Bifunctional PROTAC-type compounds targeting PXR, methods for preparing same, and therapeutic uses thereof

Abstract

The present application relates to novel bifunctional PROTAC type compounds that simultaneously bind to the target proteins PXR and E3-ubiquitin ligase, methods for preparing the same, and their use for treating cancers that overexpress PXR.

Description

[Technical field]

[0001] The present invention relates to the treatment of cancer, and more particularly to cancers that overexpress the PXR nuclear receptor, such as colorectal cancer. [Background technology]

[0002] Colorectal cancer (CRC) is the third most common cancer. It is the third leading cause of death from cancer. Current treatments include surgery, radiotherapy, and chemotherapy, sometimes in combination with targeted therapies that show only modest improvements. However, the effectiveness of these treatments is severely compromised by the frequent emergence of resistance, which leads to relapse of patients after treatment cessation (50% of patients). In recent years, it has been shown that a subpopulation of cancer cells, cancer stem cells (CSCs), are involved in tumor initiation, metastasis development, and drug resistance, thus leading to tumor recurrence.

[0003] We now demonstrate that the PXR (NR1I2) nuclear receptor is preferentially activated in cancer stem cells and that loss of its expression by RNA interference (shRNA) sensitizes this cell population, which is normally resistant to chemotherapy, and significantly delays tumor recurrence in mice. Thus, inhibition of the PXR (NR1I2) nuclear receptor makes it possible to sensitize cancer stem cells to current therapies.

[0004] However, the PXR antagonists identified to date (L-sulforaphane, ketoconazole, and SAP-70) are either nonspecific and / or toxic at the concentrations required to inactivate PXR, or have not yet been approved for clinical use.

[0005] PROTAC (Proteolysis Targeting Chimera) is a bifunctional molecule that simultaneously binds to a target protein and an E3-ubiquitin ligase. This causes the polyubiquitination of the target protein, which is then degraded into small peptides and amino acids by the proteasome complex. Thus, the PROTAC approach is a chemical protein knockdown strategy.

[0006] It is therefore desirable to provide bifunctional chimeric ligands capable of inducing targeted proteolysis of PXR according to the PROTAC strategy. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] SMBerge et al. “Pharmaceutical Salts” J. Pharm. Sci, 66: pages 1-19 (1977) [Non-Patent Document 2] Comprehensive Organic Transformations by Larock, VCH Pub., 1989 [Non-Patent Document 3] TWGreen and PGMWuts in Protective Groups in Organic Chemistry,John Wiley and Sons,1991, JFWMcOmie in Protective Groups in Organic Chemistry,Plenum Press,1973 Summary of the Invention

[0008] According to a first subject, the present invention relates to bifunctional compounds according to the general formula (I)

[0009] [ka]

[0010] During the ceremony, L(PXR) is a ligand capable of binding to the PXR nuclear receptor; L (E3 ligase) represents a ligand of E3-ubiquitin ligase; It relates to bifunctional compounds, in which the linker represents a group that allows the covalent attachment of L(PXR) to L(E3 ligase).

[0011] The ubiquitin-proteasome pathway (UPP) is an essential cellular pathway that regulates key regulatory proteins and degrades incorrectly folded or abnormal proteins. The UPP is at the heart of several cellular processes. When it is defective or disbalanced, it leads to the pathogenesis of various diseases. The covalent attachment of ubiquitin to specific protein substrates is obtained by the action of E3-ubiquitin ligases. These ligases, which include more than 500 different proteins, are divided into several classes defined by the structural elements of their E3 functional activity.

[0012] The E3 ligase ligand that constitutes the functional mode of the compound of the present invention binds to E3-ubiquitin ligase.Ligase catalyzes the covalent attachment of ubiquitin to target protein, which then induces the degradation of target protein by natural proteasome.Therefore, the compound of the present invention is designed in such a way that it utilizes natural cellular degradation process, but the degrading action is directed to undesirable target protein that is involved in the pathogenesis of disease.

[0013] Unlike conventional chemical inhibitors, the PROTACs according to the present invention act as degradative enzymes capable of supra-stoichiometric action.

[0014] The compounds according to the invention therefore have several advantages. 1) They are active at lower concentrations than the inhibitor alone and require high levels of systemic exposure to achieve saturation of the target. 2) They are capable of carrying out multiple degradative cycles leading to degradation of the target protein. 3) Compared with the rapid dissociation rate of an inhibitor from its target, restoration of protein function after PROTAC-induced degradation requires de novo synthesis of the protein by the cell, which takes much longer, thus increasing the duration of the PROTAC's effect.

[0015] L(PXR) is the functional mode of the compound that binds to PXR. In some embodiments, the targeting ligand is an analog of the PXR JMV6845 ligand.

[0016] [ka]

[0017] According to one embodiment, L(PXR) is a group of formula (II)

[0018] [ka]

[0019] During the ceremony,

[0020] [ka]

[0021] represents the attachment of the group to the linker, or a pharma- ceutically acceptable salt thereof.

[0022] Thus, the compound according to the present invention is represented by the following formula (I-1):

[0023] [ka]

[0024] wherein the linker, L (E3 ligase), is as defined above or below, may correspond to the formula, or a pharma- ceutically acceptable salt.

[0025] According to one embodiment, the E3 ligase ligand binds to cereblon. L (E3 ligase) is, in particular, - a group of formula (IIIA):

[0026] [ka]

[0027] and a group of formula (IIIB):

[0028] [ka]

[0029] or a pharma- ceutically acceptable salt thereof, In formulae (IIIA) and (IIIB), X is NH; X' is -C(O)- or -CH2-; Y represents H or a C1-C6 alkyl group;

[0030] [ka]

[0031] represents the attachment of a group to the linker.

[0032] The compounds according to the invention therefore in particular have the formula (I-2) or (I-3)

[0033] [ka]

[0034] wherein the linker, L(PXR), L(E3 ligase), X, X', and Y are as defined above or below; or a pharma- ceutically acceptable salt thereof.

[0035] More specifically, the compounds according to the invention are represented by one of the following formulae (I-4) and (I-5):

[0036] [ka]

[0037] wherein L(PXR), the linker, is as defined above or below, or a pharma- ceutically acceptable salt thereof.

[0038] The linker provides a covalent bond of the targeting ligand to the E3 ligase ligand. According to one embodiment, the linker is selected from the group -O-, -S-, -N(R')-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(NOR')-, -C(O)N(R')-, -C(O)N(R')C(O)-, -C(O)N(R')C(O)N(R')-, -N(R')C(O)-, -N(R')C(O )N(R')-, -N(R')C(O)O-, -OC(O)N(R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, - N(R')C(NR')N(R')-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -N(R')S(O)2-, -S (O)2N(R')-, -N(R')S-, -S(O)N(R')-, -N(R')S(O)2N(R')-, -N(R')S(O)N(R')-, a C1-C20 alkylene group optionally interrupted or terminated at either one and / or both ends by one of: C3-C12 cycloalkylene, 3-12 membered heterocyclene containing 1, 2 or 3 heteroatoms selected from N, O and S, 5-12 membered heteroarylene containing 1, 2 or 3 heteroatoms selected from N, O and S, or any combination thereof, wherein R' is the same or different and represents H or a C1-C6 alkyl group.

[0039] Thus, according to certain embodiments, the linker may be selected from a C4 to C20 alkylene group optionally interrupted and / or terminated by one or more groups selected from -NH-, -O-, -C(O)-, piperidinyl, piperaziylene.

[0040] More specifically, the linker may be represented in a group of formula (IV):

[0041] [ka]

[0042] In the formula, L1 and L2 are the same or different and represent an alkylene group of 1 to 12 carbon atoms, optionally interrupted or terminated by a 3- to 12-membered heterocyclene containing 1, 2 or 3 heteroatoms selected from N, O, S; L1 is linked to L(PXR)

[0043] [ka]

[0044] is ligated to L (E3 ligase), Z represents H or a C1 to C6 alkyl group.

[0045] According to a more particular embodiment, L1 is a C7-alkylene group (-C7H 14 -).

[0046] According to a more particular embodiment, L2 is a (C2-C8)-alkylene group optionally interrupted by a piperidinyl group.

[0047] According to one embodiment, the compound according to the invention may conform to the following formula (V):

[0048] [ka]

[0049] In the formula, L2 represents a C2-C8 linear alkylene group optionally interrupted by a piperidinyl group, and L (E3 ligase) is as defined above or below.

[0050] Formulas (I), (II), (IIIA), (IIIB), (IV), and (V) represented herein also cover pharma- ceutically acceptable salts thereof, isotopic derivatives thereof, and stereoisomers thereof.

[0051] As used above or below, unless otherwise specified: "Alkyl" refers to an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups have 1 to about 12 carbon atoms in the chain, particularly It has 1 to 6 carbon atoms. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkyl chain. "Lower alkyl" means about 1 to about 4 carbon atoms in the chain which may be straight or branched. The alkyls may be the same or different and include halo, cycloalkyl, hydroxy, alkoxy, amino, acylamino, aroylamino, carboxy, alkoxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, or Y. 1 Y 2 Y may be substituted with one or more "alkyl group substituents" which may include NCO-; 1 and Y 2 is independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, or optionally substituted heteroaralkyl; or Y 1 and Y 2 is Y 1 and Y 2Taken together with the N to which it is attached via, it forms a heterocyclyl of 4 to 7 atoms. Typical examples of alkyl groups include methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylethyl, benzyloxycarbonylmethyl, and pyridylmethyloxycarbonylmethyl.

[0052] "Alkylene" refers to an alkyl group, as defined above, that is divalent. Preferred alkylene groups are lower alkylene groups having 1 to about 6 carbon atoms. Typical examples of alkylene groups include methylene and ethylene.

[0053] "Cycloalkyl" means a non-aromatic monocyclic or polycyclic ring system of about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred ring sizes of the rings of the ring system contain about 5 to about 6 ring atoms, optionally substituted by one or more substituents. Exemplary monocyclic cycloalkyls include cyclopentyl, cyclohexyl, cycloheptyl, and the like. Exemplary polycyclic cycloalkyls include 1-decalin, norbornyl, adamant-(1- or 2-)yl, and the like.

[0054] "Cycloalkylene" refers to a cycloalkyl group as defined above that is saturated divalent, such as cyclohexylene.

[0055] "Heterocyclyl" means a non-aromatic saturated monocyclic or polycyclic ring system of about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms, in which one or more of the carbon atoms in the ring system are one or more heteroatoms other than carbon, such as nitrogen, oxygen, or sulfur. A preferred ring size of the ring of the ring system contains about 5 to about 6 ring atoms. The designation of aza, oxa, or thia as a prefix before heterocyclyl defines that at least one nitrogen, oxygen, or sulfur atom, respectively, is present as a ring atom. A heterocyclyl can be optionally substituted by one or more substituents which may be the same or different and are as defined herein. The nitrogen atom of a heterocyclyl can be a basic nitrogen atom. The nitrogen or sulfur atom of a heterocyclyl can also be optionally oxidized to the corresponding N-oxide, S-oxide, or S,S-dioxide. Exemplary monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

[0056] The term "heterocyclene" refers to a heterocyclyl group, as defined above, that is divalent.

[0057] "Heteroaryl" refers to a monocyclic or polycyclic aromatic ring system of about 5 to about 14 carbon atoms, preferably about 5 to about 10 carbon atoms, in which one or more of the carbon atoms in the ring system is one or more heteroelements other than carbon, such as nitrogen, oxygen, or sulfur. Preferred ring sizes include about 5 to about 6 ring atoms. "Heteroaryl" may also be substituted by one or more substituents. The designation of aza, oxa, or thia as a prefix before heteroaryl defines that at least a nitrogen, oxygen, or sulfur atom, respectively, is present as a ring atom. The nitrogen atom of a heteroaryl may be a basic nitrogen atom and may also be optionally oxidized to the corresponding N-oxide. Exemplary substituted heteroaryl and heteroaryl groups include pyrazinyl, thienyl, isothiazolyl, oxazolyl, pyrazolyl, furazanyl, pyrrolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazolyl, benzofurazanyl, azaindolyl, benzimidazolyl, benzothienyl, thienopyridyl, thienopyrimidinyl, pyrrolo, and the like. Preferred heteroaryl groups include pyridyl, imidazopyridyl, benzazaindole, 1,2,4-triazinyl, benzthiazolyl, furanyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl, and triazolyl. Preferred heteroaryl groups include pyrazinyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, and isothiazolyl.

[0058] "Heteroarylene" refers to a heteroaryl radical, as defined above, that is divalent.

[0059] "Substituents" refer to one or more identical or different groups selected from halogen, cyano, cycloalkyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, aroylamino, carboxy, alkoxycarbonyl, aralkoxycarbonyl, and heteroaralkoxycarbonyl.

[0060] The compounds of the invention can be in the form of a free acid or free base, or a pharma- ceutically acceptable salt.

[0061] The expression "pharmaceutically acceptable salts" refers to relatively non-toxic inorganic and organic acid addition salts, as well as base addition salts, of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds. In particular, acid addition salts can be prepared by separately reacting the purified compounds in their purified form with an organic or inorganic acid and isolating the salts thus formed. Examples of acid addition salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptanoate, lactobionate, sulfamate, malonate, salicylate, propionate, methylene bis-b-hydroxynaphthate, gentisic acid, isethionate, di-p-toluoyl tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, and quinic acid laurylsulfonate, and the like (see, e.g., J. Am. Soc. 1999, 144:1311-1323, incorporated herein by reference). Acid addition salts can also be prepared by separately reacting the purified compound in its acid form with an organic or inorganic base and isolating the salt so formed. Acid addition salts include amine and metal salts. Suitable metal salts include sodium, potassium, calcium, barium, zinc, magnesium, and aluminum salts. Sodium and potassium salts are preferred. Suitable basic inorganic addition salts are prepared from metal bases including sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide. Suitable basic addition salts are prepared from amines with sufficient alkalinity to form stable salts, and are preferred. or amines that are frequently used in medicinal chemistry due to their low toxicity and their acceptability for medical applications: ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids such as lysine and arginine, and dicyclohexylamine, and the like.

[0062] The compounds of the present invention may have at least one chiral center and therefore may be in the form of stereoisomers, which as used herein encompasses all isomers of individual compounds that differ only in the orientation of their atoms in space. The term stereoisomer includes mirror isomers (enantiomers, including the (R-) or (S-) configuration of a compound), mixtures of mirror isomers of the geometric compounds (cis / trans or E / Z, R / S isomers) of a compound (physical mixtures of enantiomers and racemates or racemic mixtures), and isomers of compounds with more than one chiral center that are not mirror images of each other (diastereoisomers). The chiral centers of a compound may undergo epimerization in vivo, and therefore, for these compounds, administration of a compound in its (R-) form is considered equivalent to administration of a compound in its (S-) form. Thus, the compounds of the present invention may be prepared and used in the form of individual isomers, substantially free of other isomers, or in the form of mixtures of various isomers, e.g., racemic mixtures of stereoisomers.

[0063] In some embodiments, the following compounds are suitable for binding to cereblon and PXR:

[0064] [Table 1]

[0065] [Table 2]

[0066] [Table 3]

[0067] Most specifically, the compounds according to the invention may be selected from compounds conforming to one of the following formulas:

[0068] [ka]

[0069] According to a further subject matter, the present invention also relates to a process for preparing the compounds according to the invention.

[0070] The compounds of general formula (I) can be prepared by application or adaptation of any known method per se and / or any known method within the reach of a person skilled in the art, in particular by application or adaptation of the methods described in Non-Patent Document 2 or by application or adaptation of the methods described in the Examples below.

[0071] According to the present invention, the method comprises coupling a compound of formula (B) and a compound of formula (C),

[0072] [ka]

[0073] Thus, L(PXR) and L(E3 ligase) are as defined above, and T and T' are two groups of a linker precursor, i.e., the coupling of which allows for linking to a linker group such that each has a complementary reactive terminal functional group, respectively.

[0074] As used herein, "complementary reactive functional groups" refers to two functional groups capable of reacting together to form a functional group that ensures a covalent bond between T and T'. Typically, T and T' are thus such that T has an amine-type terminal functional group and T' has a carboxylic acid-type terminal functional group.

[0075] Thus, typically, T represents a group of formula (TB):

[0076] [ka]

[0077] T' represents a group of formula (TC),

[0078] [ka]

[0079] In the formula, L1 and L2 are as defined above.

[0080] The coupling is advantageously carried out using BOP (benzotriazol-1-yloxytris (dimethylamino) This can be carried out in the presence of a peptide coupling agent such as benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, typically in the presence of an organic base such as Hunig's base N,N-diisopropylethylamine (DIPEA or DIEA).

[0081] According to one embodiment, compound (B) conforms to formula (A).

[0082] [ka]

[0083] According to one embodiment, compound (C) corresponds to formula (C-1):

[0084] [ka]

[0085] where L2 and L (E3 ligase) are as defined above.

[0086] Optionally, the process may also comprise a step consisting of isolating the product of formula (I) obtained.

[0087] In the reactions described below, it may be necessary to protect reactive functional groups, such as hydroxy, amino, imino, thio, carboxy groups, if desired in the final product, to avoid their undesired participation in the reaction. Conventional protecting groups can be used according to standard practice. For example, see Non-Patent Document 3.

[0088] The compound thus prepared can be recovered from the reaction mixture by conventional means. For example, the compound can be recovered by distilling the solvent of the reaction mixture, or, if necessary, after distilling the solvent of the mixture of solutions, pouring the remainder into water, followed by extraction with an organic solvent immiscible in water, and distilling the solvent from the extract. In addition, if desired, the product can be further purified by various techniques such as recrystallization, reprecipitation, or various chromatographic techniques, particularly column chromatography or preparative thin-layer chromatography.

[0089] It is understood that the useful compounds according to the present invention may contain asymmetric centers. These asymmetric centers may be independently R or S configuration. It will be clear to those skilled in the art that certain useful compounds according to the present invention may also have geometric isomerism. It should be understood that the present invention includes the individual geometric isomers and stereoisomers of the compounds of formula (I) above, as well as mixtures thereof, including racemic mixtures. This type of isomer can be separated from the mixture by applying or adapting known methods, such as chromatographic techniques or recrystallization techniques, or they are prepared separately from the appropriate isomers of their intermediates.

[0090] The base products or reagents used are commercially available and / or can be prepared by the application or adaptation of known methods, e.g. those described in the Reference Examples or obvious chemical equivalents thereof.

[0091] The process according to the invention makes it possible to implement intermediates of formula (A) which are novel.

[0092] Thus, according to a further subject matter, the present invention also relates to compounds of formula (A).

[0093] [ka]

[0094] Compounds of formula (A) can be prepared by coupling the following compounds:

[0095] [ka]

[0096] This coupling can typically be carried out by application or adaptation of the procedure described in Example 1.

[0097] According to the present invention, the compound of formula (I) can induce the targeted proteolysis of PXR. Therefore, the compound of formula (I) is useful for treating and / or preventing cancer, particularly cancer that overexpresses PXR.

[0098] The present invention therefore also relates to a pharmaceutical composition comprising a compound according to the invention together with a pharma- ceutically acceptable excipient.

[0099] Preferably, the composition contains an effective amount of a compound according to the present invention.

[0100] According to a further subject matter, the present invention also relates to compounds of general formula (I) for the treatment and / or prevention of cancer, in particular cancers that overexpress PXR.

[0101] Cancers that overexpress PXR are particularly colorectal cancer, as well as pancreatic, liver, and breast cancer.

[0102] Typically, the compound according to the present invention can be used in combination with anticancer drugs.Such anticancer drugs can be selected from 5-Fluorouracil (5-FU), Irinotecan (CPT11), Oxaliplatin, Cisplatin, Tamoxifen, Paclitaxel, Doxorubicin, Vonblastin, Cyclophosphamide (CPA), Isophosphamide (IFO), among others.

[0103] Preferably, said composition is administered to a patient in need thereof, in particular a patient resistant to the above-mentioned anti-cancer agents.

[0104] The type of formulation of the pharmaceutical composition of the present invention depends on the mode of administration, which may include injection, which may be enteral (e.g., oral), parenteral (e.g., subcutaneous (sc), intravenous (iv), intramuscular (im) and intrasternal), or injection techniques, which may be intravenous or arterial, intramedullary, intrathecal, intraventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal, topical mucosal, nasal, oral, sublingual injection, intratracheal instillation, bronchial instillation, and / or inhalation. In general, the most suitable route of administration depends on various factors, in particular the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract) and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). In some embodiments, the composition is formulated for oral or intravenous administration (e.g., systemic intravenous injection).

[0105] The phrase "pharmaceutically acceptable carrier" as known in the art refers to a pharma-ceutically acceptable substance, composition, or carrier that is suitable for administration of the compounds of the present invention to a mammal. Suitable supports may include, for example, liquids (both aqueous and non-aqueous and combinations thereof), solids, encapsulating materials, gases, and combinations thereof (e.g., semi-solids) that act to transport or transport the compound from one organ or body part to another. A support is "acceptable" in the sense that it is physiologically inert, compatible with other components of the formulation, and non-toxic to the subject or patient. Based on the type of formulation,

[0106] As a result, the compounds of formula I can be formulated as solid compositions (e.g., powders, tablets, dispersible granules, capsules, wafers, and suppositories), liquid compositions (e.g., solutions in which the compound is dissolved, suspensions in which particles of the compound are dispersed, emulsions and solutions containing liposomes, micelles, or nanoparticles, syrups and elixirs), semi-solid compositions (e.g., gels, suspensions, and creams), and gases (e.g., propellants for aerosol compositions). The compounds can also be formulated for rapid, intermediate, or sustained release.

[0107] Excipients suitable for solid administration are cellulose or microcrystalline cellulose derivatives for solid forms, alkaline earth carbonates, magnesium phosphate, starch, modified starch, lactose.For parenteral use, water, aqueous solutes, physiological serum, isotonic solutes are the most conveniently used carriers.

[0108] The dosage can vary within wide limits depending on the therapeutic indication and the route of administration, as well as the age and weight of the subject. [Brief description of the drawings]

[0109] [Figure 1] 1 depicts the PXR affinity of precursor PROTAC JMV6944 as measured by RT-FRET. [Diagram 2] Illustrates activation of PXR by progenitor PROTAC JMV6944 and resulting PROTACs, as measured by a luciferase reporter gene placed under the control of the CYP3A4 promoter, a target gene of PXR. [Figure 3A] 1 depicts induction of PXR target genes (i.e., CYP3A4) by pro-PROTAC JMV6944 and resulting PROTACs as measured by RT-qPCR. [Figure 3B] 1 depicts induction of PXR target genes (i.e., CYP3A4) by pro-PROTAC JMV6944 and resulting PROTACs as measured by RT-qPCR. [Figure 4A] Illustrates and depicts the effect of PROTACs JMV7048 and JMV7965 on induction of CYP34 by Western blotting. [Figure 4B] Illustrates and depicts the effect of PROTACs JMV7048 and JMV7965 on induction of CYP34 by Western blotting. [Figure 5A] Illustrates the effect of PROTACs on cell viability in different cell lines derived from colon cancer (LS174T, FIT29) and primo cultures (CRC1). [Figure 5B]Illustrates the effect of PROTACs on cell viability in different cell lines derived from colon cancer (LS174T, FIT29) and primo cultures (CRC1). [Figure 6A] 1 depicts the effect of PROTACs on the degradation of PXR protein in LS174T cells as measured by Western blotting. [Figure 6B] 1 depicts the effect of PROTACs on the degradation of PXR protein in LS174T cells as measured by Western blotting. [Figure 6C] 1 depicts the effect of PROTACs on the degradation of PXR protein in LS174T cells as measured by Western blotting. [Figure 6D] 1 depicts the effect of PROTACs on the degradation of PXR protein in LS174T cells as measured by Western blotting. [Figure 6E] 1 depicts the effect of PROTACs on the degradation of PXR protein in LS174T cells as measured by Western blotting. [Figure 7A] 1 depicts the effect of PROTACs on the degradation of PXR protein in FIEPG2 cells as measured by Western blotting. [Figure 7B] 1 depicts the effect of PROTACs on the degradation of PXR protein in ASPC1 cells as measured by Western blotting. [Figure 8A] Illustrates the importance of the proteasome pathway in the effect of PROTACs on PXR protein degradation as measured by Western blotting. [Figure 8B] Illustrates the importance of the proteasome pathway in the effect of PROTACs on PXR protein degradation as measured by Western blotting. [Figure 9A] 1 depicts the effect of JMV7048 on PXR protein degradation in vivo on xenografts of LS174T cells in SCID mice. [Figure 9B]1 depicts the effect of JMV7048 on PXR protein degradation in vivo on xenografts of LS174T cells in SCID mice. [Figure 9C] 1 depicts the effect of JMV7048 on PXR protein degradation in vivo on xenografts of LS174T cells in SCID mice. [Figure 10A] Figures 10A-10D respectively depict the effect of PROTACs on cancer stem cell populations: inhibition of ALDFI activity (10A), inhibition of their regenerative potential (10B), and sensitization to chemotherapy (10C and 10D). [Figure 10B] Figures 10A-10D respectively depict the effect of PROTACs on cancer stem cell populations: inhibition of ALDFI activity (10A), inhibition of their regenerative potential (10B), and sensitization to chemotherapy (10C and 10D). [Figure 10C] Figures 10A-10D respectively depict the effect of PROTACs on cancer stem cell populations: inhibition of ALDFI activity (10A), inhibition of their regenerative potential (10B), and sensitization to chemotherapy (10C and 10D). [Figure 10D] Figures 10A-10D respectively depict the effect of PROTACs on cancer stem cell populations: inhibition of ALDFI activity (10A), inhibition of their regenerative potential (10B), and sensitization to chemotherapy (10C and 10D). [Figure 11A] Illustrates the mode of interaction of JMV6944 with the LBD of hPXR. (11A) Overall structure of the complex. The activation helix H12 is indicated. The arrows symbolize the extension of the subsequently synthesized PROTAC. [Figure 11B] The mode of interaction of JMV6944 with the LBD of hPXR is illustrated. (11B) Extension of the output pathway of JMV6944 and superposition with the structure of the hPXR-LBD / SR12813 complex. The end of the H2' helix, residues 206-209, rearranges in the presence of ligand. [Figure 11C]The interaction mode of JMV6944 with the LBD of hPXR is illustrated. (11C) Interaction of JMV6944 with residues of the hPXR binding pocket and electron density depiction of the ligand (omit-type difference map).

[0110] The following examples illustrate the invention without, however, limiting it. The starting products used are known or are products prepared according to known procedures.

[0111] The compounds of the invention will be further understood in connection with the synthetic diagrams described in the various examples of the work, which illustrate non-limiting processes by which the compounds of the invention may be prepared. Percentages are expressed by weight unless otherwise indicated.

[0112] Example 1: Synthesis of JMV6944

[0113] [ka]

[0114] Step 1: N1-benzyl-4-nitrobenzene-1,2-diamine

[0115] [ka]

[0116] K2CO3 (13.28 g, 96.08 mmol) is added to a solution containing 2-fluoro-5-nitroaniline (5 g, 32.03 mmol) and benzylamine (7.01 ml, 64.05 mmol) in DMF (50 ml). The reaction medium is stirred at 100° C. for 24 hours. The reaction medium is diluted in an ethyl acetate / H2O mixture. The organic phase is washed successively with water, 1N KHSO4, saturated NaCl and dried over magnesium sulfate. After evaporation, the product is triturated in diethyl ether and discharged. Compound 1 N1-benzyl-4-nitrobenzene-1,2-diamine is obtained in the form of a yellow solid having a mass of 7.5 g (96% yield). ESI: M+H 244.1.

[0117] Step 2: N-{2-[4-(1-benzyl-5-nitro-1H-1,3-benzodi Azol-2-yl)butoxy]ethyl}carbamic acid (9H-fluoren-9-yl)methyl

[0118] [ka]

[0119] TFA (0.91 ml, 12.28 mmol) is added to a solution containing N1-benzyl-4-nitrobenzene-1,2-diamine (0.747 g, 3.07 mmol) and N-[8-(1H-1,2,3-benzotriazol-1-yl)-8-oxooctyl]carbamate (9H-fluoren-9-yl)methyl (1.63 g, 3.37 mmol) in a toluene / DMF (9 / 1) mixture (45 ml / 5 ml). The reaction medium is stirred at 60° C. for 6 hours. The reaction medium is cooled to room temperature and then to 0° C. The solid is drained and then washed twice with diethyl ether. The powder is dissolved in acetic acid and heated to 100° C. for 18 hours. After evaporation, compound 2 N-{2-[4-(1-benzyl-5-nitro-1H-1,3-benzodiazol-2-yl)butoxy]ethyl}carbamate (9H-fluoren-9-yl)methyl is obtained in the form of 0.55 g of a yellow oil (30% yield). ESI: M+H 589.2.

[0120] Step 3: N-[7-(5-amino-1-benzyl-1H-1,3-benzodiazol-2-yl)heptyl]carbamic acid (9H-fluoren-9-yl)methyl ester

[0121] [ka]

[0122] SnCl2 (1.2 g, 6.34 mmol) is added to a solution containing N-{2-[4-(1-benzyl-5-nitro-1H-1,3-benzodiazol-2-yl)butoxy]ethyl}carbamate (9H-fluoren-9-yl)methyl (0.75 g, 1.27 mmol) in ethanol (30 ml). The reaction medium is stirred at 80° C. for 2 hours. The reaction medium is diluted in a mixture of ethyl acetate / NaHCO3 and filtered through Celite. The organic phase is recovered and dried over MgSO4. After evaporation, compound 3 N-[7-(5-amino-1-benzyl-1H-1,3-benzodiazol-2-yl)heptyl]carbamate (9H-fluoren-9-yl)methyl is obtained in the form of 0.55 g of a yellow powder (77% yield). ESI: M+H 559.3.

[0123] Step 4: N-[2-(7-aminoheptyl)-1-benzyl-1H-1,3-benzodiazol-5-yl]-2,4,6-trimethylbenzene-1-sulfonamide

[0124] [ka]

[0125] 2-Mesitylenesulfonyl chloride (0.166 g, 0.75 mmol) per portion is added to a solution containing N-[7-(5-amino-1-benzyl-1H-1,3-benzodiazol-2-yl)heptyl]carbamate (9H-fluoren-9-yl)methyl (0.386 g, 0.69 mmol) in a pyridine / DCM (1 / 1) mixture (5 ml / 5 ml) at 0° C. The reaction medium is brought to room temperature and stirred for 18 hours. Diethylamine (2 ml) is added to the reaction medium and stirred for 2 hours. The solution is concentrated under reduced pressure. The oil obtained is purified by preparative HPLC. After lyophilization, 0.201 g of a yellow powder is obtained (56% yield). ESI: M+H 519.4. 1 H NMR(600MHz,DMSO-d6):δ 10.53(s,1H),7.77(m,3H),7.64(d,J=8.92Hz,1H),7.33(m,4H),7.20(d,J=6.81Hz,2H),7.10(dd,J=1.79,8.88Hz,1H) ,7.01(s,2H),5.63(s,2H),3.08(m,2H),2.75(m,2H),2.58(s,6H),2.21(s,3H),1.66(m,2H),1.48(m,2H),1.26(m,6H).

[0126] 13C NMR(125MHz,DMSO-d6):δ 155.3,142.7,139.2,135.8,135.4,133.9,132.3,129.4,129.3,129.3 ,128.5,127.3,117.7,113.7,47.7,39.4,39.2,28.6,28.4,27.3,26.5.

[0127] Example 2: Synthesis of JMV7048

[0128] [ka]

[0129] Step 1: 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione

[0130] [ka]

[0131] A reaction medium containing 4-fluorophthalic anhydride (2.43 g, 14.63 mmol) and 3-aminopiperidine-2,6-dione (2.38 g, 14.63 mmol) in acetic acid (50 ml) and sodium acetate (2.4 g, 29.26 mmol) is heated to 100° C. for 24 hours. After cooling to room temperature, water (150 mL) is added to the reaction mixture, the mixture is drained and washed several times with ether. After placing in a desiccator overnight at 50° C., the compound 1,2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione is obtained in the form of a pink solid having a mass of 4 g (yield 99%) ESI: M+H 277.2. 1 H NMR(600MHz,DMSO-d6):δ 11.15(s,1H),8.03-8.00(dd,J=4.59,8.02Hz,1H),7.87-7.85(dd,J=2.29,8.02Hz,1H),7.75-7.71(t,J=2.29,4.59,8.0 2Hz,1H),5.19-5.16(dd,J=5.51,13.03,1H),2.94-2.87(m,1H),2.64-2.59(m,1H),2.58-2.51(m,1H),2.10-2.05(m,1H); 13 C NMR(125MHz,DMSO-d6)δ 173.2,173.2,170.2,170.1,167.4,166.6,166.6,166.3,165.4,134. 7, 134.6, 127.9, 126.7, 126.7, 122.3, 122.1, 112.0, 111.8, 49.6, 31.3, 22.4.

[0132] Step 2: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoindolin-5-yl)piperazine-1-carboxylate

[0133] [ka]

[0134] The compound 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (500 mg, 1.81 mmol) is dissolved in NMP (7 ml) at room temperature. DIEA (0.89 ml, 5.43 mmol) and tert-butyl 1-piperazine-carboxylate (370.9 mg, 1.99 mmol) are added and the mixture is stirred at 140° C. for 24 hours. The solution is diluted in water (100 ml). It is extracted twice with ethyl acetate, the organic phase is washed with saturated NaCl and dried over magnesium sulfate. After evaporation, the oil obtained is purified on silica gel with petroleum ether / ethyl acetate eluent (3 / 1). tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoindolin-5-yl)piperazine-1-carboxylate is obtained in the form of a yellow solid having a mass of 655 mg (yield 82%). ESI: M+H 443.1. 1 H NMR(600MHz,DMSO-d6):δ 11.09(s,1H),7.70(d,J=8.56Hz,1H),7.35(d,J=2.08Hz,1H),7.26-7.24(dd,J=2.08,8.56Hz, 1H), 5.08 (m, 1H), 3.47 (s, 8H), 2.93-2.86 (m, 1H), 2.61-2.48 (m, 2H), 2.03 (m, 1H), 1.43 (s, 9H). 13C NMR(125MHz,DMSO-d6)δ 173.2,170.5,167.9,167.4,155.4,154.3,134.3,125.3,119.0,118.3,108.5,79.6,49.2,47.0,31.4,28.5,22.6.

[0135] Step 3: 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione

[0136] [ka]

[0137] tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoindolin-5-yl)piperazine-1-carboxylate (464 mg, 1.04 mmol) compound is dissolved in a 4N solution of HCl in dioxane (4 ml) and the reaction medium is stirred for 2 hours at room temperature, then concentrated and triturated with ether. The solid is obtained in the form of a yellow powder having a mass of 323 mg (90% yield). ESI: M+H 343.1 . 1 H NMR(600MHz,DMSO-d6):δ 11.09(s,1H),9.71(m,2H),7.73(d,J=8.61Hz,1H),7.44(d,J=2.08Hz,1H),7.32(dd,J=2.08,8. 61Hz, 1H), 5.09 (m, 1H), 3.73 (m, 4H), 3.19 (m, 4H), 2.89 (m, 1H), 2.61-2.48 (m, 2H), 2.03 (m, 1H). 13C NMR(125MHz,DMSO-d6)δ 173.2,170.4,167.8,167.3,154.8,134.2,125.4,120.0,119.0,109.2,49.2,44.5,42.4,31.4,22.6.

[0138] Step 4: 6-(4-(2-(2,6-dioxopiperid-3-yl)-1,3-dioxoindolin-5-yl)piperazin-1-yl)hexanoic acid

[0139] [ka]

[0140] The compound 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione (100 g, 0.29 mmol) is dissolved in acetonitrile (5 ml). 6-Bromohexanoic acid (152 mg, 0.73 mmol) and DIEA (0.193 ml, 1.16 mmol) are added and the mixture is stirred at 60° C. for 24 hours. The solution is concentrated under reduced pressure. The oil obtained is purified by preparative HPLC. After lyophilization, a yellow powder is obtained with a mass of 90 mg (65% yield). ESI: M+H 457.3. 1 H NMR(600MHz,DMSO-d6):δ 12.08(m,1H),11.04(s,1H),9.73(m,1H),7.77(d,J=8.50Hz),7.50(d,J=1.90Hz),7.37(dd,J=1.90,8.50Hz),5.10(m,1H),4.23(m,2H) ),3.59(m,2H),3.25(m,2H),3.14(m,4H),2.90(m,1H),2.59(m,2H),2.25(m,2H),2.04(m,1H),1.69(m,2H),1.55(m,2H),1.33(m,2H). 13C NMR(125MHz,DMSO-d6)δ 174.7,173.2,170.4,167.8,167.3,154.6,134.2,125.4,120.4,119.2,109.4,55.7,50.7,49.3,44.8,33.7,31.4,25.9,24.3,23.4.

[0141] Step 5: JMV7048

[0142] [ka]

[0143] BOP (52 mg, 0.12 mmol) is added to a solution containing N-[2-(7-aminoheptyl)-1-benzyl-1H-1,3-benzodiazol-5-yl]-2,4,6-trimethylbenzene-1-sulfonamide (41 mg, 0.079 mmol) (Example 1, JMV6944), 6-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperazin-1-yl)hexanoic acid (34 mg, 0.079 mmol) and DIEA (0.039 ml, 0.237 mmol) in DMF (5 ml). The reaction medium is stirred for 2 hours at room temperature. The solution is concentrated under reduced pressure. The oil obtained is purified by preparative HPLC. After lyophilization, a yellow powder having a mass of 52 mg is obtained (66% yield). ESI: M+H 958.0. 1 H NMR(600MHz,DMSO-d6):δ 11.02(s,1H),10.42(m,1H),9.78(m,1H),7.69(d,J=8.49Hz,1H),7.65(m,1H),7.54(d,J=8.89Hz,1H),7.41(d,J=2.0 1Hz,1H),7.29-7.20(m,5H),7.11(m,2H),7.00(dd,J=2.01,8.89Hz,1H),6.93(s,2H),5.02(dd,J=5.53,13.14Hz,1H).

[0144] Example 3: Synthesis of JMV7505 Step 1: 7-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}heptanoic acid

[0145] [ka]

[0146] The compound 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione (100 mg, 0.29 mmol) (Example 2, step 3) is dissolved in acetonitrile (5 ml). 7-bromoheptanoic acid (155 mg, 0.73 mmol) and DIEA (0.193 ml, 1.16 mmol) are added and the mixture is stirred at 60° C. for 24 hours. The solution is concentrated under reduced pressure. The oil obtained is purified by preparative HPLC. After lyophilization, a yellow powder is obtained with a mass of 93 mg (65% yield). ESI: M+H 471.3.

[0147] Step 2:

[0148] [ka]

[0149] BOP (52 mg, 0.12 mmol) is added to a solution containing N-[2-(7-aminoheptyl)-1-benzyl-1H-1,3-benzodiazol-5-yl]-2,4,6-trimethylbenzene-1-sulfonamide (41 mg, 0.079 mmol) (Example 1, JMV6944), 6-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperazin-1-yl)hexanoic acid (34 mg, 0.079 mmol) and DIEA (0.039 ml, 0.237 mmol) in DMF (5 ml). The reaction medium is stirred for 2 hours at room temperature. The solution is concentrated under reduced pressure. The oil obtained is purified by preparative HPLC. After lyophilization, a white powder having a mass of 52 mg is obtained (yield 68%). ESI: M+H 971.5. 1 H NMR(600MHz,DMSO-d6):δ 11.02(s,1H),10.42(m,1H),9.78(m,1H),7.69(d,J=8.49Hz,1H),7.65(m,1H),7.54(d,J=8.89Hz,1H),7.41(d,J=2.01Hz,1H ),7.29-7.20(m,5H),7.11(m,2H),7.00(dd,J=2.01,8.89Hz,1H),6.93(s,2H),5.53(s,2H),5.02(dd,J=5.53,13.14Hz,1H).

[0150] Example 4: Synthesis of JMV7506 Step 1: 8-{4-[2-(2,6-dioxopiperid-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}octanoic acid

[0151] [ka]

[0152] 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione compound (100 mg, 0.29 mmol) (Example 2, step 3) is dissolved in acetonitrile (5 ml). 8-Bromooctanoic acid (160 mg, 0.73 mmol) and DIEA (0.193 ml, 1.16 mmol) are added and the mixture is stirred at 60° C. for 24 hours. The solution is concentrated under reduced pressure. The oil obtained is purified by preparative HPLC. After lyophilization, a yellow powder is obtained with a mass of 101 mg (67% yield). ESI: M+H 485.6.

[0153] Step 2:

[0154] [ka]

[0155] BOP (52 mg, 0.12 mmol) is added to a solution containing N-[2-(7-aminoheptyl)-1-benzyl-1H-1,3-benzodiazol-5-yl]-2,4,6-trimethylbenzene-1-sulfonamide (41 mg, 0.079 mmol) (Example 1, JMV6944), 6-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperazin-1-yl)octanoic acid (36 mg, 0.079 mmol) and DIEA (0.039 ml, 0.023 mmol) in DMF (5 ml). The reaction medium is stirred for 2 hours at room temperature. The solution is concentrated under reduced pressure. The oil obtained is purified by preparative HPLC. After lyophilization, a white powder having a mass of 45 mg is obtained (61% yield). ESI: M+H 985.5.

[0156] 1H NMR(600MHz,DMSO-d6):δ 11.02(s,1H),10.42(m,1H),9.78(m,1H),7.69(d,J=8.49Hz,1H),7.65(m,1H),7.54(d,J=8.89Hz,1H),7.41(d,J=2.01Hz,1H ),7.29-7.20(m,5H),7.11(m,2H),7.00(dd,J=2.01,8.89Hz,1H),6.93(s,2H),5.54(s,4H),5.02(dd,J=5.53,13.14Hz,1H).

[0157] Example 5: Synthesis of JMV7965

[0158] [ka]

[0159] Step 1: tert-butyl 4-({4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}methyl)piperidine-1-carboxylate

[0160] [ka]

[0161] 3 ml of MeOH are added to a solution containing 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione (100 mg, 0.29 mmol) (Example 2, step 3) and tert-butyl 4-formylpiperidine-1-carboxylate (112 mg, 0.53 mmol) in DCE. The reaction medium is stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride is added in portions and the reaction medium is stirred at room temperature for 18 hours. The reaction medium is concentrated and a preparative HPLC is carried out. After lyophilization, a yellow powder with a mass of 85 mg is obtained (yield 53%). ESI: M+H 540.2.

[0162] Step 2: 2-(2,6-dioxopiperidin-3-yl)-5-{4-[(piperidin-4-yl)methyl]piperazin-1-yl}-2,3-dihydro-1H-isoindole-1,3-dione

[0163] [ka]

[0164] 4-({4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoind-5-yl]piperazin-1-yl}methyl)piperidine-1-carboxylate tert-butyl compound (100 mg, 0.19 mmol) is dissolved in DCM (50 ml). TFA (5 ml) is added dropwise to the reaction medium and stirred at room temperature for 5 hours. The solution is concentrated under reduced pressure. The oil obtained (75 mg, 92% yield) is used as is in step 3. ESI: M+FI 440.3.

[0165] Step 3: tert-butyl 2-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoind-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]acetate

[0166] [ka]

[0167] The compound 2-(2,6-dioxopiperidin-3-yl)-5-{4-[(piperidin-4-yl)methyl]piperazin-1-yl}-2,3-dihydro-1H-isoindole-1,3-dione (128 mg, 0.29 mmol) is dissolved in DCM in the presence of DIEA (0.14 ml, 0.88 mmol). tert-Butyl bromoacetate (0.043 ml, 0.29 mmol) is added and stirred at room temperature for 18 hours. The reaction medium is concentrated and a preparative HPLC is carried out. After lyophilization, a yellow powder is obtained with a mass of 85 mg (yield 53%). ESI: M+H 554.4.

[0168] Step 4: 2-[4-({4-[2-(2,6-dioxopiperidin-3-yl)- 1,3-Dioxo-2,3-dihydro-1H-isoind-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]acetic acid

[0169] [ka]

[0170] 2-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoind-5-yl]piperazin-1-yl}methyl)piperidin-1-yl] tert-butyl acetate (83 mg, 0.19 mmol) is dissolved in DCM (25 ml). TFA (5 ml) is added dropwise to the reaction medium and stirred at room temperature for 5 hours. The solution is concentrated under reduced pressure. The oil obtained (70 mg, 93% yield) is used as is in step 3. ESI: M+H 498.3.

[0171] Step 5:

[0172] [ka]

[0173] BOP (27 mg, 0.0603 mmol) is added to a solution containing N-[2-(7-aminoheptyl)-1-benzyl-1H-1,3-benzodiazol-5-yl]-2,4,6-trimethylbenzene-1-sulfonamide (21 mg, 0.0402 mmol) (Example 1, JMV6944), 2-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]acetic acid (20 mg, 0.0402 mmol) and DIEA (0.020 ml, 0.12 mmol) in DMF (5 ml). The reaction medium is stirred for 2 hours at room temperature. The solution is concentrated under reduced pressure. The oil obtained is purified by preparative HPLC. After lyophilization, a yellow powder is obtained with a mass of 25 mg (62% yield). ESI: M+H 998.3.

[0174] Example 6: Synthesis of JMV7605

[0175] [ka]

[0176] Step 1: tert-Butyl 4-{4-[(2,6-dioxopiperidin-3-yl)carbamoyl]phenyl}piperazine-1-carboxylate

[0177] [ka]

[0178] BOP (1.11 g, 2.53 mmol) is added to a solution containing 4-[4-(tert-butoxycarbonyl)piperazino]benzoic acid (0.775 g, 2.53 mmol), 3-aminopiperidine-2,6-dione HCl (0.50 g, 3.03 mmol), and DIEA (1.25 ml, 7.59 mmol) in DMF (50 ml).

[0179] The reaction medium is stirred for 2 hours at room temperature. Water is added to the reaction medium and it is extracted with ethyl acetate. The organic phase is washed successively with 1N HCl, saturated NaHCO3 and saturated NaCl. The organic phase is dried over MgSO4, filtered and concentrated under reduced pressure. A white powder is obtained with a mass of 0.4 g (38% yield). ESI: M+H 417.3.

[0180] Step 2: N-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)benzamide

[0181] [ka]

[0182] 4-{4-[(2,6-dioxopiperidin-3-yl)carbamoyl]phenyl}piperazine-1-carboxylate tert-butyl compound (0.4 g, 0.96 mmol) is dissolved in a 4N solution of HCl in dioxane (6 ml), the reaction medium is stirred at room temperature for 2 hours, then concentrated and triturated with ether. The solid is obtained in the form of a white powder having a mass of 0.285 mg (94% yield).

[0183] The reaction medium is stirred for 2 hours at room temperature. The solution is concentrated under reduced pressure. The oil obtained is purified by preparative HPLC. After lyophilization, a white powder is obtained with a mass of 45 mg (52% yield). ESI: M+H 317.3.

[0184] Step 3: 7-(4-{4-[(2,6-dioxopiperidin-3-yl)carbamoyl]phenyl}piperazin-1-yl)heptanoic acid

[0185] [ka]

[0186] N-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)benzamide compound (50 mg, 0.15 mmol) is dissolved in DMF (5 ml). 7-bromoheptanoic acid (66 mg, 0.31 mmol) and DIEA (0.078 ml, 0.47 mmol) are added and the mixture is stirred at 100° C. for 24 hours. The solution is concentrated under reduced pressure. The oil obtained is purified by preparative HPLC. After lyophilization, a yellow powder is obtained with a mass of 38 mg (55% yield). ESI: M+H 445.1.

[0187] Step 4:

[0188] [ka]

[0189] BOP (44 mg, 0.101 mmol) was dissolved in DMF (5 ml) with N-[2-(7-aminoheptyl)-1-benzyl-1H-1,3-benzodiazol-5-yl]-2,4,6-trimethylbenzene-1-sulfonamide (35 mg, 0.067 mmol) ( Example 1, JMV6944), 7-(4-{4-[(2,6-dioxopiperidin-3-yl)carbamoyl]phenyl}piperazin-1-yl)heptanoic acid (30 mg, 0.067 mmol) and DIEA (0.033 ml, 0.20 mmol) are added to a solution containing the above. The reaction medium is stirred at room temperature for 2 hours. The solution is concentrated under reduced pressure. The oil obtained is purified by preparative HPLC. After lyophilization, a white powder is obtained with a mass of 41 mg (65% yield). ESI: M+H 945.8.

[0190] Example 7: Synthesis of JMV7159 (Comparative Example)

[0191] [ka]

[0192] Step 1: 5-Fluoro-2-(1-methoxy-2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione

[0193] [ka]

[0194] The compound 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (250 mg, 0.90 mmol) is dissolved in anhydrous DMF (5 ml) and the reaction medium is stirred and brought to 0° C. NaH is added in portions and stirred for 20 minutes. Methyl iodide is added and stirred for 2 hours. The reaction is quenched with NH4Cl solution. Extract with ethyl acetate and wash the organic phase twice with saturated NaCl. Dry over MgSO4, filter and concentrate under reduced pressure. The compound 5-fluoro-2-(1-methyl-2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione is obtained in the form of a white powder having a mass of 253 mg (96% yield). ESI: M+H 291.1.

[0195] Step 2: tert-Butyl 4-[2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-carboxylate

[0196] [ka]

[0197] The compound 5-fluoro-2-(1-methyl-2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione (250 mg, 0.86 mmol) is dissolved in NMP (4 ml) at room temperature. DIEA (0.42 ml, 2.58 mmol) and 1-piperazine-carboxylate tert-butyl (176 mg, 0.94 mmol) are added and the mixture is stirred at 140° C. for 24 hours. The solution is diluted in water (100 ml). It is extracted twice with ethyl acetate, the organic phase is washed with saturated NaCl and dried over magnesium sulfate. After evaporation, the oil obtained is purified on silica gel using petroleum ether / ethyl acetate eluent (3 / 1). tert-Butyl 4-[2-(1-methyl-2,6-dioxopiperid-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-carboxylate is obtained in the form of a yellow solid having a mass of 338 mg (86% yield). ESI: M+H 457.3.

[0198] Step 3: 2-(1-methyl-2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)-2,3-dihydro-1H-isoindole-1,3-dione

[0199] [ka]

[0200] 4-[2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-carboxylate tert-butyl compound (250 mg, 0.54 mmol) is dissolved in a 4N solution of HCl in dioxane (4 ml), the reaction medium is stirred at room temperature for 2 hours, then concentrated and triturated with ether. The solid is obtained in the form of a yellow powder with a mass of 175 mg (90% yield). ESI: M+H 357.3.

[0201] Step 4: 6-{4-[2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}hexanoic acid

[0202] [ka]

[0203] The compound 2-(1-methyl-2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)-2,3-dihydro-1H-isoindole-1,3-dione (100 mg, 0.28 mmol) is dissolved in acetonitrile (5 ml). 6-Bromohexanoic acid (136 mg, 0.70 mmol) and DIEA (0.139 ml, 0.84 mmol) are added and the mixture is stirred at 60° C. for 24 hours. The solution is concentrated under reduced pressure. The oil obtained is purified by preparative HPLC. After lyophilization, a yellow powder is obtained with a mass of 85 mg (65% yield). ESI: M+H 471.3.

[0204] Step 5:

[0205] [ka]

[0206] BOP (36 mg, 0.082 mmol) is added to a solution containing N-[2-(7-aminoheptyl)-1-benzyl-1H-1,3-benzodiazol-5-yl]-2,4,6-trimethylbenzene-1-sulfonamide (28 mg, 0.055 mmol) (Example 1, JMV6944), 6-{4-[2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}hexanoic acid (26 mg, 0.055 mmol) and DIEA (0.165 ml, 0.165 mmol) in DMF (5 ml). The reaction medium is stirred for 2 hours at room temperature. The solution is concentrated under reduced pressure. The oil obtained is purified by preparative HPLC. After lyophilization, a white powder is obtained with a mass of 30 mg (56% yield). ESI: M+H 971.6.

[0207] Example 8: Biochemistry and Crystallography The human PXR receptor ligand binding domain (hPXR-LBD, residues 130-434) was produced in the form of recombinant protein in E. coli BL21-DE3 bacteria. The protein was purified on an affinity column and then by size exclusion chromatography. After concentration, hPXR-LBD was crystallized in the presence of JMV6944 ligand. The structure of the hPXR-LBD / JMV6944 complex was determined by radiation crystallography with the molecular replacement method, then reconstructed and refined based on the electron density (diffraction data collected at the ERF synchrotron, Grenoble). The structure is shown in FIG. 11. In A, the entire structure of the complex shows the binding mode of JMV6944. The originality of JMV6944 is that it is added to the parent molecule JMV6845. The position of the extension and its path to exit the protein domain. Unlike known PROTACs for other nuclear receptors, all based on the modification of antagonistic ligands, the extension grafted on the JMV6845 agonist does not extend towards the H12 helix, but instead points in the opposite direction between the H2', H6 and H7 helices and the S1 strand to finally reach the external surface of the LBD. The presence of the alkyl / NH arm (surrounded by B) induces a conformational change in the H2' end that allows this ligand to be extracted from the binding pocket and to specifically interact with the surface residue C207 (C). Within the ligand binding pocket, JMV6944 also establishes hydrogen bonds with H407 and S247, as well as hydrophobic interactions with L411 and F428, as well as with residues of the "π-trap" region (F288, W299, Y306).

[0208] Example 9: Biological Results 9.1 Measurement of precursor PROTAC / PXR affinity JMV6944 (pro-PROTAC) and PXR ligand binding domain The binding affinity between the gene expression vector and the LBD (Lingle Branching Domain) was measured using LanthaScreen TR-FRET Quantification was performed by FRET using the PXR Competitive Binding Assay Kit (Invitrogen). Molecules were incubated with PXR LBD in the presence of fluorescent reference ligand for 1:30 hours at room temperature. The displacement of the fluorescent ligand caused by the precursor PROTAC or PXR SR12813 ligand was measured by reading the emission at 520 nm and 495 nm after excitation at 337 nm on a PHERA-Star instrument (BMG LABTECH). The results are illustrated in Figure 1, which shows that the molecule JMV6944 is a PXR ligand with an affinity of 18.38 nm.

[0209] 9.2 Measuring the effect of PROTACs on the transcriptional activity of PXR (reporter gene) Treatment of LS174T cells stably transfected with an expression vector encoding the PXR protein, a luciferase reporter gene (PXR target gene) under the control of the CYP3A4 promoter, and an expression cassette encoding the GFP protein under the control of the CMV promoter for signal normalization. The cells were treated for 48 hours with 5 μM of the molecules JMV6944 (pro-PROTAC), PROTACs JMV7048 and JMV7605, and rifampicin (5 μM, PXR ligand). At the end of the treatment, the transcriptional activity of PXR is measured by the ratio of luciferase / GFP signals measured on a PHERA-Star device (BMG LABTECH). Figure 2 shows that only pro-PROTAC JMV6944 and rifampicin are able to activate the transcriptional activity of PXR.

[0210] 9.3 Measuring the effect of PROTACs on PXR transcriptional activity (CYP3A4 mRNA expression) LS174T cells were treated with 5 μM of the molecules JMV6944 (progenitor PROTAC), JMV7048, JMV7505, or JMV5159 (inactive equivalent of JMV7048 after addition of a methyl group on the CNBR ligase ubiquitin ligand) in the presence or absence of rifampicin (PXR ligand) in a final amount of 5 μM for 48 h. After lysis of the cells and purification of total RNA (Qiagen RNAeasy), complementary DNA was prepared (SuperScript® II in the presence of 6 nucleotide random primers, Invitrogen). Expression of CYP3A4 mRNA as well as RPLO and actin housekeeping genes was measured by RT-qPCR on an LC480 instrument (Roche) in the presence of SyberGreen (Millipore). Relative expression levels were calculated according to the RQ=relative quantification=2-ΔΔCt method, with untreated cells serving as calibrators set to 1. Figures 3A and 3B show that the pro-PROTAC and the inactivated PROTAC (JMV7159) have additive effects on CYP3A4 mRNA expression, whereas the PROTACs JMV7048 and JMV7965 have additive effects mediated by rifampicin. Shown to significantly reduce induction of CYP3A4.

[0211] 9.4 Measuring the effect of PROTACs on the transcriptional activity of PXR (CYP3A4 expression) LS174T cells were treated with 5 mM JMV7048 for 48 h in the presence or absence of rifampicin (PXR ligand) at 5 mM final volume. After lysis of the cells (RIPA + antiprotease), proteins were purified and assayed before being deposited (90 μg) on ​​a 10% SDS-PAGE gel. After migration on the gel, they were transferred to a nitrocellulose membrane (GE Healthcare) before being revealed with antibodies against CYP3A4 (sc-53850, Santa Cruz) and β-actin (A5441, Sigma or Ab-253283, AbCAm), then a secondary antibody coupled to peroxidase (anti-mouse HRP, Santa Cruz). The intensity of the signal was measured by a camera (BioRad MP Touch). Figures 4A and 4B show that PROTACs JMV7048 and JMV7965 reduce rifampicin-mediated induction of the CYP3A4 enzyme.

[0212] 9.5 Measuring the effect of PROTACs on cell viability The effect of PROTACs on cell viability has been tested in various strains CRC1, HT29, and LS174T. The cells were incubated for 72 hours in the presence of increasing concentrations of the molecules before being fixed and marked by sulforhodamine B (Sigma). After washing and lysis of the cells, the incorporated colorant released by the cells is directly proportional to the cell biomass. It is measured at 565 nM by a 96-well plate spectrophotometer (Tecan). The signal obtained for untreated cells is set to 100%. Figure 5A illustrates the absence of toxicity of PROTACs JMV7048, JMV7505, and JMV7605 on the LS174T strain. In Figure 5B, it can be seen that PROTAC JMV7048 does not affect the viability of HT29 cells or CRC1 protocultures (derived from a patient with colon cancer).

[0213] 9.6 Measuring the effect of PROTACs on PXR degradation in LS174T cells by in vitro Western blotting The effect of PROTACs on the expression levels of PXR protein was studied by Western blotting. LS174T cells were transplanted in the absence or presence of 50 nM siRNA targeting PXR (siPXR:NR1I2 Silencer, Thermofischer) or treated with PROTACs. After cell lysis (RIPA + anti-protease), proteins were purified and assayed before being deposited on a 10% SDS-PAGE gel (9 C^g). After migration on the gel, antibodies against PXR (sc-48340, Santa Cruz), GAPDH (sc-32233, Santa Cruz), and PXR (sc-32233, Santa Cruz) were used to detect the expression of PXR protein. Cruz) and antibodies against β-actin (A5441, Sigma or Ab-253283, AbCAm), then they were transferred to nitrocellulose membranes (GE Healthcare) before being revealed with a secondary antibody coupled to peroxidase (anti-mouse HRP, Santa Cruz). The intensity of the signal was measured by a camera (BioRad MP Touch). Figures 6A-C show that after 24 h of treatment at 5 μM, PROTACs JMV7048, JMV7505, JMV7506, JMV7605, and JMV7965, unlike the inactive mutant of JMV7048 (i.e., JMV7159), significantly reduce the expression level of PXR protein. Figures 6D and 6E illustrate the effect of JMV7048 on the expression level of PXR based on the treatment time (maximal effect reached after 3 h of treatment) and the concentration used (a dose-dependent decrease, with a maximum effect observed from 500 nM).

[0214] 9.7 Measuring the effect of PROTACs on PXR degradation in HEPG2 and ASPC1 cells by in vitro Western blotting The effect of PROTACs (5 mM, 24 h treatment) on the expression levels of PXR protein in HepG2 cells (hepatocellular carcinoma, ATCC#HB-8065™) or ASPC1 cells (human pancreatic cancer cell line, ATCC#CRL-1682) was studied by Western blotting. After lysis of the cells (RIPA+antiprotease), proteins were purified and assayed before being deposited (90 μg) on ​​a 10% SDS-PAGE gel. After migration on the gel, they were transferred to a nitrocellulose membrane (GE Healthcare) before being revealed with antibodies against PXR (sc-48340, Santa Cruz), GAPDH (sc-32233, Santa Cruz), and β-actin (A5441, Sigma or Ab-253283, AbCAm), then a secondary antibody coupled to peroxidase (anti-mouse HRP, Santa Cruz). Figures 7A and 7B illustrate the effects of PROTACs JMV7048 and JMV7965 on the expression levels of PXR in liver cancer cells (7A) or pancreatic cancer cells (7B).

[0215] 9.8 Importance of the proteasome pathway for the effect of PROTACs on PXR degradation The involvement of the proteasome pathway in the effect of PROTACs on the expression level of PXR protein was studied by Western blotting. LS174T cells were treated with JMV7048 for 24 hours in the presence or absence of CNBR ubiquitin ligase (MLN4924) or proteasome inhibitor (bortezomib). Figures 8A and 8B confirm the importance of the proteasome pathway for the reduction of the expression level of PXR protein induced by PROTAC JMV7048. The reduction of the expression level of PXR induced by JMV7048 was reversed by the CRBN ubiquitin ligase inhibitor (MLN4924, Figure 8A) or the inhibitor of the 26S proteasome (bortezomib, Bortezomib, Bz, Figure 8B), while a mutant of JMV7048 (i.e., JMV7159, which does not allow the recruitment of CNBR) does not cause a reduction in the expression level of PXR.

[0216] 9.9 Measuring the effect of PROTACs on PXR degradation by in vivo Western blotting The effect of PROTAC on the expression level of PXR protein was studied in vivo by Western blotting from xenografts of LS174T cells in SCID mice. When tumors reached 100 mm3, 10 mice were treated IV every 24 hours for 4 days with 5% EtOH vehicle, 20% Solutol in D5W, or PROTAC (25 mg / kg). Mice were weighed daily. Four hours after the last treatment, tumors were excised before being lysed in RIPA buffer with ceramic beads (Lysing matrix D, MP-Bio) using a Fast-Prep24 (MP-Bio) device. Proteins were purified and assayed before being deposited (90 μg) on ​​a 10% SDS-PAGE gel. After migration on the gel, antibodies against PXR (sc-48340, Santa Cruz Biosciences) were used to detect the PXR-specific markers. Cruz), GAPDH (sc-32233, Santa Cruz), and β-actin (A5441, Sigma or Ab-253283, AbCAm), and then transferred to a nitrocellulose membrane (GE Healthcare) before revealing with a secondary antibody coupled to peroxidase (anti-mouse HRP, Santa Cruz). The intensity of the signal was measured by a camera (Biorad MP Touch). In Figure 9A it can be seen that treatment with 25mk / kb for 4 days does not significantly modify the body weight of the mice. Figures 9B and 9C confirm that this treatment is able to induce a significant reduction in the expression level of PXR protein in the tumor.

[0217] 9.10 Measuring the effects of PROTACs on colon cancer stem cell self-renewal and chemoresistance The effect of PROTACs on colon cancer stem cell survival and self-renewal was studied in vitro on HT29 line or cancer cells isolated from patients (CRC1). were treated with or without 5 μM PROTAC for 48 h, revealing: Aldefluor marking, enzymatic activity preferentially present in cancer stem cells (Figure 10A), formation of tumor spheres under aseric and non-adherent conditions (Figure 10B), and finally resistance to chemotherapy (Figures 10C and 10D).

[0218] Figure 10A shows that PROTACs JMV7048, JMV7505, JMV7506, and JMV7965 significantly reduce the percentage of ALDH-positive cells after dissociation of CRC1 cells and marking with Aldefluor™ (STEMCELL Technologies) compared to untreated cells. Figure 10B shows that molecules JMV7048 and JMV7965 significantly reduce the number of HT29 cells that can survive anoikis and induce the formation of tumor spheres (sphere-forming cells). Tumor spheres with a diameter of more than 50 μM were counted after 10 days of treatment and culture of 200 cells per well (pretreated with poly2Hema to prevent any cell adhesion) in 100 μL of depleted BCS medium. These culture conditions only allow the survival of cancer stem cells. Figures 10C and 10D show the effect of PROTACs JMV7048 and JMV7965 on the survival (10C) and ability to form tumor spheres (10D) of HT29 cells maintained in the presence of different concentrations of 5-FU and SN38 (Folfiri 1X = 50 μg 5-FU + 500 nM SN38) and cultured in 100 μL of BCS medium in dishes pretreated with poly2Hema to prevent any cell adhesion. Tumor spheres with a diameter of more than 50 μ were counted 10 days after seeding with 200 cells / well. Thus, Figures 10A-10D show that treatment with PROTACs JMV7048 and JMV7965 at 5 μM for 2 days significantly reduces stem cell survival and chemoresistance in colon cancer cell lines.

Claims

1. A bifunctional compound having the general formula (I), 【Chemical 1】 wherein, L(PXR) is a ligand capable of binding to the PXR nuclear receptor, L(E3 ligase) represents a ligand of the E3-ubiquitin ligase, the linker represents a group that enables covalent bonding of L(PXR) to L(E3 ligase), bifunctional compound.

2. L(PXR) is a group of formula (II), 【Chemical Formula 2】 wherein, 【Chemical Formula 3】 is a group representing the attachment of said group to the linker, or a pharmaceutically acceptable salt, the bifunctional compound according to claim 1.

3. L(E3 ligase) is, - a group of formula (IIIA): 【Chemical Formula 4】 and - a group of formula (IIIB): 【Chemical Formula 5】 and is selected from pharmaceutically acceptable salts, wherein, X is NH, X' is -C(O)- or -CH ２－ and Y represents H or a C1-C6 alkyl group, 【Chemical Formula 6】 is a group representing the attachment of said group to the linker, the bifunctional compound according to claim 1.

4. The linker is a group -O-, -S-, -N(R'), -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(NO R')-, -C(O)N(R')-, -C(O)N(R')C(O)-, -C(O)N(R')C(O)N(R')-, -N(R')C(O)-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -OC(O)N(R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -S(O) ２ -, -OS(O)-, -S(O)O-, -S(O)-, -OS(O) ２ -, -N(R')S(O) ２ -, -S(O) ２ N(R')-, -N(R')S-, -S(O)N(R')-, -N(R')S(O) ２ N(R')-, -N(R')S(O)N(R')-, a C3-C12 carbocyclene, a 3- to 12-membered heterocyclene containing 1, 2, or 3 heteroatoms selected from N, O, S, a 5- to 12-membered heteroarylene containing 1, 2, or 3 heteroatoms selected from N, O, S, or any combination thereof, optionally interrupted and / or terminated at either and / or both ends by a C1-C20 alkylene group, wherein R' is the same or different and represents H or a C1-C6 alkyl group, the bifunctional compound according to claim 1.

5. the linker represents a group (IV), 【Chemical Formula 7】 wherein L １ and L ２ are the same or different and each independently represents an alkylene group having 1 to 12 carbon atoms which is optionally interrupted or terminated by a 3- to 12-membered heterocycle containing 1, 2 or 3 heteroatoms selected from N, O and S, L １ is connected to L(PXR), [Chemical 8] is linked to L(E3 ligase), Z represents H or a C1-C6 alkyl group, the bifunctional compound according to claim 1.

6. One of the following formulas (I-4) and (I-5), 【Chemical Formula 9】 wherein L(PXR), the linker is defined according to claim 1, the formula, or a pharmaceutically acceptable salt, the bifunctional compound according to claim 1.

7. A bifunctional compound that conforms to the following formula (V), 【Chemical Formula 10】 wherein L ２ represents a C2-C8 straight-chain alkylene group optionally interrupted by a piperidinyl group, and L(E3 ligase) is as defined according to claim 1, the bifunctional compound according to claim 1.

8. A bifunctional compound according to claim 1 that conforms to one of the following formulas. 【Chemical 11】

9. A method for preparing the bifunctional compound according to claim 1, comprising coupling a compound of formula (B) and a compound of formula (C), 【Chemical 12】 wherein L(PXR) and L(E3 ligase) are as defined according to claim 1, and T and T' are two groups of the linker precursor such that each has complementary reactive terminal functional groups. method.

10. Said compound (B) conforms to formula (A), 【Chemical 13】 said compound (C) conforms to formula (C-1), 【Chemical Formula 14】 wherein L ２ and L(E3 ligase) are as defined according to claim 1, the method according to claim 9.

11. Compound of formula (A). 【Chemical Formula 15】

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

13. The pharmaceutical composition according to claim 12 for use in the treatment and / or prevention of cancer overexpressing the PXR nuclear receptor.

14. The pharmaceutical composition according to claim 13 in combination with an anti-cancer agent.

15. The pharmaceutical composition according to claim 13 for administration to a patient resistant to an anticancer agent.

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