Phosphate Derivatives of RORγ Modulators and Uses Thereof

Abstract

The present invention relates to phosphate derivatives of formula (I) and their therapeutic use, preferably for treating respiratory diseases. The present invention also relates to pharmaceutical compositions and devices containing such compounds.

Description

Technical Field

[0001] The present invention relates to the field of medicaments, in particular to phosphate derivatives of RORγ modulators. The invention also relates to pharmaceutical compositions comprising such derivatives, and to their use for preventing and / or treating respiratory diseases.

Background Art

[0002] Respiratory disorders associated with airway inflammation include several severe lung diseases, including asthma and COPD (chronic obstructive pulmonary disease). In the airways of asthma patients, inflammatory leukocytes are infiltrated, and among them, eosinophils are considered the most prominent component. Inflammatory sensitization of airway neurons is thought to increase nasal mucosal sensitivity, enhance the sensation of irritation, and promote body fluid secretion, airway narrowing, and bronchoconstriction. Oxidative stress is characteristic of most acute and chronic inflammatory airway conditions, including viral infections, asthma, rhinitis, and COPD. Asthma and COPD are the main chronic diseases associated with airway obstruction. The Global Initiative for Chronic Obstructive Lung Disease defines guidelines for the differences between asthma and COPD. Asthma is considered a chronic inflammatory disease in which airway obstruction is mostly reversible, whereas in the case of COPD, airway obstruction is mostly irreversible. Asthma is also thought to be caused by the inhalation of sensitizing substances (such as allergens), as opposed to harmful substances (such as particles and certain gases) in the case of COPD. Both are thought to have an inflammatory component, but the inflammation in asthma is mostly eosinophilic and CD-4-driven inflammation, while in COPD, it is mostly neutrophilic and CD-8-driven inflammation. Emphysema is a type of COPD in which the alveoli, the small air sacs in both lungs, are filled with air. As the air continues to increase in these sacs, these sacs may expand, rupture, or be damaged, and scar tissue may form. Patients gradually become short of breath.

[0003] Retinoic acid-related orphan receptor γ (RORγ) is a member of the ROR subfamily of nuclear receptors, which includes three genes: RORA, RORB, and RORC (also called RORγ). The immune system-specific isoform RORγt is restricted to several different immune cell types. RORγt is a subset of CD4+ helper T cells and is a key lineage-determining transcription factor in the differentiation program of helper T type 17 (Th17) cells, which are the most prominent cells that produce several inflammatory cytokines such as IL-17A, IL-17F, IL-22, and IL-23, and are considered important pathogenic factors for many immune and inflammatory diseases. By modulating RORγt activity, IL-17-dependent immune and inflammatory responses are modulated. Compounds that can modulate RORγt activity are expected to provide therapeutic advantages in the treatment of many medical disorders such as respiratory diseases.

[0004] Therefore, RORγt has been specifically studied as a promising medical target, and new RORγt modulators have been discovered. For example, WO2018 / 138362 discloses novel N-{[2-(piperidin-1-yl)phenyl](phenyl)methyl}-2-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)acetamide derivatives as RORγt modulators and their use in several treatments including immune, inflammatory, metabolic, fibrotic, and cholestatic diseases.

[0005] Controlling the release of active drugs into living organisms is another research approach for new therapies currently used in the pharmaceutical field to increase their bioavailability.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Patent Document 2

Patent Document 3

Non-Patent Literature

[0007]

Non-Patent Literature 1

Non-Patent Literature 2

Summary of the Invention

Problems to be Solved by the Invention

[0008] However, there remains a need to identify novel ROR modulators with improved pharmacokinetic properties to provide more efficient treatment for ROR-related diseases such as respiratory diseases.

Means for Solving the Problems

[0009] In this context, the present inventors have provided novel phosphate derivatives of ROR modulators having improved advantageous pharmacokinetic properties. The present inventors have clarified that such phosphate derivatives exhibit improved solubility and stability in water, as well as improved metabolism in living organisms, thereby promoting the absorption of ROR modulators in living organisms, more specifically in both lungs.

[0010] Accordingly, the present invention provides a compound having the following formula (I), as well as its stereoisomers and pharmaceutically acceptable salts.

[0011]

Chemical formula

[0012] [wherein, ● A is a ring of the following formula (a),

[0013]

Chem.

[0014] · B represents an NH group, an oxygen atom, or an SO 2 group, and · R 7 represents hydrogen, a halogen, or a (C 1 ~C 6 ) alkyloxy group, and · R 8 represents hydrogen or a (C 1 ~C 6 ) alkyl group, and ● R 1a and R 1c each independently represent hydrogen, a (C 1 ~C 6 ) alkyl group, a (C 1 ~C 6 ) alkyloxy group, a halogen, or a heterocycloalkyl optionally substituted by a (C 1 ~C 6 ) alkyl group, and ● R 2 represents a (C 1 ~C 6 ) alkyl group, or a ring selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, said ring optionally substituted by at least one group selected from the group consisting of a (C 1 ~C 6 ) alkyl group and a halogen, and ● R 3 and R 3' each independently represent hydrogen or a (C 1 ~C 6 ) alkyl group, or R 3 and R 3' together with the carbon atom to which they are attached can form cycloalkyl, and ● X represents a (C 1 ~C 6 ) alkyl group, and ● R 5 and R 6 each independently represent hydrogen or a (C1 ~C 6 ) represents an alkyl group.

[0015] In certain embodiments, A has the following formula (a 1 ) or (a 2 ).

[0016]

Chemical formula

[0017] Preferably, B is an NH group.

[0018] In another particular embodiment, the compound of formula (I) ● R 1a is a (C 1 ~C 6 ) alkyl group, preferably methyl, a (C 1 ~C 6 ) alkyloxy group, halogen, or heterocycloalkyl, preferably piperidinyl, ● R 1c is hydrogen, a (C 1 ~C 6 ) alkyl group, preferably methyl, a (C 1 ~C 6 ) alkyloxy group, or halogen is a compound such as.

[0019] In another particular embodiment, R 2 represents heteroaryl, preferably furanyl, and the heteroaryl may be substituted by at least one group selected from the group consisting of a (C 1 ~C 6 ) alkyl group and halogen, preferably methyl and chlorine.

[0020] In another particular embodiment, R 5 and R 6 represent hydrogen.

[0021] In another particular embodiment, X is a linear (C 1~C 6 ) an alkyl group, preferably -CH 2 -CH 2 - group.

[0022] In another specific embodiment, the pharmaceutically acceptable salt of the compound of formula (I) is a sodium salt, a potassium salt, or a calcium salt, preferably a sodium salt.

[0023] In a preferred embodiment of the present invention, the compound of formula (I) according to the present invention is - {2-[5-(1-{[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethoxy}phosphonic acid; - disodium 2-[5-(1-{[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate; - {2-[5-(1-{[(2-methoxy-4-methylphenyl)(phenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethoxy}phosphonic acid; - disodium 2-[5-(1-{[(2-methoxy-4-methylphenyl)(phenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate; - {2-[5-(1-{[(2,4-dimethylphenyl)(6-methylpyridin-2-yl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethoxy}phosphonic acid; - disodium {2-[5-(1-{[(2,4-dimethylphenyl)(6-methylpyridin-2-yl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethoxy}phosphonic acid; - {2-[5-(1-{[(3-chlorophenyl)(2,4-dimethylphenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethoxy}phosphonic acid; - Disodium 2-[5-(1-{[(3-chlorophenyl)(2,4-dimethylphenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate; - {2-[5-(1-{[(4-methoxy-2-methylphenyl)(phenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethoxy}phosphonic acid; - Disodium 2-[5-(1-{[(4-methoxy-2-methylphenyl)(phenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate; - (2-{5-[1-({[4-methoxy-2-(pyrrolidin-1-yl)phenyl](phenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethoxy}phosphonic acid; - Disodium 2-{5-[1-({[4-methoxy-2-(pyrrolidin-1-yl)phenyl](phenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate - {2-[5-(1-{[cyclopropyl(2,4-dimethylphenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethoxy}phosphonic acid; - Disodium 2-[5-(1-{[cyclopropyl(2,4-dimethylphenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate; - (2-{5-[1-({[4-methyl-2-(morpholin-4-yl)phenyl](phenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethoxy}phosphonic acid; - Disodium 2-{5-[1-({[4-methyl-2-(morpholin-4-yl)phenyl](phenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate; - {2-[5-(1-{[(dimethyl-1,2-oxazol-4-yl)(phenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethoxy}phosphonic acid; - Disodium 2-[5-(1-{[(dimethyl-1,2-oxazol-4-yl)(phenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate; - ({5-[({[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}carbamoyl)methyl]-1H-indol-3-yl}methyloxy)phosphonic acid; - Disodium ({5-[({[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}carbamoyl)methyl]-1H-indol-3-yl}methyloxy)phosphonic acid; - {2-[5-(1-{[(2,4-dimethylphenyl)(5-chlorofuran-2-yl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethoxy}phosphonic acid; - Disodium 2-[5-(1-{[(2,4-dimethylphenyl)(5-chlorofuran-2-yl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate; - {2-[5-(1-{[(4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethoxy}phosphonic acid; - Disodium 2-[5-(1-{[(4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphonate; - 2-(5-(1-((((2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl)carbamoyl)cyclopropyl)-1H-indol-3-yl)-2-methylpropyloxy)phosphonic acid; and - Disodium 2-(5-(1-((((2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl)carbamoyl)cyclopropyl)-1H-indol-3-yl)-2-methylpropyl phosphate selected from the group consisting of.

[0024] Another object of the present invention is a compound of formula (I) as defined herein for use as a drug. Another object of the present invention is a pharmaceutical composition comprising a compound of formula (I) as defined herein and a pharmaceutically acceptable additive. In yet another specific embodiment, the present invention relates to a compound of formula (I) or a pharmaceutical composition comprising the same for use in treating respiratory diseases such as neutrophilic asthma, chronic obstructive pulmonary disease (COPD), asthma-COPD overlap syndrome (ACOS), idiopathic pulmonary fibrosis (IPF), and chronic rhinosinusitis with nasal polyps (CRSwNP).

[0025] In certain embodiments, the pharmaceutical composition takes the form of a suspension, gel, oil, powder, aerosol, or spray. In another specific embodiment, the composition is administered by nasal inhalation.

[0026] Another object of the present invention is a device comprising the pharmaceutical composition as defined herein. In a preferred embodiment, the device is a dry powder inhaler (DPI) or a metered dose inhaler (MDI). BRIEF DESCRIPTION OF THE DRAWINGS

[0027]

Figure 1

Figure 2

Figure 3A

Figure 3B

Figure 3C

Figure 3D

Mode for Carrying Out the Invention

[0028] Definition According to the present invention, the following terms have the following meanings.

[0029] For example, C 1 ~C 6 The terms described in this specification with prefixes such as C 1 ~C 2 can also be used for a smaller number of carbon atoms such as C 1 ~C 6 For example, when the term C 1 ~C 3 is used, it means that the corresponding hydrocarbon chain can contain 1 to 6 carbon atoms, particularly 1, 2, 3, 4, 5, or 6 carbon atoms. For example, when the term C

[0030] The term "alkyl" refers to a straight-chain or branched saturated aliphatic group. The term "(C 1 ~C 6 )alkyl" more specifically means methyl, ethyl, propyl, isopropyl, butyl, pentyl, or hexyl. In a preferred embodiment, "alkyl" is methyl.

[0031] The term "alkoxy" or "alkyloxy" corresponds to an alkyl group as defined above, which is bonded to the molecule by an -O- (ether) bond. Examples of (C 1 ~C 6 )alkoxy include methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, pentyloxy, or hexyloxy. In a preferred embodiment, "alkoxy" or "alkyloxy" is methoxy, ethoxy, propoxy, isopropyloxy, more preferably methoxy.

[0032] The term "cycloalkyl" corresponds to a saturated or unsaturated monocyclic, bicyclic or tricyclic alkyl group containing 3 to 20 carbon atoms. It also includes fused, bridged, or spiro-linked cycloalkyl groups. The term "cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, preferably cyclopropyl. The term "spirocycloalkyl" includes, for example, spirocyclopropyl.

[0033] The term "heterocycloalkyl" corresponds to a saturated or unsaturated cycloalkyl group as defined above, further containing at least one heteroatom such as at least one nitrogen, oxygen, or sulfur atom, preferably at least one nitrogen atom. It also includes fused, bridged, or spiro-linked heterocycloalkyl groups. Representative heterocycloalkyl groups include, but are not limited to, dioxolanyl, benzo[1,3]dioxolyl, azetidinyl, oxetanyl, pyrazolinyl, pyranyl, thiomorpholinyl, pyrazolidinyl, piperidyl, piperazinyl, 1,4-dioxanyl, imidazolinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, morpholinyl, 1,4-dithianyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, dithiolanyl, azepanyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, and tetrahydrothiophenyl. In a preferred embodiment, the heterocycloalkyl group is a morpholinyl group, a piperazinyl group, a piperidyl group, a pyrrolidinyl group, a tetrahydropyranyl group, a dithiolanyl group, and an azepanyl group, more preferably a piperidyl group.

[0034] The term "aryl" corresponds to a monocyclic or bicyclic aromatic hydrocarbon having 6 to 12 carbon atoms. For example, the term "aryl" includes phenyl, naphthyl, or anthracenyl. In a preferred embodiment, aryl is phenyl.

[0035] The term "cyclic" refers to a cycloalkyl group or an aryl group as defined above.

[0036] As used herein, the term "heteroaryl" corresponds to an aromatic monocyclic or polycyclic group containing 5 to 14 atoms and containing at least one heteroatom such as a nitrogen, oxygen or sulfur atom. As used herein, the term "heteroaryl" further encompasses "condensed arylheterocycloalkyl" and "condensed heteroarylcycloalkyl". The terms "condensed arylheterocycloalkyl" and "condensed heteroarylcycloalkyl" correspond to bicyclic groups in which the aryl or heteroaryl as defined above is bonded to the heteroalkyl or cycloalkyl as defined above by at least two carbons. In other words, the aryl or heteroaryl shares a carbon bond with the heteroalkyl or cycloalkyl, respectively. Examples of such monocyclic and polycyclic heteroaryl groups include pyridinyl, thiazolyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, triazinyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, indazolyl, purinyl, quinolidinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phthalazinyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, indolinyl, isoindolinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxyindolyl, benzoxazolyl, benzoxazolinyl, benzoxazinyl, benzothienyl, benzothiazolyl, benzodiazepinyl, benzazepinyl, benzoxazepinyl, isatinyl, dihydropyridyl, pyrimidinyl, s-triazinyl, oxazolyl, or thiophenyl.In a preferred embodiment, the heteroaryl is pyridinyl, pyrimidinyl, furanyl, thiophenyl, quinolinyl, and isoquinolinyl, more preferably furanyl.

[0037] The term "heterocyclic" refers to a heterocycloalkyl group or a heteroaryl group as defined above.

[0038] The term "halogen" corresponds to a fluorine, chlorine, bromine, or iodine atom, preferably a fluorine atom or a chlorine atom.

[0039] The expression "substituted by at least ~" means that the group is substituted by one or several groups in the list.

[0040] The expression "optionally substituted" means that the group is unsubstituted or substituted by one or several groups in the list.

[0041] "Stereoisomers" are isomeric compounds that have the same molecular formula and sequence of bonded atoms, but differ in the 3D-dimensional orientation of those atoms in space. Stereoisomers include enantiomers, diastereomers, Cis-trans and E-Z isomers, conformational isomers, tautomers, and anomers. In a preferred embodiment of the present invention, stereoisomers include diastereomers and enantiomers.

[0042] "Pharmaceutically acceptable salts" include inorganic acid salts and organic acid salts. Representative examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and the like. Representative examples of suitable organic acids include formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, maleic acid, methanesulfonic acid, and the like. Another example of a pharmaceutically acceptable inorganic acid addition salt or organic acid addition salt is the pharmaceutically acceptable salts listed in J. Pharm. Sci., 1977, 66, 2 and Handbook of Pharmaceutical Salts: Properties, Selection, and Use, edited by P. Heinrich Stahl and Camille G. Wermuth, 2002. "Pharmaceutically acceptable salts" also include inorganic base salts and organic base salts. Representative examples of suitable inorganic bases include sodium salts or potassium salts, alkaline earth metal salts, such as calcium salts or magnesium salts, or ammonium salts. Representative examples of suitable salts with organic bases include salts with, for example, methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine. In a preferred embodiment, the salt is a sodium salt, potassium salt, or calcium salt. In a more preferred embodiment, the salt is a sodium salt. In an even more preferred embodiment, the salt is a disodium salt.

[0043] As used herein, the terms "treatment", "treating", or "treatment" refer to any act intended to improve the health condition of a patient, such as the treatment, prevention, prophylaxis, and delay of a disease, particularly a respiratory disease. In some embodiments, such terms refer to the improvement or eradication of a disease or symptoms associated therewith. In other embodiments, this term refers to minimizing the spread or worsening of a disease resulting from the administration of one or more therapeutic agents to a subject with such a disease.

[0044] As used herein, the terms "subject", "individual" or "patient" are interchangeable and refer to a human being, including animals, preferably mammals, and even more preferably adults, children, neonates and pre-born humans. However, the term "subject" can also refer to non-human animals, particularly mammals such as, but not limited to, dogs, cats, horses, cows, pigs, sheep and non-human primates.

[0045] The terms "quantity", "amount", and "dosage" are used interchangeably herein and can refer to the absolute quantification of a molecule.

[0046] As used herein, the terms "active source", "active ingredient" and "pharmaceutical active ingredient" are synonymous and refer to the components of a pharmaceutical composition having a therapeutic effect.

[0047] In the present invention, the terms "ROR gamma", "RORγ" and "RORg" are used interchangeably. As used herein, a "RORγ modulator" refers to a compound that directly or indirectly modulates the activity of RORγ. In particular, a RORγ modulator directly or indirectly modulates the activity of RORγ, particularly inhibits or activates it, and more particularly inhibits it. Examples of RORγ modulators include antagonists, inverse agonists and agonists of RORγ, particularly antagonists and inverse agonists.

[0048] As used herein, the term "therapeutic effect" refers to an effect induced by an active ingredient or pharmaceutical composition according to the present invention that can prevent or delay the appearance or onset of a disease or disorder, or cure a disease or disorder or reduce the effects of a disease or disorder.

[0049] As used herein, the term "effective amount" refers to the amount of an active ingredient or pharmaceutical composition that prevents, eliminates or reduces the harmful effects of a disease, particularly a respiratory disease. It is understood that those skilled in the art can adapt the amount to be administered according to the subject to be treated, the nature of the disease, etc. In particular, the dosage and administration regimen can vary depending on the nature, stage and severity of the disease to be treated, as well as the weight, age and general health of the subject to be treated, and the judgment of the physician.

[0050] In this specification, the term "pharmaceutically acceptable additive" refers to any component other than the active ingredient present in a pharmaceutical composition. The addition may be aimed at imparting a specific hardness or other physical or taste characteristics to the final product. It is necessary that the pharmaceutically acceptable additive has no interaction with the active ingredient, especially no chemical interaction.

[0051] Compound The present invention provides a novel compound as a ROR modulator.

[0052] According to the present invention, the compound, as well as its stereoisomers and pharmaceutically acceptable salts, have the following formula (I)

[0053]

Chemical formula

[0054] [Wherein, ● A is a ring of the following formula (a),

[0055]

Chemical formula

[0056] · B represents an NH group, an oxygen atom, or an SO 2 group, · R 7 represents hydrogen, halogen, or a (C 1 ~C 6 ) alkyloxy group, · R 8 represents hydrogen or a (C 1 ~C 6 ) alkyl group, ● R 1a and R 1c are independently hydrogen, a (C 1 ~C 6 ) alkyl group, a (C 1 ~C 6 ) alkyloxy group, halogen, or a (C 1~C 6 represents a heterocycloalkyl which may be substituted by an alkyl group, ● R 2 is a (C 1 ~C 6 ) alkyl group, or represents a ring selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and the ring is optionally substituted by at least one group selected from the group consisting of a (C 1 ~C 6 ) alkyl group and a halogen, ● R 3 and R 3' each independently represent hydrogen or a (C 1 ~C 6 ) alkyl group, or R 3 and R 3' together with the carbon atom to which they are attached can form cycloalkyl, ● X represents a (C 1 ~C 6 ) alkyl group, ● R 5 and R 6 each independently represent hydrogen or a (C 1 ~C 6 ) alkyl group].

[0057] In certain embodiments, ring A is linked to the remainder of the molecule at the 3- and 5-positions of the ring. According to this embodiment, ring A can be represented by the following formula (a 1 ).

[0058]

Chemical formula

[0059] In another certain embodiment, ring A is linked to the remainder of the molecule at the 3- and 6-positions of the ring. According to this embodiment, ring A can be represented by the following formula (a 2 ).

[0060]

Chemical formula

[0061] In a preferred embodiment, ring A has the formula (a 1 ).

[0062] The compound of formula (I) according to the present invention is a compound in which B represents an NH group, an oxygen atom, or a SO 2 group. When B represents an NH group, ring A corresponds to indolyl. When B represents an oxygen atom, ring A corresponds to benzofuranyl. When B represents a SO 2 group, ring A corresponds to benzothiophene-1,1-dioxide.

[0063] In a preferred embodiment, B is an NH group.

[0064] In a more preferred embodiment, ring A has the formula (a 1 ), and B is an NH group. According to this more preferred embodiment, ring A corresponds to an indolyl group linked to the remainder of the molecule at the 3- and 5-positions of the ring.

[0065] The compound of formula (I) according to the present invention is such that R 7 represents hydrogen, halogen, or a (C 1 -C 6 ) alkyloxy group, and R 8 represents hydrogen or a (C 1 -C 6 ) alkyl group, preferably a (C 1 -C 4 ) alkyl group.

[0066] In a preferred embodiment, R 7 represents hydrogen or fluorine, more preferably hydrogen.

[0067] In a preferred embodiment, R 8 represents hydrogen or methyl, more preferably hydrogen.

[0068] In a more preferred embodiment, ring A has the formula (a 1 ), B is an NH group, and R7 represents hydrogen, and R 8 represents hydrogen.

[0069] The compound of formula (I) according to the present invention has R 1a and R 1c independently representing hydrogen, a (C 1 ~C 6 ) alkyl group, a (C 1 ~C 6 ) alkyloxy group, a halogen, or a heterocycloalkyl such as azetidinyl, pyrrolidinyl, tetrahydropyranyl, dithiolanyl, piperidinyl, azepanyl, piperazinyl, and morpholinyl, wherein the heterocycloalkyl may be substituted by a (C 1 ~C 6 ) alkyl group.

[0070] 1a In a specific embodiment, R 1 represents a (C 6 ) alkyl group, a (C 1 ~C 6 ) alkyloxy group, or a heterocycloalkyl selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, piperazinyl, and morpholinyl, wherein the heterocycloalkyl may be substituted by a (C 1 ~C 6 ) alkyl group. Preferably, R 1a represents a (C 1 ~C 6 ) alkyl group, preferably methyl, pyrrolidinyl or piperidinyl.

[0071] In a specific embodiment, R 1 c represents a (C 1 ~C 6 ) alkyl group or a (C 1 ~C 6 ) alkyloxy group. Preferably, R 1c represents a (C 1 ~C 6 ) alkyl group, more preferably methyl.

[0072] ​In a preferred embodiment, R 1a is a (C 1 ~C 6 )alkyl group, preferably methyl, a (C 1 ~C 6 )alkyloxy group, halogen, or heterocycloalkyl, preferably piperidinyl, and R 1c is hydrogen, a (C 1 ~C 6 )alkyl group, preferably methyl, a (C 1 ~C 6 )alkyloxy group, or halogen.

[0073] In a particular embodiment, R 1a and R 1c are the same. Preferably, R 1a and R 1c are a (C 1 ~C 6 )alkyl group, preferably methyl.

[0074] In another particular embodiment, R 1a and R 1c are different. Preferably, R 1a is heterocycloalkyl, preferably piperidinyl, and R 1c is a (C 1 ~C 6 )alkyl group, preferably methyl.

[0075] The compound of formula (I) according to the present invention is a compound in which R 2 represents a ring selected from the group consisting of a (C 1 ~C 6 )alkyl group, or cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and the ring is optionally substituted by at least one group selected from the group consisting of a (C 1 ~C 6 )alkyl group and halogen.

[0076] In a particular embodiment, R 2 is a (C 1 ~C 6)It represents aryl or heteroaryl which may be substituted by at least one group selected from the group consisting of an alkyl group and a halogen.

[0077] In a preferred embodiment, R 2 is phenyl, or heteroaryl selected from among furanyl, pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, or thiophenyl, which may be substituted by at least one group selected from the group consisting of an (C 1 ~C 6 ) alkyl group and a halogen. In another preferred embodiment, R 2 represents heteroaryl, preferably furanyl, and the heteroaryl may be substituted by at least one group selected from the group consisting of an (C 1 ~C 6 ) alkyl group and a halogen, preferably methyl and chlorine. In a more preferred embodiment, R 2 represents furanyl substituted by at least one group selected from the group consisting of an (C 1 ~C 6 ) alkyl group, preferably methyl, and a halogen, preferably chlorine.

[0078] The compound of formula (I) according to the present invention is a compound in which R 3 and R 3' independently represent hydrogen or an (C 1 ~C 6 ) alkyl group, or R 3 and R 3' together with the carbon atom to which they are attached can form cycloalkyl.

[0079] In a specific embodiment, R 3 and R 3' independently represent hydrogen or an (C 1 ~C 6 ) alkyl group. In a preferred embodiment, R 3 and R 3' represent hydrogen.

[0080] In another specific embodiment, R 3 and R 3' together with the carbon atom to which they are attached form a cycloalkyl. Thus, the cycloalkyl is spiro-linked to the remainder of the molecule. In a preferred embodiment, R 3 and R 3' together with the carbon atom to which they are attached form cyclopropyl or cyclobutyl, preferably cyclopropyl.

[0081] Compounds of formula (I) according to the invention are those in which R 5 and R 6 independently represent hydrogen or a (C 1 ~C 6 ) alkyl group. In a specific embodiment, R 5 and R 6 represent hydrogen.

[0082] Compounds of formula (I) according to the invention are those in which X represents a (C 1 ~C 6 ) alkyl group. Since both ends of X are substituted, considering that the valence of carbon is 4, thus when X corresponds to methyl (-CH 2 -), when X corresponds to ethyl (-CH 2 -CH 2 -), and when X corresponds to propyl (-CH 2 -CH 2 -CH 2- ). It is well understood that in a specific embodiment, X is a saturated straight-chain aliphatic group containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, and hexyl. Preferably, X is a (-CH 2 )- or (-CH 2 -CH 2 -) group, more preferably a (-CH 2 -CH 2 -) group. In another specific embodiment, X is a saturated branched aliphatic group containing 1 to 6 carbon atoms, such as 1-methylethyl (-CH(CH 3 )-CH 2-), and 2-methylpropyl (-CH 3 -CH(CH 3 )-CH 2 -), or 1,1-dimethylethyl (-C(CH 3 ) 2 -CH 2 -). Preferably, X is 2-methylpropyl (-CH 3 -CH(CH 3 )-CH 2 -), or 1,1-dimethylethyl (-C(CH 3 ) 2 -CH 2 -).

[0083] According to the present invention, the compound of formula (I) further comprises a pharmaceutically acceptable salt as defined above. In a preferred embodiment, the salt is a sodium salt, a potassium salt or a calcium salt. In a more preferred embodiment, the salt is a sodium salt. In an even more preferred embodiment, the salt is a disodium salt.

[0084] In a preferred embodiment, the compound of formula (I) is - Cpd.1: {2-[5-(1-{[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethoxy}phosphonic acid; - Cpd.2: Disodium 2-[5-(1-{[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate; - Cpd.3: {2-[5-(1-{[(2-methoxy-4-methylphenyl)(phenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethoxy}phosphonic acid; - Cpd.4: Disodium 2-[5-(1-{[(2-methoxy-4-methylphenyl)(phenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate; - Cpd.5: {2-[5-(1-{[(2,4-dimethylphenyl)(6-methylpyridin-2-yl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethoxy}phosphonic acid; - Cpd.6: Disodium {2-[5-(1-{[(2,4-dimethylphenyl)(6-methylpyridin-2-yl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethoxy}phosphonic acid; - Cpd.7: {2-[5-(1-{[(3-chlorophenyl)(2,4-dimethylphenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethoxy}phosphonic acid; - Cpd.8: Disodium 2-[5-(1-{[(3-chlorophenyl)(2,4-dimethylphenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate; - Cpd.9: {2-[5-(1-{[(4-methoxy-2-methylphenyl)(phenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethoxy}phosphonic acid; - Cpd.10: Disodium 2-[5-(1-{[(4-methoxy-2-methylphenyl)(phenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate; - Cpd.11: (2-{5-[1-({[4-methoxy-2-(pyrrolidin-1-yl)phenyl](phenyl)methyl}carbamoyl)cyclopropyl]-1H-indol-3-yl}ethoxy)phosphonic acid; - Cpd.12: Disodium 2-{5-[1-({[4-methoxy-2-(pyrrolidin-1-yl)phenyl](phenyl)methyl}carbamoyl)cyclopropyl]-1H-indol-3-yl}ethyl phosphate - Cpd.13: {2-[5-(1-{[cyclopropyl(2,4-dimethylphenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethoxy}phosphonic acid; - Cpd.14: Disodium 2-[5-(1-{[Cyclopropyl(2,4-dimethylphenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate; - Cpd.15: (2-{5-[1-({[4-Methyl-2-(morpholin-4-yl)phenyl](phenyl)methyl}carbamoyl)cyclopropyl]-1H-indol-3-yl}ethoxy)phosphonic acid; - Cpd.16: Disodium 2-{5-[1-({[4-Methyl-2-(morpholin-4-yl)phenyl](phenyl)methyl}carbamoyl)cyclopropyl]-1H-indol-3-yl}ethyl phosphate; - Cpd.17: {2-[5-(1-{[(Dimethyl-1,2-oxazol-4-yl)(phenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethoxy}phosphonic acid; - Cpd.18: Disodium 2-[5-(1-{[(Dimethyl-1,2-oxazol-4-yl)(phenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate; - Cpd.19: ({5-[({[4-Methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}carbamoyl)methyl]-1H-indol-3-yl}methyloxy)phosphonic acid; - Cpd.20: Disodium ({5-[({[4-Methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}carbamoyl)methyl]-1H-indol-3-yl}methyloxy)phosphonic acid; - Cpd.21: {2-[5-(1-{[(2,4-Dimethylphenyl)(5-chlorofuran-2-yl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethoxy}phosphonic acid; - Cpd.22: Disodium 2-[5-(1-{[(2,4-Dimethylphenyl)(5-chlorofuran-2-yl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate; - Cpd.23: {2-[5-(1-{[(4-Methyl-2-(piperidin-1-yl)phenyl)(5-methylfuran-2-yl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethoxy}phosphonic acid; - Cpd.24: Disodium 2-[5-(1-{[(4-Methyl-2-(piperidin-1-yl)phenyl)(5-methylfuran-2-yl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethylphosphonate; - Cpd.25: 2-(5-(1-(((2,4-Dimethylphenyl)(5-methylfuran-2-yl)methyl)carbamoyl)cyclopropyl)-1H-indol-3-yl)-2-methylpropyloxy)phosphonic acid; and - Cpd.26: Disodium 2-(5-(1-(((2,4-Dimethylphenyl)(5-methylfuran-2-yl)methyl)carbamoyl)cyclopropyl)-1H-indol-3-yl)-2-methylpropyl phosphate is selected from the group consisting of.

[0085] In a more preferred embodiment, the compound of formula (I) is - Cpd.2: Disodium 2-[5-(1-{[(2,4-Dimethylphenyl)(5-methylfuran-2-yl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate, - Cpd.4: Disodium 2-[5-(1-{[(2-Methoxy-4-methylphenyl)(phenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate; - Cpd.6: Disodium {2-[5-(1-{[(2,4-Dimethylphenyl)(6-methylpyridin-2-yl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethoxy}phosphonic acid; - Cpd.8: Disodium 2-[5-(1-{[(3-Chlorophenyl)(2,4-dimethylphenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate; - Cpd.10: Disodium 2-[5-(1-{[(4-methoxy-2-methylphenyl)(phenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate; - Cpd.12: Disodium 2-{5-[1-({[4-methoxy-2-(pyrrolidin-1-yl)phenyl](phenyl)methyl}carbamoyl)cyclopropyl]-1H-indol-3-yl}ethyl phosphate - Cpd.14: Disodium 2-[5-(1-{[cyclopropyl(2,4-dimethylphenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate; - Cpd.16: Disodium 2-{5-[1-({[4-methyl-2-(morpholin-4-yl)phenyl](phenyl)methyl}carbamoyl)cyclopropyl]-1H-indol-3-yl}ethyl phosphate; - Cpd.18: Disodium 2-[5-(1-{[(dimethyl-1,2-oxazol-4-yl)(phenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate; - Cpd.20: Disodium ({5-[({[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}carbamoyl)methyl]-1H-indol-3-yl}methyloxy)phosphonic acid; - Cpd.22: Disodium 2-[5-(1-{[(2,4-dimethylphenyl)(5-chlorofuran-2-yl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate; - Cpd.24: Disodium 2-[5-(1-{[(4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphonate; and - Cpd.26: Disodium 2-(5-(1-(((2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl)carbamoyl)cyclopropyl)-1H-indol-3-yl)-2-methylpropyl phosphate is selected from the group consisting of.

[0086] In an even more preferred embodiment, the compound of formula (I) is - Cpd.2: Disodium 2-[5-(1-{[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate, and - Cpd.8: Disodium 2-[5-(1-{[(3-chlorophenyl)(2,4-dimethylphenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate selected from.

[0087] In another embodiment, the compound of formula (I) is Cpd.2: Disodium 2-[5-(1-{[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate.

[0088] The compounds of formula (I) according to the present invention can be prepared according to any chemical route known to those skilled in the art, such as the general synthetic routes presented in the Examples and FIG. 1. Thus, it is understood that those skilled in organic chemistry can readily synthesize the compounds of formula (I) using commercially available or readily synthesized appropriate starting materials, ordinary chemical reactions, standard and literature procedures, and experimental conditions.

[0089] The compounds of the present invention may contain one or more asymmetric centers. The present invention includes pure or mixed stereoisomers (diastereomers, enantiomers), and racemic mixtures, as well as geometric isomers or tautomers of the compounds of formula (I). When a pure (or enriched) mixture as enantiomers is desired, it can be obtained by purification of the final product or chiral intermediate, or by asymmetric synthesis according to methods known to those skilled in the art (e.g., using chiral reactants and catalysts). Some compounds according to the present invention can have various stable tautomeric forms, and all of these tautomeric forms and their mixtures are included in the present invention. Techniques for obtaining and characterizing pure or mixed stereoisomers, and racemic mixtures, as well as geometric isomers, or tautomers are well known and described in the literature.

[0090] The compounds of formula (I) can be purified by precipitation or solid / liquid extraction after evaporation of the reaction medium. When the compound is stable in solid form, another or other purification steps can be carried out by silica gel chromatography or crystallization by applying techniques well known in the literature. Furthermore, the necessary purification and / or (re)crystallization steps suitable for isolating the compounds of formula (I) from the reaction mixture can be used to obtain amorphous, polymorphic, single crystal or polycrystalline forms. Such polymorphs can impart different pharmacological and / or chemical properties in terms of solubility, intrinsic dissolution rate, melting temperature, bioavailability, and / or possible transition from one polymorphic state to another in pharmaceutical compositions and / or biological fluids. (Re)crystallization assays can be carried out by applying various conditions such as reaction volume or temperature in a group of various solvents (such as isopropanol, acetone, methanol, diisopropyl ether or water) or mixtures thereof. The obtained samples can be analyzed by various techniques such as microscopy, calorimetry, and / or spectroscopy that enable the establishment of characteristics of a specific crystal form such as structure, solubility, stability or conversion to other forms.

[0091] Such polymorphic studies make it possible to characterize pharmaceutically acceptable crystal forms of compounds from both pharmacological and manufacturing perspectives. Some of the compounds of formula (I) can be isolated in zwitterionic form, and each of these forms is included in the present invention as well as mixtures thereof. The compounds of formula (I) and their salts can be stable in liquid or solid form. The present invention includes all solid and liquid forms of formula (I), including amorphous, polymorphic, single crystal, and polycrystalline forms. In particular, the compounds of formula (I) can exist in free form or in solvated form, i.e., in association or combination with one or more molecules of a pharmaceutically acceptable solvent such as a solvent, for example, water (hydrate) or ethanol.

[0092] The compounds of formula (I) can be obtained as specific salts, solvates, and polymorphs during the final purification step of the compound or, in the case of salts, by incorporating the salt into a pre-purified compound. The selection of the compounds of formula (I) produced according to the methods of the present invention as optimal candidates for drug development can be automated for comprehensive biopharmaceutical characterization at the scale-up stage and for solid or liquid formulations suitable for the desired route of administration and therapeutic indication.

[0093] Therapeutic applications As shown by the examples, the inventors have demonstrated the therapeutic benefits of the phosphate derivatives of the present invention. In fact, the inventors have shown that the compounds according to the present invention have improved solubility and pharmacokinetic properties such that they are useful as RORg modulators.

[0094] Accordingly, the compounds of formula (I) according to the present invention are useful as drugs.

[0095] Accordingly, the present invention relates to a compound as defined herein for use as a drug or medicament. The present invention further relates to a pharmaceutical or veterinary pharmaceutical composition comprising a compound according to the invention. Preferably, the pharmaceutical composition further comprises a pharmaceutically or veterinarily acceptable carrier or additive. The present invention relates to the use of a compound according to the invention as a drug or medicament. The present invention further relates to a method of treating a disease in a subject, comprising administering a therapeutically effective amount of a compound according to the invention to said subject in need thereof. The present invention also relates to the use of a compound according to the invention for the manufacture of a medicament. The present invention also relates to a pharmaceutical composition comprising a compound according to the invention for use as a drug. In a preferred embodiment, the compound of formula (I) according to the invention is used as a RORg modulator.

[0096] The present invention further provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier or diluent.

[0097] Accordingly, the pharmaceutical composition may further comprise one or more additives or vehicles (e.g., physiological saline, physiological solution, isotonic solution for liquid formulations) acceptable within a pharmaceutical context.

[0098] Another object of the present invention is a method of preparing a pharmaceutical composition, comprising the step of admixing a compound of formula (I) with at least one pharmaceutically acceptable carrier, vehicle, or diluent. The method requires, for example, ordinary mixing, dissolving, granulating, sugar coating, classifying, emulsifying, encapsulating, entrapping, freeze-drying process or spray-drying.

[0099] The terms "carrier", "vehicle", or "additive" refer to any substance that is not a therapeutic agent itself and is added to a pharmaceutical composition for use as a carrier, vehicle, and / or diluent for the delivery of a therapeutic agent to a subject in order to improve the handling or storage properties of the therapeutic agent or to enable or facilitate the formation of the composition into discrete articles from the dosage unit of the composition. The pharmaceutical compositions of the present invention can contain one or several agents or vehicles selected from among dispersants, solubilizers, stabilizers, preservatives, etc., individually or in combination. Agents or vehicles useful in these (liquid and / or injectable and / or solid) formulations are, in particular, methylcellulose, hydroxymethylcellulose, polysorbate 80, mannitol, gelatin, lactose, vegetable oils, liposomes, etc. Acceptable additives can be selected from among disintegrants, binders, adhesives, wetting agents, lubricants, fluidizing agents, flavoring agents, dyes, perfumes, stearic acid, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, magnesium carbonate, talc, gelatin, lactose, sucrose, starch, polymers such as polyvinyl alcohol and polyethylene glycol, and other pharmaceutically acceptable materials added to improve the taste, odor, or appearance of the composition.

[0100] The composition can be constituted in solid or liquid form, for example, in the form of a powder, aerosol, sterile solution, suspension, or emulsion, etc. The composition can be presented as a solid pre-formulation composition in which the active ingredient is evenly dispersed throughout the composition so that the composition can be easily subdivided into dosage forms that are equally effective. Moreover, the combined composition can be delivered using a sustained-release formulation.

[0101] The composition can be formulated as a suspension, gel, oil, powder, aerosol, spray, etc., by a crude drug form or device that ultimately ensures sustained and / or slow-release. In such types of formulations, it is advantageous that agents such as cellulose, carbonate, or starch can be used. In certain embodiments, the pharmaceutical compositions of the present invention take the form of a suspension, gel, oil, powder, aerosol, or spray.

[0102] The composition of the present invention can also be formulated in the form of liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of lipids, including but not limited to amphiphilic lipids such as phosphatidylcholine, sphingomyelin, phosphatidylcholine, cardiolipin, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidic acid, phosphatidylinositol, diacyltrimethylammonium propane, diacyldimethylammonium propane, and stearylamine, neutral lipids such as triglycerides, and combinations thereof.

[0103] The pharmaceutical composition of the present invention can be administered by the inhalation route, including oral and nasal inhalation formulations. In a preferred embodiment, the pharmaceutical composition is administered by nasal inhalation. Formulations suitable for oral and nasal inhalation include, but are not limited to, dry powder inhaler (DPI) formulations, metered-dose inhaler (MDI) formulations (including oral and nasal aerosols), nasal sprays, and formulations suitable for inhalation administration.

[0104] For inhalation administration, the pharmaceutical composition is advantageously delivered in the form of an aerosol spray presentation from a pressurized pack or nebulizer using a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, carbon dioxide, or other suitable gas, alone or in combination. Pressurized aerosols can be formulated as suspensions or solutions and can contain a suitable propellant formulation and various additives, such as surfactants, co-solvents, etc. In the case of pressurized aerosols, the dosage unit can be determined by providing a valve for delivering a fixed quantity. Capsules and cartridges, for example of gelatin, for use in inhalers or insufflators can be formulated to contain a powder blend of the compound and a suitable powder base such as lactose or starch.

[0105] Another object of the present invention is a device comprising the pharmaceutical composition of the present invention as defined herein. The device can be a device suitable for any route of administration. For example, for administration by inhalation, preferably nasal inhalation, suitable devices are dry powder inhalers (DPIs) or metered dose inhalers (MDIs). Preferred devices of the present invention are dry powder inhalers (DPIs) or metered dose inhalers (MDIs).

[0106] The present invention further relates to a compound of formula (I) as defined above, including any one of the disclosed embodiments, or a pharmaceutical composition comprising such a compound, for preventing and / or treating respiratory diseases. The present invention further relates to the use of a pharmaceutical composition as defined herein or a compound of formula (I) as defined above, including any one of the disclosed embodiments, for the manufacture of a medicament, pharmaceutical or drug for the treatment of respiratory diseases. The present invention also relates to a method of treating a respiratory disease in a subject in need thereof, the method comprising administering an effective amount of a compound of formula (I) as defined herein or a pharmaceutical composition as defined herein.

[0107] In a preferred embodiment, such respiratory diseases are selected from the group consisting of neutrophilic asthma, chronic obstructive pulmonary disease (COPD), asthma-COPD overlap syndrome (ACOS), idiopathic pulmonary fibrosis (IPF), and chronic rhinosinusitis with nasal polyps (CRSwNP).

[0108] Preferably, treatment with the compound of formula (I) according to the present invention or the pharmaceutical composition according to the present invention begins within less than 1 month, preferably less than 1 week, from the diagnosis of the disease. In the most preferred embodiment, treatment begins on the day of diagnosis.

[0109] The compound according to the present invention or the pharmaceutical composition according to the present invention can be administered as a single dose or multiple doses.

[0110] Preferably, the treatment is administered regularly, preferably daily to monthly, more preferably daily to every two weeks, even more preferably daily to weekly, and even more preferably the treatment is administered daily. In certain embodiments, the treatment is administered several times a day, preferably two or three times a day, and even more preferably three times a day.

[0111] The treatment period with the compound according to the invention or the pharmaceutical composition according to the invention is preferably from 1 day to 50 weeks, more preferably from 1 day to 30 weeks, even more preferably from 1 day to 15 weeks, and even more preferably from 1 day to 10 weeks. In certain embodiments, the treatment period consists of about 1 week. Alternatively, the treatment may continue as long as the disease persists. The dosage of the compound according to the invention or the pharmaceutical composition according to the invention must be determined by standard procedures well known to those skilled in the art. The patient's physiological data (e.g., age, size, and weight) and the route of administration must be taken into account to determine an appropriate dosage such that a therapeutically effective amount is administered to the patient.

[0112] In a preferred embodiment, the total compound dosage per administration of the compound according to the invention or the pharmaceutical composition according to the invention consists of 0.01 mg / day to 1000 mg / day, preferably 0.1 mg / day to 10 mg / day.

[0113] It is understood that the form of the pharmaceutical composition, the route of administration and the dosage of the compound according to the invention or the pharmaceutical composition according to the invention can be adjusted by those skilled in the art according to the type and severity of the disease, and the patient, especially the patient's age, weight, gender, and general health status.

[0114] In another specific embodiment, the compound of formula (I) can be found to be associated with said respiratory disease in a respiratory disease or medical condition and can also be formulated and / or administered in combination with one or more other therapeutically active substances that are either on the market or in development and are selected according to any other disorder that is also to be treated. Such combination administration includes two possibilities: the two agents are administered when they are substantially similar to the subject; or when the two agents are different to the subject, they are administered at independent intervals that may or may not overlap or coincide. Thus, the present invention also relates to a kit of parts for simultaneous, separate or sequential use in the treatment of respiratory diseases selected from the group consisting of the compounds of formula (I) defined herein together with another therapeutically active agent, in particular respiratory diseases, preferably neutrophilic asthma, chronic obstructive pulmonary disease (COPD), the overlap syndrome of asthma and COPD (ACOS), idiopathic pulmonary fibrosis (IPF), and chronic rhinosinusitis with nasal polyps (CRSwNP). The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) defined herein and at least one therapeutically active agent. Preferably, the additional therapeutically active agent is an agent that has a biological effect on respiratory diseases.

[0115] In the following experimental section, which is illustrative and should not be considered limiting, further aspects and effects of the present invention are disclosed.

Examples

[0116] Chemical names follow IUPAC nomenclature. Starting materials and solvents were purchased from commercial suppliers (Acros Organic, Sigma Aldrich, Combi-Blocks, Fluorochem, Fluka, Alfa Aesar or Lancaster) and used as received without further purification. Some starting materials can be readily synthesized by those skilled in the art.

[0117] Reactions sensitive to air and humidity were carried out in a nitrogen inert atmosphere and glassware was oven dried. No attempt was made to optimize the reaction yields.

[0118] Thin-layer chromatography (TLC) was performed on Merck silica gel 60 UV254 (250 μm) plates. Visualization was carried out with UV light.

[0119] Column chromatography was performed on Merck Geduran silica gel 60 (40 - 63 μm).

[0120] The melting point (mp) was recorded on a Buchi Melting Point B-545 and is uncorrected. All microwave irradiation experiments were carried out on a Biotage Initiator microwave device.

[0121] 1H spectra were recorded at 300 MHz using a Bruker Advance I spectrometer. Chemical shifts (δ) are reported in ppm (parts per million) by referencing the hydrogenated residue of the deuterated solvent as an internal standard: 2.50 ppm for DMSO-d6, 7.26 ppm for CDCl3, 3.31 and 4.78 for methanol-d4. The spectral line splitting patterns are designated as follows: s, singlet; d, doublet; dd, doublet of doublets; ddd, doublet of doublet of doublets; t, triplet; dt, doublet of triplets; q, quartet; m, multiplet; br s, broad singlet. Coupling constants (J) are given in units of 0.1 Hz.

[0122] All tested compounds were evaluated by HPLC using a Waters column Symmetry C18 (3.5 μm, 4.6 × 75 mm) with a Merck HITACHI Lachrom L-7000 series and a Merck HITACHI diode array detector L-7455, using a gradient of MeOH / 0.1% formic acid in Millipore water, and showed a chemical purity ≥ 95%. Chromatograms were analyzed with Lachrom software version 890 - 8800 - 09.

[0123] Mass spectrometric measurements were carried out using an Alliance 2695 equipped with a Waters column Symmetry C18 (3.5 μm, 4.6×75 mm) and a DAD detector 2998 equipped with a Waters Acquity QDa detector, using a gradient of MeOH / Millipore water containing 0.1% formic acid (chromatograms were analyzed with Empower 3 software), or using an apparatus equipped with a Waters 2545 Binary Gradient Module, a Waters 2489 UV / Visible detector and an Acquity QDa detector, using a Waters column Symmetry C18 (3.5 μm, 4.6×75 mm) and a gradient of MeOH / Millipore water containing 0.1% formic acid (chromatograms were analyzed with MassLynx 4.1). Mass spectrometry electrospray ionization was noted as ESI+ (positive) or ESI− (negative).

[0124] Preparative HPLC was carried out using an apparatus equipped with a Waters 2545 Binary Gradient Module, a Waters 2489 UV / Visible detector, an Acquity QDa detector and a Waters 2767 Sample Manager, using a Waters column SymmetryPrep C18 (7 μm, 19×150 mm) and a gradient of MeOH / Millipore water containing 0.1% formic acid (chromatograms were analyzed with MassLynx 4.1). All solvents were HPLC grade.

[0125] The compounds of the present invention are prepared according to the general methods and general protocols of synthesis described below. An outline of a representative procedure suitable for the preparation of the compounds of formula (I) is set out in the reaction scheme (Figure 1).

[0126] The starting materials can be synthesized according to the methods disclosed previously as specified in the protocol, or are commercially available. 1-[3-(2-Hydroxyethyl)-1H-indol-5-yl]cyclopropane-1-carboxylic acid was obtained according to the procedure described in WO2018138362.

[0127] As represented by Figure 1, the synthetic route to the compounds of the present invention involves the following steps. (1) O-alkylate the hydroxyl group of the starting material with dibenzyl chlorophosphate (Protocol B1) or bis(benzyloxy)phosphinic acid (Protocol B2); (2) Debenzylate by catalytic hydrogenation to obtain the compound according to the present invention (wherein R 5 = R 6 = H); (3) Prepare a salt to obtain the compound according to the present invention.

[0128] Reagents and conditions can be adapted and additional steps can be employed to generate alternative compounds encompassed by the present invention having alternative substituents, or to achieve such compounds in higher yields and / or higher purities.

[0129] (Example 1) Synthesis of intermediates for the synthesis of the compounds according to the present invention General work-up and purification steps are carried out by techniques well known to those skilled in the art or those described in the literature, etc. The reaction was quenched with water, brine or saturated NH 4 Cl. The aqueous layer was extracted three times with a water-immiscible solvent (e.g., diethyl ether (Et 2 O), ethyl acetate (EtOAc), dichloromethane (CH 2 Cl 2 )). The organic layer was dried over MgSO 4 and filtered, and the solution was concentrated under reduced pressure. Purification of the crude material was achieved by purification on a silica gel column chromatography using standard mixture systems notified by different protocols.

[0130] General procedure A: Synthesis of amides The amides used as starting materials in Figure 1 were prepared according to techniques well known to those skilled in the art.

[0131] To a solution of amine (1 equiv) and 1-[3-(2-hydroxyethyl)-1H-indol-5-yl]cyclopropane-1-carboxylic acid (1 equiv) in dimethylformamide (DMF), dimethylaminopyridine (DMAP) (1.1 equiv) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, HCl) (1.1 equiv) were added. The reaction was stirred at room temperature (rt) for 3 to 5 hours. The mixture was quenched with water and extracted with an aqueous solvent. The combined organic layers were washed with NH 4 Cl solution and brine, dried over MgSO 4 , and concentrated under reduced pressure. The product was purified by column chromatography.

[0132] General Procedure B: Synthesis of Dibenzyl Phosphonate Protocol B1: O-Alkylation with Bis(benzyloxy)phosphinic Acid To a solution of carboxamide (1 equiv), triphenylphosphine (2 equiv), triethylamine (4 equiv) and bis(benzyloxy)phosphinic acid (2 equiv) in tetrahydrofuran (THF), diethyl azodicarboxylate (DEAD) (2 equiv) was added. The reaction was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain dibenzyl phosphate.

[0133] Protocol B2: O-Alkylation with Dibenzyl Chlorophosphonate To a solution of carboxamide (0.24 g, 0.507 mmol) and pyridine (5 equiv) in acetonitrile (ACN), a solution of dibenzyl chlorophosphonate (6.2 equiv) in acetonitrile (1 mL per 1 mmol of carboxamide) was added dropwise. The reaction was stirred at 50 °C for 2 hours.

[0134] The mixture was quenched with water and extracted twice with EtOAc. The combined organic layers were washed twice with NH 4 Cl solution and brine, dried over MgSO 4 , and concentrated under reduced pressure. The crude product was purified by column chromatography.

[0135] General Procedure C: Synthesis of Phosphonic Acid A catalytic amount of Pd / C was added to an ethanol solution of dibenzylphosphonate. The reaction mixture was stirred at room temperature for 1 hour under atmospheric pressure hydrogen.

[0136] After completion of the reaction, the catalyst was removed by filtration. The filtrate was concentrated to dryness to obtain the corresponding phosphonic acid. The crude product crystallized.

[0137] General Procedure D: Synthesis of Phosphonate A 2N sodium hydroxide solution was added to a methanol solution of phosphonic acid (1 mL per 1 mmol of phosphonic acid). The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and lyophilized to obtain the phosphonate as the disodium salt.

[0138] Hereinafter, the compound "Ex. X" is an intermediate compound used in the synthesis of the compounds of the present invention.

[0139] Intermediate Ex.1: Preparation of Dibenzyl 2-[5-(1-{[(2,4-Dimethylphenyl)(5-methylfuran-2-yl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl Phosphate To a solution of N-[(2,4-Dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-[3-(2-hydroxyethyl)-1H-indol-5-yl]cyclopropane-1-carboxamide (Cpd.A - 0.1 g, 0.226 mmol) (synthesis protocol disclosed by WO2018 / 138362) in acetonitrile (2 mL), ethylbis(propane-2-yl)amine (0.197 mL, 1.13 mmol) and dibenzylchlorophosphonate (0.402 g, 1.356 mmol) were successively added. After stirring at room temperature for 18 hours, further ethylbis(propane-2-yl)amine (0.197 mL, 1.13 mmol) and dibenzylchlorophosphonate (0.402 g, 1.356 mmol) were added, and the reaction mixture was stirred at 50 °C for an additional 18 hours.

[0140] The reaction mixture was cooled to room temperature (rt), concentrated to dryness, and the residue was purified by column chromatography eluting with cyclohexane 7 / acetone 3 (70 / 30) to give dibenzyl 2-[5-(1-{[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate (Ex.1) (0.061 g, 0.087 mmol) as a colorless oil. Yield: 38% 1H NMR (DMSO-d6): 0.99 - 1.04 (m, 2H), 1.29 - 1.37 (m, 2H), 2.08 (s, 3H), 2.12 (s, 3H), 2.17 (s, 3H), 2.99 (t, 2H, J = 6.9Hz), 4.16 (q, 2H, J = 7.5Hz), 4.92 (s, 2H), 4.95 (s, 2H), 5.72 (d, 1H, J = 2.7Hz), 5.86 (dd, 1H, J = 3Hz, J = 0.9Hz), 6.08 (d, 1H, J = 8.1Hz), 6.69 (d, 1H, J = 8.4Hz), 6.76 (d, 1H, J = 7.8Hz), 6.85 - 6.88 (m, 1H), 6.90 - 6.92 (m, 1H), 7.10 (dd, 1H, J = 8.1Hz, J = 1.5Hz), 7.18 (d, 1H, J = 2.4Hz), 7.24 - 7.37 (m, 11H), 7.52 - 7.54 (m, 1H), 10.95 (br(s), 1H) m / z (ESI+): 725 (M+Na)+ (calcd for mass: 702)

[0141] Intermediate Ex.2: Preparation of dibenzyl 2-[5-(1-{[(2-methoxy-4-methylphenyl)(phenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate

[0142]

Table 1

[0143] Preparation of Intermediate Ex.3: Dibenzyl 2-[5-(1-{[(2,4-dimethylphenyl)(6-methylpyridin-2-yl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate

[0144] [Table 2]

[0145] Preparation of Intermediate Ex.4: Dibenzyl 2-[5-(1-{[(3-chlorophenyl)(2,4-dimethylphenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate

[0146] [Table 3]

[0147] Preparation of Intermediate Ex.5: Dibenzyl 2-[5-(1-{[(4-methoxy-2-methylphenyl)(phenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate

[0148] [Table 4]

[0149] Preparation of Intermediate Ex.6: Dibenzyl 2-{5-[1-({[4-methoxy-2-(pyrrolidin-1-yl)phenyl](phenyl)methyl}carbamoyl)cyclopropyl]-1H-indol-3-yl}ethyl phosphate

[0150] [Table 5]

[0151] Preparation of Intermediate Ex.7: Dibenzyl 2-[5-(1-{[Cyclopropyl(2,4-dimethylphenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate

[0152] [Table 6]

[0153] Preparation of Intermediate Ex.8: Dibenzyl 2-{5-[1-({[4-Methyl-2-(morpholin-4-yl)phenyl](phenyl)methyl}carbamoyl)cyclopropyl]-1H-indol-3-yl}ethyl phosphate

[0154] [Table 7]

[0155] Preparation of Intermediate Ex.9: Dibenzyl 2-[5-(1-{[(Dimethyl-1,2-oxazol-4-yl)(phenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate

[0156] [Table 8A]

[0157] [Table 8B]

[0158] (Example 2) Synthesis of the compound according to the present invention

[0159] [Table 9A]

[0160] [Table 9B]

[0161]

Table 9C

[0162]

Table 9D

[0163]

Table 9E

[0164]

Table 9F

[0165] (Example 3) Solubility of the compounds according to the present invention General procedure: The test compound was solubilized in phosphate buffer (pH = 7.4) at a given concentration (test concentration). The mixture was maintained with vigorous stirring at room temperature for 24 hours. If an insoluble solid appeared, it was removed by centrifugation and the concentration of the test compound in the solution was determined by LC-MS / MS using an appropriate method.

[0166]

Table 10

[0167] The compounds according to the present invention show better solubility than their phosphate-free counterparts. For example, Cpd.2 is at least 1500 times more soluble than its phosphate-free analog Cpd.A, and Cpd.8 is more than 100,000 times more soluble than its phosphate-free analog Ex.4a.

[0168] (Example 4) Stability of the compounds according to the present invention in water General procedure: To obtain a concentration of 5 mg / mL, Compound 2 (Cpd.2) according to the present invention was dissolved in water. The solution was stirred at room temperature for 7 days. Compound 2 was quantified by UPLC / MS at different time points (0 day, 5 days, and 7 days) using an appropriate method.

[0169] The results are expressed as a percentage of the signal area at the initial (day 0) time point of Cpd.2.

[0170] The stability of Cpd.2 at room temperature at different time points is reported in the following table.

[0171] [Table 11]

[0172] These results indicate that the compound according to the present invention has high stability in water.

[0173] (Example 5) Metabolic stability of the compound according to the present invention in bronchoalveolar lavage fluid (Balf) General procedure: Human bronchoalveolar lavage fluid (hBALf) was purchased from BioIVT. Samples were collected from individual donors. The only known information obtained about the donors was age and gender. Information regarding the health status of the donors was not known.

[0174] The hydrolysis of Compound 2 was tested at concentrations of 1 μM and 10 μM for 120 minutes (at time points of 5 minutes, 15 minutes, 30 minutes, 60 minutes, and 120 minutes). Subsequently, the compound was quantified by LC-MS / MS using an appropriate method. As shown in Figure 2, the results were expressed as a percentage of the signal area at the initial (0 minute) time point.

[0175] The quantification of Cpd.2 in hBALf is reported in the following table.

[0176] [Table 12]

[0177] These results indicate that the compounds according to the invention are rapidly hydrolyzed in biological fluids.

[0178] (Example 6) In vivo absorption study after nasal administration All experiments were conducted at the Artimmune laboratory by certified technicians regularly employed by the company and instructed by Artimmune scientists. Animal handling was carefully performed to minimize stress. All experiments were conducted in accordance with the guidelines of the French Ministry of Agriculture for experiments using laboratory animals (Decree 87 - 848). The study complied with the animal health regulations (Council Directive 2010 / 63 / UE regarding animal protection and French Decree no. 2013 - 118 of February 1, 2013) and was carried out in accordance with the Artimmune / CNRS facility certification of experimental methods (n°D45 - 234 - 6) regarding the experimental method OVA - induced inflammation model project certification (CLE - CECCO - 1085 - Procedure 2).

[0179] General procedure: Eight - week - old BALB / cByJ female mice (10 groups of animals and 1 control group, 3 animals per group) were used to determine the concentration of the compounds according to the invention in the lungs. The compounds administered to the mice were solubilized in an aqueous solution of 0.9% NaCl to reach target concentrations of 0.1 mg / mL and 2 mg / mL. 20 μL of the compound solution was administered to the animals via the intranasal route. After administration of the compound, the heart was perfused to remove circulating test compound prior to lung recovery. Lungs were harvested over time (5 minutes, 15 minutes, 60 minutes, and 2 hours) for 2 hours.

[0180] The dephosphate compounds after metabolism in the lungs were quantified by LC - MS / MS using an appropriate method.

[0181] Figures 3a and 3b show the absorption of the dephosphate derivative (Cpd.A) after nasal administration of Cpd.2 at 0.1 mpk and 2 mpk, respectively, in BALB / cByJ female mice.

[0182] Similarly, FIGS. 3c and 3d show the quantification of Cpd.2 in the lungs after instillation at 0.1 mpk and 2 mpk, respectively, in BALB / cByJ female mice.

[0183] The results show that the compounds of formula (I) according to the present invention are rapidly hydrolyzed in vivo, enabling absorption of the active compound in the lungs.

Claims

1. Compounds having the following formula (I), and stereoisomers and pharmaceutical salts thereof: 【Chemistry 1】 [In the formula, A is a ring of the following formula (a): 【Chemistry 2】 B is an NH group, an oxygen atom, or SO 2 represents a group, R 7 is hydrogen, halogen, or (C 1 ~C 6 ) an alkyloxy group; R 8 is hydrogen or (C 1 ~C 6 ) an alkyl group; ● R 1a and R 1c are independently hydrogen, (C 1 ~C 6 ) alkyl group, (C 1 ~C 6 ) an alkyloxy group, a halogen, or (C 1 ~C 6 ) heterocycloalkyl optionally substituted by an alkyl group; ● R 2 is (C 1 ~C 6 ) an alkyl group, or a ring selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, said ring being 1 ~C 6 ) may be substituted with at least one group selected from the group consisting of alkyl groups and halogens; ● R 3 and R 3' are independently hydrogen or (C 1 ~C 6 ) an alkyl group, or R 3 and R 3' together with the carbon atom to which they are attached can form a cycloalkyl, ● X is (C 1 ~C 6 ) an alkyl group; ● R 5 and R 6 are independently hydrogen or (C 1 ~C 6 ) alkyl group.

2. A is expressed by the following formula (a 1 ) or (a 2 2. The compound of claim 1 having the formula: 【Chemistry 3】

3. 3. The compound according to claim 1 or 2, wherein B is an NH group.

4. ● R 1a However, (C 1 ~C 6 ) alkyl group, (C 1 ~C 6 ) an alkyloxy group, a halogen atom, or a heterocycloalkyl group; ● R 1c But hydrogen, (C 1 ~C 6 ) alkyl group, (C 1 ~C 6 ) an alkyloxy group or a halogen; 4. A compound according to any one of claims 1 to 3.

5. R 2 represents a heteroaryl, the heteroaryl being (C 1 ~C 6 5. The compound according to claim 1, which may be substituted with at least one group selected from the group consisting of alkyl groups and halogens.

6. R 5 and R 6 6. A compound according to any one of claims 1 to 5, wherein represents hydrogen.

7. X is a linear (C 1 ~C 6 ) alkyl group.

8. 8. The compound according to any one of claims 1 to 7, wherein the pharma- ceutically acceptable salt of the compound of formula (I) is a sodium salt, a potassium salt, or a calcium salt.

9. {2-[5-(1-{[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethoxy}phosphonic acid; Disodium 2-[5-(1-{[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate; {2-[5-(1-{[(2-methoxy-4-methylphenyl)(phenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethoxy}phosphonic acid; Disodium 2-[5-(1-{[(2-methoxy-4-methylphenyl)(phenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate; {2-[5-(1-{[(2,4-dimethylphenyl)(6-methylpyridin-2-yl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethoxy}phosphonic acid; Disodium {2-[5-(1-{[(2,4-dimethylphenyl)(6-methylpyridin-2-yl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethoxy}phosphonate; {2-[5-(1-{[(3-chlorophenyl)(2,4-dimethylphenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethoxy}phosphonic acid; Disodium 2-[5-(1-{[(3-chlorophenyl)(2,4-dimethylphenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate; {2-[5-(1-{[(4-methoxy-2-methylphenyl)(phenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethoxy}phosphonic acid; Disodium 2-[5-(1-{[(4-methoxy-2-methylphenyl)(phenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate; (2-{5-[1-({[4-methoxy-2-(pyrrolidin-1-yl)phenyl](phenyl)methyl}carbamoyl)cyclopropyl]-1H-indol-3-yl}ethoxy)phosphonic acid; Disodium 2-{5-[1-({[4-methoxy-2-(pyrrolidin-1-yl)phenyl](phenyl)methyl}carbamoyl)cyclopropyl]-1H-indol-3-yl}ethyl phosphate {2-[5-(1-{[cyclopropyl(2,4-dimethylphenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethoxy}phosphonic acid; Disodium 2-[5-(1-{[cyclopropyl(2,4-dimethylphenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate; (2-{5-[1-({[4-methyl-2-(morpholin-4-yl)phenyl](phenyl)methyl}carbamoyl)cyclopropyl]-1H-indol-3-yl}ethoxy)phosphonic acid; Disodium 2-{5-[1-({[4-methyl-2-(morpholin-4-yl)phenyl](phenyl)methyl}carbamoyl)cyclopropyl]-1H-indol-3-yl}ethyl phosphate; {2-[5-(1-{[(dimethyl-1,2-oxazol-4-yl)(phenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethoxy}phosphonic acid; and Disodium 2-[5-(1-{[(dimethyl-1,2-oxazol-4-yl)(phenyl)methyl]carbamoyl}cyclopropyl)-1H-indol-3-yl]ethyl phosphate 7. The compound according to any one of claims 1 to 6, selected from the group consisting of:

10. 10. A compound according to any one of claims 1 to 9 for use as a medicament.

11. 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and a pharma- ceutically acceptable excipient.

12. 12. The pharmaceutical composition of claim 11 in the form of a suspension, gel, oil, powder, aerosol, or spray.

13. 13. A pharmaceutical composition according to claim 11 or 12 for use in preventing and / or treating a respiratory disease.

14. The pharmaceutical composition described in claim 13, wherein the respiratory disease is selected from the group consisting of neutrophilic asthma, chronic obstructive pulmonary disease (COPD), asthma-COPD overlap syndrome (ACOS), idiopathic pulmonary fibrosis (IPF), and chronic rhinosinusitis with nasal polyps (CRSwNP).

15. 15. The pharmaceutical composition of claim 13 or 14, which is administered by nasal inhalation.

16. A device comprising the pharmaceutical composition of claim 11 or 12.

17. The device of claim 16, which is a dry powder inhaler (DPI) or a metered dose inhaler (MDI).

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