[go: up one dir, main page]

WO2024042163A1 - Nouveaux dérivés d'acide 2,3,4,9-tétrahydro-1h-pyrido[3,4-b]indole carboxylique substitués, leurs procédés de préparation et leurs utilisations thérapeutiques - Google Patents

Nouveaux dérivés d'acide 2,3,4,9-tétrahydro-1h-pyrido[3,4-b]indole carboxylique substitués, leurs procédés de préparation et leurs utilisations thérapeutiques Download PDF

Info

Publication number
WO2024042163A1
WO2024042163A1 PCT/EP2023/073233 EP2023073233W WO2024042163A1 WO 2024042163 A1 WO2024042163 A1 WO 2024042163A1 EP 2023073233 W EP2023073233 W EP 2023073233W WO 2024042163 A1 WO2024042163 A1 WO 2024042163A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
methyl
compound
formula
indole
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2023/073233
Other languages
English (en)
Other versions
WO2024042163A9 (fr
Inventor
Patrick Bernardelli
Youssef El-Ahmad
Corinne Terrier
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi SA
Original Assignee
Sanofi SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sanofi SA filed Critical Sanofi SA
Priority to EP23758664.9A priority Critical patent/EP4577542A1/fr
Priority to JP2025511528A priority patent/JP2025528250A/ja
Priority to CN202380061199.6A priority patent/CN119907798A/zh
Publication of WO2024042163A1 publication Critical patent/WO2024042163A1/fr
Anticipated expiration legal-status Critical
Publication of WO2024042163A9 publication Critical patent/WO2024042163A9/fr
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the Estrogen Receptors belong to the steroid/nuclear receptor superfamily involved in the regulation of eukaryotic gene expression, cellular proliferation and differentiation in target tissues. ERs are in two forms: the estrogen receptor alpha (ER ⁇ ) and the estrogen receptor beta (ER ⁇ ) respectively encoded by the ESR1 and the ESR2 genes. ER ⁇ and ER ⁇ are ligand-activated transcription factors which are activated by the hormone estrogen (the most potent estrogen produced in the body is 17 ⁇ -estradiol). In the absence of hormone, ERs are largely located in the cytosol of the cell.
  • ERs When the hormone estrogen binds to ERs, ERs migrate from the cytosol to the nucleus of the cell, form dimers and then bind to specific genomic sequences called Estrogen Response Elements (ERE).
  • the DNA/ER complex interacts with co-regulators to modulate the transcription of target genes.
  • ER ⁇ is mainly expressed in reproductive tissues such as uterus, ovary, breast, bone and white adipose tissue.
  • Abnormal ER ⁇ signaling leads to development of a variety of diseases, such as cancers, metabolic and cardiovascular diseases, neurodegenerative diseases, inflammation diseases and osteoporosis.
  • ER ⁇ is expressed in not more than 10% of normal breast epithelium but approximately 50-80% of breast tumors.
  • Such breast tumors with high level of ER ⁇ are classified as ER ⁇ -positive breast tumors.
  • the etiological role of estrogen in breast cancer is well established and modulation of ER ⁇ signaling remains the mainstay of breast cancer treatment for the majority ER ⁇ -positive breast tumors.
  • ER ⁇ ER ⁇
  • LBD Ligand Binding Domain
  • - R1 and R2 independently represent a hydrogen atom or a deuterium atom
  • - R3 represents a hydrogen atom or a -COOH group
  • - R3’ represents a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, a cyano group, or a -COOH group
  • - R3” represents a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, or a cyano group; with the proviso that one of R3 and R3’, but not both, represents a -COOH and R3 and R3’ do not simultaneously represent a hydrogen atom
  • - R4 represents a hydrogen atom or a fluorine atom
  • - R5 and R5’ independently represent a hydrogen atom or a fluorine atom
  • - R1 and R2 independently represent a hydrogen atom or a deuterium atom
  • - R3 represents a hydrogen atom or a -COOH group
  • - R3’ represents a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, a cyano group, or a -COOH group
  • - R3” represents a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, or a cyano group; with the proviso that one of R3 and R3’, but not both, represents a -COOH and R3 and R3’ do not simultaneously represent a hydrogen atom
  • - R4 represents a hydrogen atom or a fluorine atom
  • - R5 and R5’ independently represent a hydrogen atom or a fluorine atom
  • the compounds of formula (I) can contain one or more asymmetric carbon atoms. They may therefore exist in the form of enantiomers.
  • the compounds of formula (I) may be present as well under tautomer forms.
  • the compounds of formula (I) may exist in the form of bases, acids, zwitterion or of addition salts with acids or bases.
  • compounds of formula (I) or pharmaceutically acceptable salts thereof may be prepared with pharmaceutically acceptable acids or bases, although the salts of other acids or bases useful, for example, for purifying or isolating the compounds of formula (I) are also provided.
  • hydrochloride may be cited.
  • halogen atom a fluorine, a chlorine, a bromine or an iodine atom, and in particular a fluorine and a chlorine atom
  • alkyl group a linear or branched saturated hydrocarbon-based aliphatic group comprising, unless otherwise mentioned, from 1 to 9 carbon atoms (noted “(C 1 -C 9 ) alkyl”).
  • alkene group a linear or branched unsatured or partially unsaturated aliphatic group containing conjugated or non-conjugated double bond(s), comprising, unless otherwise mentioned, from 2 to 6 carbon atoms
  • a cycloalkyl group a monocyclic alkyl group comprising, unless otherwise mentioned, from 3 to 9 carbon atoms, saturated or partially unsaturated and unsubstituted or substituted
  • - a heterocycle group a 3, 4, 5, 6, 7, 8 or 9 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S where the ring is saturated
  • a 3 or 4 membered ring may contain 1 heteroatom selected from the group consisting of O, N and S.
  • a 5 membered ring may contain zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S.
  • a 6, 7, 8 or 9 membered ring may contain zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S;
  • - a heterocycloalkyl group a 3 to 7-membered cycloalkyl group, saturated or partially unsaturated, comprising 1 to 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, in particular being oxygen or nitrogen;
  • - a fluoroalkyl group an alkyl group as previously defined where the alkyl group is substituted with at least one fluorine atom.
  • At least one hydrogen atom of the alkyl group is replaced by a fluorine atom.
  • a fluorine atom By way of example, mention may be made of -CH 2 F, -CHF 2 , -CH 2 CHF 2 , -CH 2 CH 2 F and the like.
  • the fluoroalkyl group can be named perfluoroalkyl group.
  • a fluoroalkoxy group an -O-alkyl group where the alkyl group is as previously defined and where the alkyl group is substituted with at least one fluorine atom.
  • at least one hydrogen atom of the alkyl group is replaced by a fluorine atom.
  • the fluoroalkoxy group can be named perfluoroalkoxy group.
  • perfluoroalkoxy group By way of example, mention may be made of trifluoromethoxy group and the like; - an aryl group : a monocyclic or bicyclic aromatic group containing 6 or 9 carbon atoms. - a heteroaryl group: a cyclic 5 to 10-membered aromatic group containing between 2 and 9 carbon atoms and containing between 1 and 3 heteroatoms, such as nitrogen, oxygen or sulfur. Such nitrogen atom may be substituted with an oxygen atom in order to form a -N-O bond.
  • Such -N-O bond can be in a form of a N-oxide (-N + -O-); - a zwitterion means: a globally neutral molecule with a positive and a negative electrical charge and having an acidic group and a basic group.
  • R3 represents a -COOH group.
  • R3’ represents a -COOH group.
  • R1, R2, R3, R3’, R3”, R4, R5, R5’, R6, R7, R8, , Y, n and p are as defined in formula (I) hereabove.
  • the compounds of formula (I) as defined above are of formula (II).
  • R3’ and R3” both represent a hydrogen atom.
  • R3 represents a -COOH group and R3’ and R3” both represent a hydrogen atom.
  • R3’ represents a -COOH group and R’ and R3” both represent a hydrogen atom.
  • R1 and R2 are a hydrogen atom.
  • R4 represents a hydrogen atom.
  • R5 and R5’ represent a hydrogen atom.
  • p is 0.
  • p is 1.
  • R6 represents a (C 1 -C 6 )alkyl group, said (C 1 -C 6 )alkyl group being optionally substituted with 1 to 3 substituents independently selected from a fluorine atom, a methyl group and a -OH group.
  • R6 represents a -CH 2 -CF 3 group, a -CH 2 -CF 2 -CH 2 -OH group or a -CH 2 -CF 2 -CH 3 group.
  • R7 is a halogen atom, and preferably a fluorine atom.
  • n is 0.
  • n is 1.
  • n is 2.
  • R7 represents a fluorine atom and n is 1 or 2.
  • R8 represents a (C 1 -C 6 )alkyl group, and preferably represents a methyl group.
  • Y represents -CH 2 .
  • Y represents -O-. In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, Y represents -NH-. In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, represents a single bond. In another embodiment, represents a double bond. In another embodiment, in the compounds of formula (I), (II) or (III) as defined above, p is equal to 1.
  • Another embodiment is a compound selected from the above list, or a pharmaceutically acceptable salt thereof, for use in therapy, especially as an inhibitor and degrader of estrogen receptors.
  • Another embodiment is a compound selected from the above list, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, especially breast cancer.
  • Another embodiment is a method of inhibiting and degrading estrogen receptors, comprising administering to a subject in need thereof, in particular a human, a therapeutically effective amount of a compound selected from the above list, or a pharmaceutically acceptable salt thereof.
  • Another embodiment is a method of treating ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation, comprising administering to a subject in need thereof, in particular a human, a therapeutically effective amount of a compound selected from the above list, or a pharmaceutically acceptable salt thereof.
  • Another embodiment is a method of treating cancer, comprising administering to a subject in need thereof, in particular a human, a therapeutically effective amount of a compound selected from the above list, or a pharmaceutically acceptable salt thereof.
  • Another embodiment is a pharmaceutical composition comprising as active principle an effective dose of a compound selected from the above list, or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.
  • the compounds of the formula (I), (II) or (III) can be prepared by the following processes.
  • the compounds of the formula (I), (II) or (III) and other related compounds having different substituents are synthesized using techniques and materials described below or otherwise known by the skilled person in the art.
  • solvents, temperatures and other reaction conditions presented below may vary as deemed appropriate to the skilled person in the art.
  • General below methods for the preparation of compounds of formula (I), (II) or (III) optionally modified by the use of appropriate reagents and conditions for the introduction of the various moieties found in the formula (I), (II) or (III) are described below.
  • compound 1A can be converted in STEP 1 to compound 1C by treatment with compound 1B in the presence of methylmagnesium chloride (MeMgCl) and copper chloride (CuCl).
  • MeMgCl methylmagnesium chloride
  • CuCl copper chloride
  • Compound 1C can be converted in STEP 2 to compound 1D by carbonylation with carbon monoxide (CO), in solution in MeOH or EtOH, in the presence of a palladium catalyst, for example palladium acetate or [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (Pd(dppf)Cl 2 ), complex with DCM.
  • a palladium catalyst for example palladium acetate or [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (Pd(dppf)Cl 2 ), complex with DCM.
  • Compound 1D can be converted in STEP 3 to compound 1E by treatment with TFA or HCl or chlorotrimethylsilane.
  • Compound 1E can be converted in STEP 4 to compound 1G by treatment with compound 1F (R6-LG), wherein LG is a suitable leaving group, for example a halogen atom, such as iodo, bromo or chloro or trifluoromethanesulfonate, in the presence of a suitable base, such as diisopropylethylamine (DIPEA) in a suitable solvent, such as DMF.
  • Compound 1G can be converted in STEP 5 to compound 1J by treatment with compound 1H in a Pictet-Spengler cyclization reaction in the presence of an acid, such as TFA or acetic acid, in a suitable solvent, for example toluene by heating up to reflux of solvent.
  • an acid such as TFA or acetic acid
  • compound 1J can be obtained by treatment of compound 1G with compound 1K in STEP 6 in a Pictet-Spengler cyclization reaction in the presence of an acid, such as TFA or acetic acid, in a suitable solvent, for example toluene, by heating up to reflux of solvent, followed by a coupling reaction in STEP 7 between obtained compound 1L and one of compounds 1M under coupling reaction conditions.
  • Compound 1J can be converted in STEP 8 to compound II by treatment with an aqueous solution of sodium hydroxide (NaOH) or lithium hydroxide (LiOH) in MeOH or THF. Extraction of the product could give the sodium or lithium salt of compound II.
  • compound II’ could be prepared in STEP 10 by hydrogenation of compound 1J with a catalyst, such as Pd/C or platinum oxide (PtO 2 ) under hydrogen (H 2 ) pressure followed by the treatment with an aqueous solution of NaOH or LiOH in MeOH or THF. Extraction of the product could give the sodium or lithium salt of compound II’.
  • a catalyst such as Pd/C or platinum oxide (PtO 2 ) under hydrogen (H 2 ) pressure
  • H 2 hydrogen
  • Extraction of the product could give the sodium or lithium salt of compound II’.
  • the acidification with an aqueous solution of HCl to pH 6-7 could give the neutral form of compound II’.
  • the acidification with an aqueous solution of HCl to pH 1-2 could give the hydrochloride salt of compound II’.
  • compound 1N can be obtained, in STEP 2, in a coupling reaction, by treatment of compound 1L with one of compounds 1M’ under coupling reaction conditions.
  • Compound 1N can be converted in STEP 3 to compound 1O by treatment with TFA or HCl.
  • a base such as potassium carbonate (K 2 CO 3 ) in DMF as a solvent.
  • SCHEME 1c Alternative process to prepare Intermediate 1E
  • R3a is a carboxylic ester such as -COOMe or -COOEt
  • R8 is a methyl group
  • R3’ and R3’’ are defined as described above
  • compound 1Q can be converted in STEP 1 to compound 1R in Vilsmeier-Haack reaction conditions in the presence of POCl 3 and DMF.
  • Compound 1R can be converted in STEP 2 to compound 1S by treatment with nitroethane in the presence of ammonium acetate.
  • Compound 1S can be converted in STEP 3 to compound 1T by treatment with iron in the presence of an acid such as HCl.
  • Compound 1T can be converted in STEP 4 to compound 1V in reductive amination reaction by treatment with compound 1U in the presence of NaBH3CN and acetic acid.
  • Compound 1E can be obtained in STEP 5 by hydrogenation of compound 1V in the presence of a catalyst such as Pd/C or Pd(OH)2.
  • SCHEME 1d Parts 1 and 2 General process to prepare compounds of the formula (III) SCHEME 1d – Part - 1: SCHEME 1d – Part - 2: According to SCHEME 1d – Part 1 and Part 2, in which R3a’ is a carboxylic ester such as -COOMe or -COOEt, R8 is a methyl group and R1, R2, R3, R3’, R3’’, R4, R5, R5’, R6, R7, n, p, X, Y and are defined as above, compound 1W can be converted in STEP 1 to compound 1X in Vilsmeier-Haack reaction conditions in the presence of POCl 3 and DMF.
  • R3a’ is a carboxylic ester such as -COOMe or -COOEt
  • R8 is a methyl group
  • Compound 1X can be converted in STEP 2 to compound 1Y by treatment with nitroethane in the presence of ammonium acetate (NH4OAc).
  • Compound 1Y can be converted in STEP 3 to compound 1Z by treatment with iron (Fe) in the presence of an acid such as HCl.
  • Compound 1Z can be converted in STEP 4 to compound 1Aa in reductive amination reaction by treatment with compound 1U in the presence of NaBH3CN and acetic acid.
  • Compound 1Ab can be obtained in STEP 5 by hydrogenation of compound 1Aa in the presence of a catalyst such as Pd/C or Pd(OH) 2 .
  • Compound 1Ab can be converted in STEP 6 to compound 1Ac by treatment with compound 1F (R6-LG), wherein LG is a suitable leaving group, for example a halogen atom, such as iodo, bromo or chloro or trifluoromethanesulfonate, in the presence of a suitable base, such as diisopropylethylamine (DIPEA) in a suitable solvent, such as DMF.
  • a suitable leaving group for example a halogen atom, such as iodo, bromo or chloro or trifluoromethanesulfonate
  • DIPEA diisopropylethylamine
  • compound 1Ac can be converted in STEP 7 to compound 1Ae by treatment with compound 1H in a Pictet-Spengler cyclization reaction in the presence of an acid, such as TFA or acetic acid, in a suitable solvent, for example toluene by heating up to reflux of solvent.
  • an acid such as TFA or acetic acid
  • compound 1Ae can be obtained by treatment of compound 1Ac with compound 1K in STEP 8 in a Pictet-Spengler cyclization reaction in the presence of an acid, such as TFA or acetic acid, in a suitable solvent, for example toluene, by heating up to reflux of solvent, followed by a coupling reaction in STEP 9 between obtained compound 1Ad and one of compounds 1M under coupling reaction conditions.
  • Compound 1Ae can be converted in STEP 10 to compound III by treatment with an aqueous solution of sodium hydroxide (NaOH) or lithium hydroxide (LiOH) in MeOH or THF. Extraction of the product could give the sodium or lithium salt of compound III.
  • compound III’ could be prepared in STEP 12 by hydrogenation of compound 1Ae with a catalyst, such as Pd/C or platinum oxide (PtO 2 ) under hydrogen (H2) pressure followed by the treatment with an aqueous solution of NaOH or LiOH in MeOH or THF. Extraction of the product could give the sodium or lithium salt of compound III’.
  • a catalyst such as Pd/C or platinum oxide (PtO 2 ) under hydrogen (H2) pressure
  • compound 1Ac can be converted in STEP 1 to compound 1Af by treatment with compound 1H’ in a Pictet-Spengler cyclization reaction in the presence of an acid, such as TFA or acetic acid, in a suitable solvent, for example toluene, by heating up to reflux of solvent.
  • an acid such as TFA or acetic acid
  • compound 1Af can be obtained, in STEP 2, in a coupling reaction, by treatment of compound 1Ad with one of compounds 1M’ under coupling reaction conditions.
  • Compound 1Af can be converted in STEP 3 to compound 1Ag by treatment with TFA or HCl.
  • a base such as potassium carbonate (K 2 CO 3 ) in DMF as a solvent.
  • a process for preparing a compound of formula (II) as defined above wherein a compound of formula 1J: wherein R1, R2, R3’, R3’’, R4, R5, R5’, R6, R7, R8, n, p, X and Y are defined as described above and R3a is a carboxylic ester such as -COOMe or -COOEt, is converted to compound of formula (II), in presence of a source of hydroxide ions, such as NaOH or LiOH in solution in methanol or THF, said step being optionally preceded by a step of obtaining compound 1J, wherein a compound of formula 1L:
  • R3’, R3’’, R6, R7, R8, n and X are defined as described above and R3a is a carboxylic ester such as -COOMe or -COOEt, is subjected to a coupling step with one of compounds 1M under coupling reaction conditions: wherein R1, R2, R4, R5, R5’ and p are as defined above.
  • a process for preparing a compound of formula (II) as defined above wherein a compound of formula 1J: wherein R1, R2, R3’, R3’’, R4, R5, R5’, R6, R7, R8, , n, p, X and Y are defined as described above and R3a is a carboxylic ester such as -COOMe or -COOEt, is converted to compound of formula (II), in presence of a source of hydroxide ions, such as NaOH or LiOH in solution in methanol or THF, said step being optionally preceded by a step of obtaining compound 1J, wherein a compound of formula 1G: wherein R3’, R3’’, R6 and R8 are defined as described above and R3a is a carboxylic ester such as -COOMe or -COOEt, is subjected to a Pictet-Spengler cyclization reaction in the presence of an acid, such as TFA or
  • a process for preparing a compound of formula (II) as defined above wherein a compound of formula 1J: wherein R1, R2, R3’, R3’’, R4, R5, R5’, R6, R7, R8, , n, p, X and Y are defined as described above and R3a is carboxylic ester such as -COOMe or -COOEt is converted to compound of formula (II), in presence of a source of hydroxide ions, such as NaOH or LiOH in solution in methanol or THF, said step being optionally preceded by a step of obtaining compound 1J, wherein a compound of formula 1O: wherein R3’, R3’’, R6, R7, R8, , n, p, X and Y are defined as described above and R3a is a carboxylic ester such as -COOMe or -COOEt, is converted to compound 1J, in presence of a base, such as potassium carbonate (
  • R1, R2, R3, R3’, R3’’, R4, R5, R5’, R6, R7, R8, n, p, , X and Y are defined above and R3a is a hydrogen atom or carboxylic ester such as -COOMe or -COOEt.
  • a process for preparing a compound of formula (III) as defined above wherein a compound of formula 1Ae: e wherein R1, R2, R3, R3’’, R4, R5, R5’, R6, R7, R8, n, p, X and Y are defined as described above and R3a’ is carboxylic ester such as -COOMe or -COOEt is converted to compound of formula (III), in presence of a source of hydroxide ions, such as NaOH or LiOH in solution in methanol or THF, said step being optionally preceded by a step of obtaining compound 1Ae, wherein a compound of formula 1Ad:
  • R3, R3’’, R6, R7, R8, n and X are defined as described above and R3a’ is as a carboxylic ester such as -COOMe or -COOEt, is subjected to a coupling step with one of compounds 1M under coupling reaction conditions: wherein R1, R2, R4, R5, R5’ and p are as defined above.
  • a process for preparing a compound of formula (III) as defined above wherein a compound of formula 1Ae: wherein R1, R2, R3, R3’’, R4, R5, R5’, R6, R7, R8, , n, p, X and Y are defined as described above and R3a’ is a carboxylic ester such as -COOMe or -COOEt is converted to compound of formula (III), in presence of a source of hydroxide ions, such as NaOH or LiOH in solution in methanol or THF, said step being optionally preceded by a step of obtaining compound 1Ae, wherein a compound of formula 1Ac: wherein R3, R3’’, R6 and R8 are defined as described above and R3a’ is a carboxylic ester such as -COOMe or -COOEt, is subjected to a Pictet-Spengler cyclization reaction in the presence of an acid, such as TFA or acetic
  • R3a’ is a carboxylic ester such as -COOMe or -COOEt
  • R1, R2, R3, R3’’, R4, R5, R5’, R6, R7, R8, n, p, , X and Y are defined above.
  • a process for the preparation of a compound of formula (I) comprising a deprotection step of a compound of formula 1J as defined above, optionally followed by a purification step.
  • a process for the preparation of a compound of formula (III), comprising a deprotection step of a compound of formula 1Ae as defined above, optionally followed by a purification step.
  • Said purification steps may for example consist, as illustrated in step 2 of example 1 herein after, in an acidification step, for example with an aqueous solution of hydrochloric acid.
  • the 1 H NMR Spectra at 400 and 500 MHz were performed on a Bruker Avance DRX-400 and Bruker Avance DPX-500 spectrometer, respectively, with the chemical shifts ( ⁇ in ppm) in the solvent dimethyl sulfoxide-d6 (d6-DMSO) referenced at 2.5 ppm at a temperature of 303 K. Coupling constants (J) are given in Hertz.
  • Table 1b The examples which follow describe the preparation of some compounds of formula (I), (II) and (III) described herein.
  • the numbers of the compounds exemplified below match those given in the Tables 1a and 1b above. All reactions are performed under inert atmosphere, unless otherwise stated. In the following examples, when the source of the starting products is not specified, it should be understood that said products are known compounds.
  • Step 2 Methyl (E)-3-(2-nitroprop-1-en-1-yl)-1H-indole-5-carboxylate
  • Step 2 of Intermediate 1c was prepared following a similar procedure to that of step 2 of Intermediate 1b from methyl 3-formyl-1H-indole-5-carboxylate to give 18 g (crude) of methyl (E)-3-(2-nitroprop-1-en-1-yl)-1H-indole-5-carboxylate as a yellow solid.
  • Step 3 of Intermediate 1c was prepared following a similar procedure to that of step 3 of Intermediate 1b from methyl (E)-3-(2-nitroprop-1-en-1-yl)-1H-indole-5-carboxylate to give 881 mg (50%) of methyl 3-(2-oxopropyl)-1H-indole-5-carboxylate used as such in the next step.
  • Step 4 Methyl 3-(2-((1-phenylethyl)amino)propyl)-1H-indole-5-carboxylate
  • Step 4 of Intermediate 1c was prepared following a similar procedure to that of step 4 of Intermediate 1b from methyl 3-(2-oxopropyl)-1H-indole-5-carboxylate and 1- phenylethanamine to give 1.04 g (62%) of methyl 3-(2-((1-phenylethyl)amino)propyl)-1H- indole-5-carboxylate as yellow oil.
  • Step 5 Methyl 3-(2-aminopropyl)-1H-indole-5-carboxylate, racemic mixture
  • Step 5 of Intermediate 1c was prepared following a similar procedure to that of step 5 of Intermediate 1b from methyl 3-(2-((1-phenylethyl)amino)propyl)-1H-indole-5-carboxylate to give 660 mg (crude) of methyl 3-(2-aminopropyl)-1H-indole-5-carboxylate, racemic mixture used as such in the next step.
  • Intermediate 3c Methyl 3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-5- carboxylate, racemic mixture
  • Intermediate 3c was prepared following a similar procedure to that of Intermediate 2 from methyl 3-(2-aminopropyl)-1H-indole-5-carboxylate (Intermediate 1c) and 2,2- difluoropropyl trifluoromethanesulfonate to give 400 mg (40%) of methyl 3-(2-((2,2- difluoropropyl)amino)propyl)-1H-indole-5-carboxylate, racemic mixture as yellow oil.
  • Step 2 Tert-butyl (1-(3-fluoropropyl)azetidin-3-yl)carbamate
  • Step 2 of Intermediate 7 was prepared following a similar procedure to that of Step 2 of Intermediate 6 from tert-butyl (1-(3-fluoropropyl)azetidin-3-yl)carbamate and 4-bromo-2,6- difluorobenzaldehyde to give 2.95 g (92%) of tert-butyl (3,5-difluoro-4-formylphenyl)(1-(3- fluoropropyl)azetidin-3-yl)carbamate as an orange oil.
  • Step 2 3-(4-Bromo-3,5-difluoro-phenoxy)azetidine, 2,2,2-trifluoroacetic acid
  • Step 2 of Intermediate 8 was was prepared following a similar procedure to that of Step 3 of Intermediate 7 starting from tert-butyl 3-(3,5-difluoro-4-bromophenoxy)azetidine-1- carboxylate to give 2 g (crude) of 3-(4-bromo-3,5-difluoro-phenoxy)azetidine, 2,2,2- trifluoroacetic acid used as such in the next step.
  • Step 2 Tert-butyl (Z)-3-(3,5-difluoro-4-formylbenzylidene)pyrrolidine-1-carboxylate
  • the reaction was stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25°C for 14 hrs.
  • the reaction mixture was filtered, and the filtrate was washed with brine (40 ml), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • the residue was purified by flash chromatography eluting with a gradient of petroleum ether/EtOAc from 100/00 to 75/25 to give 1.6 g (57%) of tert-butyl 3-(3,5-difluoro-4-formylbenzyl)azetidine- 1-carboxylate.
  • Step 2 1-(3-Fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)methylene)azetidine
  • Step 2 of Intermediate 11 was prepared following a similar procedure to that of step 3 of Intermediate 8 from 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine, 2,2,2-trifluoroacetic acid and 1-fluoro-3-iodopropane to give 1.05 g (60%) of 1-(3- fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine.
  • Example 2 (1S,3R)-1-(2,6-Difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3- yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-7-carboxylic acid
  • Example 2 was prepared following a similar procedure to that of Step 2 of Example 1 from methyl (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2- (2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate (Step 1 of Example 1) to give 5 mg (43%) of (1S,3R)-1
  • Example 3 (1R,3R)-1-(2,6-Difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3- yl)oxy)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-7-carboxylic acid
  • Step 1 Methyl (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3- yl)oxy)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-7-carboxylate
  • Step 1 of Example 3 was prepared following a similar procedure to that of Intermediate 14 from methyl (R)-3-(2-((2,2-di
  • Step 2 (1R,3R)-1-(2,6-Difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-2- (2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid
  • Step 2 of Example 3 was prepared following a similar procedure to that of Step 2 of Example 1 from methyl (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3- yl)oxy)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-7-carboxylate to give 52 mg (27
  • Example 4 (1R,3R)-2-(2,2-Difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-(((S)-1-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-7-carboxylic acid
  • Step 1 Methyl (1R,3R)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-1-(2,6- difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate
  • Step 1 of Example 4 was prepared following a similar procedure to that of Intermediate 14 from methyl (R)-3-(2-((3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)amino)propyl)- 1H-indole-6-carboxylate (Intermediate 4) and (S)-2,6-difluoro-4-((1-(3- fluoropropyl)pyrrolidin-3-yl)amino)benzaldehyde (Intermediate 5) to give 680 mg (crude) of methyl (1R,3R)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-1-(2,6-difluoro- 4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydr
  • Step 3 (1R,3R)-2-(2,2-Difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-(((S)-1-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-7-carboxylic acid
  • Step 3 of Example 4 was prepared following a similar procedure to that of Step 2 of Example 1 from methyl (1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-(((S)-1-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-7-carboxylate
  • Example 5 1R,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3- methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid
  • Step 1 Methyl (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3- yl)amino)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-7-carboxylate
  • Step 1 of Example 5 was prepared following a similar procedure to that of Intermediate 14 from methyl (R)-3-(2-((2,2,2-trifluoroethyl)amino)propyl)-1H-indole-6-carboxylate (Intermediate 2) and 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)benzaldehyde (Intermediate 7) to give 71 mg (44%) of methyl (1R,3R)-1-(2,6-
  • Step 2 of Example 5 was prepared following a similar procedure to that of Step 2 of Example 1 from methyl (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)- 3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate to give 5 mg (7%) of 1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3- yl)amino)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-7-carboxylic acid.
  • Example 6 (1R,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3- methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid
  • Step 1 Methyl (1R,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)- 3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate
  • Step 1 of Example 6 was prepared following a similar procedure to that of Intermediate 14 from methyl (R)-3-(2-((2,2,2-trifluoroeth
  • Step 2 (1R,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3- methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid
  • Step 2 of Example 6 was prepared following a similar procedure to that of Step 2 of Example 1 from methyl (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3- methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate to give 12 mg (6%) of (1
  • Step 1 Methyl (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-2- (2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate
  • Step 1 of Example 7 was prepared following a similar procedure to that of Intermediate 13 from methyl (R)-3-(2-((2,2-difluoropropyl)amino)propyl)-1H-indole-6-carboxylate (Intermediate 3a) and 2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzaldehyde (Intermediate 8) to give 50 mg (27%) of methyl (1R,3R)-1-(2,6-difluoro-4-
  • Step 2 (1R,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-2-(2,2- difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid
  • Step 2 of Example 7 was prepared following a similar procedure to that of Step 2 of Example 1 from methyl (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-2- (2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate to give 8 mg (17%) of (1R,3R)
  • Example 8 (1R,3R)-2-(2,2-Difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-7-carboxylic acid
  • Step 1 Methyl (1R,3R)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-1-(2,6- difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indole-7-carboxylate
  • Step 1 of Example 8 was prepared following a similar procedure to that of Intermediate
  • Step 2 Methyl (1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-7-carboxylate
  • Step 2 of Example 8 was prepared following a similar procedure to that of Step 2 of Example 4 from methyl (1R,3R)-2-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-1-(2,6- difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H- pyrido
  • Step 3 (1R,3R)-2-(2,2-Difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-7-carboxylic acid
  • Step 3 of Example 8 was prepared following a similar procedure to that of Step 2 of Example 1 from methyl (1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-1-(2,6-difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-7-carboxylate to give 23 mg
  • Example 9 (1R,3R)-1-(2,6-Difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3- yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-7-carboxylic acid
  • Step 1 Methyl (1R,3R)-1-(4-((tert-butoxycarbonyl)((S)-1-(3-fluoropropyl)pyrrolidin-3- yl)amino)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indole-7-carboxylate
  • Step 1 of Example 9 was prepared following a similar procedure to that of Intermediate 14 from
  • Step 2 Methyl (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3- yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-7-carboxylate
  • Step 2 of Example 9 was prepared following a similar procedure to that of Step 3 of Intermediate 7 from methyl (1R,3R)-1-(4-((tert-butoxycarbonyl)((S)-1-(3- fluoropropyl)pyrrolidin-3-yl)amino)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl- 2,3,4,9-tetrahydro-1H-pyrido[3,4-
  • Step 3 (1R,3R)-1-(2,6-Difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)amino)phenyl)- 2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid
  • Step 3 of Example 9 was prepared following a similar procedure to that of Step 2 of Example 1 from methyl (1R,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3- yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-7-carboxylate to give
  • Example 10 (1R,3R)-1-(2,6-Difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3- ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-7-carboxylic acid
  • Step 1 Methyl (1R,3R)-1-(4-((Z)-(1-(tert-butoxycarbonyl)pyrrolidin-3-ylidene)methyl)- 2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-7-carboxylate
  • Step 1 of Example 10 was prepared following a similar procedure to that of Intermediate 13 from methyl (R)-3-(2-
  • Step 2 Methyl (1R,3R)-1-(2,6-difluoro-4-((Z)-pyrrolidin-3-ylidenemethyl)phenyl)-2-(2,2- difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate, 2,2,2- trifluoroacetic acid
  • Step 2 of Example 10 was prepared following a similar procedure to that of Step 3 of Intermediate 7 from methyl (1R,3R)-1-(4-((Z)-(1-(tert-butoxycarbonyl)pyrrolidin-3- ylidene)methyl)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole-7-carboxylate
  • Step 3 Methyl (1R,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3- ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-7-carboxylate
  • Step 3 of Example 10 was prepared following a similar procedure to that of Step 1 of Intermediate 6 from methyl (1R,3R)-1-(2,6-difluoro-4-((Z)-pyrrolidin-3- ylidenemethyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-7-carboxylate, 2,2,2-trifluoroace
  • Step 4 (1R,3R)-1-(2,6-Difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3- ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-7-carboxylic acid
  • Step 4 of Example 10 was prepared following a similar procedure to that of Step 2 of Example 1 from methyl (1R,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3- ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-7-carboxylic acid
  • Example 11 (1R,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)- 2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid
  • Example 12 (1S,3S)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)- 2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid
  • Step 1 Methyl 1-(4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-2,6-difluor
  • Step 2 Methyl 1-(4-(azetidin-3-ylmethyl)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3- methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate, 2,2,2-trifluoroacetic acid, mixture of trans isomers
  • Step 2 of Examples 11 and 12 was prepared following a similar procedure to that of Step 3 of Intermediate 7 from methyl 1-(4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-2,6- difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-7-carboxylate, mixture of trans isomers to give 214 mg (cruididin-3-ylmethyl)-2,6-
  • Step 3 Methyl 1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2- difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate, mixture of trans isomers
  • Step 3 of Examples 11 and 12 was prepared following a similar procedure to that of Step 1 of Intermediate 6 from methyl 1-(4-(azetidin-3-ylmethyl)-2,6-difluorophenyl)-2-(2,2- difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylate, 2,2,2- trifluoroacetic acid, mixture of trans isomers and 1-fluoro-3-iodo
  • Step 4 1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2- difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid, mixture of trans isomers
  • Step 4 of Examples 11 and 12 was prepared following a similar procedure to that of Step 2 of Example 1 from methyl 1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3- yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-7-carboxylate, mixture of trans isomers to give 150 mg (41%) of 1-
  • Example 13 (1R,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)- 2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylic acid
  • Step 1 Methyl 1-(4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-2,6-difluorophenyl)-2- (2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylate, mixture of trans isomers
  • Step 1 of Example 13 was prepared following a similar procedure to that of Intermediate 14 from methyl 3-(2-((2,2-difluoropropyl)amino)
  • Step 2 Methyl 1-(4-(azetidin-3-ylmethyl)-2,6-difluorophenyl)-2-(2,2-difluoropropyl)-3- methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylate, 2,2,2-trifluoroacetate, mixture of trans isomers
  • Step 2 of Example 13 was prepared following a similar procedure to that of Step 3 of Intermediate 7 from methyl 1-(4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-2,6- difluorophenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-6-carboxylate, mixture of trans isomers to give 490 mg (crude) of
  • Step 3 Methyl 1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-(2,2- difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylate, mixture of trans isomers
  • Step 3 of Example 13 was prepared following a similar procedure to that of Step 1 of Intermediate 6 from methyl 1-(4-(azetidin-3-ylmethyl)-2,6-difluorophenyl)-2-(2,2- difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylate, 2,2,2- trifluoroacetate, mixture of trans isomers and 1-fluoro-3-iodopropane
  • Step 4 (1R,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2- (2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid
  • Step 4 of Examples 13 was prepared following a similar procedure to that of Step 2 of Example 1 from methyl 1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3- yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-6-carboxylate, mixture of trans isomers to give 70 mg (87%) of 1-(
  • Step 5 (1R,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2- (2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylic acid
  • Example 14 (1R,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)- 2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid
  • Step 1 Methyl (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3- yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-7-carboxylate
  • Step 2 (1R,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-2- (2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid
  • Step 2 of Example 14 was prepared following a similar procedure to that of Step 2 of Example 1 from methyl (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3- yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-7-carboxylate to give 13 mg (17%)
  • reaction mixture was diluted with EtOAc (10 ml) and water (5 ml). The aqueous layer was separated and extracted again with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure.
  • Step 2 (1R,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)- 2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carboxylic acid
  • Step 2 of Example 15 was prepared following a similar procedure to that of Step 2 of Example 1 from methyl (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3- yl)amino)phenyl)-2-(2,2-difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole-7-carboxylate to give 28 mg (38
  • Estrogen receptor degradation activity Said test involves measuring the in vitro degradation activity of the compounds of the table 1. The measurements of the degradation activities were made using a breast cancer cell ER ⁇ in cell western assay as described hereunder. MCF7 cells (ATCC) were seeded in 384 wells microplate (collagen coated) at a concentration of 10000 cells/ 30 ⁇ L per well in red phenol free MEM alpha medium (invitrogen) containing 5% charcoal dextran striped FBS.
  • LI-COR blocking buffer was removed and cells were incubated overnight at cold room with 50 ⁇ L anti-ER rabbit monoclonal antibody (Thermo scientific MA1-39540) diluted at 1:1000 in LI-COR blocking buffer containing 0.1% tween-20. Wells which were treated with blocking buffer but no antibody were used as background control. Wells were washed twice with PBS (0.1% tween-20) and incubated at 37 °C for 60 minutes in LI-COR (0.1% tween-20) containing goat anti-rabbit antibody Alexa 488 (1:1000) and Syto-64 a DNA dye (2 ⁇ M final concentration). Cells were then washed 3 times in PBS and scanned in ACUMEN explorer (TTP-Labtech).
  • Integrated intensities in the green fluorescence and red fluorescence were measured to determine the levels of ER ⁇ and DNA respectively.
  • the degradation activity with respect to estrogen receptors in this test is given by the concentration which degrades 50% of the estrogen receptor (or IC 50 ) in nM.
  • the Table 2 below indicates the estrogen receptor degradation activity results for the compounds of table 1 tested at 0.3 ⁇ M, and demonstrates that said compounds have a significant degradation activity on estrogen receptors. Table 2:
  • the compounds of formula (I), (II) and (III) can therefore be used for preparing medicaments, especially medicaments which are degraders of estrogen receptors. Accordingly, also provided herein are medicaments which comprise a compound of the formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof. Herein are also provided the compounds of formula (I), (II) or (III) defined above, or pharmaceutically acceptable salts thereof, for use as medicines.
  • a particular aspect is a compound of formula (I), (II) or (III) defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.
  • the cancer is a hormone dependent cancer.
  • the cancer is an estrogen receptor dependent cancer, particularly the cancer is an estrogen receptor ⁇ dependent cancer.
  • the cancer is selected from breast, ovarian, endometrial, prostate, uterine, cervical and lung cancer, or a metastasis thereof.
  • the metastasis is a cerebral metastasis.
  • the cancer is breast cancer.
  • the breast cancer is an estrogen receptor positive breast cancer (ER ⁇ positive breast cancer).
  • the cancer is resistant to anti-hormonal treatment.
  • the compound of formula (I), (II) or (III) is as used as single agent or in combination with other agents such as CDK4/6, mTOR or PI3K inhibitors.
  • a method of treating the pathological conditions indicated above comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof.
  • the subject is a human.
  • a compound of the formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament useful in treating any of the pathological conditions indicated above, more particularly useful in treating cancer.
  • pharmaceutical compositions comprising as active principle a compound of formula (I), (II) or (III).
  • compositions comprise an effective dose of at least one compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.
  • excipients are selected, in accordance with the pharmaceutical form and method of administration desired, from the customary excipients, which are known to a person skilled in the art.
  • compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intra-tracheal, intranasal, transdermal or rectal administration the active principle of formula (I), (II) or (III) above, or its base, acid, zwitterion or salt thereof, may be administered in a unit administration form, in a mixture with conventional pharmaceutical excipients, to animals and to human beings for the treatment of the above disorders or diseases.
  • the unit administration forms appropriate include oral forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intra-tracheal, intra-ocular and intra-nasal administration forms, forms for inhalative, topical, transdermal, subcutaneous, intra-muscular or intravenous administration, rectal administration forms and implants.
  • oral forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions
  • sublingual, buccal, intra-tracheal, intra-ocular and intra-nasal administration forms forms for inhalative, topical, transdermal, subcutaneous, intra-muscular or intravenous administration, rectal administration forms and implants.
  • topical application it is possible to use the compounds of formula (I), (II) or (III) in creams, gels, ointments or lotions.
  • a unit administration form of a compound of formula (I), (II) or (III) in tablet form may comprise the following components: Compound of formula (I) 50.0 mg Mannitol 223.75 mg Sodium croscarmellose 6.0 mg Corn starch 15.0 mg Hydroxypropylmethylcellulose 2.25 mg Magnesium stearate 3.0 mg There may be particular cases in which higher or lower dosages are appropriate. According to usual practice, the dosage that is appropriate for each patient is determined by the doctor according to the mode of administration and the weight and response of the said patient.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

Des composés de formule I, ou des sels pharmaceutiquement acceptables correspondants sont divulgués dans la présente invention. (I) dans laquelle R1 et R2 représentent indépendamment un atome d'hydrogène ou un atome de deutérium ; R3 représente un atome d'hydrogène ou un groupe -COOH ; R3' représente un atome d'hydrogène, un groupe méthyle, un groupe méthoxy, un atome de chlore, un atome de fluor, un groupe cyano ou un groupe -COOH ; R3" représente un atome d'hydrogène, un groupe méthyle, un groupe méthoxy, un atome de chlore, un atome de fluor ou un groupe cyano ; à condition que l'un de R3 et R3', mais pas les deux, représente un groupe -COOH et R3 et R3' ne représentent pas simultanément un atome d'hydrogène ; R4 représente un atome d'hydrogène ou un atome de fluor ; R5 et R5' représentent indépendamment un atome d'hydrogène ou un atome de fluor ; Y représente -CH2-, -CH=, -CR9=, -O- ou -NH-, R9 représentant un atome de fluor ou un groupe alkyle en (C1-C3) ; représente une liaison simple ou une double liaison ; p vaut 0 ou 1 ; X représente -CH=, -N= ou -CR"=, R" représentant un groupe alkyle en (C1-C3) ou un atome d'halogène, tel qu'un atome de fluor ou de chlore, un groupe cyano, ou un groupe fluoroalkyle en (C1-C3), tel qu'un trifluorométhyle ; R7 représente indépendamment un groupe alkyle en (C1-C3), tel qu'un groupe méthyle, un atome d'halogène, tel qu'un atome de fluor, un groupe cyano, ou un groupe fluoroalkyle en (C1-C3), tel qu'un groupe trifluorométhyle ; n vaut 0, 1 ou 2 ; et R6 représente un groupe alkyle en (C1-C9) éventuellement substitué, et R8 représente en particulier un groupe alkyle en (C1-C6). Sont divulgués en outre, un procédé de préparation de ceux-ci, des compositions pharmaceutiques les comprenant ainsi que lesdits composés de formule (I) pour une utilisation en tant qu'inhibiteur et agent de dégradation des récepteurs des œstrogènes, en particulier dans le traitement d'un dysfonctionnement ovulatoire, d'un cancer, d'une endométriose, d'une ostéoporose, d'une hypertrophie bénigne de la prostate ou d'une inflammation.
PCT/EP2023/073233 2022-08-25 2023-08-24 Nouveaux dérivés d'acide 2,3,4,9-tétrahydro-1h-pyrido[3,4-b]indole carboxylique substitués, leurs procédés de préparation et leurs utilisations thérapeutiques Ceased WO2024042163A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP23758664.9A EP4577542A1 (fr) 2022-08-25 2023-08-24 Nouveaux dérivés d'acide 2,3,4,9-tétrahydro-1h-pyrido[3,4-b]indole carboxylique substitués, leurs procédés de préparation et leurs utilisations thérapeutiques
JP2025511528A JP2025528250A (ja) 2022-08-25 2023-08-24 新規な置換２，３，４，９－テトラヒドロ－１ｈ－ピリド［３，４－ｂ］インドールカルボン酸誘導体、その調製方法及びその治療用途
CN202380061199.6A CN119907798A (zh) 2022-08-25 2023-08-24 新颖的取代的2,3,4,9-四氢-1h-吡啶并[3,4-b]吲哚甲酸衍生物、其制备方法及其治疗用途

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP22306262 2022-08-25
EP22306262.1 2022-08-25

Publications (2)

Publication Number Publication Date
WO2024042163A1 true WO2024042163A1 (fr) 2024-02-29
WO2024042163A9 WO2024042163A9 (fr) 2025-04-24

Family

ID=83271271

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2023/073233 Ceased WO2024042163A1 (fr) 2022-08-25 2023-08-24 Nouveaux dérivés d'acide 2,3,4,9-tétrahydro-1h-pyrido[3,4-b]indole carboxylique substitués, leurs procédés de préparation et leurs utilisations thérapeutiques

Country Status (4)

Country Link
EP (1) EP4577542A1 (fr)
JP (1) JP2025528250A (fr)
CN (1) CN119907798A (fr)
WO (1) WO2024042163A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016097072A1 (fr) * 2014-12-18 2016-06-23 F. Hoffmann-La Roche Ag Modulateurs des récepteurs des oestrogènes tétrahydro-pyrido[3,4-b]indole et utilisations associées
WO2017136688A1 (fr) * 2016-02-05 2017-08-10 Inventisbio Inc. Agents de dégradation sélectifs des récepteurs des œstrogènes et leurs utilisations
WO2017140669A1 (fr) 2016-02-15 2017-08-24 Sanofi Dérivés de 6,7-dihydro-5h-benzo[7]annulène utilisés en tant que modulateurs de récepteurs des oestrogènes
WO2017216280A1 (fr) * 2016-06-16 2017-12-21 F. Hoffmann-La Roche Ag Modulateurs des récepteurs des oestrogènes tétrahydro-pyrido[3,4-b]indoles et utilisations associées
WO2017216279A1 (fr) * 2016-06-16 2017-12-21 F. Hoffmann-La Roche Ag Modulateurs des récepteurs des œstrogènes hétéroaryles et leurs utilisations
WO2018091153A1 (fr) 2016-11-17 2018-05-24 Sanofi Nouveaux composés n-(3-fluoropropyl)-pyrrolidine substitués, leurs procédés de préparation et leurs utilisations thérapeutiques

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016097072A1 (fr) * 2014-12-18 2016-06-23 F. Hoffmann-La Roche Ag Modulateurs des récepteurs des oestrogènes tétrahydro-pyrido[3,4-b]indole et utilisations associées
WO2017136688A1 (fr) * 2016-02-05 2017-08-10 Inventisbio Inc. Agents de dégradation sélectifs des récepteurs des œstrogènes et leurs utilisations
WO2017140669A1 (fr) 2016-02-15 2017-08-24 Sanofi Dérivés de 6,7-dihydro-5h-benzo[7]annulène utilisés en tant que modulateurs de récepteurs des oestrogènes
WO2017216280A1 (fr) * 2016-06-16 2017-12-21 F. Hoffmann-La Roche Ag Modulateurs des récepteurs des oestrogènes tétrahydro-pyrido[3,4-b]indoles et utilisations associées
WO2017216279A1 (fr) * 2016-06-16 2017-12-21 F. Hoffmann-La Roche Ag Modulateurs des récepteurs des œstrogènes hétéroaryles et leurs utilisations
WO2018091153A1 (fr) 2016-11-17 2018-05-24 Sanofi Nouveaux composés n-(3-fluoropropyl)-pyrrolidine substitués, leurs procédés de préparation et leurs utilisations thérapeutiques

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
LIANG JUN ET AL: "Discovery of GNE-149 as a Full Antagonist and Efficient Degrader of Estrogen Receptor alpha for ER+ Breast Cancer", ACS MEDICINAL CHEMISTRY LETTERS, vol. 11, no. 6, 26 May 2020 (2020-05-26), US, pages 1342 - 1347, XP093008663, ISSN: 1948-5875, DOI: 10.1021/acsmedchemlett.0c00224 *
LIANG JUN ET AL: "GDC-9545 (Giredestrant): A Potent and Orally Bioavailable Selective Estrogen Receptor Antagonist and Degrader with an Exceptional Preclinical Profile for ER+ Breast Cancer", JOURNAL OF MEDICINAL CHEMISTRY, vol. 64, no. 16, 12 July 2021 (2021-07-12), US, pages 11841 - 11856, XP093008476, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.1c00847 *
SHAO PENGCHENG: "A New Era in ER+ Breast Cancer: Best-in-Class Oral Selective Estrogen Receptor Degrader (SERD) Designed as an Endocrine Backbone Treatment", JOURNAL OF MEDICINAL CHEMISTRY, vol. 64, no. 16, 2 August 2021 (2021-08-02), US, pages 11837 - 11840, XP093008646, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.1c01268 *
XU JIE ET AL: "First-Generation Asymmetric Synthesis of the Selective Estrogen Receptor Degrader GDC-9545 (Giredestrant) Featuring a Highly Efficient Pictet-Spengler Reaction and a C-N Coupling Reaction", ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 26, no. 3, 5 November 2021 (2021-11-05), US, pages 560 - 567, XP093008474, ISSN: 1083-6160, DOI: 10.1021/acs.oprd.1c00262 *
ZHANG XIAOMENG ET AL: "Dynamics-Based Discovery of Novel, Potent Benzoic Acid Derivatives as Orally Bioavailable Selective Estrogen Receptor Degraders for ER[alpha]+ Breast Cancer", JOURNAL OF MEDICINAL CHEMISTRY, vol. 64, no. 11, 31 May 2021 (2021-05-31), US, pages 7575 - 7595, XP055919028, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.1c00280 *

Also Published As

Publication number Publication date
JP2025528250A (ja) 2025-08-26
EP4577542A1 (fr) 2025-07-02
CN119907798A (zh) 2025-04-29
WO2024042163A9 (fr) 2025-04-24

Similar Documents

Publication Publication Date Title
EP4228757A1 (fr) Composés de 6,7-dihydro-5h-benzo[7]annulène substitués, leurs dérivés, procédés permettant leur préparation et utilisations thérapeutiques associées
KR20230092971A (ko) 신규한 치환 6,7-디히드로-5h-벤조[7]아눌렌 유도체, 이의 제조 방법 및 이의 치료적 용도
WO2024052518A1 (fr) Dérivés de tétrahydrocyclohepta[e]indole substitués, leurs procédés de préparation et leurs utilisations thérapeutiques
JP2025531033A (ja) 新規の置換２－カルボニル－ベンゾチオフェン－６－カルボン酸誘導体、それらの調製のためのプロセス及びその治療的使用
WO2023198907A1 (fr) Dérivés de 6,7-dihydro-5h-benzo[7]annulène substitués, procédés pour leur préparation et utilisations thérapeutiques associées
WO2024042163A1 (fr) Nouveaux dérivés d'acide 2,3,4,9-tétrahydro-1h-pyrido[3,4-b]indole carboxylique substitués, leurs procédés de préparation et leurs utilisations thérapeutiques
CN116438177A (zh) 靶向嵌合化合物、含其的药物组合物及其制备方法和用途
EP4577534A1 (fr) Nouveaux dérivés d'acide tétrahydroisoquinoléine-6-carboxylique substitués, leurs procédés de préparation et leurs utilisations thérapeutiques
WO2023198903A1 (fr) Nouveaux composés de n-propyl-pyrrolidine et de n-propyl-azétidine fluorés substitués, leurs procédés de préparation et leurs utilisations thérapeutiques
EP4508032A1 (fr) Nouveaux composés de de vinyl-n-propyl-pyrrolidine fluorés substitués, leurs procédés de préparation et leurs utilisations thérapeutiques
JP2025512050A (ja) 新規の置換された４－アミノ－４－オキソ－ブト－２－エニル誘導体、それらの調製のためのプロセス及びその治療的使用
WO2023198904A1 (fr) Dérivés de 6,7-dihydro-5h-benzo[7]annulène substitués, leurs procédés de préparation et leurs utilisations thérapeutiques
WO2024042187A1 (fr) Nouveaux dérivés d'acide benzothiophène-6-carboxylique substitués, leurs procédés de préparation et leurs utilisations thérapeutiques
JP2025528249A (ja) 新規な置換キノリン及びテトラヒドロナフタレンカルボン酸誘導体並びにその治療的使用
CN118984820A (zh) 新颖的取代的氟化n-丙基-吡咯烷化合物、用于其制备的方法及其治疗用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23758664

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2025511528

Country of ref document: JP

Ref document number: 202380061199.6

Country of ref document: CN

WWE Wipo information: entry into national phase

Ref document number: 2023758664

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2023758664

Country of ref document: EP

Effective date: 20250325

WWP Wipo information: published in national office

Ref document number: 202380061199.6

Country of ref document: CN

WWP Wipo information: published in national office

Ref document number: 2023758664

Country of ref document: EP