C), 56.3 (CH), 31.3-29.6 (6CH ₃ ) 24.0 (CH ₂ ), 11.4 (CH ₃ )

³¹ P NMR (500MHz, DMSO) δ -14.5

MS m / z 507 [(M + Na) ⁺ ]

HRMS m / z [(M + Na) ⁺ ] calcd for C ₂₆ H ₃₃ N ₂ O ₅ NaP 507.2025 found 507.2035

[α] _D = +34.9 (DMSO-D ₆ , c = 0.53).

Example 21: (5R) -5-Ethyl-7-oxo-5,6,7,8-tetrahydro-benzo [5,6] azepino [3,4-b] indol-11-yl dihydrogen phosphate; 27 (R)

0.28 g (0.58 mmol) of 26 (R) in 7.9 ml of CH ₂ Cl ₂ are dissolved and 1 ml (13 mmol) of TFA is slowly added while cooling and stirring in a bath of ice / water. The temperature is allowed to rise to room temperature and stirring is continued for a further 1.5 hours. The solvent and TFA are removed in vacuo and the product is triturated with Et ₂ O, filtered and washed well with Et _{2 to} give the desired product as a solid. white with a yield of 88%.

Characteristics :

m.p. 267-269 ° C

LR. (without solvent, cm ^-1 ) v 3330, 2312, 1537, 1296, 1251, 962

1 H-NMR (500 MHz, DMSO-D ₆ -90 ° C) δ 11.61 (brs, 1H), 8.03-7.87 (m, 2H), 7.81 (brs, 1H), 7.55-7.38 (m, 3H), 7.38-7.31 (m, 1H), 7.21-7.12 (m, 1H), 4.09-3.96 (m, 1H) ), 2.05-1.80 (m, 2H), 1.04-4.88 (m, 3H)

¹³ C NMR (125 MHz, DMSO-D ₆ -90 ° C) δ 162.6 (CO), 146.4 (C), 139.4 (C), 133.5 (C), 132.7 ( C), 131.3 (C), 127.4 (CH), 126.4 (CH), 124.6 (C), 118.3 (CH), 115.9 (C), 113, 1 (CH); ), 111.0 (CH), 56.4 (CH), 24.0 (CH ₂ ), 11.3 (CH ₃ )

³¹ P NMR (500MHz, DMSO) δ -5.3 MS w / 371 [(MH) ^" ]

HRMS m / z [(MH) ^"] calculated for Ci ₈ Hi ₆ N ₂ 0 ₅ P 371.0797 found 371.0779,

[α] _D = +38.3 (DMSO-D ₆ , c = 0.55)

Anal Calcd (%) for Ci ₈ Hi ₇ N ₂ O5P.0,9H ₂ O: C, 55.65; H, 4.88; N, 7.21; found C, 55.83; H, 4.60; N, 7.20,

Example 22: 5R) -5-ethyl-7-oxo-5,6,7,8-tetrahydrobenzo [5,6] azepino [3,4-b] indol-11-yl disodium phosphate; 28 (R)

0.33 mmol of 27 (R) in 2 ml of MeOH and 20 ml (13 mmol) of H ₂ O are dissolved. DOWEX Na ^{+ is added} and the suspension is stirred for 3 hours. the filter. The solvent is removed in vacuo and the desired product is obtained as an orange-brown solid with a yield of 97%.

Characteristics :

m.p. 202 ° C

IR (neat, cm ^-1 ) v 3325, 1620, 1529, 1503, 1462, 1194, 1150, 1077, 914, 760 1 H-NMR (500 MHz, DMSO-D ₆ -90 ° C) δ 11.29 ( broad, 1H), 8.00-7.74 (m, 3H), 7.51-7.14 (m, 5H), 4.06-3.95 (m, 1H), 2.02-1. , 84 (m, 2H), 1.04-0.88 (m, 3H)

¹³ C-NMR (125 MHz, DMSO-D ₆ -90 ° C) δ 162.8 (CO), 152.0 (C), 139.2 (C), 131.4 (C), 130.6 ( C), 129.6 (C), 127.4 (CH), 126.0 (CH), 115.4 (CH), 115, 1 (C), 113.2 (CH), 112, 1 (C), ), 104.3 (CH), 56.5 (CH), 24.0 (CH ₂ ), 11.3 (CH ₃ )

³¹ P NMR (500 MHz, DMSO) δ-3.5

MS m / z 371 [(M + H-2Na) ^" ]

HRMS m / z [(M + 2Na-H) ^'] calculated for Ci ₈ Hi ₆ N ₂ 0 ₅ P 371.0797 found 371.0815

[a] _D = +26.2 (DMSO-D ₆ , c = 0.59) Example 23: Ethyl-3-iodoindole-2-carboxylate; 33

Sulfuric acid (3.3 mL, 62 mmol, 2 eq) is added to a solution of indole-2-carboxylic acid (5.0 g, 31.0 mmol) in absolute ethanol (100 mL). The reaction mixture is refluxed overnight. After cooling to room temperature, the solvent is removed, the residue dissolved in CH ₂ Cl ₂ (70 mL) and the resulting organic phase washed with 1 M aqueous NaHCO ₃ (3 x 40 mL) and water. (2x40 mL), then dried (MgS0 _4), filtered and concentrated to give ethyl ester (33) in the form of a solid with a yield of 98%. The ethyl ester (33) (3.59 g, 19.0 mmol) is then dissolved in 11 ml of DMF and potassium hydroxide (4.05 g, 72.4 mmol) is added in portions. The reaction mixture is stirred at room temperature for 20 minutes and a solution of iodine (4.84 g, 19.0 mmol) in DMF (11 mL) is added. This mixture is stirred at room temperature for an additional 45 minutes and is poured into an aqueous solution consisting of 25% NaHSO ₃ (8 mL), 33% aqueous NH ₄ OH solution (16 mL) and water. water (320 mL). The resulting precipitate is filtered and dried under vacuum to give the desired product as a pale yellow solid in 87% yield.

Characteristics :

Mp 137 ° C.

R _f 0.83 (heptane / ethyl acetate 1/1)

LR. (without solvent, cm ^-1 ) v 3291, 1681, 742

1H NMR (500 MHz, CDCl ₃ ) δ 9.21 (bs, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.38-7.24 (m, 3H), 4.55 (q, J = 7.2 Hz, 2H) , 1.48 (t, J = 7.1 Hz, 3H)

¹³ C NMR (75 MHz, CDCl ₃ ) δ 161.1 (C), 136.2 (C), 131.5 (C), 127.2 (C), 126.7 (CH), 123.6 (CH), 121.7 (CH), 112.0 (CH) , 66.1 (C), 61.5 (CH ₂ ), 14.4 (CH ₃ )

MS w / z 338 [(M + Na) ⁺ ] Anal. Calc'd (%) for C n H ₀ INO ₂ : C, 41.93; H, 3.30; N, 4.45; found C, 41.95; H, 3.21: N, 4.21.

Example 24: N- (1-Benzenesulfonyl) -1H-3iodoindole-2-carboxylic acid ethyl ester; 34

Prepared according to the general procedure of protection of indoles. The desired product is obtained as a yellow solid with a yield of 85%.

A solution of ethyl 3-iodoindole-2-carboxylate (2.79 g, 14.8 mmol) in THF (70 mL) is added at 0 ° C. under argon to a suspension of sodium hydride (0.89 g, 22.3 mmol, 60% in oil, 1.5 eq) in dry THF (70 mL). The reaction mixture is stirred for 45 minutes at 0 ° C and benzenesulfonyl chloride (6.0 mL, 29.8 mmol, 2 eq) is slowly added. The reaction mixture is warmed to room temperature overnight. The solvent is removed under vacuum and the residue is dissolved with CH ₂ Cl ₂ (100 mL) and washed with water (20 mL). The aqueous phase is extracted with CH ₂ Cl ₂ (3 × 20 mL). The combined organic phases are washed with water (40 mL) and an aqueous solution of 1 M NaHCO ₃ ( ₂ × 20 mL), then dried (MgSO ₄ ), filtered and concentrated in vacuo. The resulting solid is purified by flash chromatography on silica gel (heptane / CH ₂ Cl ₂ 2/1 by volume) to obtain the desired product as a yellow solid with a yield of 85%.

Characteristics :

Mp 137 ° C (hexane / Et ₂ O)

R _f 0.36 (heptane / CH ₂ Cl ₂ 4/6)

LR. (without solvent, cm ^-1 ) v 3092, 1723, 1169, 724

1 H NMR (300 MHz, CDCl ₃ ) δ 8.00 (m, 3H), 7.65-7.30 (m, 6H), 4.55 (q, J = 7.2 Hz, 2H), 1.48 (t, 7 = 7.1 Hz, 3H) ¹ C NMR (75 MHz, CDCl ₃ ) δ 161.7 (C), 137.3 (C), 135.5 (C), 134.2 (CH), 133.4 (C), 131.4 (C), 129.1 (2CH), 127.4 (CH) , 127.3 (2CH), 124.8 (CH), 123.1 (CH), 114.7 (CH), 63.5 (C), 62.8 (CH ₂ ), 14.0 (CH ₃ )

MS m / z 477.9 [(M + Na) ⁺ ].

Example 25: Ethyl 3 - ((- formylphenyl) -1- (phenylsulfonyl) -1H-indole-2-carboxylate; 35

Prepared according to the general cross-coupling procedure of Suzuki-Miyaura B, 17 (3.5 g, 7.25 mmol).

The resulting crude was purified by flash chromatography on silica gel (heptane / AcOEt 95/5 to 75/25) to obtain the desired product as an off-white foam with a yield of 81%.

Characteristics :

R _f 0.41 (heptane / ethyl acetate 6/4)

LR. (without solvent, cm ^-1 ) v 1723, 1693, 1370, 1176

1H NMR (500 MHz, CDCl ₃ ) δ 9.74 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H), 8.06 (d, J = 7.6 Hz, 3H), 7.61 (t, J = 7.0 Hz, 1H), 7.54-7.49 (m, 2H), 7.45-7.40 (m, 3H), 7.34 (d, J = 7.3 Hz, 1H), 7.22-7.14 (m, 2H), 4.20 (q, J = 7.0 Hz). , 2H), 1.06 (t, J = 7.0 Hz, 3H)

1 ³ C NMR (75 MHz, CDCl ₃ ) δ 190.7 (CO), 161.4 (CO), 137.4 (C), 136.2 (C), 135.0 (C), 134.4 (CH), 134.1 (C), 133.8 (CH) ), 131.4 (CH), 130.3 (C), 129.8 (C), 129.2 (2CH), 127.6 (CH), 127.5 (CH), 127.4 (2CH), 125.0 (CH), 124.2 (C), 121.1 (CH), ), 115.4 (CH), 62.3 (CH ₂ ), 13.7 (CH ₃ )

MS m / z 456 [(M + Na) ⁺ ]

HRMS m / z [(M + Na) ⁺ ] calcd for C ₂₄ H19N0 ₅ NaS 456.0882 found 456.0876 Example 26: Ethyl 3- (2 - (((ieri-butylsulfinylimino) methyl) phenyl) -1- (phenylsulfonyl) -1H-indole-2-carboxylate; 36 (S)

Prepared according to the general procedure for preparing tert-butylsulfinimines, (2.3 g, 5.31 mmol, 1.1 eq)

The crude product obtained is purified by flash chromatography on silica gel (heptane / AcOEt / CH ₂ Cl ₂ 50/95/5) making it possible to obtain the desired product in the form of a mixture of 2 atropoisomers (1.1). in the form of a white foam with a yield of 90%.

Characteristics :

R _f 0.38 heptane / AcOEt / CH ₂ Cl ₂ 50/95/5)

LR. (without solvent, cm ^-1 ) v 1724, 1370, 1186

1H NMR (300 MHz, CDC1 ₃₎ δ 8.47 (s, 1H), 8.46 (s, 1H), 8.17-8.02 (m, 4H), 8.17- 8.02 (m, 4H), 7.62-7.52 (m, 5H) , 7.62-7.52 (m, 5H), 7.45-7.32 (m, 2H), 7.45-7.32 (m, 2H), 7.25-7.09 (m, 2H), 7.25-7.09 (m, 2H), 4.28-4.12 ( m, 2H), 4.28-4.12 (m, 2H), 1.15 (s, 9H), 1.08 (s, 9H), 1.17 1.04 (m, 3H), 1.17-1.04 (m, 3H);

The carbon peaks were difficult to identify, therefore the assignment was made only where possible

¹³ C NMR (75 MHz, CDCl ₃ ) δ 161.5 (CO), 161.4 (CO), 161.4 (C), 161.3 (C), 137.9 (C), 137.9 (C), 136.2 (C), 136.0 (C) , 134.1 (CH), 134.0 (CH), 133.5 (2C), 132.8 (C), 132.7 (C), 131.8 (CH), 131.6 (4CH), 130.1 (C), 129.8 (C), 129.4 (5CH) , 129.2 (CH), 129.0 (3CH), 127.4 (4CH), 127.1 (CH), 127.0 (CH), 125.7 (C), 125.0 (C), 124.5 (CH), 124.3 (CH), 121.3 (CH) , 121.2 (CH), 115.0 (CH), 114.9 (CH), 62.1 (CH ₂ ), 61.9 (CH ₂ ), 57.7 (C), 57.6 (C), 22.7 (3CH ₃ ), 22.4 (3CH ₃ ), 13.7 (2CH ₃ ) MS m / z 559 [(M + Na) ⁺ ]

HRMS m / z [(M + Na) ^+] calcd for C _i if sN ^ _î _î Osnas 559.1337 found 559.1342

Example 27: Ethyl 3- (2 - ((1R) - (1,1-dimethylethylsulphinamido) (phenyl) methyl) phenyl) -1- (phenylsulfonyl) -1H-indole-2-carboxylate; 37 (SR)

Prepared according to the general procedure for addition of Grignard reagents to tert-butylsulfinimines 36 (S) (0.25 g, 0.47 mmol)

The crude product obtained is purified by flash chromatography on silica gel (heptane / AcOEt 8 / 2-6 / 4) making it possible to obtain the desired product in the form of a mixture of 2 atropoisomers (1/2) in the form of pale yellow foam with a yield of 73%.

Characteristics :

R _f 0.20 (heptane / ethyl acetate 6/4)

LR. (without solvent, cm ^-1 ) v 1724, 1479, 1368, 1187

1H NMR (300 MHz, CDCl ₃ ) δ 8.19-8.01 (m, 6H), 7.95-7.80 (m, 2H), 7.69-7.55 (m, 4H), 7.55-7.44 (m, 4H), 7.43-7.04 ( m, 8H), 6.97-6.89 (m, 2H), 6.81-6.65 (m, 4H), 6.35-6.02 (m, 4H), 5.58-5.54 (m, 2H), 4.47-3.70 (m, 4H), 3.61-3.35 (m, 2H), 1.29-1.25 (2s, 18H), 1.13-0.74 (2t, 7 = 7.0 Hz, 6H)

1 ³ C NMR (75 MHz, CDCl ₃ ) δ 161.5 (CO), 160.9 (CO), 141.5, 141.3, 140.6, 138.4, 137.2, 136.3, 134. 1, 133.9, 131.8, 130.8, 130.6, 130.6, 130.5, 129.5, 129.3, 129.0, 128.8, 128.8, 128.6, 128.5, 128.2, 128.2, 128.1, 127.7, 127.6, 127.5, 127.4, 127.3, 127.1, 126.9 (CH), 126.5 (CH), 124.9 (CH), 124.0 (CH), 122.0 (CH), 121.3 (CH), 115.0 (CH), 115.0 (CH), 62.0 (CH ₂ ), 61.4 ( CH ₂ ), 59.5 (CH), 59.0 (CH), 56.2 (C), 56.0 (C), 22.8 (6CH ₃ ), 13.8 (CH ₃ ), 13.3 (CH ₃ )

MS m / z 637 [(M + Na) ⁺ ]

HRMS m / z [(M + Na) ^+] calcd for C 4 H ₃ N ₂ 0 ₅ ₃₄ NaS ₂ 637.1807 found 637.1799.

Example 28 Ethyl 3- (2 - ((1R) -1- (1,1-dimethylethylsulfinamido) -2-phenylethyl) phenyl) -1- (phenylsulfonyl) -1H-indole-2-carboxylate; 38 (SR)

Prepared according to the general procedure of addition of Grignard reagents to tert-butylsulfinimines 36 (S) (0.3 g, 0.56 mmol).

The crude product obtained is purified by flash chromatography on silica gel (heptane / AcOEt 8/2 6/4) making it possible to obtain the desired product in the form of a mixture of 2 atropoisomers (1 / 1.3) in the form of a white foam with a 73% yield

Characteristics :

R _f 0.17 atropisomer 1, atropisomer 2 0.50 (heptane / ethyl acetate 6/4)

LR. (neat, cm ^-1 ) v 3273, 1729, 1446, 1365, 1186, 1043, 744

1H NMR (300 MHz, CDCl ₃ ) δ 8.14 (d, J = 8.2 Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H), 8.08 (d, J = 8.2 Hz, 2H), 8.01 (d, J = 8.2 Hz, 2H), 7.77-7.69 (m, 3H), 7.63 (d, J = 7.9 Hz, 1H), 7.61 (t, J = 7.3 Hz, 1H), 7.54 (t, J = 7.3 Hz, 1H), 7.52-7.44 (m, 2H), 7.50 (t, J = 7.6 Hz, 1H), 7.40-7.33 (m, 4H), 7.37 (t, J = 8.2 Hz, 1H), 7.26 (t, J); = 7.9 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.23-7.17 (m, 4H), 6.98-6.91 (m, 2H), 6.94-6.90 (m, 2H), 6.88 (t, J = 7.3 Hz, 1H), 6.61 (t, J = 7.6 Hz, 2H), 6.07 (t, J = 7.6 Hz, 3H), 5.17 (bs, 1H), 4.60-4.52 (m, 1H), 4.45-4.40 (m, 1H), 4.43-4.15 (m, 2H), 4.28 (q, J = 7.3 Hz, 2H), 3.63 (d, J = 5.8 Hz, 1H). , 3.37 (dd, J = 13.1 Hz, J '= 5.2 Hz, 1H), 3.07 (dd, J = 13.4 Hz, J = 3.1 Hz, 1H), 2.79 (dd, J = 13.4 Hz, f = 10.1 Hz, 1H), 2.79 (dd, J = 13.1 Hz, J '= 10.4 Hz, 1H), 1.31 (s, 9H), 1.26 (t, J = 7.0 Hz, 3H), 1.13 (d, J = 7.3 Hz). , 3H), 0.75 (s, 9H) The carbon peaks were difficult to identify, therefore the assignment was made only where possible.

¹³ C NMR (75 MHz, CDCl ₃ ) δ 162.0 (C), 161.9 (C), 142.1 (C), 141.6 (C), 137.8 (C), 137.8 (C), 137.0 (C), 136.9 (C) , 136.3 (C), 136.1 (C), 134.1 (CH), 134.0 (CH), 131.1 (C), 130.8 (CH), 130.4 (C), 130.1 (C), 129.7, 129.6, 129.5, 129.4, 129.4 , 129.2, 129.1, 129.1, 129.0, 128.5, 128.2, 128.0, 127.8, 127.5, 127.4, 127.2 (CH), 127.1 (CH), 127.0 (CH), 126.9 (C), 126.7 (CH), 126.0 (CH) , 124.8 (CH), 124.4 (CH), 122.5 (CH), 122.0 (CH), 115.6 (CH), 115.0 (CH), 62.4 (CH ₂ ), 62.2 (CH ₂ ), 59.0 (CH), 56.5 ( C), 56.4 (CH), 55.8 (C), 43.9 (CH ₂ ), 41.1 (CH ₂ ), 22.9 (3CH ₃ ), 22.1 (3CH ₃ ), 13.8 (2CH ₃ )

MS w / 651 [(M + Na) ⁺ ]

HRMS m / z [(M + Na) ^+] calcd for C ₃₅ H ₃₆ N ₂ 0 ₅ NaS ₂ 651.1963 found 651.1955

Ethyl 2 9: 3- (2 - ((1R) -1- (1,1-dimethylethylsulfinamido) allyl) phenyl) -1- (phenylsulfonyl) -1H-indole-2-carboxylate; 39 (SR)

Prepared according to the general procedure of addition of Grignard reagents to tert-butylsulfinimines 36 (S) (0.25 g, 0.47 mmol).

The crude product obtained is purified by flash chromatography on silica gel (heptane / AcOEt 8/2 to 6/4) making it possible to obtain the desired product in the form of a mixture of 2 atropoisomers (1 / 1.4) in the form of a pale yellow foam with a yield of 82%. Characteristics :

R _f 0.20 (heptane / ethyl acetate 6/4)

LR. (without solvent, cm ^-1 ) v 1724, 1447, 1370, 1307, 1258, 1180, 748

1H NMR (300 MHz, CDCl ₃ ) δ 8.17-8.00 (m, 6H), 7.65-6.95 (m, 20H), 6.01-5.79 (m, 2H), 5.08-4.75 (m, 5H), 4.46-4.15 ( m, 5H), 3.61-3.34 (m, 2H), 1.22-1.13 (m, 24H) The carbon peaks were difficult to identify, therefore the assignment was made only where possible.

¹³ C NMR (75 MHz, CDC1 ₃₎ δ 161.7 (CO), 161.5 (CO), 140.8 (C), 140.2 (C), 138.8, 138.5, 137.7, 137.2, 136.5, 136.2, 134.1, 134.0, 13 1. 1, 130.6, 130.5, 130.3, 130.0,

129.5, 129.2, 129.1, 129.0, 127.7, 127.5, 127.4, 127.3, 127.0, 126.9, 124.8, 124.2,

122.0, 121.9, 117.5, 116.2, 115.4, 115.1, 62.0 (CH ₂ ), 61.9 (CH ₂ ), 58.9 (CH), 58.2 (CH),

56 (C), 55.9 (C), 22.6 (6CH ₃ ), 13.8 (CH ₃ ), 13.7 (CH ₃ )

MS m / z 587 [(M + Na) ⁺ ]

HRMS m / z [(M + Na) ⁺ ] calcd for C ₃₀ H ₃₂ N ₂ O ₅ NaS ₂ 587.1650 found 587.1645

Example 30 Ethyl 3- (2 - ((1R) -1- (1,1-dimethylethylsulfinamido) pent-4-enyl) phenyl) -1- (phenylsulfonyl) -1H-indole-2-carboxylate; 40 (SR)

Prepared according to the general procedure for addition of Grignard reagents to tert-butylsulfinimines 36 (S) (0.23 g, 0.43 mmol).

The crude product obtained is purified by flash chromatography on silica gel (heptane / AcOEt 8/2 to 6/4) to obtain the desired product in the form of a mixture of 2 atropoisomers (1 / 1.3) in the form of a white foam with a yield of 92%. Characteristics :

R _f 0.20 (heptane / ethyl acetate 6/4)

LR. (without solvent, cm ^-1 ) v 1724, 1446, 1370, 1307, 1257, 1180, 1142, 748

1H NMR (300 MHz, CDCl ₃ ) δ 8.18-7.99 (m, 6H), 7.69-7.41 (m, 12H), 7.35-7.17 (m, 6H), 7.13-7.03 (m, 2H), 5.64-5.17 ( m, 2H), 4.95-4.57 (m, 4H), 4.38-4.18 (m, 6H), 3.96 (d, J = 4.0 Hz, 1H), 3.39 (d, J = 4.0 Hz, 1H), 1.95-1.50. (m, 8H), 1.25 (s, 9H), 1.21 (s, 9H), 1.13 (t, J = 7.0 Hz, 3H), 1.11 (t, J = 7.0 Hz, 3H)

The carbon peaks were difficult to identify, therefore the allocation was made only where possible.

1 ³ C NMR (75 MHz, CDCl ₃ ) δ 161.9 (C), 161.7 (C), 143.0 (C), 142.1 (C), 137.8, 137.4, 137.2, 137.1, 136.6, 135.9, 134.1, 134.0, 1.1 , 130.9, 130.2, 129.7, 129.4, 129.3, 129.2, 129.1, 129. 1, 128.9, 128.8, 127.9, 127.4, 127.3, 127.2, 127.1, 127.0, 126.9, 126.8, 126.4, 124.8, 124.6, 121.9, 121.3, 115.6 , 115.4, 115.0, 114.8, 62.2 (CH ₂ ), 62.0 (CH ₂ ), 56.4 (C), 55.9 (2CH), 55.7 (C), 37.4 (CH ₂ ), 36.1 (CH ₂ ), 30.1 (CH ₂₎ ), 29.5 (CH ₂ ), 22.8 (3CH ₂ ), 22.7 (3CH ₂ ), 13.8 (2CH ₃ )

MS w / 615 [(M + Na) ⁺ ]

HRMS m / z [(M + Na) ⁺ ] calcd for C ₃₂ H ₃₆ N ₂ O ₅ NaS ₂ 615.1963 found 615.1949

Ethyl 3 1: 3- (2 - ((R) -amino (phenyl) methyl) phenyl) -1- (phenylsulfonyl) -1H-indole-2-carboxylate; 41 (R)

Prepared according to the general procedure for the deprotection of tert-butylsulfinimines, 37 (SR) (0.20 g, 0.33 mmol). The crude product obtained is purified by flash-chromatography on silica gel (CH ₂ Cl ₂ / MeOH 10/0 to 9/1) making it possible to obtain the desired product in the form of a mixture of 2 atropoisomers (1/2). with a yield of 92%. Characteristics :

R _f 0.25 (CH ₂ Cl ₂ / MeOH 97/3)

LR. (without solvent, cm ^-1 ) v 1720, 1146, 1370, 1258, 1180, 746

1H NMR (300 MHz, CDCl ₃ ) δ 8.22-8.15 (m, 2H), 8.09-8.01 (m, 4H), 7.59-7.26 (m, 16H), 7.25-6.92 (m, 14H), 5.03-4.96 ( 2s, 2H), 4.39-4.08 (m, 4H), 1.90 (bs, 4H), 1.17-1.02 (2 t, J = 7.0 Hz, 6H)

¹³ C NMR (75 MHz, CDC1 ₃₎ δ 162.0 (C), 161.6 (C), 146.0 (C), 145.5 (C), 144.8 (C), 144.4 (C), 137.6 (C), 137.5 (C) , 136.5 (C), 136.4 (C), 134.1 (CH), 133.9 (CH), 130.8, 130.5, 130.0, 129.6, 129.5, 129.3, 129.0, 129.0, 128.9, 128.5, 128.1, 128.0, 127.4, 127.3, 127.2 , 127.1, 126.9, 126.8, 126.7, 126.6, 126.5, 124.8 (CH), 124.6 (CH), 121.5 (CH), 121.1 (CH), 115.7 (CH), 115.4 (CH), 62.3 (CH ₂ ), 61.9 (CH ₂ ), 55.9 (CH), 55.6 (CH), 13.8 (CH ₃ ), 13.6 (CH ₃ )

MS w / 511 [(M + H) ⁺ ]

HRMS m / z [(M + H) ⁺ ] calcd for C ₃₀ H ₂₇ N ₂ O ₄ S 511.1692 found 511.1700.

Ethyl 32: 3- (2 - ((R) -1-amino-2-phenylethyl) phenyl) -1- (phenylsulfonyl) -1H-indole-2-carboxylate; 42 (R)

Prepared according to the general procedure of deprotection of tert butylsulfinimines, 38 (SR) (0.18 g, 0.29 mmol).

The crude product obtained is purified by flash chromatography on silica gel (CH ₂ Cl ₂ / MeOH 10/0 to 9/1) making it possible to obtain the desired product in the form of a mixture of 2 atropoisomers (1 / 1.3 ) with 97% efficiency.

Characteristics :

R _f 0.20 (CH ₂ Cl ₂ / MeOH 97/3)

LR. (without solvent, cm ^-1 ) v 1734; 1448, 1371, 1259, 1187, 748

1 H NMR (300 MHz, CDCl ₃ ) δ 8.15 (d, J = 8.2 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 8.11 (d, J = 8.2 Hz, 2H), 7.97 (d, J = 8.2 Hz, 2H), 7.83 (d, J = 7.7 Hz, 1H), 7.70 (d, J = 7.7 Hz, 1H), 7.56 (t, J = 7.3 Hz, 1H), 7.56-7.41 ( m, 5H), 7.51-7.38 (m, 4H), 7.37-7.24 (m, 1H), 7.31-7.25 (m, 1H), 7.27-7.13 (m, 6H), 7.11 (t, J = 7.9 Hz, 1H), 7.07-7.01 (m, 2H), 6.95-6.88 (m, 2H), 6.91 (t, J = 7.5 Hz, 2H), 6.59 (d, J = 7.4 Hz, 1H), 6.48 (d , J = 7.0 Hz, 2H), 4.30-4.16 (m, 2H), 4.26 (q, J = 7.0 Hz, 2H), 4.03 (dd, J = 10.0 Hz, J = 2.8 Hz, 1H), 3.92 (t , J = 7.2 Hz, 1H), 3.27 (brs, 2H), 2.89 (d, J = 7.2 Hz, 2H), 2.91 (dd, J = 13.2 Hz, J = 2.8 Hz, 1H), 2.58 (dd, J) = 13.2 Hz, J = 10.0 Hz, 1H), 1.60 (brs, 2H), 1.13 (t, J = 7.0 Hz, 3H), 1.11 (t, J = 7.3 Hz, 3H)

1 ³ C NMR (75 MHz, CDC1 ₃₎ δ 162.2 (C), 162.0 (C), 145.2 (C), 143.9 (C), 139.2 (C), 138.2 (C), 138.0 (C), 137.2 (C ), 136.5 (C), 136.0 (C), 134.1 (CH), 134.0 (CH), 130.8 (C), 130.7 (CH), 129.8, 129.7, 129.4, 129.3, 129.2, 129.1, 129.0, 129.0, 129.0, 128.7, 128.7, 128.4, 128.2, 127.4, 127.3, 127.1, 127.0, 127.0, 127.0 (CH), 126.8 (CH), 126.5 (CH), 126.3 (C), 126.1 (CH), 125.9 (CH), 124.8 ( CH), 124.5 (CH), 121.6 (CH), 121.0 (CH), 115.3 (CH), 115.1 (CH), 62.4 (CH ₂ ), 62.1 (CH ₂ ), 54.0 (CH), 53.7 (CH), 45.4 (CH ₂ ), 43.8 (CH ₂ ), 13.7 (2CH ₃ )

MS m / z 525 [(M + H) ⁺ ]

HRMS m / z [(M + H) ^+] calcd for C ₂₉ N ₃ iH ₂ 0 ₄ S 525.1848 525.1837 found. Example 33 3- (2 - ((R) -1-aminoallyl) phenyl) -1- (phenylsulfonyl) -1H-indole-2-carboxylic acid ethyl ester; 43 (R)

Prepared according to the general procedure for the deprotection of tert-butylsulfinimines, 39 (SR) (0.20 g, 0.35 mmol).

The crude product obtained is purified by flash-chromatography on silica gel

(CH ₂ Cl ₂ / MeOH 10/0 to 9/1) making it possible to obtain the desired product in the form of a mixture of 2 atropoisomers (1 / 1.4) with a yield of 85%.

Characteristics :

R _f 0.60 (CH ₂ Cl ₂ / MeOH 9/1)

LR. (without solvent, cm ^-1 ) v 1722, 1445, 1370, 1307, 1258, 1180, 748

1H NMR (300 MHz, CDCl ₃ ) δ 8.19-7.90 (m, 6H), 7.61-7.32 (m, 12H), 7.28-6.97 (m, 8H), 5.99-5.71 (m, 2H), 5.09-4.67 ( m, 4H), 4.35-4.08 (m, 6H), 1.54 (bs, 4H), 1.02-0.98 (2 t, 7 = 7.0 Hz, 6H)

¹³ C NMR (75 MHz, CDCl ₃ ) δ 161.9 (C), 161.7 (C), 144.6 (C), 144.2 (C), 141.5 (CH), 140.9 (CH), 137.6 (C), 137.5 (C) , 136.3 (C), 136.3 (C), 134.1 (CH), 134.0 (CH), 130.7, 130.5, 130.4, 130.0, 129.4, 129.3, 129.2, 127.9, 127.7, 127.4, 127.1, 127.0, 127.0, 126.9, 126.6 , 124.7 (CH), 124.6 (CH), 121.5 (CH), 121.0 (CH), 1 15.4 (CH), 1 15.4 (CH), 113.9 (CH ₂ ), 112.9 (CH ₂ ), 62.2 (CH ₂ ) , 61.9 (CH ₂ ), 54.4 (CH), 54.1 (CH), 13.8 (CH ₃ ), 13.7 (CH ₃ )

MS w / 461 [(M + H) ⁺ ]

HRMS m / z [(M + H) ⁺ ] calcd for C ₂₆ H ₂₅ N ₂ O ₄ S 461.1535 found 461.1548

Example 34 Ethyl 3- (2 - ((R) -1-aminopent-4-enyl) phenyl) -1- (phenylsulfonyl) -1H-indole-2-carboxylate; 44 (R)

Prepared according to the general procedure for the deprotection of tert-butylsulfinimines, 40 (SR) (0.20 g, 0.34 mmol).

The crude product obtained is purified by flash-chromatography on silica gel

(CH ₂ Cl ₂ / MeOH 10/0 to 9/1) making it possible to obtain the desired product in the form of a mixture of 2 atropoisomers (1/1 .3) in the form of a white foam with a yield of 87% . Characteristics :

R _f 0.55 (CH ₂ Cl ₂ / MeOH 9/1)

LR. (neat, cm ^"1) v 1720, 1446, 1370, 1307, 1256, 1186, 1140, 748 1H NMR (300 MHz, CDC1 ₃₎ δ 8.20-7.95 (m, 6H), 7.69-7.40 (m, 12H ), 7.32-7.05 (m, 8H), 5.69-5.31 (m, 2H), 4.93-4.60 (m, 4H), 4.37-4.12 (m, 4H), 3.77-3.61 (m, 2H), 2.44 (s). broad, 4H), 1.93-1.45 (m, 8H), 1.14-1.11 (2t, 7 = 7.2 Hz, 6H)

1 ³ C NMR (75 MHz, CDC1 ₃₎ δ 162.0 (C), 161.8 (C), 145.7 (C), 145.3 (C), 138.1, 137.8, 137.8, 137.3, 136.6, 136.0, 134.0, 134.0, 130.9, 130.7, 130.1, 130.0, 129.6, 129.5, 129.3, 129.2, 129.0, 128.7, 128.5, 127.4, 127.4, 127.4, 127.3, 127.2, 126.9, 126.7, 126.7, 125.9, 125.7, 124.7, 124.6, 121.5, 121.0, 115.6, 115.2, 114.4, 114.3, 62.3 (CH ₂ ), 62.0 (CH ₂ ), 51.8 (2CH), 38.4 (CH ₂ ), 36.7 (CH ₂ ), 30.6 (CH ₂ ), 30.4 (CH ₂ ), 13.8 ( CH ₃ ), 13.7 (CH ₃ )

MS m / z 488 [(M + H) ⁺ ]

HRMS m / z [(M + H) ⁺ ] calcd for C ₂₈ H ₂₉ N ₂ O ₄ S 489.1848 found 489.1859 Example 35: (R) -5-Phenyl-5,8-dihydroindolo [2,3-d] [2] benzazin-7 (6H) -one; 45

(R)

Prepared according to the general procedure for the preparation of Lactams B, 41 (R) (0.10 g, 0.20 mmol).

The crude product obtained is purified by flash chromatography on silica gel (CH ₂ Cl ₂ / MeOH 10/0 to 9/1) to give the desired lactam as a white foam with a yield of 63%.

Characteristics :

R _f 0.55 (CH ₂ Cl ₂ / MeOH 9/1)

LR. (without solvent, cm- ¹ ) v 3235, 1634, 1534, 1502, 1469, 1413, 1332, 1275, 740, 721

1H NMR (500 MHz, DMSO-D ₆ -90 ° C) δ 11.50 (bs, 1H), 8.53 (bs, 1H), 8.03 (d, J = 7.6 Hz, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.58-7.50 (m, 1H), 7.49-7.43 (m, 1H), 7.41-7.32 (m, 2H), 7.28-7.21 (m, 1H), 7.19-7.01 (m, 6H). , 5.60-5.53 (m, 1H)

1 ³ C NMR (125 MHz, DMSO-D ₆ -90 ° C) δ 163.3 (CO), 140.5 (C), 139.2 (C), 136.6 (C), 132.8 (C), 130.2 (C), 129.2 ( CH), 128.2 (CH), 128.0 (CH), 127.8 (2CH), 126.7 (CH), 126.4 (CH), 126.3 (2CH), 124.5 (C), 124.0 (CH), 120.9 (CH), 120.4 (CH), CH), 116.2 (C), 112.6 (CH), 58.8 (CH)

MS m / z 325 [(M + H) ⁺ ]

HRMS m / z [(M + H) ⁺ ] calcd for C ₂₂ H ₇ N ₂ 0 325.1341 found 325.1331

[a] _D = +62.6 (acetone, c = 0.32).

Anal. Calculated (%) for C ₂₂ Hi ₆ N ₂ O.0.45 H ₂ 0: C, 79.47; H, 5.12; N, 8.43; found C, 79.74; H, 5.49; N, 8.12 Example 36: (R) -5-Benzyl-5,8-dihydroindolo [2,3-dl [21benza-zepin-7fH) -one 46 (R)

Prepared according to the general procedure for the preparation of Lactam B, 42 (R) (0.12 g, 0.23 mmol).

The crude product obtained is purified by flash chromatography on silica gel (CH ₂ Cl ₂ / MeOH 10/0 to 9/1) to give the desired lactam in the form of a white foam with a yield of 72%.

Characteristics :

R _f 0.65 (CH ₂ Cl ₂ / MeOH 9/1)

LR. (neat, cm ^-1 ) v 3235, 1630, 1524, 1495, 1464, 1404, 1331, 743

1H NMR (500 MHz, DMSO-D ₆ -90 ° C) 1 δ 1.66 (bs, 1H), 8.06 (d, J = 7.6 Hz, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.92 (s wide, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.53-7.38 (m, 2H), 7.37-7.28 (m, 2H), 7.28-7.05 (m, 6H), 4.53-4.41 ( m, 1H), 3.06-2.85 (m, 2H)

1 ³ C NMR (125 MHz, DMSO-D ₆ -90 ° C) δ 162.5 (CO), 139.3 (C), 138.6 (C), 136.9 (C), 132.8 (C), 130.4 (C), 129.1 ( 2CH), 128.1 (2CH), 127.9 (CH), 127.6 (CH), 126.3 (2CH), 126.1 (CH), 124.6 (C), 124.2 (CH), 120.9 (CH), 120.6 (CH), 1 16.0 (C), 1 12.7 (CH), 55.5 (CH), 37.0 (CH ₂ )

MS w / 361 [(M + Na) ⁺ ]

HRMS m / z [(M + Na) ^+] calcd for C ₂₃ Hi ₈ N ₂ ONa 361.1317 found 361.1331

[α] δ = -8.8 (acetone, c = 0.53).

Anal Calcd (%) for C ₂₃ Hi ₈ N ₂ O.0.4 H ₂ 0: C, 79.93; H, 5.48; N, 8.1%; found C, 80.04; H, 5.56; N, 7.71.

Example 37: R) -5-Vinyl-5,8-dihydroindolo [2,3-d] [2] benzazin-7 (6H) -one; 47 (R)

Prepared according to the general procedure for the preparation of B, 43 (R) Lactams (0.10 g, 0.22 mmol).

The crude product obtained is purified by flash chromatography on silica gel (CH ₂ Cl ₂ / MeOH 10/0 to 9/1) to give the desired lactam in the form of a white foam with a yield of 42%.

Characteristics :

R _f 0.55 (CH ₂ Cl ₂ / MeOH 9/1)

LR. (without solvent, cm ^-1 ) v 3200, 1626, 1525, 1496, 1464, 1410, 1332, 1298, 740

1 H NMR (300 MHz, MeOD) δ 8.15-7.97 (m, 2H), 7.64-7.30 (m, 5H), 7.27-7.16 (m,

1H), 6.82-5.65 (m, 1H), 5.65-5.19 (m, 1H), 5.48-5.15 (m, 2H)

¹³ C NMR (125 MHz, MeOD) δ 165.9 (CO), 140.4 (C), 138.6 (C), 137.0 (CH), 134.1 (C), 130.3 (C), 129.7 (CH), 129.1 (CH), 128.6 (C), 128.0 (CH), 126.3 (CH), 126.0 (CH), 122.4 (CH), 121.9 (CH), 19.7 (C), 17.5 (CH ₂ ), 13.6 (CH), 59.4 (CH)

MS m / z 297 [(M + Na) ⁺ ]

HRMS m / z [(M + Na) ^+] calcd for Ci ₈ Hi ₄ N ₂ ONa 297.1004 found 297.0997

[a] _D = -19.0 (acetone, c = 0.23)

Example 38: (7?) - 5- (3-butenyl) -5,8-dihydroindolo [2,3-d] [2] benzazin-7 (6H) -one;

48 (R)

Prepared according to the general procedure for the preparation of Lactam B, 44 (R) (0.13 g, 0.27 mmol).

Characteristics :

R _f 0.40 (CH ₂ Cl ₂ / MeOH 95/5)

LR. (without solvent, cm ^-1 ) v 3235, 1625, 1521, 1495, 1463, 1403, 1331, 741

1H NMR (500 MHz, DMSO-D ₆ -90 ° C) δ 11.63 (bs, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.98 (d, J = 7.3 Hz, 2H), 7.59 ( d, J = 8.2 Hz, 1H), 7.51-7.40 (m, 2H), 7.40-7.26 (m, 2H), 7.24-7.14 (m, 1H), 5.86-5.73 (m, 1H), 5.03-4.88 ( m, 2H), 4.20-4.09 (m, 1H), 2.29-1.85 (m, 4H)

¹³ C NMR (125MHz, DMSO-D ₆ -90 ° C) δ 162.7 (CO), 139.4 (C), 137.7 (CH), 136.8 (C), 132.8 (C), 130.4 (C), 127.8 (CH) , 127.5 (CH), 126.4 (CH), 124.6 (C), 124.1 (2CH), 120.9 (CH), 120.5 (CH), 116.0 (C), 115.0 (CH ₂ ), 112.8 (CH), 54.0 (CH), ), 30.4 (CH ₂ ), 30.2 (CH ₂ )

MS m / z 325 [(M + Na) ⁺ ]

HRMS m / z [(M + Na) ^+] calcd for C ₂₀ Hi ₈ N ₂ ONa 325.1317 found 325.1324

[a] _D = +51.2 (acetone, c = 0.41)

Anal Calcd (%) for C ₂₀ Hi ₈ N ₂ O.0.4 H ₂ 0: C, 77.60; H, 6.12; N, 9.05; found C, 77.71; H, 6.22; N, 8.78

Example 39: Cytotoxic activities

The newly synthesized compounds were first tested for cytotoxicity against HCT 116 (human colon cancer) cells and the results were compared to those obtained with comoed 14, colchicine and NAC.

1: Colchicine 8: NAC Table 1: IC50 Cytotoxicity of Compounds in HCT1 16 and HUVEC Cells

only 25% inhibition at 10 mg / mL

From these results, we can see that:

1) Although a C5 phenyl group gives a completely inactive product (45 (R)), its replacement with a benzyl group provides a highly cytotoxic product (46 (R), IC ₅₀ = 70 nM)

2) The 5-vinyl derivative (47 (R)) is more than 4-fold more active (IC ₅₀ = 15 nM) than the benzyl derivative (46 (R)) while the prolongation of the 1-butenyl chain (48 (R)) gives a product as active (65 nM) as the benzyl derivative 46 (R). These two results suggest a great possibility of modulating the cytotoxic activity of this family of molecules by modifying the nature of the C5 substituent. 3) Hydroxylated derivatives (R) and (5) proved to be the most cytotoxic in the series with IC _50's of 7 nM and 18 nM respectively (compared to 40 nM for derivative 14 without OH). On the other hand, all the benefit of this OH group is lost if substituents are also introduced on the second phenyl ring (33, 34, whose IC ₅₀ are 170 nM, 220 nM and 4000 nM, respectively).

4) The phosphate derivative 27 (R) and its water-soluble disodium salt 28 (R) are both almost as cytotoxic (IC ₅₀ of respectively 18 nM and 24 nM) as the hydroxy compound (R). This supports the hypothesis that compounds 27 (R) and 28 (R) are transformed by phosphatases present in the cell medium to give 25 (R).

5) The most active compounds (25 (R) and 25 (5), 27 (R) and 28 (R)) were also tested on human umbilical cord endothelial cells (HUVEC). The results obtained indicate that all the molecules tested showed an equivalent cytotoxicity (respectively, 14 nM, 29 nM, 7 nM and 17 nM) to that visualized on the malignant cells.

The most active of these racemic mixture compounds of (R) and (5) was also tested on other cancer cell lines including skin melanoma, small cell lung cancer and cancer. breast (Table 1). This compound has a cytotoxic activity at least equivalent (50-70 nM) or even higher (see, 9 nM in B 16F 10 cells) to those of the reference products (colchicine and NAC).

Table 2: Antiproliferative activities of the racemic mixture of 25 (R) and 25 (5) on different cancer cell lines after 72 hours of treatment (IC ₅₀ , nM)

Cell lines: B 16F 10 = melanoma of the skin

A549 = non-small cell lung cancer

MDA-MB435, MDA-MB231 = breast cancer Example 40: Inhibition of the polymerization of tubulin

We have already demonstrated that compound 14, possessing a C5 ethyl-type alkyl chain, is an excellent inhibitor of tubulin polymerization in vitro (IC ₅₀ = 1.9 μΜ) ¹⁷ and more active than colchicine (2, 2 μΜ) or NAC (1.9 μΜ) (Table 3). As for cytotoxicity, the compounds possessing a C5 (47 (R), 48 (R)) unsaturated chain are also very good inhibitors (respectively 4, 1 and 2.2 μΜ) while the presence of a very strong cumbersome as C5 benzyl (46 (R)) does not decrease this activity (2.4 μΜ). On the other hand, the 5-phenyl derivative 45 (R) is ten times less active on tubulin (23 μl) and this result can be correlated with the lack of cytotoxicity presented by this same compound as well as the compound 27 (R). Among the phenolic derivatives (25 (R), 25 (S), 33, 34, 35), the derivatives (R) and 25 (S) are the most active (respectively 3.2 and 1.8 μΜ). It is interesting to note that the disodium phosphate derivative of (R), i.e., compound 28 (R), weakly inhibits tubulin polymerization (13 μl) although it is highly cytotoxic ( 24 nM). This result is expected since the tubulin preparation used in the tests does not contain phosphatases that can regenerate the active product (R), unlike the presence of these enzymes in the cells used in this study.

Table 3: Inhibition of Tubulin Polymerization by Table 1 Compounds

Compound ΟΙ50 (μΜ)

1 (Colchicine) 2.2

8 (NAC) 3

14 1.9

25 (R) 3.2

25 (5) 1.8

49 7.4

50 4, 1

51 NA ¹

21 {R) -

28 (R) 13

45 (R) 23 47 (R) 4.1

46 (R) 2.4

48 (R) 2.2

only 25% inhibition at 10 mg / mL

Example 41: Study of the effects of a racemic mixture of 25 (R) and 25 (S) on vascular models

The effect of the racemic mixture of (R) and (5) was first evaluated on endothelial cell morphology (HUVEC, human umbilical cord endothelial cells). HUVECs were incubated for 40 minutes with the racemic mixture of (R) and (5) at concentrations ranging from 10 ^-5 to 10 ^-9 M and the results obtained were compared with those of colchicine and ZD 6126. tested at the same concentrations. Microscopic observations of the stained cells made it possible to demonstrate changes in the morphology of cells treated with the racemic mixture of 25 (R) and 25 (5), just as with colchicine and ZD 6126. These changes in morphology visualized from a concentration of 0, 1 μΜ, were more pronounced when the concentration is greater than 1 μΜ (see Figure 1).

Another in vitro study was performed on Matrigel (a basement membrane preparation containing growth factors and allowing endothelial cell organization into vascular tubes) to determine the capacity of the racemic mixture of 25 (R) and 25 ( 5) to disrupt already formed vascular structures. The racemic mixture of (R) and (5) was added at a concentration of 0.1 μM in Matrigel carrying well formed capillaries for 18 hours. After 3 hours of treatment, significant destruction of the vascular network on the Matrigel is observed (see Figure 2). This effect is even more important after 6 hours of treatment. All of these results suggest that the racemic mixture of (R) and (5) has a strong anti-vascular activity.

Although promising, the lack of solubility of the compound (R) in aqueous media has made the study of its biological activities difficult and has therefore hampered the in vivo evaluation of this molecule. Indeed, the first attempts to study the antitumor activity of 25 (R) in mice have not been conclusive. That is why we have developed a water-soluble form of this molecule, phosphate 28 (R) in the form of its disodium salt, whose anti-vascular and anti-tumor activities are described below. Example 42: Study of the effects of the water-soluble 28 (R) compound in ovo

The in ovo experimental model based on human tumor grafting on the chicken embryo chorioallantoic membrane (CAM), which is a richly vascularized tissue, allows in a few days to evaluate the tumor progression and the vascularization level. of the tumor. By simply applying to the tumor, the ability of new therapeutically effective molecules to modulate tumor growth via their effects on angiogenesis and tumor vascularization can thus be easily measured. Thus, the anti-vascular activity of the disodium salt of the phosphate derivative of the compound (R), i.e., the compound (R), has been studied on the growth of a solid tumor (human glioblastoma) grafted on the chorioallantoic membrane of the chicken embryo. Five j bear after transplantation, when the tumor has grown and becomes vascularized, compound 28 (R) was deposited at different concentrations (2x10 ^"4 M, ^{2x10" 5} M, 2x10 ^"6 M) in a volume of 40 μl on the surface of the tumor formed Tumor images were taken at day 0 (before treatment) and then every 24 hours after the addition of compound 28. This test was carried out on 20 carrier eggs Tumors in exactly the same conditions observed that a single treatment with the compound 28 (R) at the concentration of 2 × 10 ^-4 M induces a massive haemorrhage at the level of the grafted tumor which indicates an important anti-vascular activity of this compound (see Figure 3).

Images of histological sections made from control glioblastoma and treated with 28 (R) were then analyzed (see Figure 4). These photos confirm that a single treatment with the product 28 (R) at the concentration of 2x10 ^-4 M induces massive hemorrhage at the tumor.

Example 43: Study of the antitumor effects of 28 (R) in vivo in transplanted mice.

In view of the excellent results obtained with compound 28 (R) in anti-vascular models, the anti-tumor activity of this compound was tested in vivo in female mice bearing breast tumor ETM6 grafted subcutaneously. Ten days after the transplantation, the mice bearing homogeneous tumors with a size of about 200 mm ³ were selected and divided into two groups: controls and treated. Compound 28 (R) in solution in saline was administered intraperitoneally at a dose of 50 mg / kg once daily for four consecutive days from day 10 to day 13 of tumor growth. The group of control mice received injections of only physiological saline according to the same experimental protocol. The animals were sacrificed three weeks after the graft when the tumors reached a volume of 1500 mm ³ and the tumors were removed and weighed. The results of two experiments show that the administration of compound 28 (R) consistently induces a 50% decrease in tumor mass compared to controls. These results demonstrate that compound 28 (R) has significant antitumor activity (see Figure 5).

CONCLUSION: (R) - and (, S) -5-alkyl-5,8-dihydroindolo [2,3-i] [2] benzazepin-7 (6H) -des are known for their cytotoxic and antimitotic activities, inhibiting the polymerization of tubulin into microtubules. This activity is largely influenced by the R or S configuration of the C-5 alkyl substituent. We therefore describe here a new stereocontrolled synthesis of these molecules making it possible to obtain only one of the two enantiomers. We also show that the replacement of the C-5 alkyl group by an unsaturated unit (vinyl, butenyl, benzyl, etc.) provides molecules that are also (or even more) active at the cytotoxic and antimitotic levels.

The lack of solubility of these compounds in aqueous media limits their use in vivo for anti-tumor treatments. Indeed, the first attempts in this direction have not been conclusive. We thus show here that the introduction of an OH function at the Cl-position of the 5-alkyl 5,8-dihydroindolo [2,3- <i] [2] benzazepin-7 (6H) -one ring has the effect of 1) to provide products as cytotoxic as analogs without OH function, 2) which can inhibit the polymerization of tubulin even more strongly than the control molecules, colchicine and ZD 6126 and 3) demonstrate very pronounced anti-vascular properties. Significantly, the OH function can be used to form water-soluble salts, for example disodium salt-form phosphate 28 (R) for evaluating the antitumor effects of these molecules in vivo. Thus, it has been shown that the in vivo treatment of Mice carrying ETM6 mammary tumors grafted subcutaneously for 4 days at a daily dose of 50 mg / kg induces a 50% reduction in the tumor mass, presumably via the strongly anti-vascular effect of this molecule. Example 44: Test results facts in silico

In silico modeling studies, using the GOLD software (Verdonk et al., Proteins, 2003, 52, 609-623), were performed to identify the mode of attachment of the (R) - type compounds. (S) -14 with the colchicine site from the tubulin X-ray structure (PDB code 1 SA0) complexed with colchicine. These studies demonstrate that the C5 alkyl substituents of compounds 14 occupy the same pocket as the C-ring of colchicine and favorable hydrophobic interactions with this pocket could explain the better biological activity of these compounds compared to unsubstituted C5 derivatives. This docking model also shows that significant steric interactions with the pocket result from the incorporation of substituents at the 2 and / or 3 positions of the benzene ring of compound 14 thus explaining the low activity of such molecules (for example, compounds 33, 34, 35). On the other hand, this model also indicates that the incorporation of substituents at the Cl and / or C4 positions of the same benzene ring should not have any adverse steric interactions with tubulin and could even offer additional attachment points that favor Fixing of ol oleum on the tubular.

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Claims

1. Water-soluble indole derivatives having the general formula (A):

(AT)

in which:

RI represents a hydroxyl group, phosphate, organophosphate, sulfate, organo sulfate, nitro, carboxylic acid, carboxylate, amine, ammonium, alkyl amine to C ₆ linear or branched, ammonium alkyl linear C ₆ or branched, amino acid, a peptide chain of 2 to 10 amino acids, a group of formula (B) linked by the bond *:

O

R6 R7

(B)

in which :

R2 represents a hydrogen atom, an alkyl group at C _4,

R4 represents a hydrogen atom, halogen, hydroxyl, nitro, carboxylic acid, carboxylate, amine, ammonium, alkyl amine -C ₆ linear or branched, linear or branched C ₁ -C ₆ alkyl, alkoxy

Ci to C ₆ linear or branched, an amino acid,

2. Compound (A) according to claim 1, characterized in that:

RI is a phosphate or organophosphate group of formula (D)

sulphate or organosulfate group of formula (E) linked by the bond *:

0

I 0

- 0-P = 0 _* I l

I - O-S-O-R10

0 ^ I l

R9 0

(D) (E)

wherein,

C ₂ to C ₆ , a potassium ion, a sodium ion or a cesium ion;

Compound (A) according to claim 1 or 2, characterized in that the carbon (5) is of configuration R only.

4. Compound (A) according to claim 3, characterized in that R ₁ represents a phosphate group (D) in which R ₈ and R ₉ are sodium ions,

R2 represents a hydrogen atom,

- R3 is alkyl to C ₄ linear or branched;

R4 represents a hydrogen atom,

R5 represents a hydrogen atom,

the carbon (5) is of configuration R only.

5. Compound (A) according to claim 1, characterized in that:

- RI represents a hydroxyl group,

R2 represents a hydrogen atom,

- R3 is alkyl to C ₄ linear or branched;

R4 represents a hydrogen atom,

R5 represents a hydrogen atom,

the carbon (5) is of configuration R only.

6. Compound (A) according to claim 1, characterized in that

- R3 represents a benzyl group;

and the carbon (5) is of configuration R only.

7. Compound (A) according to claim 1 characterized in that:

R 3 represents an ethylene, or a propyl-2-ene,

and the carbon (5) is of configuration R only. 8. Process for obtaining salts of compound (A) according to claim 1, characterized in that the compound of formula

(AT)

in which:

RI represents a hydroxyl group,

R2 represents a hydrogen atom, an alkyl group at C _4,

1 - reaction phosphitylation or sulfonation of the RI group,

3 - salt formation.

9. Method according to claim 8, characterized in that:

step 1 is made from phosphoramidite, optionally followed by oxidation.

10. Process according to claim 8 or 9, characterized in that:

step 2 is carried out in an acidic condition, preferably with TFA.

11. Method according to any one of claims 8 to 10, characterized in that: step 3 of forming the salt is done with an ion exchange resin, preferably DOWEX® Na type.

12. A compound according to any one of claims 1 to 7 for use as a medicament.

13. A compound according to any one of claims 1 to 7 for use as an anticancer agent. A compound according to any one of claims 1 to 7 for use in targeting the tumor vasculature.

15. An injectable composition comprising a compound according to any one of claims 1 to 7.

16. The injectible composition of claim 15 further comprising a pharmaceutical carrier.