Antibacterial compounds that eliminate dormant bacterial cells

Abstract

The present invention relates to a compound of formula (I) or its pharma- ceutically acceptable salt and / or solvate.The present invention further relates to the use of the compound of the present invention as an anti-infective agent.In particular, the compound of the present invention can be used as an antibacterial and / or anti-persistent agent, especially for the treatment of infectious diseases.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to aminosteroid derivatives of formula (I) for use as anti-infective agents, in particular for use as antibacterial and / or anti-persistent agents. The compounds of the present invention are particularly useful in the treatment of infectious diseases. [Background technology]

[0002] 2. Background of the Invention Bacteria cause many infectious diseases that are harmful and sometimes fatal to humans and animals. For many reasons, including the overuse of antibiotics, more and more bacterial strains are multi-drug resistant, which severely limits the efficiency of treating bacterial infectious diseases. However, drug resistance is not the only cause of the loss of efficacy of antimicrobial drugs. In fact, even high doses of antimicrobial drugs may not be able to eliminate "dormant" cells, especially persisters and viable but non-culturable cells (VBNCs). Viable dormant cells play an important role in recurrence of infections. In addition to limiting the effectiveness of antimicrobial drugs, dormant cells may be involved in chronic diseases. In contrast to drug resistance, the persistence and activation of dormant cells are strongly related to individual and environmental factors.

[0003] Few options are currently available to eliminate dormant cells, as most treatments are designed to kill active cells. One strategy to specifically target persisters is the use of drugs, e.g., antimicrobial peptides, that directly interact with cell membranes and are therefore effective even against metabolically inactive bacteria. Another option is to first reactivate dormant cells, e.g., by sugars, and then eliminate the reactivated cells using common antibacterial drugs. However, these methods have limited applicability, and no therapeutic solutions favorable to persister elimination are available so far.

[0004] Squalamine was isolated in 1993 from the tissues of the small shark Squalus acanthias and has the following formula: [ka] It is a natural compound.

[0005] It is an active substance that exhibits antiangiogenic activity, especially against cells, as well as strong antiviral and antibacterial activity. Squalamine has also proven to be effective against antimicrobial-resistant bacteria, such as Gram-negative and Gram-positive bacteria. Chemically, squalamine is a polycationic aminosterol: it contains a non-polar central part (cholestane type) and two polar ends, namely a polyamine chain and a sulfate group. It therefore has amphiphilic properties and is also water-soluble. Squalamine was initially considered interesting due to its antiangiogenic and antimicrobial properties against various Gram-positive bacteria (Staphylococcus aureus, Enterococcus faecalis) and Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa), fungi (Candida albicans, Candida tropicalis) and protozoa.

[0006] Since natural sources of squalamine are very limited, derivatives or analogs of squalamine have been synthesized and studied. In particular, aminosteroid analogs containing polyamine chains at the 3- or 7-positions on the 10,13-dimethyl-17-octane-cholestane or cholestene ring are represented by the formulae a, b, c, and d below. [ka] (WO2011 / 067501 A1, Brunel, J.-M. et al.).

[0007] These compounds have squalamine-like antibacterial activity against various drug-resistant gram-positive and gram-negative bacteria (WO 2011 / 067501, Brunel, J.-M. et al.). These derivatives have been proposed for use in the curative treatment of pulmonary infections, particularly by the aerosol route. However, it has been observed that some of these compounds exhibit significant cytotoxicity. Furthermore, the compounds of formula IIc and IId above have weak activity against some gram-negative bacteria, such as E. coli. Furthermore, no antipersistent effect has been reported for these molecules.

[0008] Thus, there remains a need for new derivatives or analogs of squalamine that exhibit improved biological and / or chemical properties, preferably analogs of squalamine that have anti-persistent activity.

[0009] The applicant has identified that novel squalamine analogs, i.e., aminosteroid derivatives of formula (I), exhibit good antibacterial activity against various gram-positive and gram-negative bacteria and / or have low cytotoxicity.In particular, the compounds of the present invention can be used as antipersistent agents.Compared to squalamine, the compounds of the present invention are also more simply synthesized. Summary of the Invention [Problem to be solved by the invention]

[0010] [Means for solving the problem]

[0011] The present invention relates to a compound represented by formula (I) [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined herein) or a pharma- ceutically acceptable salt and / or solvate thereof. Effect of the Invention

[0012] According to one embodiment, the compound according to the invention is selected from the following: and pharma- ceutically acceptable salts and / or solvates thereof: [Table 1] TIFF2025513630000006.tif238159TIFF2025513630000007.tif239159TIFF20255136300 00008.tif236159TIFF2025513630000009.tif235159TIFF2025513630000010.tif121159

[0013] The present invention further relates to pharmaceutical compositions comprising a compound according to the invention and at least one pharma- ceutically acceptable carrier.

[0014] The present invention further relates to a compound or pharmaceutical composition according to the invention for use as a medicament.The present invention further relates to a compound or pharmaceutical composition according to the invention for use in the treatment of an infectious disease, preferably in the treatment of a bacterial, viral, fungal or parasitic disease.According to one embodiment, the infectious disease is selected from cystic fibrosis, urinary tract infection and chronic otitis media, and / or is a bacterial or fungal disease caused by a gram-positive bacterium selected from Staphylococcus, Enterococcus and Mycobacterium.

[0015] The present invention further relates to a compound selected from the following and pharma- ceutically acceptable salts and / or solvates thereof, for use as an antipersistent agent in the treatment of an infectious disease, preferably in the treatment of a bacterial or fungal disease: [Table 2]

[0016] The present invention further relates to the non-therapeutic use of the compounds according to the invention as anti-infective agents for the disinfection of surfaces and / or the clarification of liquids, preferably as anti-persister agents for the disinfection of surfaces and / or the clarification of liquids, wherein the surface or liquid is not part of the human or animal body.

[0017] The present invention further relates to a process for preparing a compound according to the invention, comprising the steps of: (a) reacting a carboxylic acid function at position 20 of a bile acid with a secondary amine function of an amino acid, thereby obtaining an amide; (b) oxidizing a hydroxyl (OH) at position 3 of the bile acid intermediate obtained in step (a), thereby obtaining a ketone; (c) converting the ketone of the bile acid intermediate obtained in step (b) into a compound of formula R 6 (c) reacting NH with a primary amine, thereby obtaining an imine; and (d) reducing the imine obtained in step (c), thereby obtaining a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof.

[0018] definition In the present invention, the following terms have the following meanings. Chemical Substance Definitions When a chemical substituent is a combination of chemical groups, the point of attachment of the substituent to the molecule is through the last chemical group listed to the right of the name of the substituent. For example, an arylalkyl substituent is linked to the remainder of the molecule through an alkyl moiety and can be represented as follows: "aryl-alkyl-". Unless otherwise indicated, compounds were named using ChemDraw® Professional 15.0 (PerkinElmer).

[0019] "Alkoxy" refers to an alkyl-O- group.

[0020] Alkyl refers to a saturated linear or branched hydrocarbon chain typically containing 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 4 carbon atoms. In the present invention, alkyl groups can be monovalent or polyvalent (i.e., "alkylene groups" as defined herein are encompassed by the "alkyl" definition), but alkyl groups are typically monovalent. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl, pentyl and its isomers (e.g., n-pentyl, iso-pentyl), and hexyl and its isomers (e.g., n-hexyl, iso-hexyl). Preferred alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl.

[0021] "Alkylene" refers to a divalent alkyl group. Non-limiting examples of alkylene groups include methylene, ethylene, n-propylene, i-propylene, divalent butyl, divalent pentyl, and divalent hexyl. Preferred alkylene groups include methylene, ethylene, n-propylene, n-butylene, and n-butylene.

[0022] "Amine" refers to a derivative of ammonia (NH3) in which one or more hydrogen atoms have been replaced with a substituent such as, for example, alkyl or aryl.

[0023] "Aryl" refers to a cyclic polyunsaturated aromatic hydrocarbyl group containing at least one aromatic ring and containing 5 to 12 carbon atoms, preferably 6 to 10 carbon atoms. An aryl group may have a single ring (e.g., phenyl) or multiple aromatic rings that are fused (e.g., naphthyl) or covalently linked. The aromatic ring may optionally contain 1 to 2 additional rings (either cycloalkyl, heterocycloalkyl, or heteroaryl) fused thereto. This definition of "aryl" includes the partially hydrogenated derivatives of the carbocyclic ring systems enumerated herein, so long as at least one ring is aromatic. Non-limiting examples of aryl groups include phenyl, biphenyl, biphenylenyl, 5- or 6-tetralinyl, naphthalene-1-yl or naphthalene-2-yl, 4-, 5-, 6- or 7-indenyl, 1-, 2-, 3-, 4- or 5-acenaphthylenyl, 3-, 4- or 5-acenaphthenyl, 1- or 2-pentalenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, 1-, 2-, 3-, 4- or 5-pyrenyl. A particularly preferred aryl group is phenyl.

[0024] "Cycloalkyl" refers to a cyclic monovalent alkyl group, as defined herein, containing from 3 to 11 carbon atoms, preferably from 4 to 9 carbon atoms, and more preferably from 5 to 7 carbon atoms. This definition of "cycloalkyl" includes polycyclic cycloalkyl (e.g., bicyclic) and bridged cycloalkyl structures.

[0025] The "C" before the group name x -C y " or "(C x -C y )" means, in accordance with common terminology in the chemical arts, that the group contains x to y carbon atoms.

[0026] "Heteroaryl" refers to an aromatic ring or ring system containing 5 to 12 carbon atoms, preferably 6 to 10 carbon atoms, having one or two rings that are fused or covalently linked, at least one ring is aromatic, and one or more carbon atoms in one or more of these rings are substituted with oxygen, nitrogen and / or sulfur atoms. The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Non-limiting examples of heteroaryl groups include furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3-d][1,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, iso ... benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3- Includes benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[1,2-a]pyridinyl, 6-oxopyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 6-oxopyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl and quinoxalinyl.

[0027] "Heteroalkyl" refers to an alkyl group, as defined herein, in which one or more carbon atoms are replaced with a heteroatom selected from oxygen, nitrogen, and sulfur. In a heteroalkyl group, the heteroatoms are bonded only to carbon atoms along the alkyl chain, i.e., each heteroatom is separated from any other heteroatom by at least one carbon atom. The nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroalkyl group may further include one or more =O and / or =S groups. The heteroalkyl is bonded to another group or molecule only through carbon atoms, i.e., the bond atom is not selected from among the heteroatoms contained therein. Non-limiting examples of heteroalkyl include alkoxy, ethers and polyethers, secondary and tertiary amines and polyamines, thioethers and polythioethers, and combinations thereof.

[0028] "Heterocycloalkyl" refers to a cyclic monovalent heteroalkyl, typically containing 2 to 7 carbon atoms, preferably 3 to 6 carbon atoms, more preferably 4 to 5 carbon atoms. Heterocycloalkyls are typically 3 to 7 members, preferably 5 or 6 members. Heterocycloalkyls are typically monocyclic or bicyclic, preferably monocyclic. This definition includes polycyclic heterocycloalkyl (e.g., bicyclic) and bridged heterocycloalkyl structures. Non-limiting examples of heterocycloalkyls include monovalent or divalent aziridine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, tetrahydrofuran, and tetrahydropyran.

[0029] "Heterocyclyl" refers collectively to "heterocycloalkyl" and "heteroaryl" groups as defined herein.

[0030] "Hydroxy" refers to the group --OH.

[0031] general definition "About" is used herein to mean approximately, approximately, around, or in the region. The term "about" before a number means more than or less than 10% of the numerical value. When used in conjunction with a numerical range, the term "about" modifies that range by extending the boundaries above and below the stated numerical values ​​by 10%.

[0032] "Administration" or variations thereof (e.g., "administering") means providing a therapeutic agent (e.g., a compound of the invention), either alone or as part of a pharma- ceutically acceptable composition, to a patient to be treated for a condition, symptom, or disease.

[0033] "Comprise" or variations thereof (e.g., "comprises", "comprising") are used herein in accordance with typical patent application drafting language. Thus, "comprise" preceding an object and followed by an element means that the presence of the element in the object is necessary (typically as a component of a composition), but does not preclude the presence of any additional element(s) in the object. Furthermore, any occurrence of "comprise" or variations thereof herein, unless otherwise stated, encompasses the narrower phrase "consisting essentially of", the even narrower phrase "consist of" and any variations thereof (e.g., "consists of", "consisting of").

[0034] "Infection" refers to the unwanted presence and / or growth of a pathogen (typically a bacterium, virus, fungus or parasite) in a subject. Such unwanted presence of a microorganism can negatively impact the health and well-being of a host patient. The term "infection" should not be construed as encompassing the normal growth and / or presence of a microorganism normally present in a subject, for example, in the digestive tract of a subject, but may encompass the pathological overgrowth of such a microorganism. An infection can be caused by the growth and / or presence of a microorganism, such as a bacterium, virus, fungus or parasite. "Chronic infection", "recurrent infection", "refractory infection" and "persistent infection" refer to a bacterial infection that is resistant to the host immune system and antibiotic treatment and is capable of reactivating into a clinically significant disease with chronic symptoms.

[0035] "Infectious disease" refers to a pathological condition or disorder resulting from an infection. Specific examples of infectious diseases include "bacterial disease", "viral disease", "fungal disease" and "parasitic disease", which are infectious diseases caused by bacteria, viruses, fungi or parasites, respectively. Therapeutic agents for the treatment of infectious diseases are "anti-infective" agents.

[0036] "Human" refers to a male or female human subject at any stage of development, including a neonate, infant, juvenile, adolescent and adult.

[0037] "Kit" or "kit of parts" are synonymous and refer to any article of manufacture (e.g., package or container) that contains a pharmaceutical composition that includes a compound according to the invention. The kit may be promoted, distributed, or sold as a unit for performing the methods of the invention.

[0038] "Persister" refers to any type of dormant variant of a normal cell, especially persisters and viable but non-culturable cells (VBNCs). Persisters are prone to cause infectious diseases. Persisters are typically bacteria, but fungal persister cells and yeast persister cells are also included in this definition. Persisters represent a small subpopulation of genetically identical metabolically slow-growing cells that spontaneously enter a dormant non-dividing state and can survive very high antibiotic doses. When the population is treated with antibiotics, the normal cells die but the persisters survive. To kill, antibiotics require an active target, which explains the resistance of persisters. In contrast, resistance mechanisms prevent antibiotics from binding to their targets. Resistance is measured by observing the ability of cells to grow in the presence of antibiotics. In most cases, the molecular mechanisms that result in persistence are unknown. As used herein, "persister cells" refers to metabolic variants of wild-type microbial cells that are phenotypically characterized by a slow growth rate that is typically 30%, 25%, 20%, 15%, 10%, 5% or less of the growth rate of their wild-type counterparts. In some embodiments, persister cells are dormant, e.g., with no detectable cell division over a 24-hour period. Furthermore, persister cells typically form colonies that are approximately 30%, 25%, 20%, 15%, 10%, 5% or less in size than colonies formed by their wild-type counterparts.

[0039] "Persister-associated infection" refers to any infection involving persister cells.

[0040] "Patient" refers to a subject awaiting medical care, or a subject receiving medical care or a subject who has been / is / will be the subject of a medical procedure, or a subject being monitored for the development of a targeted disease or condition, such as, for example, an infectious disease.

[0041] "Pharmaceutically acceptable" means that the components of the composition are compatible with each other and not harmful to the patient to whom they are administered.

[0042] A "pharmaceutically acceptable carrier" refers to an excipient that does not produce adverse, allergic, or other unpleasant reactions when administered to an animal, preferably a human. It includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. If administered to humans, preparations must meet sterility, pyrogenicity, general safety and purity standards as required by regulatory authorities, such as, for example, the FDA or EMA. Examples of pharma- ceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances (e.g., sodium carboxymethylcellulose), polyethylene glycol, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and wool fat.

[0043] "Prodrug" refers to a pharmacologically acceptable derivative of a therapeutic agent (e.g., a compound of the present invention) whose in vivo biotransformation product is the therapeutic agent (active drug). Prodrugs are typically characterized by increased bioavailability and are readily metabolized in vivo to the active compound. Non-limiting examples of prodrugs include amide prodrugs and carboxylic acid ester prodrugs, particularly alkyl esters, cycloalkyl esters, and aryl esters.

[0044] "Selected from" is used herein in accordance with common patent application drafting language to introduce a list of elements from which one or more item(s) are selected. Any occurrence of "selected from" herein may be replaced with "selected from the group including or consisting of" without changing the meaning.

[0045] "Solvate" refers to a molecular complex that includes a compound with stoichiometric or substoichiometric amounts of one or more molecules of one or more solvents, where the solvent is typically a pharma- ceutically acceptable solvent such as, for example, ethanol. The term "hydrate" refers to a solvate where the solvent is water (HO).

[0046] "Subject" refers to an animal, typically a warm-blooded animal, preferably a mammal. The term "mammal" as used herein refers to any mammal, including humans, farm and livestock animals, as well as zoo, sport, or pet animals, such as dogs, cats, cows, horses, sheep, pigs, goats, rabbits, and the like. Preferably, the mammal is a primate, more preferably a human. In one embodiment, the subject is a "patient" as defined herein. In one embodiment, the subject is an adult (e.g., a subject aged 18 years or older). In one embodiment, the subject is a child (e.g., a subject aged under 18 years). In one embodiment, the subject is a male. In one embodiment, the subject is a female. In one embodiment, the subject suffers from, and is preferably diagnosed with, an infectious disease. In one embodiment, the subject is at risk of developing an infectious disease. Examples of risk factors include, but are not limited to, a genetic predisposition to, or a family history of, an infectious disease.

[0047] "Therapeutic agent", "pharmacologically active" and "active ingredient" refer to a compound for treatment and related to health. In particular, a therapeutic agent (e.g., a compound of the present invention) may be indicated for the treatment of a disease. An active ingredient may also be indicated for the improvement of the therapeutic activity of another therapeutic agent.

[0048] A "therapeutically effective amount" (short, "effective amount") refers to an amount of a therapeutic agent (e.g., a compound of the invention) sufficient to achieve a desired therapeutic, prophylactic, or preventative effect in the patient to which it is administered, without causing significant negative or adverse side effects to the patient. A therapeutically effective amount may be administered prior to the onset of a disease, disorder, or condition for a prophylactic or preventative effect. Alternatively, or additionally, a therapeutically effective amount may be administered after the initiation of a disease, disorder, or condition for a therapeutic effect.

[0049] "Treating", "treatment", or "alleviating" refers to both therapeutic and prophylactic or preventative measures, where the objective is to prevent or slow down (reduce) the targeted condition or disorder (i.e., "disease"). Those in need of treatment include those already with the disease, as well as those susceptible to the disease or those in whom the condition or disease is to be prevented. A patient is successfully "treated" with a disease if, following administration of a therapeutic amount of a therapeutic agent (e.g., a compound according to the invention), the patient shows an observable and / or measurable reduction or absence of one or more of the following: a reduction in the number of pathogens (e.g., infectious agents); a reduction in the percentage of total cells that are pathogenic; and / or some alleviation of one or more symptoms associated with a particular disease; a reduction in morbidity and mortality, and an improvement in quality of life issues. The above parameters for assessing successful treatment and improvement of a disease are readily measurable by routine procedures well known to physicians.

[0050] Detailed Description compound The present invention relates to bile acid derivatives obtainable from the conjugation of a bile acid with a polyamine chain and a bile acid with an amino acid derivative. In the present invention, the amino acids can be natural or non-natural (e.g. synthetic or semi-synthetic). According to one embodiment, the amino acids are natural.

[0051] The present invention relates to a compound represented by formula (I) [ka] (In the formula, R 1 represents H, OH or SO3H; R 2 represents H, OH or SO3H; R 3 is H, C1-C8 alkyl, C6-C 10 Aryl or C6-C 10 represents aryl-C1-C8 alkyl; wherein the alkyl group is optionally substituted with at least one of OH, COOH, -C(O)NH2, NH2, -NH-C(=NH)-NH2, imidazolyl, indolyl, SH, S-CH3, or SeH; wherein in the aryl or arylalkyl group, the aryl is optionally substituted with at least one OH; R 4 is H, C1-C8 alkyl or C6-C 10 represents aryl; or R 3 and R 4 together with the nitrogen and carbon atoms to which they are attached form a 5-membered heterocycloalkyl; R 5 is H, C1-C8 alkyl or C6-C 10 represents aryl; R 6 is -(CR 7 R 8 ) m -[X-(CR 9 R 10 ) n ] p -NR 11 R 12 represents In the formula, R 7 , R 8 , R 9 and R 10 each occurrence independently represents H or C1-C8 alkyl; R 11 and R 12 each independently represents H, C1-C8 alkyl, or R 11 and R 12 are one to three R 13 forming a 5-7 membered heterocyclyl optionally substituted by; In the formula, R 13 represents =O or =S; X is independently at each occurrence -NR 14 -, or a divalent 5- to 7-membered heterocycloalkyl containing at least one nitrogen atom; In the formula, R 14 is H, C1-C6 alkyl or -(CH2) q -NH2; in the formula, q represents an integer ranging from 1 to 5; m is an integer ranging from 2 to 10; n is an integer ranging from 1 to 5; p is an integer ranging from 0 to 4. or a pharma- ceutically acceptable salt and / or solvate thereof.

[0052] The carbon atoms in formula (I) are represented by the formula: [ka] Based on the above carbon atom numbering, in the compound of formula (I) according to the present invention, the polyamine chain is attached at its 3-position and the amino acid is attached at its 20-position.

[0053] According to one embodiment, R 1 represents H or OH. According to one embodiment, R 2 represents H or OH. In one embodiment, R 1 stands for H, and R 2 represents OH. In one embodiment, R 1 represents OH, and R 2 represents H. In one embodiment, R 1 and R 2 and R both represent H. In one embodiment, R 1 and R 2 Both represent OH.

[0054] According to one embodiment, R 1 and R 2 represents H or OH, and their stereochemical configurations are the following bile acids: [ka] 1. As shown in any one of the following:

[0055] These bile acids may be used as starting materials for the preparation of compounds of formula (I), as described below. According to one embodiment, the bile acids are selected from deoxycholic acid, cholic acid, chenodeoxycholic acid and lithocholic acid.

[0056] According to one embodiment, R 3is H, C1-C8 alkyl, or C6-C 10 It represents aryl-C1-C8 alkyl, where the alkyl group is optionally substituted with at least one OH, COOH, -C(O)NH2, NH2, -NH-C(=NH)-NH2, imidazolyl, indolyl, SH, S-CH3 or SeH; in the arylalkyl group, the aryl is optionally substituted with at least one OH. In a preferred embodiment, the C1-C8 alkyl is unsubstituted.

[0057] According to one embodiment, R 3 represents H. According to one embodiment, R 3 represents C1-C8 alkyl. In one embodiment, R 3 represents a C1-C6 alkyl. In one embodiment, R 3 represents C1-C4 alkyl. In one embodiment, R 3 represents methyl, propyl (e.g., i-propyl), or butyl (e.g., i-butyl or s-butyl). In a preferred embodiment, R 3 represents methyl, propyl (eg, i-propyl), or butyl (eg, i-butyl or s-butyl).

[0058] According to one embodiment, R 3 represents a C1-C8 alkyl substituted with at least one substituent selected from OH, COOH, -C(O)NH2, NH2, -NH-C(=NH)-NH2, imidazolyl, indolyl, SH, S-CH3 and SeH. In one embodiment, the alkyl is substituted with exactly one substituent selected from the previous list. In one embodiment, the imidazolyl substituent is 4-imidazolyl, i.e., the imidazolyl is attached to the alkyl as in the histidine (His) amino acid. In one embodiment, the indolyl substituent is 3-indolyl, i.e., the indolyl is attached to the alkyl as in the tryptophan (Trp) amino acid.

[0059] According to one embodiment, R 3 is a C6-C aryl group optionally substituted with at least one OH; 10represents aryl-C1-C8 alkyl. In one embodiment, alkyl is C1-C6 alkyl. In one embodiment, alkyl is C1-C4 alkyl. In one embodiment, alkyl is C1-C2 alkyl. In one embodiment, aryl is substituted with exactly one OH. In one embodiment, aryl is phenyl. In one embodiment, R 3 represents phenyl-(CH2)2- or benzyl (i.e., phenyl-CH2-), where phenyl is optionally substituted with at least one OH. In one embodiment, phenyl is substituted with exactly one OH. In one preferred embodiment, R 3 represents benzyl or para-hydroxybenzyl.

[0060] According to one embodiment, R 4 represents H.

[0061] According to one embodiment, R 3 and R 4 together with the nitrogen atom and carbon atom to which they are attached form a 5-membered heterocycloalkyl. According to one embodiment, R 3 and R 4 together with the nitrogen atom and carbon atom to which they are attached form a 5-membered heterocycloalkyl containing exactly one nitrogen atom. 3 and R 4 together with the nitrogen and carbon atoms to which they are attached form a divalent pyrrolidine (eg, divalent 1,2-pyrrolidine).

[0062] According to one embodiment, R 5 represents H. According to one embodiment, R 5 represents C1-C8 alkyl. In one embodiment, R 5 represents a C1-C6 alkyl. In one embodiment, R 5 represents C1-C4 alkyl. In a preferred embodiment, R 5 represents methyl.

[0063] According to a preferred embodiment, R 7 and R 8Both represent H. According to one embodiment, R 9 and R 10 and R both represent H. In one embodiment, R 7 , R 8 , R 9 and R 10 represents H.

[0064] According to a preferred embodiment, R 11 and R 12 both represent H. In a preferred embodiment, R 7 and R 8 Both represent H, and R 11 and R 12 Both represent H.

[0065] According to one embodiment, R 11 and R 12 together with the nitrogen atom to which they are attached, optionally one to three R 13 According to one embodiment, R 11 and R 12 together with the nitrogen atom to which they are attached, optionally one to three R 13 In one embodiment, R 11 and R 12 together with the nitrogen atom to which they are attached, optionally one to three R 13 In one embodiment, the heterocyclyl forms a 5- or 6-membered heterocycloalkyl substituted with R 13 or exactly one R 13 has been replaced with.

[0066] According to one embodiment, X is -NR 14 - represents R 14 is as defined herein. In one embodiment, X represents -NH-, i.e., R 14 represents H. In one embodiment, R 14 represents a C1-C6 alkyl. In one embodiment, R 14 represents C1-C4 alkyl. In one embodiment, R14 represents methyl. In one embodiment, R 14 represents methyl. In one embodiment, R 14 Ha-(CH2) q wherein q ranges from 1 to 5. In one embodiment, q ranges from 2 to 4. In one embodiment, q is 3.

[0067] According to one embodiment, X represents a divalent 5-7 membered heterocycloalkyl containing at least one nitrogen atom. In one embodiment, the heterocycloalkyl is 5 or 6 membered. In one embodiment, the heterocycloalkyl is 6 membered. In one embodiment, the heterocycloalkyl contains at least two nitrogen atoms. In one embodiment, the heterocycloalkyl contains only nitrogen atoms as heteroatoms. In one embodiment, X represents a divalent piperazine (e.g., a divalent 1,4-piperazine).

[0068] According to one embodiment, m is in the range of 2 to 6. In one embodiment, m is in the range of 2 to 4. In one embodiment, m is 2 or 3. In one embodiment, n is in the range of 2 to 5. In one embodiment, n is 2, 3 or 4. According to one embodiment, p is in the range of 0 to 3. In one embodiment, p is 1 or 2.

[0069] According to one embodiment, R 6 is H2N-(CH2) r -, where r is an integer ranging from 1 to 12. In one embodiment, r is in the range of 1 to 10. In one embodiment, r is in the range of 1 to 6.

[0070] According to one embodiment, R 6 is expressed as follows: [ka] (In the formula, the dotted bond represents R 6 to the nitrogen atom) It represents one of the following:

[0071] According to one embodiment, R 6is expressed as follows: [ka] (In the formula, the dotted bond represents R 6 to the nitrogen atom) It represents one of the following:

[0072] According to one embodiment, the compound of formula (I) is selected from the compounds in Table 1 below, and pharma- ceutically acceptable salts and / or solvates thereof. [Table 3] TIFF2025513630000018.tif237159TIFF2025513630000019.tif234159TIFF2025513630000020.tif233159TIFF202 5513630000021.tif232159TIFF2025513630000022.tif233159TIFF2025513630000023.tif228159TIFF20255136300 00024.tif239159TIFF2025513630000025.tif238159TIFF2025513630000026.tif227159TIFF2025513630000027.t if233159TIFF2025513630000028.tif239159TIFF2025513630000029.tif226159TIFF2025513630000030.tif187159

[0073] According to one embodiment, the compound of formula (I) is selected from the compounds in Table 2 below, and pharma- ceutically acceptable salts and / or solvates thereof. [Table 4]

[0074] According to one embodiment, the compound of formula (I) is selected from the compounds in Table 3 below. [Table 5]

[0075] According to one embodiment, the compound is selected from the compounds in Table 2 and / or Table 3 herein.

[0076] All references herein to compounds of the invention (e.g., compounds of formula (I)) include references to salts, solvates, multi-component complexes and liquid crystals thereof. All references herein to compounds of the invention include references to their polymorphic and crystalline propensities. All references herein to compounds of the invention include references to their isotopically labeled compounds, including deuterated compounds thereof. All references herein to compounds of the invention include references to their stereoisomers. All references herein to compounds of the invention include references to their pharma- ceutically acceptable prodrugs and predrugs.

[0077] In particular, the compounds of the present invention (e.g., compounds of formula (I)) may be in the form of pharma- ceutically acceptable salts. According to one embodiment, the compounds of the present invention are pharma- ceutically acceptable salts. Pharmaceutically acceptable salts include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methyl sulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinafoate. Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum salts, arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, 2-(diethylamino)ethanol salts, diolamine salts, ethanolamine salts, glycine salts, 4-(2-hydroxyethyl)morpholine salts, lysine salts, magnesium salts, meglumine salts, morpholine salts, olamine salts, potassium salts, sodium salts, tromethamine salts and zinc salts. Hemisalts of acids and bases can also be formed, such as hemisulfate salts and hemicalcium salts. When a compound contains an acidic group as well as a basic group, the compound may form internal salts, and such compounds are within the scope of the present invention. When a compound contains a hydrogen-donating heteroatom (e.g., NH), the present invention also includes salts and / or isomers formed by the transfer of said hydrogen atom to a basic group or atom within the molecule.Pharmaceutically acceptable salts of the compounds of the present invention can be prepared by one or more of these methods: (i) by reacting the compound with a desired acid; (ii) by reacting the compound with a desired base; (iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound, or by ring-opening a suitable cyclic precursor, such as a lactone or lactam, with a desired acid, and / or (iv) by converting one salt of the compound to another by reaction with a suitable acid or by a suitable ion exchange column. All of these reactions are typically carried out in solution. The salt may be precipitated from the solution and collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to nearly non-ionized.

[0078] According to one embodiment, the salt of the compound of formula (I) is selected from the salt of citric acid (citrate), the salt of hydrochloric acid (HCl) (chloride) and the salt of lactate (lactate). In one embodiment, the salt of the compound of formula (I) is the citrate. In one embodiment, the salt of the compound of formula (I) is the salt of hydrochloric acid (HCl). In one embodiment, the salt of the compound of formula (I) is the lactate.

[0079] In particular, the compounds of the present invention (e.g., "compounds of formula (I)") may be in the form of pharma- ceutically acceptable solvates. According to one embodiment, the compounds of the present invention are pharma- ceutically acceptable solvates. According to one embodiment, the compounds of the present invention are pharma- ceutically acceptable salts and solvates.

[0080] In particular, the compounds of the invention (e.g., "compounds of formula (I)") contain at least one asymmetric center(s) and therefore can exist in different stereoisomeric forms. Thus, all references to the compounds of the invention include all possible stereoisomers, including not only racemates but also individual enantiomers and non-racemic mixtures thereof. Non-racemic mixtures can contain any amount of each separate stereoisomer, for example, one stereoisomer can predominate (e.g., a 90 / 10 or 80 / 20 mixture) or the enantiomeric ratio can be closer to a racemic mixture (e.g., a 40 / 60 mixture). When a compound as a single enantiomer is desired, such a single enantiomer can be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods, each of which are known in the art. Resolution of the final product, intermediate, or starting material can be carried out by any suitable method known in the art. The diastereoisomeric ratio can be determined by methods known in the art, such as, for example, high performance liquid chromatography (HPLC). The enantiomeric ratio can be determined by methods known in the art, such as, for example, chiral HPLC (i.e., HPLC in which the stationary phase is a chiral column).

[0081] According to one embodiment, the compound of the present invention is a mixture of two diastereomers (beta / alpha), and the beta isomer is present in the mixture in an amount equal to or greater than about 90%. In one embodiment, the beta isomer is present in the mixture in an amount equal to or greater than about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99%. In one embodiment, the beta isomer is present in the mixture in an amount equal to or greater than about 94%. In one embodiment, the beta isomer is present in the mixture in an amount equal to or greater than about 95%. In one embodiment, the compound of the present invention consists essentially of the beta isomer.

[0082] According to another embodiment, the compound of the present invention is a mixture of two diastereomers (beta / alpha), wherein the beta isomer is present in the mixture in an amount equal to or less than about 75%, about 80%, or about 85%. In one embodiment, the beta isomer is present in the mixture in an amount equal to or less than about 80%.

[0083] In one embodiment, the compound of the present invention is selected from the pharma- ceutically acceptable salts and / or stereoisomers of the compounds of formula (I) listed in Table 4 below, and solvates thereof. [Table 6] TIFF2025513630000034.tif99159

[0084] The compounds of Table 4 can be prepared, for example, as described in the experimental section (Example 1 below).

[0085] In one embodiment, the compound of the present invention is selected from the pharma- ceutically acceptable salts and / or stereoisomers of the compounds of formula (I) listed in Table 5 below, and solvates thereof. [Table 7]

[0086] In one embodiment, the compound of the present invention is selected from the pharma- ceutically acceptable salts and / or stereoisomers of the compounds of formula (I) listed in Table 6 below, and solvates thereof. [Table 8]

[0087] According to one embodiment, the compound is selected from the compounds in Table 5 and / or Table 6 herein.

[0088] Pharmaceutical Compositions Another object of the present invention is a composition comprising the compound according to the present invention as described herein.In one embodiment, said composition is a pharmaceutical composition and further comprises at least one pharma- ceutically acceptable carrier.Therefore, another object of the present invention is a pharmaceutical composition comprising the compound according to the present invention as described herein and at least one pharma- ceutically acceptable carrier.

[0089] According to a first embodiment, the pharmaceutical composition comprises a compound according to the invention as the only therapeutic agent. In one embodiment, the pharmaceutical composition does not comprise any other anti-infective agent. In one embodiment, the pharmaceutical composition does not comprise any other antibacterial agent. According to a second embodiment, the pharmaceutical composition further comprises at least another therapeutic agent. In one embodiment, the pharmaceutical composition further comprises at least another anti-infective agent. In one embodiment, the other anti-infective agent is selected from cyclins, macrolides, phenicols and beta-lactams.

[0090] Another object of the invention is a medicament comprising a compound according to the invention as described herein.

[0091] kit Another object of the present invention is a kit comprising a compound according to the invention as described herein and instructions for use.

[0092] The present invention also provides a pharmaceutical composition comprising a compound according to the invention, and - a separate pharmaceutical composition comprising at least another therapeutic agent, such as an anti-infective agent The present invention relates to a kit comprising:

[0093] Medical Use of the Compound The present invention also relates to a compound, composition or pharmaceutical composition according to the invention as described herein for use as a medicament.

[0094] The present invention also relates to a compound, composition or pharmaceutical composition according to the invention as described herein for use in the treatment of an infectious disease.

[0095] The present invention also relates to a compound, composition or pharmaceutical composition according to the invention as described herein for use as an anti-persistent agent in the treatment of an infectious disease.

[0096] The present invention also relates to a compound, composition, or pharmaceutical composition according to the present invention described herein for use in treating a chronic infection, a recurrent infection, a refractory infection, a persistent infection, a persister-associated infection, a persistent infection, a persistent infection associated with a persistent infection associated with a chronic infection, a persistent infection associated with a recurrent infection, a persistent infection associated with a persistent infection associated with a refractory infection, or a persistent infection associated with a persistent infection. The present invention also relates to a compound, composition, or pharmaceutical composition according to the present invention described herein for use in killing or inhibiting the growth of persistent cells. The present invention also relates to a compound, composition, or pharmaceutical composition according to the present invention described herein for use in treating a microbial infection comprising at least one persistent cell.

[0097] The present invention further relates to a method of treating an infectious disease in a subject in need thereof, comprising administering to the subject a compound, composition, or pharmaceutical composition according to the present invention as described herein.The present invention further relates to a method of treating a chronic infection, a recurrent infection, a refractory infection, a persistent infection, a persister-associated infection, a persister-associated chronic infection, a persister-associated recurrent infection, a persister-associated refractory infection, or a persister-associated persistent infection in a subject in need thereof, comprising administering to the subject a compound, composition, or pharmaceutical composition according to the present invention as described herein.The present invention further relates to a method of killing or inhibiting the growth of persister cells in a subject in need thereof, comprising administering to the subject a compound, composition, or pharmaceutical composition according to the present invention as described herein.The present invention further relates to a method of treating a microbial infection comprising at least one persister cell in a subject in need thereof, comprising administering to the subject a compound, composition, or pharmaceutical composition according to the present invention as described herein.

[0098] The present invention further relates to the use of a compound, composition, or pharmaceutical composition according to the present invention as described herein for the manufacture of a medicament for the treatment of an infectious disease in a subject in need thereof. The present invention further relates to the use of a compound, composition, or pharmaceutical composition according to the present invention as described herein for the manufacture of a medicament for the treatment of a chronic infection, a recurrent infection, a refractory infection, a persistent infection, a persistent infection, a persistent infection associated with a cell, a persistent infection associated with a cell, a chronic infection associated with a cell, a persistent ...

[0099] The present invention also relates to the use of a compound, composition, or pharmaceutical composition according to the present invention described herein for treating an infectious disease in a subject in need thereof. The present invention also relates to the use of a compound, composition, or pharmaceutical composition according to the present invention described herein for treating a chronic infection, a recurrent infection, a refractory infection, a persistent infection, a persistent infection, a persistent infection associated with a cell, a persistent infection associated with a cell, a chronic infection associated with a cell, a persistent ...

[0100] According to one embodiment, the compound is selected from the compounds in Table 2 and / or Table 3 herein. In one embodiment, the compound is selected from the compounds in Table 2 herein. In one embodiment, the compound is selected from the compounds in Table 3 herein. According to one embodiment, the compound is selected from the compounds in Table 4 and / or Table 5 herein. In one embodiment, the compound is selected from the compounds in Table 4 herein. In one embodiment, the compound is selected from the compounds in Table 5 herein.

[0101] According to one embodiment, the infectious disease is a bacterial disease, a viral disease, a fungal disease or a parasitic disease. In one embodiment, the infectious disease is a bacterial disease. In one embodiment, the infectious disease is a viral disease. In one embodiment, the infectious disease is a fungal disease. In one embodiment, the infectious disease is a parasitic disease. In one embodiment, the infectious disease is a bacterial disease or a fungal disease. In one embodiment, the bacterial or fungal disease is selected from cystic fibrosis, urinary tract infections and chronic otitis media.

[0102] In one embodiment, the bacterial disease is caused by a gram-positive bacterium. In one embodiment, the bacterial disease is caused by a gram-negative bacterium. As used herein, "gram-positive bacteria" refers to bacteria that retain the color of the crystal violet stain used in the gram staining method to identify bacteria. Gram-positive bacteria are characterized by a bacterial cell wall composed of a thick layer of peptidoglycan. In contrast, "gram-negative bacteria" refers to bacteria that do not retain the crystal violet stain used in the gram staining method. Gram-negative bacteria are characterized by a bacterial cell wall composed of a thin layer of peptidoglycan between the inner cytoplasmic cell membrane and the bacterial outer membrane. In one embodiment, the gram-positive bacteria is selected from Staphylococcus, Enterococcus, and Mycobacterium. In one embodiment, the Staphylococcus is Staphylococcus epidermidis or Staphylococcus aureus. In one embodiment, the Enterococcus is Enterococcus faecium. In one embodiment, the Mycobacterium is Mycobacterium tuberculosis. In one embodiment, the Gram-negative bacterium is selected from Pseudomonas, Escherichia, Klebsiella, Acinetobacter, Enterobacter, or Legionella. In one embodiment, the Pseudomonas bacterium is Pseudomonas aeruginosa. In one embodiment, the Escherichia bacterium is Escherichia coli. In one embodiment, the Klebsiella bacterium is Klebsiella pneumoniae. In one embodiment, the Acinetobacter bacterium is Acinetobacter baumannii.

[0103] According to one embodiment, the subject is a human. According to one embodiment, the subject is a non-human. In one embodiment, the subject is selected from cows, sheep, goats, pigs and poultry. In one embodiment, the subject is a meat-producing animal or a milk-producing animal.

[0104] Route of administration and dosage The medicament, composition, or pharmaceutical composition according to the present invention described herein is formulated for use in administration to a subject. In one embodiment, the medicament, composition, or pharmaceutical composition is administered parenterally, orally, by inhalation, by aerosol, rectally, nasally, or via an implanted reservoir. In one embodiment, the medicament, composition, or pharmaceutical composition is administered by injection, including but not limited to subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Examples of forms adapted for injection include, but are not limited to, solutions such as, for example, sterile aqueous solutions, gels, dispersions, emulsions, suspensions, solid forms suitable for use in preparing solutions or suspensions by adding liquids prior to use, such as, for example, powders, liposomal forms, and the like.

[0105] In one embodiment, the medicament, composition, or pharmaceutical composition is administered to a subject in need thereof in a therapeutically effective amount.

[0106] However, it will be understood that the total daily use of the compound, composition, pharmaceutical composition or medicament according to the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend on a variety of factors, including the disease and severity of the disease being treated; the activity of the compound used; the age, weight, general health, sex and diet of the subject; the time of administration, the route of administration and the excretion rate of the particular therapeutic agent used; the duration of treatment; drugs used in combination with or simultaneously with the particular therapeutic agent used; and similar factors well known in the medical field. For example, it is well within the scope of the skilled artisan to start the dose of the compound at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. The total dose required for each treatment may be administered in multiple doses or in a single dose.

[0107] In one embodiment, the dosage of the compound is generally about 0.01-500 mg / kg of patient body weight per day, which can be administered in a single dose or multiple doses. Preferably, the dosage level is about 0.1-250 mg / kg per day, more preferably about 0.5-100 mg / kg per day. Suitable dosage levels can be about 0.01-250 mg / kg per day, about 0.05-100 mg / kg per day, or about 0.1-50 mg / kg per day. Within this range, the dosage can be about 0.05-0.5, about 0.5-5, or about 5-50 mg / kg per day. For oral administration, the composition is preferably provided in the form of a tablet containing about 1.0 to 1000 milligrams of active ingredient, in particular about 1.0, about 5.0, about 10.0, about 15.0, about 20.0, about 25.0, about 50.0, about 75.0, about 100.0, about 150.0, about 200.0, about 250.0, about 300.0, about 400.0, about 500.0, about 600.0, about 750.0, about 800.0, about 900.0, and about 1000.0 milligrams of active ingredient, in order to symptomatically adjust the dosage for the patient being treated. The compound may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. However, it will be understood that the specific dose level and frequency of administration for any particular patient may vary and will depend upon a variety of factors including the activity of the particular compound used, the metabolic stability and length of action of the compound, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host being treated.

[0108] Simultaneous administration According to a first embodiment, the medicament, composition or pharmaceutical composition according to the invention described herein should be administered as the only therapeutic agent. In one embodiment, the medicament, composition or pharmaceutical composition is not administered in combination with any other anti-infective agent.

[0109] According to a second embodiment, the medicament, composition or pharmaceutical composition according to the invention described herein is administered before, simultaneously with or after at least another therapeutic agent, such as, for example, an anti-infective or anti-proliferative agent.

[0110] Co-administration of a compound, composition, pharmaceutical composition or medicament according to the present invention with a particular therapeutic agent can be selected from, but is not limited to, those listed herein and will depend on the disease or condition being prevented and / or treated, as will be appreciated by those skilled in the art. Some examples of anti-infective agents suitable for co-administration according to the present invention include, but are not limited to, cyclins, macrolides, phenicols, beta-lactams.

[0111] non-medical use The present invention also relates to the non-therapeutic use of the compounds according to the invention described herein as anti-infective agents.The present invention also relates to the non-therapeutic use of the compounds according to the invention described herein as anti-persistent agents.

[0112] According to one embodiment, the compound is selected from the compounds in Table 2 and / or Table 3 herein. In one embodiment, the compound is selected from the compounds in Table 2 herein. In one embodiment, the compound is selected from the compounds in Table 3 herein.

[0113] According to one embodiment, the use of the compound is for the disinfection of a surface. In this embodiment, "disinfection of a surface" refers to the case where the surface is not part of a human or animal body. For example, human or animal skin is not considered a "surface" in the sense of this embodiment. In one embodiment, the surface is comprised in a medical device, a fabric, a vehicle, or a building. In one embodiment, the surface is comprised in a medical device, such as a prosthesis, a bandage, or a hospital bed. In one embodiment, the surface is comprised in a fabric, such as a medical blouse. In one embodiment, the surface is comprised in a vehicle, such as an ambulance. In one embodiment, the surface is comprised in a building, such as a floor, a wall, a window, or a pipe.

[0114] According to one embodiment, the use of the compound is for the purification of liquids. In this embodiment, "purification of liquids" refers to the case where the liquid is not part of a human or animal body. For example, human or animal blood is not considered a "liquid" in the sense of this embodiment. In one embodiment, the liquid is contained in a container, furniture or building. In one embodiment, the liquid is contained in a container, such as, for example, a bottle or a bag. In one embodiment, the liquid is contained in a furniture or building, such as, for example, a pool, a reservoir or a tank.

[0115] According to one embodiment, the use of the compound is for eliminating any one of the above bacteria, or any one of their combinations. In this embodiment, "elimination of bacteria" refers to the case where the bacteria is not present in or in contact with the human or animal body.

[0116] The present invention also relates to a method for disinfecting a surface and / or purifying a liquid, where "disinfecting a surface" and "purifying a liquid" have the meanings defined above.

[0117] The present invention also relates to a method for eliminating any one of the above bacteria, wherein "elimination of bacteria" has the meaning defined above.

[0118] Manufacturing Process The compounds of the invention described herein can be prepared by synthetic methods well known in the art.

[0119] The present invention also relates to processes for making the compounds of the present invention described herein.

[0120] According to one embodiment, the process comprises: (a) reacting the carboxylic acid functional group at position 20 of a bile acid with a secondary amine functional group of an amino acid, thereby obtaining an amide; (b) oxidizing the hydroxyl (OH) at the 3-position of the bile acid intermediate obtained in step (a), thereby obtaining a ketone; (c) reacting the bile acid intermediate ketone obtained in step (b) with a primary amine, thereby obtaining an imine; (d) reducing the imine obtained in step (c), thereby obtaining a compound of the present invention.

[0121] This embodiment is illustrated in Scheme 1 below. [ka]

[0122] Non-limiting examples of suitable bile acids are represented by formula (I) above. According to one embodiment, the bile acid is selected from deoxycholic acid, cholic acid, chenodeoxycholic acid, ursodeoxycholic acid and lithocholic acid. In one embodiment, the bile acid is selected from deoxycholic acid, cholic acid, chenodeoxycholic acid and lithocholic acid. In the process of the present invention, the amino acid may be natural or unnatural. According to one embodiment, the amino acid is natural.

[0123] According to one embodiment, step (c) of reacting the ketone of the bile acid and step (d) of reducing the imine obtained in step (c) are carried out in the same reaction medium (in situ), i.e. both reactions are carried out without any intermediate purification and / or isolation steps of the imine.

[0124] The process according to the invention may further comprise purification and / or separation steps as are known in the art.

[0125] The process according to the present invention has the advantage over state of the art processes for producing squalamine since the preparation of squalamine requires more than 13 steps whereas the process according to the present invention involves only three or four steps.

[0126] Working Example The present invention is further illustrated by the following examples.

[0127] Example 1: Synthesis of Compounds Materials and Methods All syntheses were carried out using solvents purified according to the usual methods. Commercially available reagents obtained from TCI Europe and Sigma-Aldrich were used directly without prior purification. The progress of the reactions was monitored by thin layer chromatography (TLC) using a 10% solution of phosphomolybdic acid in absolute ethanol as a visualizing agent. Reactions under microwave irradiation were carried out using a Biotage Initiator+ instrument. The following abbreviations were used for the names of the solvents: PET: petroleum ether, EtOAc: ethyl acetate, CH2Cl2: dichloromethane, MeOH: methanol, and NH4.OH: 32 wt.% aqueous ammonia. The chemical structures of the obtained products were characterized by proton ( 1 H) and carbon ( 13 C) NMR (nuclear magnetic resonance) analysis. Chemical shifts (d) are expressed in parts per million (ppm). Residual solvent peaks were referenced to the following values: deuterated chloroform (CDCl3) d 1 H=7.26ppm, d 13 C = 77.16 ppm; deuterated methanol (CD3OD) d 1 H=4.87ppm, d 13 C=49.00 ppm. Using the following abbreviations: 1 H spectrum: s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet were generated. Coupling constants (J) expressed in Hz were determined for the doublets, triplets, and quartets. Mass spectrometry of the final product (Sonamine) was performed using a SYNAPT G2 HDMS (Waters) after electrospray ionization (ESI-MS). Samples were ionized in positive mode electrospray with the following conditions: electrospray voltage: 2.8 kV; orifice voltage: 20 V; nebulizer gas flow rate (nitrogen): 100 L / h.

[0128] The diastereomeric ratio was determined by high performance liquid chromatography (HPLC) using an Agilent 1100 series instrument and a brand new Ascentis® HPLC column (Express C18, 4.6 mm×100 mm, 2.7 μm) with a water / methanol gradient (A: water+0.1% trifluoroacetic acid (TFA), B: methanol+0.1% TFA) according to the following procedure: [Table 9] [ka]

[0129] All alcohols I′ presented in this section were synthesized from bile acids and methyl esters of the amino acids under study following the same procedure detailed for the synthesis of methyl-L-valinate chenodeoxycholate 1.

[0130] [ka] Methyl-L-valinate chenodeoxycholate 1. In a flask equipped with a magnetic stir bar, 2 g (5.095 mmol) of chenodeoxycholic acid, 0.856 g (5.095 mmol) of L-valine methyl ester and 2.25 g (5.095 mmol) of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate are dissolved in 40 mL of CHCl and 3.5 mL (20.38 mmol) of diisopropylethylamine are added. After stirring for 12 hours at 20 ° C, 20 mL of saturated ammonium chloride solution is added and the medium is stirred for 2 hours. The two phases are separated, the organic phase is washed twice with 20 mL of saturated ammonium chloride solution and the aqueous phase is extracted with 20 mL of CHCl. ​​The combined organic phases are washed twice with 20 mL of saturated sodium chloride solution. The organic phase is dried over anhydrous sodium sulfate and filtered. The crude product thus obtained is purified by silica gel chromatography (eluent: PET, then PET / EtOAc (1 / 1), then EtOAc). Methyl-L-valinate chenodeoxycholate 1 is obtained as a white solid in more than 95% yield. Methyl-L-valinate chenodeoxycholate 1 (C 30 H 51 NO5). NMR 1 H (250 MHz, CDCl3): δ (ppm) = 5.97 (d, J = 5.94 Hz, 1H), 4.58 (m, 1H), 4.15 (q, J1= 4.15 Hz, J2= 4.12 Hz 1H), 3.85-3.78 (m, 2H), 3.51 (m, 1H), 2.36-2.05 (m, 7H), 2.00-1.02 (m, 35H), 0.64 (s, 3H). NMR 13C (63 MHz, CDCl3): δ (ppm) = 173.61, 172.93, 72.12, 68.62, 60.53, 56.94, 55.96, 52.26, 50.54, 42.80, 41.57, 39.90, 39.52, 35.56, 35.14, 34.67, 33.58, 32.92, 31.78, 31.44, 30.74, 28.31, 23.80, 22.88, 20.68, 19.05, 18.47, 17.97, 14.31, 11.88.

[0131] [ka] Methyl-L-phenylalaninate chenodeoxycholate 2(C 34 H 51 NO5). NMR 1 H (250 MHz, CD3OD): δ (ppm) = 7.60-7.28 (m, 5H), 5.56 (t, J = 5.58 Hz, 1H), 4.27-4.08 (m, 1H), 3.87 (s, 1H), 3.77 (s, 3H), 3.51-3.41 (m, 1H), 2.48-2.22 (m, 3H), 2.10-0.94 (m, 33H), 0.74 (s, 3H). NMR 13 C (63 MHz, CD3OD): δ (ppm) = 176.31, 172.67, 152.15, 137.55, 129.86, 128.77, 72.81, 68.97, 61.49, 58.12, 57.32, 52.94, 51.49, 43.65, 43.15, 41.02, 40,75, 40,44, 36,76, 36,56, 36,19, 35,90, 34,02, 33,48, 33,03, 31,35, 29,20, 24,61, 23,43, 21,78, 20,87, 18,93, 14,47, 12,23. Efficiency: Over 95%.

[0132] [ka] Methyl-L-glycinate chenodeoxycholate 3(C 27 H 45 NO5). NMR 1 H (250 MHz, CD3OD): δ (ppm) = 4.06 (s, 1H), 3.98-3.88 (m, 1H), 3.39-2.96 (m, 3H), 2.88-2.63 (m, 1H), 2.48-1.54 (m, 22H), 1.41-0.99 (m, 14H), 0.80 (s, 3H). NMR 13 C (63 MHz, CD3OD): δ (ppm) = 177.10, 171.83, 72.78, 68.94, 57.31, 55.82, 52.53, 51.48, 43.76, 43.63, 43.10, 41.80, 40.72, 40.41, 36.52, 36.16, 35.86, 33.70, 33.02, 31.32, 29.18, 24.58, 23.40, 21.75, 18.90, 13.08, 12.21. Yield: >95%.

[0133] [ka] Methyl-L-alaninate chenodeoxycholate 4(C 28 H 47 NO5). NMR 1 H (250 MHz, CD3OD): δ (ppm) = 4.57 (m, 1H), 4.04-3.83 (m, 2H), 3.56-3.43 (m, 2H), 3.37-3.26 (m, 1H), 2.54-1.53 ​​(m, 21H), 1.43-0.90 (m, 17H), 0.79 (s, 3H). NMR 13C (63 MHz, CD3OD): δ (ppm) = 176.40, 174.73, 72.76, 68.91, 57.31, 55.80, 52.65, 51.46, 49.32, 43.61, 43.08, 41.00, 40.70, 40.38, 36.74, 36.52, 35.85, 33.62, 33.02, 31.31, 29.18, 24.56, 23.41, 21.74, 18.92, 17.34, 13.07, 12.22. Yield: >95%.

[0134] [ka] Methyl-L-leucinate chenodeoxycholate 5(C 31 H 53 NO5). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 4.38 (d, J = 4.38 Hz, 1H), 3.81 (s, 1H), 3.72 (s, 1H), 2.37-2.17 (m, 3H), 2.03-1.46 (m, 17H), 1.39-1.09 (m, 14H), 1.01-0.92 (m, 13H), 0.71 (s, 3H). NMR 13 C (101 MHz, CD3OD): δ (ppm) = 176.71, 173.68, 72.71, 68.87, 58.11, 57.26, 55.71, 52.36, 51.41, 43.57, 43.01, 40.95, 40.63, 40.30, 38.07, 36.76, 36.48, 36.09, 35.81, 33.91, 33.57, 33.16, 29.19, 26.30, 24.54, 23.42, 21.72, 18.91, 15.98, 12.23, 11.64. Yield: >95%.

[0135] [ka] Methyl-L-tyrosinate chenodeoxycholate 6(C 34 H 51NO6). NMR 1 H (250 MHz, CD3OD): d (ppm) = 7.06 (m, 2H), 6.76 (m, 2H), 4.62 (m, 1H), 3.90-3.74 (m, 2H), 3.69-3.42 (m, 1H), 3.34-2.84 (m, 5H), 2.39-1.46 (m, 20H), 1.36-0.87 (m, 15H), 0.73 (s, 3H). NMR 13 C (63 MHz, CD3OD): δ (ppm) = 176.56, 173.74, 157.31, 131.13, 128.76, 116.21, 72.79, 68.98, 57.28, 55.76, 55.34, 52.60, 51.45, 43.60, 43.09, 40.99, 40,69, 40,41, 37,59, 36,74, 36,52, 36,15, 35,86, 33,99, 33,71, 33,12, 31,32, 29,17, 24,58, 23,41, 21,75, 18,88, 18,00, 12,23. Yield: 76%

[0136] [ka] Methyl-L-isoleucinate chenodeoxycholate 7(C 31 H 53 NO5). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 4.39 (q, J1= 4.55 Hz, J2= 4.54 Hz, 1H), 3.78-3.67 (m, 1H), 2.29-1.06 (m, 33H), 0.95-0.86 (m, 13H), 0.64 (s, 3H).NMR 13C (101 MHz, CD3OD): δ (ppm) = 176.50, 174.57, 72.60, 68.73, 57.17, 55.63, 52.60, 51.87, 51.30, 43.48, 42.90, 41.10, 40.87, 40.54, 40.19, 36.61, 36.44, 36.01, 33.81, 33.61, 33.04, 31.19, 29.12, 25.78, 24.48, 23.44, 23.32, 21.79, 18.89, 13.05, 12.25. Yield: >95%.

[0137] [ka] Methyl-L-prolinate chenodeoxycholate 8(C 30 H 49 NO5). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 3.93-3.83 (m, 5H), 3.79-3.72 (m, 1H), 3.55-3.48 (m, 1H), 3.35 (q, J1= 4.41 Hz, J2= 4.39 Hz, 1H), 2,57-1.88 (m, 13H), 1.80-1.57 (m, 7H), 1.55-1.39 (m, 13H), 1.13 (d, J = 2.17 Hz, 2H), 1.06 (s, 3H), 0.84 (s, 3H). 13 C (101 MHz, CD3OD): δ (ppm) = 174.56, 174.17, 72.52, 68.62, 59.95, 57.05, 55.57, 52.60, 51.26, 43.57, 43.42, 42.84, 40.83, 40.50, 40.14, 36.59, 35.96, 35.71, 33.76, 32.06, 31.19, 30.04, 29.09, 25.52, 24.45, 23.42, 21.63, 19.03, 13.00, 12.25. Yield: 89%.

[0138] [ka] メチル-L-バリネートコール acid chlorine 9 (C 30 H 51 NO6). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 4.34 (d, J = 4.36 Hz, 1H), 4.01 (s, 1H), 3.89-3.74 (m, 7H), 3.31-3.22 (m, 3H), 2.42-1.56 (m, 21H), 1.20-1.04 (m, 5H), 1.03-0.96 (m, 10H), 0.76 (s, 3H). NMR 13 C (63 MHz, CD3OD): δ (ppm) = 174.35, 172.75, 73.18, 71.93, 68.57, 57.32, 55.68, 52.16, 50.42, 46.72, 46.45, 43.62, 41.70, 41.48, 39.45, 35.41, 34.80, 33.20, 31.71, 31.11, 30.30, 27.59, 26.42, 23.26, 22.45, 18.98, 17.99, 17.42, 12.76, 12.48. Yield: over 95%.

[0139]

change

[0140] [ka] Methyl-L-valinate deoxycholate 11(C 30 H 51 NO5). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 4.34 (d, J = 4.35 Hz, 1H), 4.01 (s, 1H), 3.81-3.75 (m, 4H), 3.58-3.54 (m, 1H), 3.39 (s, 7H), 3,27 (q, J1= NMR 13 C (63 MHz, CD3OD): δ (ppm) = 176.78, 173.54, 73.75, 72.34, 59.18, 55.70, 52.35, 49.86, 49.11, 48.03, 47.47, 43.67, 37.34, 36.72, 36.42, 35.20, 34.68, 33.16, 31.56, 31.00, 29.85, 28.60, 28.38, 27.41, 24.83, 23.79, 19.53, 18.68, 17.70, 13.26. The product was obtained after purification by silica gel chromatography (eluent: CH2Cl2, then CH2Cl2 / MeOH (9 / 1)). Yield: >95%.

[0141] [ka] Methyl-L-phenylalaninate deoxycholate 12(C 34 H 51 NO5)NMR 1 H (250 MHz, CD3OD): δ (ppm) = 7.45-7.30 (m, 5H), 5.48 (s, 1H), 3.96 (s, 1H), 3.77-3.66 (m, 3H), 3.36 (s, 1H), 3.22 (q, J1= 3.23 Hz, J2= 3.20 Hz, 2H), 2.40- 2.16 (m, 2H), 2.02-1.09 (m, 33H), 0.68 (s, 3H). NMR 13 C (63 MHz, CD3OD): δ (ppm) = 176.27, 172.55, 137.35, 129.83, 129.48, 128.66, 73.85, 72.38, 58.03, 55.67, 52.96, 49.85, 49.12, 47.42, 43.66, 43.42, 37,28, 37,07, 36,62, 36,32, 35,16, 34,65, 33,40, 32,93, 30,94, 29,77, 28,56, 28,31, 27,37, 24,80, 23,72, 17,60, 13,21, 13,07. The product was obtained after purification by silica gel chromatography (eluent: CH2Cl2, then CH2Cl2 / MeOH (9 / 1)). Yield: 100%.

[0142] [ka] Methyl-L-valinate trithocholate 13(C 30 H 51 NO4). NMR 1H (400 MHz, CD3OD): δ (ppm) = 4.31 (d, J = 4.32 Hz, 1H), 3.73 (s, 3H), 3.59-3.52 (m, 1H), 3.37 (s, 2H), 2.38-0.93 (m, 41H), 0.71 (s, 3H).NMR 13 C (101 MHz, CD3OD): δ (ppm) = 177.07, 173.79, 72.42, 59.28, 57.94, 57.51, 52.39, 43.93, 43.54, 41.89, 41.55, 37.24, 37.17, 36.83, 36.48, 35.68, 33.63, 33.25, 31.66, 31.19, 29.27, 28.36, 27.66, 25.26, 23.93, 21.95, 19.50, 18.87, 18.63, 12.49. Yield: >95%.

[0143] B. Oppenauer Oxidation Procedure Synthesis of alcohol 14

[0144] [ka] Methyl-L-phenylalaninate 3-oxocholic acid salt 14. In a 10-20 mL microwave reactor, 299 mg (0.52 mmol) of methyl-L-phenylalaninate cholate and 2 equivalents of aluminum tri-sec-butylate (274 mg, 1.1 mmol) dissolved in 10 mL of toluene and 6 mL of acetone are introduced. The reactor is sealed and placed in a Biotage Initiator+ microwave system. The reaction is carried out for 10 min at 150 °C under microwave irradiation (400 watts) using normal mode and pre-stirring for 20 s. After completion of the reaction, 5 mL of NH4.OH are added. After stirring for 15 min, the mixture is filtered over Celite, rinsed with CH2Cl2 and concentrated in vacuum. In this way, methyl-L-phenylalaninate 3-oxocholic acid salt 14 is obtained as a yellow oil in 81% yield without purification. Methyl-L-phenylalaninate 3-oxocholic acid salt 14(C 34 H 49NO6). NMR 1 H (101 MHz, CDCl3): δ (ppm) = 7.23-6.88 (m, 3H), 6.80-6.57 (m, 2H), 4.95 (s, 1H), 4.79 (s, 1H), 4.57 (m, 1H), 4.24- 3.74 (m, 4H), 3.65 (s, 2H), 3.31 (s, 4H), 3.24-2.98 (m, 2H), 2.85-2.35 (m, 6H), 2.24-1.45 (m, 20H), 0.68 (s, 3H). NMR 13 C (400 MHz, CDCl3): δ (ppm) = 216.26, 176.49, 173.69, 157.32, 131.10, 128.66, 116.23, 73.73, 68.70, 55.32, 52.60, 47.49, 46.55, 44.71, 42.89, 40.87, 37,74, 37,58, 36,94, 36,71, 35,96, 35,80, 35,01, 33,73, 33,07, 29,82, 29,57, 28,33, 26,25, 24,12, 22,15, 17,72, 13,07, 9,75.

[0145] B.1. Application to ketosterol synthesis [ka] The ketosterol II' was prepared from the corresponding alcohol I' obtained earlier. Three different procedures were used to obtain the product II. First, the ketosterol II'A, second, the product II'B, and finally the intermediate II'C.

[0146] B.1.a. Procedure for Obtaining Ketosterol II'A The procedure to obtain the ketosterol II'A is the same for all these products, and the synthesis of compound 15 is detailed below.

[0147] [ka] Methyl-L-valinate 3-oxo chenodeoxycholate 15. In a 10-20 mL microwave reactor, 250 mg (0.451 mmol) of methyl-L-valinate chenodeoxycholate 1 and 292 mg (1.81 mmol) of aluminum triethanolate dissolved in 10 mL of toluene and 6 mL of acetone are introduced. The reactor is sealed and placed in a Biotage Initiator+ microwave system. The reaction is carried out at 150 °C for 1 h under microwave irradiation (400 watts) using normal mode and pre-stirring for 20 s. After completion of the reaction, 5 mL of 2N sulfuric acid solution is added and the medium is stirred for 15 min. The phases are separated, the organic phase is washed with 5 mL of aqueous sodium bicarbonate solution (10%) and the aqueous phase is extracted twice with 5 mL of CHCl. ​​The combined organic phase is dried over anhydrous sodium sulfate and filtered. The crude product thus obtained is purified by silica gel chromatography (eluent: PET, then PET / EtOAc (8 / 2), then PET / EtOAc (1 / 1)). Methyl-L-valinate 3-oxo-chenodeoxycholate 15 is obtained as a yellow oil in 66% yield. Methyl-L-valinate 3-oxo-chenodeoxycholate 15 (C 30 H 49 NO5). NMR 1 H (300 MHz, CD3OD): δ (ppm) = 4.39 (d, J = 4.39 Hz, 1H), 3.99-3.41 (m, 6H), 2.58-1.19 (m, 27H), 1.11-1.01 (m, 12H), 0.81-0.76 (m, 3H). NMR 13 C (75 MHz, CD3OD): δ (ppm) = 216.05, 176.79, 173.66, 68.74, 59.12, 57.36, 52.40, 51.42, 46.57, 44.77, 43.67, 40.91, 40.67, 37.94, 37.70, 36.82, 36.38, 35.12, 34.50, 33.63, 33.23, 31.63, 29.56, 29.22, 24.56, 22.42, 22.14, 19.54, 18.66, 12.31.

[0148] [ka] Methyl-L-glycinate 3-oxo-chenodeoxycholate 16(C 27 H 43 NO5). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 3.97-3.89 (m, 2H), 3.54 (t, J = 3.56 Hz, 1H), 3.39 (s, 2H), 2.55-1.77 (m, 14H), 1.66-1.14 (m, 21H), 0.79-0.75 (m, 3H).NMR 13 C (101 MHz, CD3OD): δ (ppm) = 216.11, 177.06, 171.32, 68.78, 62.13, 57.32, 51.43, 46.58, 44.79, 43.67, 42.00, 40.91, 40.67, 37.94, 37.70, 36.79, 36.39, 35.11, 34.50, 33.70, 33.06, 29.21, 24.55, 22.39, 22.13, 18.94, 12.28. Yield: 29%.

[0149] [ka] Methyl-L-alaninate 3-oxo-chenodeoxycholate 17(C 28 H 45 NO5). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 4.44-4.36 (m, 1H), 4.22-4.10 (m, 2H), 3.88 (s, 1H), 3.74 (s, 2H), 3.52 (t, J = 3.53 Hz, 1H), 2.50-1.75 (m, 13H), 1.65-1.13 (m, 22H), 0.77 (s, 3H). NMR 13C (101 MHz, CD3OD): δ (ppm) = 216.24, 176.50, 174.79, 68.85, 65.22, 57.39, 52.68, 51.47, 46.60, 44.83, 43.70, 40.94, 40.70, 37.95, 37.71, 36.80, 36.42, 35.12, 34.54, 33.67, 33.09, 29.24, 24.56, 22.37, 22.14, 18.94, 17.37, 12.26. The product was obtained after purification by silica gel chromatography (PET, then PET / EtOAc (1 / 1), then PET / EtOAc (3 / 7)). Yield: 42%.

[0150] [ka] Methyl-L-leucinate 3-oxo-chenodeoxycholate 18(C 31 H 51 NO5). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 4.39 (d, J = 4.38 Hz, 1H), 3.89-3.87 (m, 1H), 3.52 (t, J = 3.53 Hz, 1H), 2.53-1.13 (m, 34H), 1.03-0.88 (m, 11H), 0.76 (s, 3H). NMR 13 C (101 MHz, CD3OD): δ (ppm) = 216.25, 176.83, 173.76, 68.84, 58.17, 57.40, 52.35, 51.47, 46.60, 44.83, 43.71, 40.94, 40.69, 38.22, 37.96, 37.71, 36.84, 36.42, 35.12, 34.53, 33.64, 33.24, 29.25, 26.39, 24.56, 22.37, 22.14, 18.94, 16.01, 12.26, 11.66. The product was obtained after purification by silica gel chromatography (PET, then PET / EtOAc (1 / 1), then PET / EtOAc (3 / 7)). Yield: 43%.

[0151] [ka] Methyl-L-phenylalaninate 3-oxodeoxycholate 19(C 34 H 49 NO5). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 7.43-7.34 (m, 5H), 5.52 (s, 1H), 4.17-4.09 (m, 2H), 3.72 (s, 2H), 2.85 (t, J = 2.87 Hz, 1H), 2.60-2.51 NMR 13 C (101 MHz, CD3OD): δ (ppm) = 216.09, 176.33, 172.65, 137.52, 129.87, 129.51, 128.78, 73.86, 65.20, 65.14, 58.11, 52.95, 48.15, 47.63, 45.82, 43,17, 38,00, 37,85, 36,99, 36,74, 35,53, 34,74, 33,53, 33,01, 30,07, 28,63, 27,68, 26,65, 24,81, 22,74, 17,68, 16,44, 16,38, 13,24. The product was obtained after purification by silica gel chromatography (PET, then PET / EtOAc (1 / 1), then PET / EtOAc (3 / 7)). Yield: 44%.

[0152] [ka] Methyl-L-valinate 3-oxolithocholate 20(C 30 H 49 NO4). NMR 1H (400 MHz, CD3OD): δ (ppm) = 4.33 (d, J = 4.33 Hz, 1H), 3.74 (s, 3H), 2.85 (t, J = 2.85 Hz, 1H), 2.52-1.12 (m, 38H), 1.07 (s, 3H), 0.76 (s, 3H).NMR 13 C (101 MHz, CD3OD): δ (ppm) = 216.04, 176.93, 173.74, 59.21, 57.57, 57.51, 52.39, 45.91, 43.94, 43.23, 41.74, 41.32, 38.17, 37.95, 36.92, 36.82, 36.01, 33.68, 33.26, 31.66, 29.26, 27.78, 26.87, 25.24, 23.04, 22.31, 19.52, 18.91, 18.64, 12.55. The product was obtained after purification by silica gel chromatography (PET, then PET / EtOAc (7 / 3)). Yield: 34%.

[0153] B.1.b. Procedure for Obtaining Ketosterol II'B The procedure for obtaining ketosterol II'B is the same for all of these products, except for the reaction time for changing from one product to another. The general procedure for the synthesis of compound 23 is detailed below.

[0154] [ka] Methyl-L-valinate 3-oxodeoxycholate 23. In a 10-20 mL microwave reactor, 250 mg (0.494 mmol) of methyl-L-valinate deoxycholate 11 and 487 mg (1.98 mmol) of aluminum tri-sec-butylate are introduced, dissolved in 10 mL of toluene and 6 mL of acetone. The reactor is sealed and placed in a Biotage Initiator+ microwave system. The reaction is carried out for 30 min at 150 °C under microwave irradiation (400 watts) using normal mode and pre-stirring for 20 s. After completion of the reaction, 5 mL of NH4.OH are added. After stirring for 15 min, the mixture is filtered over Celite, rinsed with CH2Cl2 and concentrated in vacuum. The crude product thus obtained is purified by silica gel chromatography (eluent: PET, then PET / EtOAc (1 / 1), then EtOAc). Methyl-L-valinate 3-oxodeoxycholic acid 23 was obtained as a yellow oil in 32% yield. 30 H 49 NO5). NMR 1 H (250 MHz, CD3OD): δ (ppm) = 4.28 (d, J = 4.30 Hz, 1H), 4.01 (s, 1H), 3.70 (s, 3H), 2.82 (t, J = 2.82 Hz, 1H), 2.59-1.21 (m, 29H), 1.08-0.92 (m, 11H), 0.73 (s, 3H). NMR 13 C (63 MHz, CD3OD): δ (ppm) = 216.09, 176.98, 173.74, 73.88, 59.17, 52.41, 49.19, 48.17, 47.64, 45.84, 43.18, 38.01, 37.86, 37.00, 36.84, 35.54, 34.74, 33.67, 33.25, 31.64, 30.09, 28.67, 27.69, 26.66, 24.81, 22.74, 19.53, 18.64, 17.70, 13.23.

[0155] [ka] Methyl-L-valinate 3-oxocholate 21. The reaction is carried out at 150° C. for 1 h under microwave irradiation (400 watts) using normal mode with pre-stirring for 20 s. Methyl-L-valinate 3-oxocholate 21 (C 30 H 49 NO6). NMR 1 H (250 MHz, CD3OD): δ (ppm) = 4.89 (s, 7H), 4.79 (s, 1H), 4.28 (d, J = 4.27 Hz, 1H), 3.99 (m, 1H), 3.83 (m, 1H), 3.71 (s, 3H), 3.61- 3.46 (m, 1H), 3.33 (s, 1H), 2.64-1.12 (m, 30H), 0.73 (s, 3H). NMR 13 C (63 MHz, CD3OD): δ (ppm) = 216.57, 177.10, 173.80, 73.85, 68.78, 59.24, 52.42, 48.11, 47.58, 44.90, 43.00, 40.96, 37.83, 37.64, 36.92, 36.08, 35.05, 33.67, 33.28, 31.65, 29.84, 28.74, 28.37, 24.16, 22.13, 19.51, 18.63, 17.71, 13.03. The product was obtained after purification by silica gel chromatography (CH2Cl2, then CH2Cl2 / EtOAc (1 / 1), then EtOAc). Yield: 21%.

[0156] [ka] Methyl-L-tyrosinate 3-oxocholate 22. The reaction is carried out three times in succession at 150° C. for 10 min under microwave irradiation (400 watts) using normal mode with pre-stirring for 20 s. Methyl-L-tyrosinate 3-oxocholate 22 (C 34 H 49 NO7). The product is used crude for the reductive amination reaction.

[0157] B.1.c.II'C Procedure for Obtaining Ketosterols The procedure to obtain ketosterol II'C is the same for all these products and is detailed below for the synthesis of compound 24.

[0158] [ka] Methyl-L-phenylalaninate 3-oxo chenodeoxycholate 24. In a 10-20 mL microwave reactor, 200 mg (0.361 mmol) of methyl-L-phenylalaninate chenodeoxycholate 2 and 295 mg (1.44 mmol) of aluminum triethanolate dissolved in 8 mL of toluene and 4 mL of acetone are introduced. The reactor is sealed and placed in a Biotage Initiator+ microwave system. The reaction is carried out at 150 °C for 1 h under microwave irradiation (400 watts) using normal mode and pre-stirring for 20 s. This operation is repeated for 10 different batches. After the completion of the 10 reactions, they are combined and 50 mL of a 2N sulfuric acid solution is added. The medium is stirred for 15 minutes and the phases are separated. The organic phase is washed with 50 mL of an aqueous solution of sodium bicarbonate (10%) and the aqueous phase is extracted twice with 50 mL of CHCl and washed with 50 mL of a saturated aqueous solution of sodium chloride. The combined organic phases are dried over anhydrous sodium sulfate and filtered. The crude product thus obtained is purified by silica gel chromatography (eluent: PET, then PET / EtOAc (8 / 2), then PET / EtOAc (1 / 1)). Methyl-L-phenylalaninate 3-oxo-chenodeoxycholate 24 was obtained as a yellow oil in 51% yield. Methyl-L-phenylalaninate 3-oxo-chenodeoxycholate 24 (C 34 H 49 NO5). NMR 1 H (300 MHz, CD3OD): δ (ppm) = 7.49-7.37 (m, 5H), 5.61 (s, 1H), 3.95-3.93 (m, 1H), 3.77 (s, 3H), 3.60 (t, J = 3.62 Hz, 1H), 2.73-0.94 (m, 35H), 0.82-0.75 (m, 3H). NMR 13C (75 MHz, CD3OD): δ (ppm) = 215.95, 176.04, 172.52, 137.45, 129.81, 129.43, 128.69, 68.65, 57.97, 57.22, 52.95, 51.34, 46.52, 44.66, 43.59, 42,12, 40,82, 40,60, 37,87, 37,66, 36,68, 36,31, 35,05, 34,42, 33,43, 29,53, 29,15, 24,52, 22,42, 22,09, 18,98, 18,15, 15,11, 12,34.

[0159] [ka] Methyl-L-tyrosinate 3-oxo-chenodeoxycholate 25(C 34 H 49 NO6). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 6.90 (d, J = 6.90 Hz, 2H), 6.59 (d, J = 6.60 Hz, 2H), 3.73 (s, 1H), 3.38 (t, J = 3.38 Hz, 1H), 3.24 (s, 1H), 2.97-2.71 (m, 3H), 2.37-0.99 (m, 32H), 0.90 (s, 2H), 0.82 (m, 3H), 0.59 (s, 3H). NMR 13 C (101 MHz, CD3OD): δ (ppm) = 216.11, 176.39, 173.64, 157.23, 131.11, 128.61, 116.17, 68.70, 57.16, 55.24, 52.61, 51.31, 46.50, 44.61, 43,56, 40,78, 40,54, 37,83, 37,65, 37,55, 36,66, 36,28, 35,01, 34,41, 33,63, 33,03, 29,13, 24,49, 22,37, 22,05, 18,91, 12,30. Yield: 47%.

[0160] [ka] Methyl-L-isoleucinate 3-oxo-chenodeoxycholate 26(C 31 H 51 NO5). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 4.49-4.44 (m, 1H), 4.21-4.10 (m, 1H), 3.89-3.87 (m, 1H), 3.52 (t, J = 3.53 Hz, 1H), 2.53-1.13 (m, 34H), 1.03-0.88 (m, 10H), 0.77 (s, 3H). NMR 13 C (101 MHz, CD3OD): δ (ppm) = 216.25, 176.81, 174.77, 68.83, 57.40, 52.61, 52.04, 51.47, 46.59, 44.83, 43.71, 41.34, 40.94, 40.69, 37.96, 37.71, 36.78, 36.42, 35.12, 34.53, 33.73, 33.20, 29.25, 26.01, 24.57, 23.34, 22.37, 22.14, 21.78, 18.92, 12.27. Yield: 50%.

[0161] [ka] Methyl-L-prolinate 3-oxo-chenodeoxycholate 27(C 30 H 47 NO5). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 4.46-4.41 (m, 1H), 3.90-3.80 (m, 1H), 3.74 (s, 2H), 3.71-3.49 (m, 2H), 3.38 (s, 1H), 2.54-1.13 (m, 33H), 1.07-0.89 (m, 7H), 0.78-0.72 (m, 3H). NMR 13C (101 MHz, CD3OD): δ (ppm) = 216.19, 174.96, 174.46, 68.82, 60.19, 57.34, 52.68, 51.46, 46.59, 44.82, 43.70, 43.67, 40.93, 40.70, 37.96, 37.71, 36.83, 36.42, 35.12, 34.53, 32.24, 32.06, 30.24, 29.25, 25.73, 24.58, 22.38, 22.14, 19.06, 12.27. Yield: 46%.

[0162] C. Stereoselective Reductive Amination Procedure All products presented in this section were synthesized from ketosterol II' and the corresponding polyamine following the same procedure detailed below for the synthesis of methyl-L-valinate 3β-norspermidino-chenodeoxycholate 007.

[0163] [ka] Methyl-L-valinate 3β-norspermidino-chenodeoxycholate 007. In a 50 mL flask equipped with a magnetic stir bar, 870 mg (1.74 mmol) of methyl-L-valinate 3-oxo chenodeoxycholate 15 are dissolved in 30 mL of MeOH. Subsequently, 3 equivalents of norspermidine (0.73 mL, 5.21 mmol) and 4 equivalents of titanium tetraisopropylate (2.06 mL, 6.96 mmol) are added. After stirring for 12 hours at 20 ° C, the flask is placed at −78 ° C and 4 equivalents of sodium borohydride (50 mg, 1.36 mmol) are added with stirring. The reaction medium is left stirring at this temperature for 2 hours. The reaction medium is then transferred to an ice bath at 0 ° C and allowed to slowly rise to 20 ° C for 5 hours with stirring. Once that temperature is reached, 8.7 mL of water are added to neutralize the reaction. After stirring for another 30 min, the mixture is filtered over Celite, rinsed with MeOH, CHCl and EtOAc, and then concentrated in vacuo. The crude reaction product thus obtained is purified by silica gel chromatography (eluent: MeOH, then CHCl / MeOH / NHOH (7 / 3 / 1)). Methyl-L-valinate 3β-norspermidino-chenodeoxycholate 007 is obtained in the form of a yellow oil with a yield of 20% (a mixture of two diastereomers (β / α) in a ratio of 96 / 4, herein "007-a1" as a mixture). Methyl-L-valinate 3β-norspermidino-chenodeoxycholate 007 (C 36 H 66 N4O4). NMR 1 H (300 MHz, CD3OD): δ (ppm) = 4.30 (d, J = 4.31 Hz, 1H), 3.80 (s, 1H), 3.74 (s, 1H), 3.71 (s, 2H), 2.82-2.64 (m, 7H), 2.52-1.10 (m, 35H), 1.02-0.91 (m, 14H), 0.70 (s, 3H). NMR 13C (75 MHz, CD3OD): δ (ppm) = 176.94, 173.74, 68.91, 59.29, 59.23, 57.45, 52.40, 51.55, 48.86, 48.19, 45.58, 43.68, 43.52, 41.08, 40.81, 40.56, 37.29, 36,99, 36,89, 36,63, 35,91, 34,06, 33,65, 33,28, 32,98, 31,65, 29,66, 29,28, 28,03, 24,62, 23,58, 21,78, 19,53, 18,94, 18,66, 12,25. MS (ESI + ): m / z 619.5157 ([M+H] + ).

[0164] Compound 007-a1 (β / α:96 / 04) prepared by the above method was used to prepare the corresponding hydrochloride salt S007 (β / α:96 / 04) as described below (section "D. Preparation of Different Salts").

[0165] Other batches prepared according to the above method yielded compound 007 as mixtures exhibiting slightly different stereochemical ratios, designated 007-a2 (β / α:94 / 06) and 007-a3 (β / α:90 / 10), respectively, which were used to prepare the corresponding hydrochloride salts S019 (β / α:94 / 06) and S021 (β / α:90 / 10), as described below (Section D. Preparation of Different Salts).

[0166] [ka] Methyl-L-valinate 3β-spermino-chenodeoxycholate 001(C 40 H 75 N5O4). NMR 1H (250 MHz, CD3OD): δ (ppm) = 4.95-4.68 (m, 9H), 4.24 (d, J = 3.34 Hz, 1H), 3.89-3.64 (m, 3H), 3.45-3.17 (m, 2H), 2.96-2.53 (m, 15H), 2.42-0.87 (m, 42H), 0.73 (s, 3H). NMR 13 C (63 MHz, CD3OD): δ (ppm) = 176.89, 173.73, 68.84, 59.25, 57.50, 52.39, 51.57, 50.20, 49.85, 48.09, 45.48, 43.69, 43.45, 41.09, 40.81, 40.46, 36.88, 36,58, 35,87, 34,08, 33,70, 33,29, 32,69, 32,12, 31,64, 29,27, 28,88, 27,91, 27,68, 24,61, 23,53, 21,79, 19,53, 18,96, 18,68, 18,47, 12,26.MS (ESI + ): m / z 690.6 ([M+H] + ). Yield: 41%. Mixture of two diastereomers (β / α) in a ratio of 95 / 05.

[0167] [ka] Methyl-L-valinate 3β-(1,4-bis(3-aminopropyl)piperazine)-chenodeoxycholate 002(C 40 H 73 N5O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 4.33 (d, J = 4.35 Hz, 1H), 3.83 (s, 1H), 3.75 (s, 1H), 3.39 (s, 4H), 2.96-1.93 (m, 27H), 1.87-0.94 (m, 36H), 0.74 (s, 3H). NMR 13C (63 MHz, CD3OD): δ (ppm) = 176.88, 173.69, 68.69, 59.22, 58.97, 57.77, 57.53, 57.23, 54.06, 53.75, 52.42, 51.60, 49.85, 45.93, 43.66, 43.23, 41.13, 40.78, 36,88, 36,48, 35,83, 35,80, 34,10, 33,66, 33,29, 31,62, 29,33, 29,27, 29,16, 29,03, 27,28, 24,60, 23,44, 21,82, 21,74, 19,56, 18,97, 18,68, 12,29. MS (ESI + ): m / z 688.6 ([M+H] + ). Yield: 90%. Mixture of two diastereomers (β / α) in a ratio of 95 / 05.

[0168] [ka] Methyl-L-valinate 3β-(tris(3-aminopropyl)amine)-chenodeoxycholate 003(C 39 H 73 N5O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 3.84 (s, 1H), 3.39 (s, 10H), 3.28 (m, 1H), 2.83-2.68 (m, 6H), 2.55 (s, 4H), 2.39-0.76 (m, 48H), 0.75 (s, 3H).NMR 13C (63 MHz, CD3OD): δ (ppm) = 176.94, 173.74, 68.87, 59.36, 59.24, 57.43, 54.06, 53.32, 52.63, 52.63, 52.44, 51.55, 49.43, 49.14, 48.47, 48.13, 45.92, 43.66, 41,08, 40,85, 40,77, 37,11, 36,89, 36,61, 34,06, 33,63, 33,29, 31,63, 30,05, 29,28, 27,89, 26,87, 24,64, 23,58, 21,79, 19,55, 18,95, 18,67, 12,27. MS (ESI + ): m / z 676.5735 ([M+H] + ). Yield: 51%. Mixture of two diastereomers (β / α) in a ratio of 95 / 05.

[0169] [ka] Methyl-L-glycinate 3β-spermino-chenodeoxycholate 004(C 37 H 69 N5O4). NMR 1 H (250 MHz, CD3OD): δ (ppm) = 4.79 (s, 1H), 3.94-3.68 (m, 3H), 3.40-3.17 (m, 5H), 2.97-2.59 (m, 11H), 2.32-2.17 (m, 4H), 1.96-1.58 (m, 17H), 1.45-1.13 (m, 16H), 1.02-0.86 (m, 9H), 0.67 (s, 3H). NMR 13C (75 MHz, CD3OD): δ (ppm) = 177.36, 172.63, 69.02, 57.35, 51.57, 49.38, 47.45, 46.66, 44.65, 43.68, 43.17, 41.07, 40.77, 39.71, 37.44, 36.99, 36.54, 36,39, 36,21, 35,92, 34,06, 33,87, 33,00, 31,36, 29,30, 28,51, 28,37, 26,53, 26,37, 26,06, 25,34, 24,63, 23,39, 23,30, 21,78, 18,97, 12,19.MS (ESI + ): m / z 648.5 ([M+H] + ). The product was obtained after purification by silica gel chromatography (MeOH, then CH2Cl2 / MeOH / NH4.OH (7 / 3 / 2)). Yield: 14% (mixture of two diastereomers (β / α) in a ratio (95 / 05), referred to herein as the mixture "004-a1"). The corresponding hydrochloride salt S004 (β / α: 95 / 05) was prepared starting from 004-a1 as described below (section "D. Preparation of different salts").

[0170] [ka] Methyl-L-glycinate 3β-(tris(3-aminopropyl)amine)-chenodeoxycholate 005(C 36 H 67 N5O4). NMR 1 H (400 MHz, CD3OD): d (ppm) = 3.84 (s, 3H), 3.63 (t, J = 3.64 Hz, 1H), 3.50-3.37 (m, 2H), 3.33-3.26 (m, 3H), 3.12 (s, 1H), 2.82-2.51 (m, 10H), 2.38-2.21 (m, 4H), 2.07-1.16 (m, 33H), 1.10-0.93 (m, 7H), 0.75 (s, 3H). NMR 13C (101 MHz, CD3OD): δ (ppm) = 177.30, 171.78, 72.87, 69.04, 57.38, 57.35, 52.86, 52.24, 51.58, 49.85, 49.50, 49.28, 49.07, 46.06, 44.76, 43.70, 43.20, 41,08, 40,84, 40,50, 38,65, 36,96, 36,57, 36,23, 35,94, 34,08, 33,87, 33,01, 29,50, 29,27, 27,48, 24,63, 23,39, 21,79, 18,95, 12,19.MS (ESI + ): m / z 634.5 ([M+H] + ). Yield: 14%. Mixture of two diastereomers (β / α) in a ratio of 95 / 05.

[0171] [ka] Methyl-L-glycinate 3β-(1,4-bis(3-aminopropyl)piperazine)-chenodeoxycholate 006(C 37 H 67 N5O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 3.84 (s, 3H), 3.46-3.40 (m, 2H), 3.33-3.26 (m, 2H), 2.91 (t, J = 2.89 Hz, 1H), 2.77-2.19 (m, 20H), 2.08-1.14 (m, 31H), 1.09-0.95 (m, 8H), 0.73 (s, 3H). NMR 13C (101 MHz, CD3OD): δ (ppm) = 177.20, 171.71, 72.86, 69.02, 57.36, 57.29, 56.93, 54.87, 53.91, 53.87, 51.56, 49.85, 46.14, 43.69, 43.66, 43.20, 41.08, 40,94, 40,80, 40,50, 38,72, 36,94, 36,57, 36,22, 35,93, 34,07, 33,87, 32,98, 31,38, 29,82, 29,26, 27,26, 24,63, 23,40, 21,79, 18,95, 12,20.MS (ESI + ): m / z 646.5 ([M+H] + ). Yield: 17%. Mixture of two diastereomers (β / α) in a ratio of 95 / 05.

[0172] [ka] Methyl-L-valinate 3β-(ethylenediamine)-chenodeoxycholate 008(C 32 H 57 N3O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 4.37 (d, J = 4.38 Hz, 1H), 3.87-3.85 (m, 1H), 3.78 (s, 2H), 3.42 (s, 1H), 2.91-2.69 (m, 4H), 2.55-0.97 (m, 45H), 0.76 (s, 3H). NMR 13C (101 MHz, CD3OD): δ (ppm) = 176.93, 173.75, 68.94, 59.38, 59.24, 57.45, 52.38, 51.54, 49.36, 43.70, 43.58, 41.82, 41.09, 40.84, 37.65, 37,08, 36,87, 36,65, 35,95, 34,07, 33,67, 33,27, 31,66, 29,26, 28,38, 24,62, 23,60, 21,79, 19,51, 18,96, 18,66, 12,26.MS (ESI + ): m / z 548.4 ([M+H] + ). Yield: 44%. Mixture of two diastereomers (β / α) in a ratio of 95 / 05.

[0173] [ka] Methyl-L-valinate 3β-(1,10-diaminodecane)-chenodeoxycholate 009(C 40 H 73 N3O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 4.36 (d, J = 4.35 Hz, 1H), 3.92-3.78 (m, 1H), 3.76 (s, 2H), 2.89-2.57 (m, 4H), 2.41-1.49 (m, 24H), 1.38 (s, 19H), 1.25-0.91 (m, 19H), 0.75 (s, 3H). NMR 13C (75 MHz, CD3OD): δ (ppm) = 176.93, 173.73, 68.96, 59.38, 59.22, 57.43, 52.40, 51.52, 49.79, 48.20, 47.49, 43.70, 43.61, 42.56, 41.08, 40.83, 37.15, 36.88, 36.68, 35,96, 34,05, 33,79, 33,65, 33,28, 31,66, 30,67, 30,56, 30,37, 29,28, 28,52, 28,37, 28,04, 24,63, 23,65, 22,42, 21,81, 19,54, 18,97, 18,67, 12,28. MS (ESI + ): m / z 660.6 ([M+H] + ). The product was obtained after purification by silica gel chromatography (MeOH, then CH2Cl2 / MeOH / NH4.OH (7 / 3 / 0.5)). Yield: 32%. Mixture of two diastereomers (β / α) in a ratio of (95 / 05).

[0174] [ka] Methyl-L-phenylalaninate 3β-(triethylenetetramine)-chenodeoxycholate 010(C 40 H 67 N5O4). NMR 1 NMR 13C (75 MHz, CD3OD): δ (ppm) = 176.86, 175.19, 141.85, 129.45, 129.25, 128.79, 128.43, 128.13, 68.84, 60.64, 60.16, 59.35, 57.45, 54.82, 54.02, 51.57, 51.24, 49.79, 49,41, 48,59, 46,11, 45,90, 43,69, 43,40, 41,26, 41,07, 40,82, 38,64, 36,79, 36,56, 35,82, 34,25, 34,07, 33,20, 29,27, 24,62, 23,49, 21,78, 18,97, 12,27. MS (ESI + ): m / z 682.5 ([M+H] + ). Yield: 28%. Mixture of two diastereomers (β / α) in a ratio of 95 / 05.

[0175] [ka] Methyl-L-valinate 3β-norspermino-chenodeoxycholate 011(C 39 H 73 N5O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 4.35 (d, J = 4.35 Hz, 1H), 3.85 (s, 1H), 3.76 (s, 3H), 3.45-3.40 (m, 1H), 3.29-3.19 (m, 1H), 3.04-1.86 (m, 22H), 1.75-1.07 (m, 26H), 1.04-0.91 (m, 15H), 0.74 (s, 3H). NMR 13C (101 MHz, CD3OD): δ (ppm) = 177.02, 173.79, 68.96, 59.39, 59.16, 57.66, 56.40, 53.69, 52.52, 52.40, 52.25, 51.43, 49.82, 48.12, 46.34, 43.71, 43.45, 41.23, 41,00, 40,60, 37,04, 36,67, 34,12, 33,89, 33,69, 33,22, 31,72, 31,61, 29,38, 29,13, 24,61, 24,50, 23,45, 19,61, 19,39, 18,74, 18,54, 18,32, 12,29. MS (ESI + ): m / z 676.6 ([M+H] + ). Yield: 6%. Mixture of two diastereomers (β / α) in a ratio of 95 / 05.

[0176] [ka] Methyl-L-valinate 3β-(triethylenetetramine)-chenodeoxycholate 012(C 36 H 67 N5O4). NMR 1 H (300 MHz, CD3OD): δ (ppm) = 4.33-4.22 (m, 1H), 3.83 (s, 1H), 3.73 (s, 1H), 3.37 (s, 1H), 3.20-1.82 (m, 31H), 1.62-1.16 (m, 16H), 1.07-0.92 (m, 13H), 0.72 (s, 3H). NMR 13C (75 MHz, CD3OD): δ (ppm) = 175.97, 173.79, 68.78, 61.34, 59.29, 57.48, 53.91, 52.40, 51.62, 48.82, 48.62, 48.57, 43.70, 41.09, 40.79, 40.16, 38.05, 37,00, 35,70, 34,51, 34,10, 33,47, 32,69, 31,65, 29,30, 27,57, 26,09, 24,60, 23,32, 21,77, 20,24, 19,50, 18,97, 18,64, 18,44, 12,24. MS (ESI + ): m / z 634.5 ([M+H] + ). The product was obtained after purification by silica gel chromatography (MeOH, then MeOH / NH4.OH (10 / 1)). Yield: 10%. Mixture of two diastereomers (β / α) in a ratio of (95 / 05).

[0177] [ka] Methyl-L-valinate 3β-(bis(3-aminopropyl)ethylenediamine)-N,N-diisopropylchenodeoxycholate 013(C 38 H 71 N5O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 4.30-4.20 (m, 1H), 3.81 (s, 1H), 3.71 (s, 1H), 3.35 (s, 4H), 3.18-2.70 (m, 13H), 2.51-0.90 (m, 48H), 0.70 (s, 3H).NMR 13C (101 MHz, CD3OD): δ (ppm) = 178.45, 176.10, 68.78, 61.21, 59.29, 57.47, 52.40, 51.63, 49.85, 47.20, 47.03, 46.65, 45.07, 43.70, 43.36, 43.00, 40.77, 39.09, 37,00, 36,33, 36,16, 35,48, 34,43, 34,06, 33,49, 32,55, 31,65, 29,31, 26,34, 24,58, 23,22, 21,79, 20,20, 19,50, 18,98, 18,64, 18,45, 12,22.MS (ESI + ): m / z 662.6 ([M+H] + ). Yield: 25%. Mixture of two diastereomers (β / α) in a ratio of 95 / 05.

[0178] [ka] Methyl-L-phenylalaninate 3β-spermino-chenodeoxycholate 014(C 44 H 75 N5O4). NMR 1 NMR 13C (101 MHz, CD3OD): δ (ppm) = 175.95, 173.81, 139.38, 130.52, 129.48, 129.32, 129.18, 128.47, 68.73, 59.28, 57.38, 56.61, 52.42, 51.58, 49.83, 47.84, 46.02, 45.85, 43.67, 42.99, 41,03, 40,76, 39,08, 37,89, 36,89, 36,32, 36,16, 35,50, 34,02, 33,83, 33,30, 31,65, 30,73, 29,26, 25,31, 25,11, 24,43, 23,23, 22,59, 22,06, 21,78, 19,36, 12,21. + ): m / z 738.6 ([M+H] + ). The product was obtained after purification by silica gel chromatography (MeOH, then MeOH / NH4.OH (10 / 3)). Yield: 15%. Mixture of two diastereomers (β / α) in a ratio of (95 / 05).

[0179] [ka] Methyl-L-phenylalaninate 3β-(ethylenediamine)-chenodeoxycholate 015(C 36 H 57 N3O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 7.29-7.12 (m, 5H), 4.49-4.46 (m, 1H), 3.78 (s, 1H), 3.51-3.18 (m, 3H), 3.08-2.48 (m, 7H), 2.36-0.89 (m, 37H), 0.65 (s, 3H). NMR 13C (101 MHz, CD3OD): δ (ppm) = 178.40, 175.66, 139.66, 130.61, 129.11, 127.29, 68.77, 59.28, 57.36, 57.26, 51.55, 49.85, 46.63, 43.66, 43.63, 43.22, 41.05, 40,77, 39,70, 39,39, 36,91, 36,51, 36,45, 35,71, 35,62, 34,34, 34,06, 33,30, 29,24, 26,69, 24,58, 23,37, 21,76, 18,94, 12,29, 12,26. MS (ESI + ): m / z 596.4 ([M+H] + ). The product was obtained after purification by silica gel chromatography (MeOH, then MeOH / NH4.OH (10 / 0.25)). Yield: 21%. Mixture of two diastereomers (β / α) in a ratio of (95 / 05).

[0180] [ka] Methyl-L-phenylalaninate 3β-(1,3-diaminopropane)-chenodeoxycholate 016(C 37 H 59 N3O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 7.32-7.13 (m, 5H), 4.52-4.47 (m, 1H), 3.82 (s, 1H), 3.36 (s, 3H), 3.29-2.64 (m, 8H), 2.48-0.91 (m, 38H), 0.68 (s, 3H). NMR 13C (101 MHz, CD3OD): δ (ppm) = 178.28, 175.73, 139.65, 130.61, 130.30, 129.52, 129.10, 127.28, 68.72, 59.35, 57.38, 56.61, 51.60, 49.85, 43.65, 42.99, 42.66, 41,06, 40,76, 39,34, 38,06, 36,92, 36,32, 35,49, 34,32, 34,08, 33,31, 29,24, 28,62, 25,81, 25,23, 24,56, 23,22, 21,76, 18,91, 17,31, 12,22. MS (ESI + ): m / z 610.5 ([M+H] + ). The product was obtained after purification by silica gel chromatography (MeOH, then MeOH / NH4.OH (10 / 0.5)). Yield: 5%. Mixture of two diastereomers (β / α) in a ratio of (95 / 05).

[0181] [ka] Methyl-L-valinate 3β-(1,3-diaminopropane)-chenodeoxycholate 018(C 33 H 59 N3O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 4.33-4.22 (m, 1H), 3.84 (s, 1H), 3.73 (s, 1H), 3.43-3.37 (m, 3H), 3.20-2.75 (m, 6H), 2.52-0.95 (m, 44H), 0.73 (s, 3H). NMR 13C (101 MHz, CD3OD): δ (ppm) = 177.97, 176.25, 68.73, 60.98, 59.45, 57.53, 52.40, 51.61, 43.71, 43.02, 42.61, 41.07, 40.80, 37.92, 36.99, 36,17, 35,52, 34,35, 34,07, 33,87, 33,45, 32,34, 31,66, 29,31, 25,50, 25,15, 24,60, 23,24, 21,80, 20,12, 19,03, 18,52, 12,26. MS (ESI + ): m / z 562.5 ([M+H] + ). The product was obtained after purification by silica gel chromatography (MeOH, then MeOH / NH4.OH (10 / 1)). Yield: 10%. Mixture of two diastereomers (β / α) in a ratio of (95 / 05).

[0182] [ka] Methyl-L-valinate 3β-(diethylenetriamine)-chenodeoxycholate 020(C 34 H 62 N4O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 4.31 (d, J = 4.31 Hz, 1H), 3.97-3.90 (m, 1H), 3.82 (s, 1H), 3.72 (s, 3H), 3.48-2.64 (m, 8H), 2.51-1.76 (m, 15H), 1.61-0.94 (m, 30H), 0.71 (s, 3H). NMR 13C (101 MHz, CD3OD): δ (ppm) = 177.04, 173.77, 68.95, 62.36, 59.29, 57.52, 52.42, 51.56, 51.19, 45.96, 45.79, 43.85, 43.67, 43.14, 41.03, 40.70, 36,90, 36,54, 36,32, 36,09, 33,30, 31,61, 29,27, 23,50, 23,39, 21,75, 20,19, 19,52, 18,90, 18,65, 18,50, 16,82, 14,57, 12,20. MS (ESI + ): m / z 591.15 ([M+Na] + ). The product was obtained after purification by silica gel chromatography (MeOH, then MeOH / NH4.OH (10 / 0.25)). Yield: 10%. Mixture of two diastereomers (β / α) in a ratio of (95 / 05).

[0183] [ka] Methyl-L-phenylalaninate 3β-norspermino-chenodeoxycholate 022(C 43 H 73 N5O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 7.28-7.13 (m, 5H), 4.52-4.49 (m, 1H), 3.80 (s, 1H), 3.52-2.89 (m, 18H), 2.75-0.85 (m, 45H), 0.67 (s, 3H).NMR 13C (101 MHz, CD3OD): δ (ppm) = 177.98, 175.80, 139.56, 130.58, 129.49, 129.31, 129.13, 127.33, 68.72, 57.37, 57.00, 51.58, 49.71, 49.50, 45.95, 43.65, 42.98, 41.06, 40.77, 39.26, 37,87, 36,92, 36,56, 36,32, 36,22, 36,16, 35,49, 34,28, 34,06, 33,31, 31,27, 29,30, 29,24, 27,11, 26,47, 25,47, 24,64, 24,58, 23,22, 21,78, 18,91, 16,49, 12,22. + ): m / z 725.6 ([M+H] + ). Yield: 7%. Mixture of two diastereomers (β / α) in a ratio of 95 / 05.

[0184] [ka] Methyl-L-valinate 3β-(1,6-diaminohexane)-chenodeoxycholate 023(C 36 H 65 N3O4). NMR 1 NMR 13C (101 MHz, CD3OD): δ (ppm) = 177.04, 173.79, 69.02, 59.28, 57.42, 52.40, 51.56, 49.71, 49.50, 49.28, 44.91, 43.69, 41.58, 40.63, 36.98, 36.89, 36.32, 33,65, 33,29, 31,66, 30,11, 29,27, 28,50, 27,81, 27,32, 26,63, 24,57, 23,22, 20,20, 19,76, 19,50, 18,90, 18,63, 18,38, 12,69, 12,20.MS (ESI + ): m / z 604.5 ([M+H] + ). The product was obtained after purification by silica gel chromatography (MeOH, then MeOH / NH4.OH (10 / 0.5)). Yield: 4%. Mixture of two diastereomers (β / α) in a ratio of (95 / 05).

[0185] [ka] Methyl-L-phenylalanine 3β-(diethylenetriamine)-chenodeoxycholate 024(C 38 H 62 N4O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 7.29-7.13 (m, 5H), 4.50-4.47 (m, 1H), 3.87-3.81 (m, 1H), 3.71-3.51 (m, 1H), 3.35-2.57 (m, 16H), 2.49-0.89 (m, 35H), 0.68 (s, 3H). NMR 13C (101 MHz, CD3OD): δ (ppm) = 178.36, 175.72, 139.67, 130.62, 130.33, 129.49, 129.11, 127.29, 68.76, 59.21, 57.37, 57.28, 51.59, 49.07, 47.18, 46.12, 45.16, 43,65, 43,06, 41,05, 40,76, 40,23, 39,37, 36,93, 36,32, 36,25, 35,52, 34,32, 34,07, 33,91, 33,31, 29,25, 25,26, 24,57, 23,24, 21,76, 18,91, 12,22. MS (ESI + ): m / z 639.5 ([M+H] + ). The product was obtained after purification by silica gel chromatography (MeOH, then MeOH / NH4.OH (10 / 0.5)). Yield: 7%. Mixture of two diastereomers (β / α) in a ratio of (95 / 05).

[0186] [ka] Methyl-L-phenylalaninate 3β-(1,4-bis(3-aminopropyl)piperazine)-chenodeoxycholate 025(C 44 H 73 N5O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 7.31-7.19 (m, 5H), 4.52 (t, J = 4.53 Hz, 1H), 3.81 (s, 1H), 3.42-3.36 (m, 3H), 3.26-2.81 (m, 8H), 2.69-0.87 (m, 52H), 0.68 (s, 3H). NMR 13C (101 MHz, CD3OD): δ (ppm) = 176.56, 173.53, 138.55, 130.33, 130.20, 129.48, 127.80, 72.85, 69.04, 57.33, 57.07, 56.95, 56.31, 53.86, 53.83, 51.55, 49.85, 49.71, 49.50, 49.28, 49,07, 43,66, 43,17, 41,05, 40,76, 40,48, 39,11, 38,83, 36,92, 36,55, 36,22, MS (ESI + ): m / z 736.6 ([M+H] + ). The product was obtained after purification by silica gel chromatography (MeOH, then MeOH / NH4.OH (10 / 0.5)). Yield: 5%. Mixture of two diastereomers (β / α) in a ratio of (95 / 05).

[0187] [ka] Methyl-L-valinate 3β-(bis(3-aminopropyl)methylamine)-chenodeoxycholate 026(C 37 H 68 N4O4). NMR 1 NMR 13C (101 MHz, CD3OD): δ (ppm) = 177.03, 173.79, 68.75, 61.22, 59.28, 57.43, 56.43, 54.24, 52.40, 51.63, 49.82, 49.71, 49.50, 49.28, 49.07, 43.70, 43.04, 41,06, 40,77, 36,91, 34,51, 33,69, 33,28, 32,78, 31,66, 29,28, 24,63, 24,58, 23,24, 21,77, 20,22, 19,50, 18,95, 18,89, 18,63, 18,37, 12,21.MS (ESI + ): m / z 633.5 ([M+H] + The product was obtained after purification by silica gel chromatography (MeOH, then MeOH / NH4.OH (10 / 0.5)). Yield: 4%. Mixture of two diastereomers (β / α) in a ratio of 95 / 05.

[0188] [ka] Methyl-L-phenylalaninate 3β-norspermidino-chenodeoxycholate 028(C 40 H 66 N4O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 7.28-7.12 (m, 5H), 4.52-4.47 (m, 1H), 3.80 (s, 1H), 3.70-3.50 (m, 1H), 3.34 (s, 1H), 3.26-2.80 (m, 12H), 2.71-0.81 (m, 42H), 0.67 (s, 3H). NMR 13C (101 MHz, CD3OD): δ (ppm) = 178.38, 175.70, 139.67, 130.62, 130.33, 129.31, 129.11, 127.28, 68.71, 64.40, 59.34, 57.38, 57.26, 54.02, 51.59, 49.85, 49.71, 49.50, 49,28, 49,07, 47,71, 43,65, 43,01, 40,76, 39,36, 38,09, 37,99, 36,93, 36,34, 34,32, 34,07, 30,08, 29,43, 25,28, 24,58, 23,25, 21,77, 18,92, 12,24, 12,21. MS (ESI + ): m / z 667.5 ([M+H] + ). The product was obtained after purification by silica gel chromatography (MeOH, then MeOH / NH4.OH (10 / 2)). Yield: 10%. Mixture of two diastereomers (β / α) in a ratio of (95 / 05).

[0189] [ka] Methyl-L-phenylalaninate 3β-(bis(3-aminopropyl)ethylenediamine)-chenodeoxycholate 029(C 42 H 71 N5O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 7.30-7.13 (m, 5H), 4.51-4.48 (m, 1H), 3.80 (s, 1H), 3.69-3.51 (m, 1H), 3.35 (s, 3H), 3.24-2.67 (m, 16H), 2.51-2.41 (m, 1H), 2.23-0.82 (m, 40H), 0.68 (s, 3H). NMR 13C (101 MHz, CD3OD): δ (ppm) = 178.24, 175.72, 139.65, 130.62, 129.48, 129.10, 127.85, 127.29, 68.80, 59.44, 57.34, 57.21, 55.16, 52.66, 51.62, 49.85, 49.50, 49.28, 49.07, 47,40, 46,78, 43,66, 43,00, 40,75, 39,34, 36,92, 36,32, 35,46, 34,29, 33,90, 33,32, 32,14, 30,75, 29,25, 26,47, 25,30, 25,17, 24,56, 23,22, 21,77, 18,90, 12,20. + ): m / z 710.6 ([M+H] + ). The product was obtained after purification by silica gel chromatography with MeOH, then MeOH / NH4.OH (10 / 2). Yield: 8%. Mixture of two diastereomers (β / α) in a ratio of (95 / 05).

[0190] [ka] Methyl-L-phenylalaninate 3β-(1,4-diaminobutane)-chenodeoxycholate 030(C 38 H 61 N3O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 7.29-7.13 (m, 5H), 4.52-4.48 (m, 1H), 4.14-3.68 (m, 2H), 3.55-3.35 (m, 2H), 3.24-3.15 (m, 2H), 3.07-2.85 (m, 5H), 2.72-2.38 (m, 1H), 2.23-0.85 (m, 40H), 0.67 (s, 3H). NMR 13C (101 MHz, CD3OD): δ (ppm) = 177.99, 175.81, 139.56, 130.57, 130.34, 129.31, 129.14, 127.34, 68.72, 59.25, 57.40, 57.01, 55.16, 54.03, 52.66, 51.58, 44.56, 43,65, 43,01, 41,05, 40,75, 39,60, 39,26, 38,00, 36,92, 36,32, 36,17, 35,50, 34,28, 34,06, 33,80, 33,31, 25,26, 23,92, 23,24, 21,76, 18,92, 12,22. MS (ESI + ): m / z 624.5 ([M+H] + ). The product was obtained after purification by silica gel chromatography (MeOH, then MeOH / NH4.OH (10 / 1)). Yield: 10%. Mixture of two diastereomers (β / α) in a ratio of (95 / 05).

[0191] [ka] Methyl-L-phenylalaninate 3β-(bis(3-aminopropyl)methylamine)-chenodeoxycholate 031(C 41 H 68 N4O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 7.30-7.14 (m, 5H), 4.68-4.50 (m, 1H), 3.85-3.76 (m, 1H), 3.70-3.52 (m, 1H), 3.36 (s, 2H), 3.25-2.67 (m, 7H), 2.53-0.87 (m, 48H), 0.68 (s, 3H). NMR 13C (101 MHz, CD3OD): δ (ppm) = 176.69, 173.66, 139.93, 130.33, 130.20, 129.48, 129.31, 127.29, 68.92, 64.40, 59.33, 57.44, 56.96, 56.40, 55.15, 54.01, 52.66, 51.58, 49.50, 49,28, 49,07, 45,78, 43,67, 43,44, 42,12, 41,09, 40,80, 39,40, 38,34, 38,00, 36,94, 36,82, 36,59, 35,83, 34,10, 30,10, 26,70, 24,60, 23,47, 21,77, 12,21. MS (ESI + ): m / z 682.5 ([M+H] + ). Yield: 17%. Mixture of two diastereomers (β / α) in a ratio of 95 / 05.

[0192] [ka] Methyl-L-phenylalaninate 3β-(1,10-diaminodecane)-chenodeoxycholate 032(C 44 H 73 N3O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 7.28-7.12 (m, 5H), 4.49 (q, J1= 4.50 Hz, J2= 4.48 Hz, 1H), 3.86-3.80 (m, 1H), 3.34 (s, 1H), 3.23-3.18 (m, 1H), 3.04-2.59 (m, 7H), 2.38-0.85 (m, 54H), 0.66 (s, 3H). NMR 13C (101 MHz, CD3OD): δ (ppm) = 178.28, 175.62, 139.65, 130.64, 129.08, 127.27, 68.77, 59.27, 57.35, 57.20, 51.57, 49.85, 46.27, 43.64, 43.18, 41.67, 41.05, 40.77, 39.41, 36.90, 36.43, 35,66, 35,10, 34,32, 34,08, 33,93, 33,29, 31,31, 31,28, 30,54, 30,51, MS (ESI + ): m / z 708.42 ([M+H] + ). The product was obtained after purification by silica gel chromatography (MeOH, then MeOH / NH4.OH (10 / 0.1)). Yield: 13%. Mixture of two diastereomers (β / α) in a ratio of (95 / 05).

[0193] [ka] Methyl-L-alaninate 3β-(bis(3-aminopropyl)ethylenediamine)-chenodeoxycholate 034(C 36 H 67 N5O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 4.21 (d, J = 4.22 Hz, 1H), 3.82-3.71 (m, 2H), 3.55-3.43 (m, 1H), 3.16-2.65 (m, 13H), 2.48-1.77 (m, 18H), 1.67-0.88 (m, 29H), 0.71 (s, 3H). NMR 13C (101 MHz, CD3OD): δ (ppm) = 179.88, 175.57, 68.83, 59.40, 57.40, 51.83, 51.61, 49.85, 49.71, 49.50, 49.28, 49.07, 47.77, 43.69, 42.99, 41.01, 40.75, 39,68, 36,99, 36,32, 36,16, 34,34, 34,06, 33,21, 32,14, 30,75, 30,08, 29,27, 26,67, 25,43, 24,56, 23,22, 21,76, 19,49, 18,94, 12,17.MS (ESI + ): m / z 634.5 ([M+H] + ). The product was obtained after purification by silica gel chromatography (MeOH, then MeOH / NH4.OH (10 / 3)). Yield: 29%. Mixture of two diastereomers (β / α) in a ratio of (95 / 05).

[0194] [ka] Methyl-L-leucinate 3β-(bis(3-aminopropyl)ethylenediamine)-chenodeoxycholate 035(C 39 H 73 N5O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 4.37 (s, 1H), 3.82 (s, 1H), 3.72 (s, 2H), 2.97-2.66 (m, 13H), 2.51-2.17 (m, 4H), 2.05-0.90 (m, 49H), 0.72 (s, 3H).NMR 13C (101 MHz, CD3OD): δ (ppm) = 176.95, 173.83, 68.83, 59.23, 58.24, 57.62, 52.35, 51.65, 49.82, 49.71, 49.50, 49.28, 48.18, 46.13, 45.21, 43.71, 43.23, 41.10, 40,77, 40,28, 38,22, 36,91, 36,47, 35,70, 34,13, 33,74, 33,29, 30,76, 30,08, 29,28, 29,27, 26,42, 24,57, 23,33, 21,76, 18,89, 15,98, 12,20, 11,61. MS (ESI + ): m / z 676.86 ([M+H] + ). The product was obtained after purification by silica gel chromatography (MeOH, then CH2Cl2 / MeOH / NH4.OH (7 / 3 / 0.75)). Yield: 2%. Mixture of two diastereomers (β / α) in a ratio of (95 / 05).

[0195] [ka] Methyl-L-leucinate 3β-spermino-chenodeoxycholate 036(C 41 H 88 N5O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 4.37-4.26 (m, 1H), 3.81 (s, 1H), 3.72 (s, 2H), 3.40-3.18 (m, 4H), 2.99-1.07 (m, 52H), 1.00-0.90 (m, 14H), 0.71 (s, 3H).NMR 13C (101 MHz, CD3OD): δ (ppm) = 176.93, 173.81, 68.93, 60.85, 59.28, 58.23, 57.56, 52.35, 51.60, 50.37, 49.71, 49.50, 49.28, 49.07, 45.54, 43.71, 43.48, 41.12, 40.82, 40,53, 39,53, 38,23, 36,61, 34,52, 34,10, 33,71, 33,45, 33,29, 29,29, 28,12, 26,42, 26,14, 24,61, 23,49, 22,17, 21,78, 18,92, 16,46, 16,00, 12,22, 11,63.MS (ESI + ): m / z 704.6 ([M+H] + ). Yield: 4%. Mixture of two diastereomers (β / α) in a ratio of 95 / 05.

[0196] [ka] Methyl-L-phenylalaninate 3β-(tris(3-aminopropyl)amine)-chenodeoxycholate 037(C 43 H 73 N5O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 7.28-7.14 (m, 5H), 4.48-4.45 (m, 1H), 3.80 (s, 1H), 3.25-3.07 (m, 2H), 2.99-2.82 (m, 7H), 2.72-2.39 (m, 9H), 2.24-1.06 (m, 38H), 1.01-0.88 (m, 7H), 0.67 (s, 3H). NMR 13C (101 MHz, CD3OD): δ (ppm) = 178.46, 175.75, 139.68, 130.58, 130.33, 129.31, 129.15, 127.33, 68.77, 64.40, 59.29, 57.37, 54.03, 52.52, 52.29, 51.63, 44.72, 43.66, 43.07, 41.06, 40,74, 40,14, 39,91, 39,40, 37,99, 36,95, 36,38, 36,27, 35,58, 34,32, 34,11, 33,33, 30,74, 29,26, 27,13, 27,02, 25,88, 25,15, 24,56, 23,27, 21,76, 18,95,12,24. + ): m / z 724.16 ([M+H] + ). The product was obtained after purification by silica gel chromatography (MeOH, then CH2Cl2 / MeOH / NH4.OH (7 / 3 / 1.5)). Yield: 7%. Mixture of two diastereomers (β / α) in a ratio of (95 / 05).

[0197] [ka] Methyl-L-alaninate 3β-spermino-chenodeoxycholate 038(C 38 H 71 N5O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 4.27-4.18 (m, 1H), 3.94-3.79 (m, 1H), 3.51-3.40 (m, 1H), 3.35 (s, 2H), 3.27-3.02 (m, 2H), 2.92-2.57 (m, 13H), 2.43-0.90 (m, 48H), 0.70 (s, 3H). NMR 13C (101 MHz, CD3OD): δ (ppm) = 179.94, 175.53, 68.84, 66.21, 59.22, 57.40, 51.87, 51.62, 50.01, 49.91, 49.85, 48.25, 48.00, 43.70, 43.33, 41.10, 40.80, 40.32, 40,29, 37,79, 36,99, 36,69, 36,53, 34,30, 34,10, 33,83, 33,35, 33,23, 31,36, 29,30, 27,72, 24,61, 23,41, 21,77, 19,49, 18,98, 17,13, 12,19. MS (ESI + ): m / z 663.6 ([M+H] + ). The product was obtained after purification by silica gel chromatography (MeOH, then CH2Cl2 / MeOH / NH4.OH (7 / 3 / 1.5)). Yield: 4%. Mixture of two diastereomers (β / α) in a ratio of (95 / 05).

[0198] [ka] Methyl-L-tyrosinate 3β-spermino-chenodeoxycholate 039(C 44 H 75 N5O5). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 7.05-6.99 (m, 2H), 6.71-6.65 (m, 2H), 3.80 (s, 1H), 3.68 (s, 2H), 3.35 (s, 1H), 3.23-3.02 (m, 2H), 2.90-2.47 (m, 15H), 2.27-0.92 (m, 47H), 0.68 (s, 3H). NMR 13C (101 MHz, CD3OD): δ (ppm) = 176.69, 173.84, 157.57, 131.17, 128.75, 116.29, 68.93, 59.26, 57.46, 57.38, 55.44, 52.61, 51.58, 50.33, 50.19, 49.85, 49.50, 49.28, 49.07, 48.16, 45.52, 43,68, 43,45, 41,08, 40,79, 40,50, 37,61, 36,84, 36,71, 36,59, 35,85, MS (ESI + ): m / z 754.6 ([M+H] + ). The product was obtained after purification by silica gel chromatography (MeOH, then CH2Cl2 / MeOH / NH4.OH (7 / 3 / 1.5)). Yield: 7%. Mixture of two diastereomers (β / α) in a ratio of (95 / 05).

[0199] [ka] Methyl-L-tyrosinate 3β-norspermidino-chenodeoxycholate 040(C 40 H 66 N4O5). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 7.06-6.97 (m, 2H), 6.75-6.65 (m, 2H), 4.61-4.57 (m, 1H), 3.81 (s, 1H), 3.69 (s, 2H), 3.52-3,35 (m, NMR 13C (101 MHz, CD3OD): δ (ppm) = 176.71, 173.85, 157.48, 131.58, 131.18, 128.82, 116.25, 115.88, 68.95, 64.38, 63.80, 61.09, 57.48, 57.35, 55.43, 53.69, 52.61, 51.58, 49,71, 49,50, 49,28, 49,07, 43,68, 41,07, 41,06, 40,78, 39,64, 37,61, 36,83, 36,56, 34,09, 33,76, 33,19, 30,75, 29,24, 24,60, 23,43, 21,76, 18,85, 12,20. MS (ESI + ): m / z 683.5 ([M+H] + ). The product was obtained after purification by silica gel chromatography (MeOH, then CH2Cl2 / MeOH / NH4.OH (7 / 3 / 0.75)). Yield: 4%. Mixture of two diastereomers (β / α) in a ratio of (90 / 10).

[0200] [ka] Methyl-L-isoleucinate 3β-(bis(3-aminopropyl)ethylenediamine)-chenodeoxycholate 041(C 39 H 73 N5O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 4.36 (d, J = 4.35 Hz, 1H), 3.78 (s, 1H), 3.70 (s, 2H), 3.34 (s, 1H), 3.26-3.14 (m, 1H), 2.91-2.61 (m, NMR 13C (101 MHz, CD3OD): δ (ppm) = 176.62, 173.55, 68.66, 59.07, 57.98, 57.26, 52.14, 51.34, 49.64, 49.39, 49.33, 48.05, 45.22, 43.46, 43.26, 40.85, 40.58, 40.27, 37,98, 36,65, 36,47, 36,38, 35,67, 33,84, 33,45, 33,06, 32,59, 30,76, 29,35, 29,06, 27,57, 26,19, 24,40, 23,33, 21,56, 18,72, 15,81, 12,04, 11,45. MS (ESI + ): m / z 676.6 ([M+H] + ). Yield: 21%. Mixture of two diastereomers (β / α) in a ratio of 95 / 05.

[0201] [ka] Methyl-L-tyrosinate 3β-(bis(3-aminopropyl)ethylenediamine)-chenodeoxycholate 042(C 42 H 71 N5O5). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 7.06-6.99 (m, 2H), 6.71-6.64 (m, 2H), 3.79 (s, 1H), 3.68 (s, 1H), 3.50-3.33 (m, 2H), 3.24-0.90 (m, 60H), 0.67 (s, 3H). NMR 13C (101 MHz, CD3OD): δ (ppm) = 176.67, 173.84, 157.50, 131.17, 128.78, 116.27, 68.85, 59.24, 57.47, 55.43, 52.62, 51.59, 49.85, 48.21, 47.56, 45.59, 45.30, 43.66, 43.30, 41.07, 40,77, 40,36, 37,60, 36,93, 36,83, 36,63, 36,51, 36,07, 35,76, 34,08, 33,76, 33,18, 31,68, 29,93, 29,24, 28,46, 27,00, 24,59, 23,40, 21,76, 18,86, 12,21. + ): m / z 726.6 ([M+H] + ). Yield: 9%. Mixture of two diastereomers (β / α) in a ratio of 95 / 05.

[0202] [ka] Methyl-L-valinate 3β-(1,4-diaminobutane)-chenodeoxycholate 043(C 34 H 61 N3O4). NMR 1 NMR 13C (101 MHz, CD3OD): δ (ppm) = 177.05, 173.79, 68.96, 59.28, 57.51, 52.40, 51.57, 49.85, 46.81, 43.70, 43.47, 42.00, 41.08, 40.80, 36.94, 36.91, 36,88, 36,61, 35,85, 34,08, 33,68, 33,29, 31,66, 30,91, 29,27, 27,72, 27,56, 24,60, 23,50, 21,77, 19,50, 18,91, 18,63, 12,21. MS (ESI + ): m / z 576.5 ([M+H] + ). The product was obtained after purification by silica gel chromatography (MeOH, then CH2Cl2 / MeOH / NH4.OH (7 / 3 / 0.6)). Yield: 3%. Mixture of two diastereomers (β / α) in a ratio of (95 / 05).

[0203] [ka] Methyl-L-isoleucinate 3β-spermino-chenodeoxycholate 044(C 41 H 77 N5O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 4.36 (d, J = 4.35 Hz, 1H), 3.79 (s, 1H), 3.71 (s, 2H), 3.35 (s, 1H), 3.24-3.16 (m, 1H), 2.92-2.61 (m, NMR 13C (101 MHz, CD3OD): δ (ppm) = 176.91, 173.80, 68.91, 59.27, 58.22, 57.53, 52.35, 51.59, 50.35, 50.22, 49.85, 49.50, 49.28, 49.07, 48.68, 48.16, 45.51, 43.70, 43.47, 41,10, 40,81, 40,50, 38,22, 36,96, 36,88, 36,60, 35,86, 34,09, 33,69, 33,29, 32,52, 29,29, 28,06, 26,41, 24,61, 23,50, 21,78, 18,92, 16,00, 12,22, 11,63. MS (ESI + ): m / z 704.6 ([M+H] + ). The product was obtained after purification by silica gel chromatography (MeOH, then CH2Cl2 / MeOH / NH4.OH (7 / 3 / 1.5)). Yield: 14%. Mixture of two diastereomers (β / α) in a ratio of (95 / 05).

[0204] [ka] Methyl-L-prolinate 3β-norspermidino-chenodeoxycholate 045(C 36 H 64 N4O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 4.43-4.14 (m, 1H), 3.86-3.77 (m, 2H), 3.71 (s, 2H), 3.68-3.34 (m, 4H), 2.95-2.66 (m, 7H), 2.59-0.93 (m, 45H), 0.72 (s, 3H). NMR 13C (101 MHz, CD3OD): δ (ppm) = 175.06, 174.52, 68.90, 60.24, 59.24, 57.47, 52.68, 51.60, 51.54, 49.28, 48.72, 48.50, 48.06, 45.47, 43.69, 43.39, 41.08, 40,80, 40,42, 36,89, 36,75, 36,56, 35,79, 34,09, 32,32, 32,20, 32,10, 30,26, 29,27, 28,69, 25,74, 24,61, 23,45, 21,76, 19,02, 12,20.MS (ESI + ): m / z 617.5 ([M+H] + ). The product was obtained after purification by silica gel chromatography (MeOH, then CH2Cl2 / MeOH / NH4.OH (7 / 3 / 0.7)). Yield: 10%. Mixture of two diastereomers (β / α) in a ratio of (95 / 05).

[0205] [ka] Methyl-L-prolinate 3β-(bis(3-aminopropyl)ethylenediamine)-chenodeoxycholate 046(C 38 H 69 N5O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 4.42-4.13 (m, 1H), 3.80-3.76 (m, 1H), 3.70 (s, 2H), 3.67-3.33 (m, 4H), 3.19-3.06 (m, 1H), 2.96-2.63 (m, 11H), 2.56-0.92 (m, 46H), 0.71 (s, 3H). NMR 13C (101 MHz, CD3OD): δ (ppm) = 175.04, 174.51, 68.88, 62.22, 60.23, 59.27, 57.45, 52.69, 51.57, 49.55, 49.48, 49.28, 48.67, 48.49, 48.25, 45.38, 43.68, 43.42, 41,06, 40,79, 40,44, 36,88, 36,67, 36,57, 34,06, 32,48, 32,30, 32,09, 30,26, 29,27, 29,19, 27,51, 25,73, 24,60, 23,48, 21,76, 19,03, 12,22.MS (ESI + ): m / z 661.6 ([M+H] + ). Yield: 21%. Mixture of two diastereomers (β / α) in a ratio of 95 / 05.

[0206] [ka] Methyl-L-valinate 3β-(tetraethylenetetramine)-chenodeoxycholate 049(C 38 H 72 N6O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 6.93 (m, 1H), 4.47-4.45 (m, 1H), 3.93-3.82 (m, 2H), 3.51-3.47 (m, 3H), 3.05-2.99 (m, 2H), 2.97-2.86 NMR 13C (101 MHz, CD3OD): δ (ppm) = 174.40, 173.62, 68.85, 56.12, 55.75, 54.74, 54.51, 51.81, 50.50, 48.39, 46.94, 46.83, 46.73, 45.47, 45.37, 42.62, 41.96, 40.96, 39.74, 39.50, 37.80, 36.36, 36.25, 36.15, 36.06, 35.39, 33.56, 33.10, 31.28, 28.50, 28.22, 23.58, 22.90, 18.90, 17.82, 12.15, 11.69.MS (ESI + ): m / z 678.89 ([M+H] + ). The product was obtained after purification by silica gel chromatography (MeOH, then MeOH / NH4.OH (10 / 3)). Yield: 19%. Mixture of two diastereomers (β / α) in a ratio of (95 / 05).

[0207] [ka] Methyl-L-isoleucinate 3β-norspermidino-chenodeoxycholate 050(C 37 H 68 N4O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 6.94 (m, 1H), 3.93-3.83 (m, 2H), 3.76-3.70 (m, 1H), 3.51-3.47 (m, 3H), 2.99-2.87 (m, 2H), 2.81-2.65 (m, 2H), 2.64-2.56 (m, 2H), 2.55-2.49 (m, 4H), 2.29-2.17 (m, 2H), 2.13-1.93 (m, 2H), 1.91-1.08 (m, 30H), 1.02-0.82 (m, 14H), 0.70-0.68 (m, 3H).NMR 13C (101 MHz, CD3OD): δ (ppm) = 174.41, 172.73, 68.85, 57.24, 56.12, 55.75, 52.00, 50.50, 46.94, 46.00, 45.97, 42.62, 40.96, 39.74, 39.50, 39.21, 37.80, 36.54, 36.36, 36.25, 36.15, 36.06, 35.39, 33.56, 33.10, 28.50, 28.21, 27.14, 25.00, 24.25, 23.58, 22.90, 18.90, 15.72, 12.15, 11.99, 11.68.MS (ESI + ): m / z 634.05 ([M+H] + ). The product was obtained after purification by silica gel chromatography (MeOH, then MeOH / NH4.OH (10 / 3)). Yield: 31%. Mixture of two diastereomers (β / α) in a ratio of (95 / 05).

[0208] [ka] Methyl-glycinate 3β-sperminocholate 051(C 37 H 69 N5O5). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 7.06-7.03 (m, 1H), 4.12-3.71 (m, 8H), 2.99-2.91 (m, 7H), 2.81-2.49 (m, 8H), 2.29-1.20 (m, 31H), 1.17-0.81 (m, 10H), 0.73-0.69 (m, 3H). NMR 13C (101 MHz, CD3OD): δ (ppm) = 173.69, 173.36, 73.55, 69.98, 55.75, 52.58, 47.98, 47.60, 47.49, 46.94, 46.42, 45.97, 44.61, 43.56, 43.34, 40.96, 39.21, 39.03, 37.80, 36.36, 36.06, 35.34, 35.12, 34.33, 33.50, 31.32, 29.34, 28.50, 27.38, 27.14, 25.38, 25.28, 24.25, 24.02, 21.43, 18.20, 12.71.MS (ESI + ): m / z 664.59 ([M+H] + ). The product was obtained after purification by silica gel chromatography (MeOH, then MeOH / NH4.OH (10 / 3)). Yield: 27%. Mixture of two diastereomers (β / α) in a ratio of (95 / 05).

[0209] [ka] Methyl-L-valinate 3β-sperminodeoxycholate 052(C 40 H 75 N5O4). NMR 1 H (250 MHz, CD3OD): δ (ppm) = 5.11-4.63 (m, 2H), 4.28 (m, 1H), 3.92 (s, 1H), 3.69 (m, 3H), 3.39-3.31 (m, 1H), 2.88-2.46 (m, 15H), 2.34-1.23 (m, 34H), 1.14-0.82 (m, 15H), 0.67 (s, 3H). NMR 13C (63 MHz, CD3OD): δ (ppm) = 177.02, 173.74, 74.02, 59.22, 58.90, 57.17, 52.41, 50.71, 50.42, 49.16, 48.18, 47.61, 45.62, 43.89, 40.54, 40.15, 38.21, 37.42, 36.87, 35,82, 35,73, 34,79, 34,19, 33,66, 33,29, 32,84, 31,65, 29,82, 28,70, 28,46, 28,10, 27,49, 27,24, 24,90, 24,06, 23,92, 19,55, 18,66, 17,70, 13,24. MS (ESI + ): m / z 690.5892 ([M+H] + ). Yield: 71%. Mixture of two diastereomers (β / α) in a ratio of 95 / 05.

[0210] [ka] Methyl-L-valinate 3β-(1,4-bis(3-aminopropyl)piperazine)-deoxycholate 053(C 40 H 73 N5O4). NMR 1 H (400 MHz, CD3OD): d (ppm) = 4.35 (d, J = 3.34 Hz, 1H), 4.02 (s, 1H), 3.76 (s, 2H), 3.40 (s, 1H), 3.29 (s, 2H), 3.12 (s, 1H), 3.00-2.87 (m, 5H), 2.70-2.13 (m, 16H), 2.00-1.33 (m, 26H), 1.23-0.93 (m, 15H), 0.76 (s, 3H). NMR 13C (101 MHz, CD3OD): δ (ppm) = 177.31, 174.04, 74.17, 59.52, 59.09, 57.73, 54.29, 54.04, 52.60, 50.06, 49.93, 49.71, 49.50, 49.28, 49.07, 48.88, 47.87, 46.07, 43.80, 41,52, 40,85, 37,61, 37,14, 36,59, 36,39, 35,75, 35,12, 34,04, 33,51, 31,88, 28,92, 28,40, 26,88, 25,03, 19,69, 18,85, 17,90, 17,90, 17,89, 13,38. MS (ESI + ): m / z 688.6 ([M+H] + ). Yield: 8%. Mixture of two diastereomers (β / α) in a ratio of 95 / 05.

[0211] [ka] Methyl-L-valinate 3β-(tris(3-aminopropyl)amine)-deoxycholate 054(C 39 H 73 N5O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 4.35 (d, J = 4.35 Hz, 1H), 4.02 (s, 1H), 3.75 (s, 2H), 3.39 (s, 3H), 3.11-2.12 (m, 19H), 1.94-1.29 (m, 29H), 1.20-0.90 (m, 15H), 0.76 (s, 3H). NMR 13C (101 MHz, CD3OD): δ (ppm) = 177.09, 173.82, 73.98, 59.30, 54.88, 52.80, 52.38, 49.85, 49.71, 49.50, 49.28, 49.07, 48.85, 48.69, 48.18, 47.65, 43.71, 42.78, 40,51, 37,40, 36,91, 35,61, 34,90, 33,80, 33,29, 31,67, 29,85, 28,69, 27,44, 27,24, 25,71, 24,84, 23,70, 19,48, 18,64, 17,69, 17,27, 17,08, 13,19.MS (ESI + ): m / z 676.6 ([M+H] + ). Yield: 7%. Mixture of two diastereomers (β / α) in a ratio of 95 / 05.

[0212] [ka] Methyl-L-phenylalaninate 3β-(tris(3-aminopropyl)amine)-deoxycholate 055(C 43 H 73 N5O4). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 7.45-7.19 (m, 5H), 5.25 (s, 1H), 3.96 (s, 1H), 3.35 (s, 6H), 3.08-3.01 (m, 6H), 2.83-0.89 (m, 49H), 0.69-0.66 (m, 3H).NMR 13C (101 MHz, CD3OD): δ (ppm) = 176.84, 175.34, 141.83, 129.23, 129.20, 128.43, 128.40, 128.12, 74.06, 60.63, 60.56, 58.97, 52.73, 52.37, 49.85, 49.71, 49.50, 49.28, 47.66, 44.11, 43,46, 39,64, 37,32, 36,87, 36,13, 35,43, 34,71, 34,32, 34,26, 33,24, 30,85, MS (ESI + ): m / z 724.6 ([M+H] + ). The product was obtained after purification by silica gel chromatography (MeOH, then MeOH / NH4.OH (10 / 2)). Yield: 12%. Mixture of two diastereomers (β / α) in a ratio of (95 / 05).

[0213] [ka] Methyl-L-valinate 3β-(1,4-bis(3-aminopropyl)piperazine)-lithocholate 056(C 40 H 75 N5O3). NMR 1 H (400 MHz, CD3OD): δ (ppm) = 4.30 (d, J = 4.31 Hz, 1H), 4.23 (t, J = 4.23 Hz, 1H), 3.71 (s, 2H), 3.47-2.71 (m, 17H), 2.47-1.80 (m, 16H), 1.62-0.86 (m, 33H), 0.71 (s, 3H). NMR 13C (101 MHz, CD3OD): δ (ppm) = 177.02, 173.79, 59.29, 57.92, 57.71, 57.56, 52.40, 49.83, 49.71, 49.49, 49.28, 49.07, 43.95, 43.31, 41.81, 41.52, 41.32, 38.14, 37.13, 36,91, 36,84, 36,08, 35,78, 33,69, 33,28, 32,52, 31,66, 29,27, 27,93, 27,49, 25,23, 23,73, 21,93, 20,15, 19,51, 18,93, 18,88, 18,64, 18,44, 12,50. MS (ESI + ): m / z 672.6 ([M+H] + ). The product was obtained after purification by silica gel chromatography (MeOH, then MeOH / NH4.OH (10 / 0.75)). Yield: 6%. Mixture of two diastereomers (β / α) in a ratio of (95 / 05).

[0214] [ka] Methyl-L-valinate 3β-spermino-lithocholate 057(C 40 H 75 N5O3). NMR 1 NMR 13C (101 MHz, CD3OD): δ (ppm) = 178.68, 175.99, 61.34, 58.86, 58.05, 57.53, 50.04, 49.89, 49.50, 49.28, 49.07, 48.49, 47.98, 45.47, 43.94, 43.61, 41.92, 41.57, 40.18, 37,17, 36,92, 36,61, 35,98, 34,40, 33,46, 33,15, 32,70, 30,62, 29,30, 28,22, 28,12, 27,75, 27,61, 25,25, 23,96, 21,95, 20,24, 18,92, 18,43, 12,50. MS (ESI + ): m / z 674.6 ([M+H] + ). Yield: 4%. Mixture of two diastereomers (β / α) in a ratio of 95 / 05.

[0215] [ka] Methyl-L-valinate 3β-spermino-cholate 058(C 40 H 75 N5O5). NMR 1 H (250 MHz, CD3OD): d (ppm) = 4.79 (m, 11H), 4.35-3.26 (m, 6H), 2.98-2.66 (m, 13H), 2.40-1.14 (m, 33H), 1.09-1.05 (m, 3H), 1.01-0.94 (m, 6H), 0.75 (s, 3H). NMR 13C (63 MHz, CD3OD): δ (ppm) = 177.01, 173.76, 73.87, 68.84, 59.27, 59.21, 52.39, 50.13, 48.17, 48.07, 47.54, 45.46, 43.43, 43.01, 41.06, 40.44, 36.93, 36.72, 36,57, 36,21, 33,77, 33,30, 31,95, 31,85, 31,65, 29,59, 28,73, 27,93, 27,89, 27,26, 24,20, 23,26, 20,26, 19,51, 18,67, 18,45, 17,76, 13,04. MS (ESI + ): m / z 706.6 ([M+H] + ). The product was obtained after purification by silica gel chromatography (MeOH, then CH2Cl2 / MeOH / NH4.OH (7 / 3 / 2)). Yield: 45%. Mixture of two diastereomers (β / α) in a ratio of (95 / 05).

[0216] [ka] Methyl-L-valinate 3β-(1,4-bis(3-aminopropyl)piperazine)-cholate 059(C 40 H 73 N5O5). NMR 1 H (250 MHz, CD3OD): δ (ppm) = 4.71 (m, 2H), 4.10-3.31 (m, 6H), 2.94-2.07 (m, 30H), 2.02-1.14 (m, 29H), 1.11-1.06 (m, 3H), 0.73 (s, 3H).NMR 13C (63 MHz, CD3OD): δ (ppm) = 177.07, 173.80, 73.89, 68.86, 59.27, 57.28, 53.93, 53.90, 52.39, 49.78, 49.23, 48.18, 47.55, 45.91, 43.46, 43.03, 40.93, 37.65, 36.94, 36,74, 36,22, 34,23, 33,74, 33,30, 32,78, 31,67, 29,78, 29,61, 28,71, 27,99, 27,99, 27,29, 26,09, 24,21, 23,27, 19,50, 18,65, 17,74, 16,39, 13,04. MS (ESI + ): m / z 704.6 ([M+H] + ). Yield: 28%. Mixture of two diastereomers (β / α) in a ratio of 95 / 05.

[0217] [ka] Methyl-L-valinate 3β-(tris(3-aminopropyl)amine)-cholate 060(C 39 H 73 N5O5). NMR 1 H (250 MHz, CD3OD): d (ppm) = 4.95 (s, 1H), 4.88 (s, 11H), 4.79 (s, 1H), 4.27 (d, J = 4.27 Hz, 1H), 3.96-3.51 (m, 5H), 3.43-3.23 (m, 3H), 3.05-2.47 (m, 13H), 2.32-1.07 (m, 35H), 0.67 (s, 3H). NMR 13C (63 MHz, CD3OD): δ (ppm) = 177.11, 173.79, 73.85, 68.81, 59.28, 59.18, 52.62, 52.41, 49.95, 49.85, 48.79, 48.47, 47.50, 47.46, 45.48, 43.19, 42.99, 41.05, 40,65, 40,48, 37,00, 36,11, 35,89, 33,78, 33,69, 33,31, 31,65, 31,14, 29,58, 28,91, 27,98, 25,68, 25,24, 24,19, 23,16, 19,51, 18,64, 17,71, 13,02. MS (ESI + ): m / z 692.6 ([M+H] + ). Yield: 12%. Mixture of two diastereomers (β / α) in a ratio of 95 / 05.

[0218] [ka] Methyl-L-tyrosinate 3β-spermino-cholate 061(C 44 H 75 N5O6). NMR 1 H (250 MHz, CD3OD): δ (ppm) = 6.93 (m, 2H), 6.61 (m, 2H), 4.71 (s, 1H), 4.47 (q, J1= 4.51 Hz, J2= 4.48 Hz, 1H), 3.87-3.43 (m, 6H), 3.31-3.14 (m, 3H), 2.88-2.70 (m, 11H), 2.39-1.19 (m, 46H), 0.62 (s, 3H). NMR 13C (63 MHz, CD3OD): δ (ppm) = 176.72, 173.83, 157.42, 131.18, 128.81, 116.26, 73.83, 68.84, 59.31, 55.45, 52.65, 51.66, 50.60, 50.12, 49.84, 49.50, 48.09, 47.49, 45.86, 43.03, 40.95, 39,00, 37,63, 36,24, 36,02, 36,02, 34,41, 33,18, 29,54, 29,47, 28,80, MS (ESI + ): m / z 770.6 ([M+H] + ). Yield: 25%. Mixture of two diastereomers (β / α) in a ratio of 95 / 05.

[0219] D. Preparation of Different Salts D.1 From hydrochloric acid Compounds 001-061 obtained as above were all prepared as hydrochloride salts for biological testing following the general procedure described below for compound 007.

[0220] [ka] Methyl-L-valinate 3β-norspermidino-chenodeoxycholate 007 as hydrochloride salt. In a flask, 50 mg (0.0808 mmol) of 007 (007-a1, β / α: 96 / 04) are dissolved in a minimum amount of methanol. With vigorous stirring, 0.24 mL (0.242 mmol) of 2N hydrochloric acid solution is added. Stirring is continued for a few minutes and the solution is evaporated. The resulting solid is dissolved in diethyl ether and filtered. The derivative S007 (007.3HCl) (β / α, 96 / 04) is obtained as a yellow solid in quantitative yield.

[0221] Other hydrochloride salts S019 (β / α: 94 / 06) and S021 (β / α: 90 / 10) were prepared from compounds 007-a2 (β / α: 94 / 06) and 007-a3 (β / α: 90 / 10), respectively, according to the method described above.

[0222] A similar procedure can be applied to other inorganic or organic acids such as lactic acid, citric acid, malic acid, tartaric acid, etc.

[0223] D.2 From lactic acid Compounds obtained by the above reductive amination reaction can be prepared as lactate salts for biological testing following the procedure described above for compound 007 using hydrochloric acid, substituting lactic acid for hydrochloric acid.

[0224] Methyl-L-valinate 3β-norspermidino-chenodeoxycholate 007 as the lactate salt (007.3 lactic acid), i.e., compound S047, was prepared from compound 007 (007-a1, β / α:96 / 4) according to this method and obtained as a pale yellow solid in quantitative yield.

[0225] D.3 From citric acid Compounds obtained by the above reductive amination reaction can be prepared as lactate salts for biological testing following the procedure described above for compound 007 using hydrochloric acid, substituting citric acid for hydrochloric acid.

[0226] Methyl-L-valinate 3β-norspermidino-chenodeoxycholate 007 as the citrate salt (007.3 citric acid), i.e., compound S048, was prepared from compound 007 (007-a1, β / α:96 / 4) according to this method and obtained as a pale yellow solid in quantitative yield.

[0227] E. Synthesis of diastereomeric mixtures [ka] Diastereomeric mixture of methyl-L-valinate norspermidino-chenodeoxycholate (007-b1). In a 50 mL flask equipped with a magnetic stirring bar, 870 mg (1.74 mmol) of methyl-L-valinate 3-oxo chenodeoxycholate 15 are dissolved in 30 mL of MeOH. Subsequently, 3 equivalents of norspermidine (0.73 mL, 5.21 mmol) and 4 equivalents of titanium tetraisopropylate (2.06 mL, 6.96 mmol) are added. After stirring for 12 hours at 20 ° C, the flask is placed at 0 ° C and 4 equivalents of sodium borohydride (50 mg, 1.36 mmol) are added with stirring. The reaction medium is stirred for 2 hours at this temperature. The reaction is then neutralized by adding 8.7 mL of water. After 30 min of further stirring, the mixture is filtered over Celite, rinsed with MeOH, CHCl and EtOAc, and then concentrated in vacuum. The crude product thus obtained is purified by silica gel chromatography (eluent: MeOH, then CHCl / MeOH / NHOH (7 / 3 / 1)). Methyl-L-valinate 3β-norspermidino-chenodeoxycholate 007 is obtained in the form of a yellow oil (a mixture of two diastereomers (β / α) in a ratio (80 / 20) herein referred to as the mixture as "007-b1") with a yield of 32%. The corresponding hydrochloride salt S017 (β / α: 80 / 20) was prepared according to the method described above.

[0228] Following a similar method, methyl-L-glycinate 3β-spermino-chenodeoxycholate 004 was obtained in 53% yield in the form of a yellow oil (a mixture of two diastereomers (β / α) in a ratio of 80 / 20, referred to herein as the mixture as "004-b1"). The corresponding hydrochloride salt S027 (β / α: 80 / 20) was prepared according to the above method.

[0229] Example 2: Intrinsic antibacterial activity of compounds The aim of this experiment was to test the antibacterial activity of 61 compounds according to the invention (S001-S061).

[0230] Materials and Methods The antibacterial activity of the compounds was measured using a standard microdilution assay based on the Clinical and Laboratory Standards Institute (CLSI) guidelines. This method was slightly modified. In fact, the assay volume was increased to 200 μL to improve reproducibility. The compounds tested were in the form of salt for biological testing.

[0231] Bacteria tested The antibacterial activity of the compounds was tested against Staphylococcus aureus (ATCC25923), Enterococcus faecalis (ATCC29212), Escherichia coli (ATCC28922) and Pseudomonas aeruginosa (ATCC27853).

[0232] Preparation of precultures To obtain individual colonies, Mueller Hinton agar plates were inoculated with frozen organisms and the plates were incubated for 24 hours at 35-37°C. Three colonies of similar appearance were picked, resuspended in 5 mL of fresh Mueller Hinton Broth 1X (MHB) and incubated overnight at 35-37°C with shaking (160 rpm).

[0233] Minimal inhibition Preparation of microplates for determining concentrations (MIC) 0.1 mL of overnight suspension was added to the culture at 10 8 The bacteria were diluted in 10 ml of pre-warmed Mueller Hinton broth 1X with shaking (160 rpm) at 35-37 °C until an absorbance of 0.08-0.13 at 625 nm was reached, corresponding to CFU / mL. 0.1 mL of exponentially growing bacteria was suspended in 9.9 mL of MHB (1:100 dilution). 0.1 mL of the 1:100 dilution was transferred to wells of a microplate containing 0.1 mL of serial dilutions of compound, with approximately 5 × 10 5CFU / mL. In parallel, stock solutions of compounds were first diluted in the appropriate solvent to a final concentration of 5 mg / mL. 8 μL was dispensed into the first well of a microplate containing 0.1 ml of sterile broth and 0.5-fold serial dilutions were performed in MHB starting from 0.2 mg / mL. One control was made for each strain tested. After 20 h of incubation at 35-37°C, the MIC, defined as the minimum concentration of compound that inhibited growth, was determined. Tests were performed in triplicate.

[0234] cytotoxicity : Test WST1 was used to measure the cytotoxic activity of the compounds of the invention. Test WST1 is a colorimetric test that allows the measurement of the degree of viability and cell growth. It is based on the cleavage of the colorless tetrazolium salt WST1 (4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzenedisulfonate) by mitochondrial dehydrogenases into the yellow formazan derivative, which can be quantified by spectrophotometry at 420-480 nm. The WST1 test was carried out on Chinese Hamster Ovary (CHO) cells. CHO-K1 cells (ATCC, USA) were cultured in McCoy's 5A medium supplemented with 10% fetal bovine serum, 2 mM L-glutamine and a mixture of penicillin-streptomycin (100 U / ml: 10 μg / mL). Cultures were incubated at 37°C in an atmosphere enriched with CO2 (5%) and subcultured every 2 days. Cells were transferred to 96-well plates (25,000 cells / mL) in complete McCoy's 5A medium and maintained for 24 h at 37°C in a humidified atmosphere enriched with CO2 (5%). Increasing concentrations of test compounds were added to the wells, each compound was tested in replicates, and eight growth controls containing cells in medium alone were included in each series of tests. After 24 h at 37°C (5% CO2), the medium was removed, the cells were rinsed with phosphate buffered saline (PBS), and 50 μL of PBS containing 10% of the reagent WST1 was added to each well. After 20 min of incubation at 37°C, results were read spectrophotometrically at 450 nm. Results are expressed as dose-response relationships modeled by nonlinear regression analysis using TableCurve software. The 50% inhibitory concentration (IC50 ) represents the concentration of compound capable of reducing cell viability by 50%.

[0235] Reading the results After incubation, the filters were replaced with transparent film and then optical density readings were taken on an iEMS plate spectrophotometer at 620 nm.Minimum inhibitory concentration (MIC) calculations were performed.

[0236] result The antibacterial activity results for each compound are shown in Table 7 below.

[0237] As shown in Table 7, all the tested compounds exhibit antibacterial activity against all the tested bacteria. All the compounds exhibit the strongest antibacterial activity against Staphylococcus aureus.

[0238] Table 7: Antibacterial activity and cytotoxicity of compounds. * indicates experiments performed in triplicate. [Table 10] TIFF2025513630000125.tif236159TIFF2025513630000126.tif234159TIFF2025513630000127.tif27159

[0239] Example 3: Antipersister activity of compounds The purpose of this experiment was to test the antipersistence activity of 18 compounds according to the invention (S010, S013, S014, S017, S019, S039, S041, S042, S044, S046, S047, S048, S052, S060) in comparison with the negative control ciprofloxacin.

[0240] Materials and Methods Antipersister activity test: E. coli persister cells were produced and isolated as described by MARQUES, CNH et al. (Applied and Environmental Microbiology 2014, Vol. 80, No. 22, pp. 6976-6991). E. coli persister cells were compared to E. coli non-persister cells. 1 mL of persister or non-persister bacterial culture was added to 1.5 mL microtubes with each of the compounds to be tested or ciprofloxacin as a negative control and incubated for 4 hours at 37°C with shaking at 160 rpm. After 4 hours of treatment with the compounds, the microtubes were centrifuged at 3,500 g for 5 minutes and the pellets were resuspended in 1 mL of fresh drug-free RM broth (10 g / L M9 salts, 2% casamino acids, 1 mM MgCl2, 1% glycerol). The resuspended bacteria were then plated on LB agar plates and incubated at 37°C. Bacterial colonies were counted after 24, 48 and 96 hours and viability was estimated.

[0241] cytotoxicity The same WST1 test was used as described in Example 2 above. result The viability results obtained for each test compound are shown in Table 8 below.

[0242] Compounds S046, S019, S039, S010, and S060 show low persister cell viability associated with higher non-persister cell viability. These results suggest that compounds S046, S019, S039, S010, and S060 have very strong anti-persister activity. Furthermore, S019, S039, S010, and S060 show good toxicity results.

[0243] Compounds S044, S052, S013, S047, S048 and S014 show low persister and non-persister cell viability, suggesting that they have both antipersister and antibacterial activity. In addition, they all show good toxicity results.

[0244] Compounds S042, S041 and S017 demonstrate good activity against non-persister cells with low non-persister cell viability, but their activity is not as good against persister cells as shown by higher persister cell viability. S042 and S017 have good toxicity results.

[0245] Table 8: Antipersister activity and cytotoxicity of compounds [Table 11]

Claims

1. Equation (I) 【Chemistry 1】 (In the formula, R １ is H, OH, or SO ３ Represents H; R ２ is H, OH, or SO ３ Represents H; R ３ represents H, C １ to C ８ alkyl, C ６ to C １０ aryl or C ６ to C １０ aryl-C １ to C ８ alkyl, and Here, the alkyl group is optionally at least one OH, COOH, -C(O)NH ２ NH ２ , -NH-C(=NH)-NH ２ Imidazolyl, indolyl, SH, S-CH ３ Or it is replaced with SeH; Here, in the aryl group or arylalkyl group, the aryl is optionally substituted with at least one OH group; R ４ H, C １ ~C ８ Alkyl or C ６ ~C １０ Represents an arrow; or R ３ and R ４ They form a five-membered heterocycloalkyl group together with the nitrogen and carbon atoms to which they are bonded; R ５ H, C １ ~C ８ Alkyl or C ６ ~C １０ Represents an arrow; R ６ is, -(CR ７ R ８ ) ｍ -[X-(CR ９ R １０ ) ｎ ] ｐ -NR １１ R １２ This represents, In the formula, R ７ , R ８ , R ９ and R １０ Each instance is independently, and each is independently, H or C １ ~C ８ Represents alkyl; R １１ and R １２ These are H or C, respectively, independently. １ ~C ８ Represents alkyl, or R １１ and R １２ Along with the nitrogen atom to which they are bonded, there are 1 to 3 R １３ It forms a 5- to 7-member heterocycline which is optionally substituted by; In the formula, R １３ = represents O or = S; X is independently -NR each time it appears. １４ - or represents a divalent 5- to 7-membered heterocycloalkyl group containing at least one nitrogen atom; In the formula, R １４ H, C １ ~C ６ Alkyl or -(CH ２ ) q -NH ２ This represents; in the expression, q represents an integer in the range of 1 to 5; m is an integer in the range of 2 to 10; n is an integer in the range of 1 to 5; p is an integer in the range of 0 to 4. Compounds thereof or pharmaceutically acceptable salts and / or solvates thereof.

2. R １ and R ２ The compound according to claim 1, wherein each independently represents H or OH.

3. R ３ However, H, C １ ~C ８ Alkyl or phenyl-(CH ２ ) ２ - represents the phenyl which is optionally substituted with at least one OH, preferably R ３ C １ ~C ６ Represents alkyl, more preferably R ３ is C １ ~C ４ Represents alkyl; or R ３ and R ４ The compound according to claim 1, wherein the nitrogen and carbon atoms to which they are bonded form a divalent pyrrolidine.

4. R ７ and R ８ Both represent H, and / or R ９ and R １０ Both represent H, preferably R ７ , R ８ , R ９ and R １０ The compound according to claim 1, wherein is represented by H.

5. R １１ and R １２ The compound according to claim 1, wherein both represent H.

6. X is -NR １４ - Represents a divalent piperazine, preferably where X is -NR １４ It represents -, more preferably X represents -NH-, R １４ The compound according to claim 1, wherein the compound is as defined in claim 1.

7. The compound according to claim 1, wherein m is 2 or 3, n is 2, 3 or 4, and / or p is 1 or 2.

8. The aforementioned compound, Table 1 The compound according to claim 1, selected from and pharmaceutically acceptable salts and / or solvates thereof.

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 and at least one pharmaceutically acceptable carrier.

10. A pharmaceutical composition for use in the treatment of infectious diseases, comprising a compound according to any one of claims 1 to 8 and at least one pharmaceutically acceptable carrier.

11. The pharmaceutical composition for use according to claim 10, wherein the infectious disease is a bacterial disease, a viral disease, a fungal disease, or a parasitic disease.

12. The aforementioned infectious disease, A bacterial or fungal disease selected from cystic fibrosis, urinary tract infections, and chronic otitis media; and / or Caused by Gram-positive bacteria selected from Staphylococcus, Enterococcus, and Mycobacterium. A pharmaceutical composition for use according to claim 10.

13. In the treatment of infectious diseases, preferably for use as an antiperspirant in the treatment of bacterial or fungal diseases, Table 2 A pharmaceutical composition comprising compounds selected from and pharmaceutically acceptable salts and / or solvates thereof.

14. Non-therapeutic use of any one of claims 1 to 8 as an anti-infective agent for disinfecting surfaces and / or purifying liquids, preferably as an antiperspirant agent for disinfecting surfaces and / or purifying liquids, where the surface or liquid is not part of a human or animal body.

15. A process for producing a compound defined in any one of claims 1 to 8, wherein (a) formula (A) 【Chemistry 2】 The carboxylic acid functional group at the 20th position of the bile acid is given by formula 【Transformation 3】 A process of reacting the secondary amine functional group of an amino acid with the amino acid to obtain an amide; (b) A step of oxidizing the hydroxyl (OH) at the 3-position of the bile acid intermediate obtained in step (a) to obtain a ketone; (c) reacting the ketone of the bile acid intermediate obtained in step (b) with a primary amine of the formula R ６ NH ２ to thereby obtain an imine; and (d) A step of reducing the imine obtained in step (c) to obtain the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof. A process that includes this.

Images