FR3065000A1 - PYRAZOLE DERIVATIVES AS REVERSE AGONISTS OF GAMMA ORPHAN RECEPTOR ASSOCIATED WITH ROR GAMMA RETINOIDS (T) - Google Patents

Abstract

The present invention relates to particular sulfonamide derivatives, their pharmaceutically acceptable addition salts, their hydrates and / or their solvates and their use as inverse agonists of the orphan gamma receptor associated with retinoids RORyt. The invention also relates to a pharmaceutical composition comprising such compounds as well as its use for the topical and / or oral treatment of inflammatory diseases mediated by RORyt receptors, in particular acne, psoriasis and / or atopic dermatitis. .

Description

Holder (s): GALDERMA RESEARCH & DEVELOPMENT General partnership.

Extension request (s)

Agent (s): CASALONGA.

PYRAZOLA DERIVATIVES AS INVERTED AGONISTS OF THE ORPHAN GAMMA RECEPTOR ASSOCIATED WITH ROR GAMMA RETINOIDS (T).

The present invention relates to particular sulfonamide derivatives, their pharmaceutically acceptable addition salts, their hydrates and / or their solvates, as well as their use as an orphan agonist of the orphan gamma receptor associated with RORyt retinoids. .

The invention also relates to a pharmaceutical composition comprising such compounds as well as its use for the topical and / or oral treatment of inflammatory diseases mediated by RORyt receptors, in particular acne, psoriasis and / or atopic dermatitis .

i

Pyrazole derivatives as inverse orphan gamma receptor agonists associated with gamma (t) MMR retinoids

The present invention relates to particular sulfonamide derivatives, their pharmaceutically acceptable addition salts, their hydrates and / or their solvates, as well as their use as an inverse agonist of the orphan gamma receptor associated with RORyt retinoids.

The invention also relates to a pharmaceutical composition comprising such compounds as well as its use for the topical and / or oral treatment of inflammatory diseases mediated by RORyt receptors, in particular acne, atopic dermatitis and / or psoriasis .

Nuclear receptors form a large family (called a superfamily) of transcription factors that correspond to proteins capable of being activated by a ligand, binding to specific DNA sequences and regulating the transcription of target genes. These receptors are therefore involved in the regulation of a wide variety of biological functions, including growth, development, reproduction, differentiation and metabolism in a multitude of living organisms.

The first members of this superfamily to have been identified and described in the scientific literature are the nuclear receptors for steroid hormones such as glucocorticoid receptors and estrogen receptors. This superfamily also includes among its members many receptors for which no ligand has been identified. These nuclear receptors are called "orphan receptors".

The orphan receptors associated with retinoids (Retinoidrelated orphan receptors in English) therefore constitute a subfamily of nuclear receptors. This subfamily is composed of three members each with their own expression profile: ROR alpha (called RORa), ROR beta (called ROR3) and ROR gamma (called RORy). Two isoforms of the orphan RORy receptors have already been identified, namely RORyl, which is expressed in a variety of tissues such as the thymus, the kidneys, the muscles and the liver, and RORy2 (also known as RORyt) in cells of the immune system.

In particular, the RORyt receptor plays an important regulatory role in the cellular differentiation of Thl7 lymphocytes which correspond to T helper lymphocytes whose function is to ensure the defense of the organism against a large number of extracellular pathogens such than bacteria and fungal infections.

However, it has been shown that Thl7 lymphocytes are also involved in a wide variety of inflammatory disorders, such as acne, and autoimmune diseases such as psoriasis, atopic dermatitis, rheumatoid arthritis or sclerosis. en plaques (Peck A, Mellins ED. Precarious balance; Thl7 cells in host defense. Infect Immun. 2010 Jan; 78 (1): 32-8; SuarezFarinas: J. Allergy Clin. Immunol. 2014; J. Invest. Dermatol. 2008, 128 (11), 2625).

Indeed, Thl7 lymphocytes produce many cytokines with distinct profiles such as interleukin-17A (IL17A), interleukin-17F (IL-17F), interleukin-26 (IL-26), interleukin -21 (IL-21), interleukin-22 (IL-22) and TNFα whose development, survival and proliferation depend on interleukin-23 (IF-23). These cytokines are capable of activating different types of effector cells, such as keratinocytes, thus leading to their hyperproliferation and to the additional production of pro-inflammatory cytokines, chemokines and antimicrobial peptides, which in turn recruit and activate other cells of the immune system in inflamed skin, which can lead to an amplification of the inflammatory response.

Thus the activation of Thl7 lymphocytes is responsible for the recruitment of cytokines, in particular interleukin-17 (IF17), and other types of pro-inflammatory cells which will lead to the mediation of inflammatory disorders such as acne and / or autoimmune diseases such as psoriasis.

Experiments carried out on mice show that a decrease in the expression of the RORyt receptor leads to a decrease in the activity of Thl7 lymphocytes, which consequently makes it possible to greatly reduce the expression of interleukin-17 ( IL17) (Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR: Cell 2006, 126, 1121-1133) and effectively treat inflammatory disorders and autoimmune diseases mediated by these cytokines, especially those for which significant levels of interleukin-17 (IL-17) are detected.

To this end, patent application WO 2013/160418 describes sulfonamide compounds used as inverse agonists of the RORyt receptor in order to be able to treat inflammatory disorders and autoimmune diseases. Similarly, applications WO 2016/097389, WO 2016/097394, WO 2016/097391, WO 2016/097393 and WO 2016/097392 describe sulfonamide compounds used as reverse agonists of the RORyt receptor. Likewise, other compounds have also been developed as inverse agonists of the RORyt receptor such as those described in patent applications WO 2014/090712, WO 2014/008214, WO 2013/169588, WO 2013/160419, WO 2013/1002027, WO 2013/092939, WO 2013/092941, WO 2013/085890 and WO 2012/100732.

There is therefore a real need to develop new compounds as reverse agonists of the RORyt receptor in order to be able to effectively treat the diseases mediated by such a receptor, in particular inflammatory disorders, such as acne and / or auto- immune systems such as psoriasis or atopic dermatitis.

On the other hand, there is a real need to identify reverse RORyt agonists with less hypophilia. Indeed, most of the inverse agonists known to date, tend to exhibit strong lipophilicity (logD> 4) making them very poorly soluble in aqueous media and impacting their selectivity vis-à-vis other proteins such as the channel hERG.

This goal is achieved thanks to the use of specific pyrazole derivatives as described below which make it possible to modulate the activity of the RORyt receptor and consequently to effectively treat inflammatory disorders and autoimmune diseases of certain pathologies.

The subject of the present invention therefore in particular is one or more compounds of formula (I), their pharmaceutically acceptable addition salts, their hydrates and / or their solvates:

Formula (I) in which:

• Ri represents an alkyl radical, linear or branched, in CiC5, a methylcycloalkyl radical in C3-C5, a cycloalkyl radical in C3-C5 or a heterocycloalkyl radical in C3-C6, • R2 represents a group - (X) _m (CHR5 ) _n Y, • m = 0 or 1, • n = 0, 1 or 2 • X represents a group -NRô or a heteroatom chosen from oxygen or sulfur, • Y represents an alkyne group, substituted or not by a C1-C3 alkyl group, C1-C3 alkoxy group, hydroxy group, C3-C6 heterocycloalkyl group, C5-C9 heterobicycloalkyl group, C3-C5 cycloalkyl radical or heteroaromatic group, • R3 and R4, identical or different, represent a hydrogen atom, a linear or branched C1-C5 alkyl radical, or • R3 and R4 can together form a C3-C5 cycloalkyl ring or a C3-C6 heterocycloalkyl, • Rs and Rô, identical or different, represent a hydrogen atom, an al radical kyl, linear or branched, in C1-C5 or a cycloalkyl radical in C3-C5, • A is a pyrazole derivative among the formulas Al, A-2 and A-3 below

A-1

A-3 • R9 and R12, identical or different, represent a hydrogen atom, a halogen atom, a linear or branched C1-C5 alkyl radical, a C3-C5 cycloalkyl radical, a C1-alkoxy radical -C5, a cyano group -CN or a group - (CFpH2-p) qCFrH ₃ -r, • p denotes 0, 1 or 2, • q denotes 0 or 1, • r denotes 1, 2 or 3, • R7 denotes a hydrogen atom, an alkyl radical, linear or branched C1-C5, a cycloalkyl radical C3-C5, • Rs and R11, identical or different, represent a hydrogen atom, a halogen atom, a radical linear or branched C1-C5 alkyl, a C3-C5 cycloalkyl radical, a C1-C5 alkoxy radical, a cyano group -CN, an amido group -C (= O) N (Ri3) (Ri4) or a -C (Ris) (Ri6) OH group, • Rio represents a hydrogen atom, a linear or branched C1-C5 alkyl radical, a C3-C5 cycloalkyl radical, a keto-C (= O) Ri3 group , an amido group -C (= O) NRi3Ri4, a group -SO2R13, • Rx and R9 or R9 and R11 can together form a C ₅ -C ₇ cycloalkyl, • Rio and R11 or Rio and R12 can together form a heterocycloalkyl ring in C3-C6, • R13, R14, Ris and Riô, identical or different, represent a hydrogen atom or a linear or branched C1-C3 alkyl radical, or • R13 and R14 can together form a heterocycloalkyl in

C3-C6, • R15 and Ri6, can together form a C3C5 cycloalkyl, or a C3-C6 heterocycloalkyl, • it being understood that the alkyl, alkoxy, cycloalkyl, heterocycloalkyl or heteroaromatic radicals may be optionally substituted by one or more atoms of halogen, one or more C1-C3 alkyl radicals, one or more C1-C3 alkoxy radicals, one or more -COOH carboxylic groups or one or more -C (O) C1-C5 alkyl groups.

The compounds according to the invention correspond to derivatives comprising in their structure at least one pyrazole group and at least one phenyl ring substituted at least by a hydroxy group and attached to the pyrazole group by a sulfonamide group.

The compounds according to the invention make it possible to modulate, that is to say to inhibit, the activity of the RORyt receptor.

The present invention also relates to the compound or compounds as defined above as a medicament and cosmetic.

Another subject of the invention relates to the compound or compounds as defined above for their use in the treatment of diseases mediated by the RORyt receptor, in particular inflammatory disorders and / or autoimmune diseases mediated by the RORyt receptor, in especially acne, atopic dermatitis and / or psoriasis.

Furthermore, the invention also relates to a pharmaceutical composition comprising, in a pharmaceutically acceptable medium, one or more compounds of formula (I) as defined above, their pharmaceutically acceptable addition salts, their hydrates and / or their solvates.

The present invention also relates to the pharmaceutical composition as described above for its use in the treatment of diseases mediated by the RORyt receptor, in particular inflammatory disorders and / or autoimmune diseases mediated by the RORyt receptor, in particular acne, atopic dermatitis and / or psoriasis.

Finally, the invention relates to a method of treatment of diseases mediated by the RORyt receptor comprising the administration, in particular topically or orally, of a therapeutically effective amount of one or more compounds as defined above to a patient.

Other objects and characteristics, aspects and advantages of the invention will appear even more clearly on reading the description and the examples which follow.

Within the meaning of the present invention, by C1-C5 alkyl radical is meant a hydrocarbon chain comprising from 1 to 5 carbon atoms.

The alkyl radicals of 1 to 5 carbon atoms are straight or branched chains, preferably chosen from methyl, ethyl, propyl, butyl, i-butyl, t-butyl and pentyl.

According to the invention, the alkyl radicals of 1 to 3 carbon atoms are straight or branched chains preferably chosen from methyl, ethyl, i-propyl and n-propyl.

For the purposes of the present invention, the expression “C3-C5 methylcycloalkyl radical” means a hydrocarbon chain comprising a methyl radical linked to a saturated cyclic alkyl radical, the cyclic alkyl radical comprising from 3 to 5 carbon atoms.

For the purposes of the present invention, the term “cycloalkyl radical” means a saturated cyclic hydrocarbon chain.

Within the meaning of the present invention, the term C 3 -C 5 cycloalkyl radical preferably means a radical chosen from cyclopropane, cyclobutane and cyclopentane.

Within the meaning of the present invention, the expression C5C7 cycloalkyl radical preferably means a radical chosen from cyclopentane, cyclohexane and cycloheptane.

Within the meaning of the present invention, by C3-C6 heterocycloalkyl radical is meant a cyclic saturated hydrocarbon chain interrupted by one or more heteroatoms and comprising from 3 to 6 carbon atoms.

By heteroatom within the meaning of the present invention means any atom different from carbon and hydrogen, and in particular oxygen, nitrogen and sulfur.

In accordance with the invention, the C3-C6 heterocycloalkyl radicals are preferably chosen from azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl and thiomorpholinyl.

Within the meaning of the present invention, by alkyne radical means a hydrocarbon chain comprising a carbonecarbon triple bond.

Within the meaning of the present invention, by C1-C3 alkoxy radical is meant an alkyl radical having from 1 to 3 carbon atoms linked to the rest of the molecule by an oxygen atom. In other words, by C1-C3 alkoxy radical is meant an oxygen atom substituted by a hydrocarbon radical having from 1 to 3 carbon atoms.

Preferably, the C1-C3 alkoxy radical is chosen from methoxy, ethoxy and isopropyloxy radicals.

Within the meaning of the present invention, by C1-C5 alkoxy radical is meant an alkyl radical having from 1 to 5 carbon atoms linked to the rest of the molecule by an oxygen atom.

Preferably, the C1-C5 alkoxy radical is chosen from methoxy, ethoxy, isopropyloxy, tert-butoxy and pentoxy radicals.

Within the meaning of the present invention, the term “heteroaromatic” denotes an aromatic cycle comprising one or more heteroatoms.

Within the meaning of the invention, the term “C5-C9 heterobicycloalkyl” denotes a saturated, bicyclic hydrocarbon chain comprising from 5 to 9 carbon atoms and comprising one or more heteroatoms.

Within the meaning of the present invention, halogen is designated, the chemical elements from the I7 ^th column of the periodic table of elements, especially fluorine, chlorine, bromine and iodine.

For the purposes of the present invention, the expression "at least one" is equivalent to the expression "one or more".

As explained above, in formula (I), Ri represents a C1-C5 linear or branched alkyl radical, a C3-C5 methylcycloalkyl radical, a C3-C5 cycloalkyl radical or a C3-C6 heterocycloalkyl radical.

Preferably, R 1 represents a branched C 1 -C 5 alkyl radical, preferably branched C 3 -C 5, a methylcycloalkyl C 3 -C 5 radical or a cycloalkyl C 3 -C 5 radical.

In a particularly preferred manner, Ri represents a radical chosen from isobutyl, cyclobutane, cyclopentane, cyclohexane and methylcyclopropane.

As explained above, in formula (I), R2 represents a group - (X) _m (CHR5) _n Y, with:

• m = 0 or 1, • n = 0, 1 or 2, • X represents a group -NRô or a heteroatom chosen from oxygen or sulfur, • Y represents an alkyne group, substituted or not by an alkyl group in C1-C3, a C1-C3 alkoxy group, a hydroxy group, a C3-C6 heterocycloalkyl group, a C5-C9 heterobicycloalkyl group, a C3-C5 cycloalkyl radical or a heteroaromatic group, and ίο • R-5 and R6, identical or different, represent a hydrogen atom, a linear or branched C1-C5 alkyl radical or a C3-C5 cycloalkyl radical.

Preferably, R2 represents a group - (X) _m (CHR5) _n Y with:

• m = 1, • n = 1, • X represents a heteroatom chosen from oxygen or sulfur, and preferably is oxygen, • R5 represents a hydrogen atom or an alkyl radical, linear or branched, in C1-C5, and preferably represents a hydrogen atom, • Y represents a heterocycloalkyl group at C3-C6, preferably represents an oxacyclobutane, oxacyclopentane or oxacyclohexane group.

In a particularly preferred manner, R2 represents a group - (X) _m (CHR5) _n Y with:

• m = 1, • n = 1, • X represents an oxygen atom, • R5 represents a hydrogen atom, • Y represents an oxacyclobutane or oxacyclohexane group.

As explained previously, R3 and R4, identical or different, represent a hydrogen atom, a linear or branched C1-C5 alkyl radical, or R3 and R4 can together form a C3-C5 cycloalkyl ring or a heterocycloalkyl C3-C6.

Preferably, R3 and R4, identical or different, preferably identical, represent a hydrogen atom or an alkyl radical, linear in C1-C5, or R3 and R4 together form a C ₃ -C ₅ cycloalkyl ring.

In a particularly preferred manner, R3 and R4, identical or different, preferably identical, represent a hydrogen atom or a methyl radical, or R3 and R4 together form a C3 cycloalkyl ring.

Very particularly preferably, R3 and R4 represent a hydrogen atom.

According to a particularly preferred embodiment of the invention,

Ri represents a radical chosen from isobutyl, cyclobutane, cyclopentane, cyclohexane and methylcyclopropane,

- R2 represents a group - (X) _m (CHR5) _n Y with:

• m = 1, • n = 1, • X represents an oxygen atom, • R5 represents a hydrogen atom, • Y represents an oxacyclobutane or oxacyclohexane group,

- R3 and R4, identical or different, preferably identical, represent a hydrogen atom or a linear C1-C5 alkyl radical, or R3 and R4 together form a C3-C5 cycloalkyl ring.

As explained above, A is a pyrazole derivative from the following formulas A-1, A-2 and A-3:

A-3 with R7, Rs, R9, Rio, R11 and R12 as defined above. Preferably, R7, Rs, R9, Rio, R11 and R12, independently of each other, represent a hydrogen atom or a linear or branched C1-C5 alkyl radical.

Preferably, R9 represents a hydrogen atom or a linear or branched, preferably linear, C1-C5 alkyl radical,

R.7 and Rio, independently of one another, represent a linear or branched, preferably linear, C1-C5 alkyl radical,

Rs, R11 and R12, independently of each other, represent a hydrogen atom or a linear or branched alkyl radical, preferably linear in C1-C5.

Very particularly preferably, R7, Rs, R9, Rio, R11 and R12, independently of each other, represent a hydrogen atom, a methyl radical or an ethyl radical.

Preferably according to the present invention, in formula (I), A is a pyrazole derivative of formula A-1.

According to a first variant of the invention, in formula (I), A is a pyrazole derivative of formula A-1.

Preferably in this first variant:

• R7 represents a hydrogen atom or an alkyl radical, linear or branched, preferably linear, in C1-C5, • Rs represent a hydrogen atom, an alkyl radical, linear or branched, preferably linear, in C1- C5, an amido group -C (= O) N (Ri3) (Ri4) or a group -C (Ri5) (Riô) OH, • R9 represents a hydrogen atom or an alkyl radical, linear or branched, preferably linear, in C1-C5; in particular a hydrogen atom, • R13, R14, Ris and Riô, identical or different, represent a hydrogen atom or an alkyl radical, linear or branched, preferably linear, in C1-C3.

In a particularly preferred manner in this first variant:

• R7 represents a hydrogen atom, a methyl radical or an ethyl radical, • Rs represent a hydrogen atom, a methyl radical, an amido group -C (= O) N (Ri3) (Ri4) or a group - C (Ri5) (Riô) OH, with R13 and R14 representing a methyl radical and R15 and Riô representing a hydrogen atom, • R9 represents a hydrogen atom or a methyl radical, in particular a hydrogen atom.

According to a second variant of the invention, in formula (I), A is a pyrazole derivative of formula A-2.

Preferably in this second variant:

• R9, Rio, R11, identical or different, represent a hydrogen atom or an alkyl radical, linear or branched C1-C5, preferably linear.

In a particularly preferred manner in this second variant:

• R9 and R11, represent a hydrogen atom, • Rio represents an ethyl radical.

According to a third variant of the invention, in formula (I), A is a pyrazole derivative of formula A-3.

Preferably in this third variant:

• R9, Rio, R12, identical or different, represent a hydrogen atom or an alkyl radical, linear or branched C1-C5, preferably linear.

In a particularly preferred manner in this third variant:

• R9 represents a hydrogen atom or a methyl radical, • Rio represents a methyl radical or an ethyl radical, • R12 represents a hydrogen atom or a methyl radical.

In a first particular embodiment of the invention, the compound of formula (I) is chosen from the compounds of formula (II) below:

Formula (II) in which Ri and A are as defined above for formula (I).

In particular, in this first particular mode, R 1 is preferably a tert-butyl radical.

In a second particular embodiment of the invention, the compound of formula (I) is chosen from the compounds of formula (III) below:

(III)

Formula (III) in which R3, R4 and A are as defined above for formula (I).

In particular in this second particular mode, R3 and R4 preferably represent hydrogen atoms.

In a third particular embodiment of the invention, the compound of formula (I) is chosen from the compounds of formula (IV) below:

Formula (IV) in which R2 and A are as defined above for formula (I).

In particular in this third particular mode, R2 preferably represents a group of formula (V) below:

(IV)

(V)

In a fourth particular embodiment of the invention, the compound of formula (I) is chosen from the compounds of formula (VI) below:

OH (VI)

Formula (VI) in which R3, R4 and A are as defined above for formula (I).

In particular in this fourth particular mode, R3 and R4 preferably represent a methyl radical or together form a C3 cycloalkyl ring.

In a fifth particular embodiment of the invention, the compound of formula (I) is chosen from the compounds of formula (VII) below:

R.

OH ‘4

O (VII)

Formula (VII) in which R3, R4 and A are as defined above for formula (I).

In particular in this fifth particular mode, R3 and R4 are preferably identical and represent a hydrogen atom or a methyl radical or together form a C3 cycloalkyl ring.

Preferably, the compound according to the invention is chosen from those of formula (I).

The compounds of formula (I) can be in the form of pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts are described in Berge et al., 1977, "pharmaceutically acceptable salts", J. Pharm. Sci., Vol. 66, pp 1 -19.

In particular, when the compounds of formula (I) according to the invention are in the form of salts then the electroneutrality of said compounds is ensured by an external cationic counter ion W which can be organic or mineral.

W can be chosen from appropriate inorganic cations such as alkali metal ions, in particular Na ⁺ , K ⁺ , alkaline earth metal ions, in particular Ca ²⁺ , Mg ²⁺ , or also other cations such as aluminum ion Al ^{3 +} .

W can be chosen from appropriate organic cations such as the ammonium ion NH4 ⁺ , the substituted ammonium ions such as NH3R ⁺ , NHR2 ⁺ , NR ₄ ⁺ with R representing a C1-C4 alkyl radical.

In particular, the substituted ammonium ions are those chosen from derivatives of ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, amino acids such as lysine and arginine.

An example of a quaternary ammonium ion may be the N ⁺ (CH ₃ ) 4 ion.

The compound or compounds according to the invention can be in the form of their solvates.

For the purposes of the present invention, the term "solvated" means a complex of solute (that is to say the compound according to the invention or the salt of said compound) and of solvent.

If the solvent is water then the solvate can be conveniently regarded as a hydrate, for example, a semi-hydrate, a monohydrate, a dihydrate, a trihydrate, etc.

For example, the solvates and / or hydrates can be obtained directly at the end of the synthesis process, the target compound being isolated in the form of a hydrate, for example a monohydrate or hemi-hydrate, or in the form of a solvated reaction solvent and / or purification solvent.

Unless otherwise indicated, any reference to a compound according to the invention also includes the solvate or the hydrate of the corresponding compound.

Typical procedures for the preparation and identification of hydrates and solvates are well known to those skilled in the art, see for example, pages 202-209 of KJ Guillory, "Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids" in Polymorphism in Pharmaceutical Solids, edition. Harry G. Britain, Vol. 95, Marcel Dekker, Inc., New York, 1999.

Hydrates and solvates can be isolated and characterized by methods known in the art such as thermogravimetric analysis (TGA), TGA-mass spectroscopy, TGA-infrared spectroscopy, X-ray powder diffraction, titration by Karl Fisher, high resolution X-ray diffraction and the like.

Surprisingly, the pyrazoles described in the invention made it possible to maintain a strong inverse agonism on RORyt while bringing the benefits linked to a reduced lipophilicity (increased aqueous solubility and decreased hERG inhibition) (reference: Fauber, BP; Magnusson, SJ Med. Chem. 2014, 57, 5871; Monique B. van Niel, Benjamin P. Fauber, Matthew Cartwright, Simon Gaines, Jonathan C. Killen, Olivier René, Stuart I. Ward, Gladys de Leon Boenig, Yuzhong Deng, Céline Eidenschenk , Christine Everett,

Emanuela Gancia, Arunima Ganguli, Alberto Gobbi, Julie Hawkins, Adam R. Johnson, James R. Kiefer, Hank La, Peter Lockey, Maxine Norman, Wenjun Ouyang, Ann Qin, Nicole Wakes, Bohdan Waszkowycz, Harvey Wong Bioorg. Med. Chem. Lett. 2014.24, 5769:

Benjamin P. Fauber, Olivier René, Gladys de Leon Boenig, Brenda Burton, Yuzhong Deng, Céline Eidenschenk, Christine Everett, Alberto Gobbi, Sarah G. Hymowitz, Adam R. Johnson, Hank La, Marya Liimatta, Peter Lockey, Maxine Norman, Wenjun Ouyang, Weiru Wang, Harvey Wong Bioorg. Med. Chem. Lett. 2014, 24, 3891).

Preferably, the compound of formula (I), as well as its pharmaceutically acceptable addition salts, its hydrates and / or its solvates is chosen from the following compounds:

Table I

Structure IC50 hRORg cat IC50 hCD4 / IL17 cat Compound 1 OH 0 ^ / © V ry ⁿ - \ B B Compound 2 OH O ^ / OAAy. where ^ΝΛ VS B Compound 3 OH O _n V ^N - \ B B Compound 4 ° ÇJV AV ^N_N ^ B B

Compound 5 OH θο® © XJ - vs ND Compound 6 σ '~ · AT AT Compound 7 θ ' © J cf B AT Compound 8 OH 0 _o V © XJ X © X cf B AT Compound 9 OH On © W '^ JXv cf Vf VS VS

Compound 10 oC OH y y -GG vs VS l · OH Compound 11 vs OH y y y > iG AT O vs ND Compound 12 OH y iG vs ND J \ OH Compound 13 oC OH y y iG A ^J AT AT Compound 14 oC OH y y AT ί’Λ G · ' AT AT

Compound 15 OH o _n Y □ XX xj x ^f ' AT AT Compound 16 ° WW oXX xj (Z AT AT Compound 17 OH O _n X © □ XX xj • X AT AT Compound 18 OH O _{Q o} XX X _N J X AT AT Compound 19 OH O _Q Y WJ ₀ X ^, A _N J X AT AT

Compound 20 oh ° o σ ' AT AT Compound 21 Oh on A J AT AT

ND: not determined; A: IC50 <100 nM; B: IC50 = 100-ΙμΜ. C: IC50> 1 μΜ

In Table I described above, the median inhibitory concentrations IC50 for the compounds belonging to formula (I) according to the invention were given according to the GAL4-RORyt transactivation and IL-17A secretion models, such as described below.

Preferably, the compound of formula (I) is chosen from compounds 1 to 21, in particular compounds 6, 7, 8, 13, 14, 15, 16, 18, 19, 20 and 21.

The compounds of formula (I) according to the invention can be prepared according to the following reaction schemes 1, 2 or 3:

Diagram 1

NH,

I *

AT

DMAP, pyridine -►

100 ° C, pwave

LiBH ₄ , MeOH, THF ° C to rt, 24h

Diagram 2 ketone or aldehyde NaBHOAc3, AcOH

Diagram 3

In accordance with the reaction schemes above, the radicals

R2, A and Ri correspond to the radicals as defined above for formula (I).

In accordance with the reaction schemes above, the term "pwave" means a step of heating in the microwave.

In accordance with reaction scheme 2 above, the terms ketone or aldehyde correspond to precursors in the form of ketone or aldehyde which, after reaction with an amine, make it possible to obtain an N-Ri radical, with Ri as defined above for formula (I).

Preferably in the reaction schemes above, R2 corresponds to the group of formula (V) as described above.

The invention also relates to the compound or compounds as described above as a medicament and cosmetic.

Preferably, the invention also relates to the compound or compounds as described above as a medicament.

Indeed, the compounds according to the invention have interesting pharmacological properties because said compounds modulate, that is to say inhibit, the activity of the RORyt receptor.

Thus these properties make the compound or compounds of formula (I) as described above usable as a medicament in the treatment of diseases mediated by the RORyt receptor.

Preferably, the compound or compounds according to the invention are used in the treatment of inflammatory disorders and / or autoimmune diseases mediated by the RORyt receptor.

More preferably, the compound or compounds according to the invention are used in the treatment of acne, atopic dermatitis and / or psoriasis.

According to one embodiment, compounds 1 to 21 of formula (I) are used in the treatment of acne, atopic dermatitis and / or psoriasis.

Preferably according to this embodiment, the compounds 6, 7, 8, 13, 14, 15, 16, 18, 19, 20 and 21 are used in the treatment of acne, atopic dermatitis and / or psoriasis .

According to another embodiment, the compounds are used for the cosmetic treatment of the skin.

As indicated above, the present invention also relates to a pharmaceutical composition comprising, in a pharmaceutically acceptable medium, one or more compounds of formula (I) as defined above, their pharmaceutically acceptable addition salts, their hydrates and / or their solvates.

The administration of the pharmaceutical composition according to the invention can be carried out orally or topically.

Preferably, the pharmaceutical composition is packaged in a form suitable for topical application.

Orally, the composition can be in the form of tablets, capsules, dragees, syrups, suspensions, solutions, powders, granules, emulsions, suspensions of microspheres or nanospheres or lipid vesicles or polymers allowing controlled release.

By topical route, the pharmaceutical composition according to the invention is more particularly intended for the treatment of the skin and the mucous membranes and can be presented in liquid, pasty or solid form, and more particularly in the form of ointments, creams, milks , ointments, powders, soaked tampons, syndets, solutions, gels, sprays, mousses, suspensions, sticks, shampoos, or washing bases. It can also be in the form of suspensions of microspheres or nanospheres or of lipid or polymeric vesicles or of polymeric or gelled patches allowing controlled release.

The compound (s) of formula (I) may be present in the pharmaceutical composition in a content ranging from 0.01 to 10% by weight, preferably in a content ranging from 0.1 to 8% by weight, relative to the weight total of the composition.

The pharmaceutical composition is preferably used in the treatment of diseases mediated by the RORyt receptor, preferably for the treatment of inflammatory disorders and / or autoimmune diseases mediated by the RORyt receptor.

Even more preferably, the pharmaceutical composition is used in the treatment of acne, atopic dermatitis and / or psoriasis.

The invention also relates to a method for the treatment of diseases mediated by the RORyt receptor comprising the administration, in particular topically or orally, of a therapeutically effective amount of the pharmaceutical composition as defined above to a patient.

Preferably, the pharmaceutical composition is applied topically.

The following examples serve to illustrate the invention without, however, being limiting in nature.

Methods for Measuring the IC50s of the Compounds of the Invention

IC50 measurements are performed with the GAL4-RORy Transactivation and IL-17A Secretion tests.

GAL4-RORy Transactivation

The RORy transactivation model was developed from the HG5LN line which is an HeLa line stably expressing a reporter luciferase gene controlled by a pentamer of the yeast GAL4 recognition domain and a β-globin promoter. The HG5LN line was stably transfected with the DNA-binding domain (DBD) (or DNA-binding domain) of GAL4 fused to the ligandbinding domain (LBD) ROR gamma. Molecules that inhibit ROR gamma constitutive activity reduce the expression of luciferase, thereby inducing a reduction in the luminescence emitted.

The cells are seeded in 384-well plates (5000 cells in 45 μL / well of culture medium containing 10% fetal calf serum) and incubated for a period of 4 hours at a temperature of 37 ° C., 5% CO 2. 5 μL of the molecules to be tested (compounds (I) according to the invention) are then added to each well and the plates are incubated for 18 hours at a temperature of 37 ° C under 5% CO2. 20 μL of the luciferase substrate (Promega) are added to each well and the emitted luminescence is read by a microplate reader.

The luminescence units ('RLU') are normalized by positive controls ('POS' containing a saturated concentration of benzene sulfonamide, N- (2,2,2-trifluoroethyl) -N- [4- [2,2,2 -trifluoro-lhydroxy-l- (trifluoromethyl) ethyl] phenyl]) and negative controls ('NEG' containing DMSO):% inhibition = ((RLU-NEG) * 100) / (POSNEG). IC50 values are calculated from a 4-parameter logistics model using XLFit software (IDBS).

IL-17A secretion

This model measures the effect of inhibitors on the secretion of IL-17A by CD4 + cells. The cells are frozen CD4 + cells (STEMCELL, # 70026), isolated from peripheral human blood and activated by anti-CD3 and anti-CD28 antibodies. The amount of IL17A secreted is measured by TR-FRET technology (HTRF® Human Interleukin 17A kit (Cisbio, # 64H17PEC)).

The cells are thawed quickly, resuspended in their culture medium (RPMI 10% SVF inactivated) supplemented with soluble anti-CD28 antibodies and seeded (100,000 cells / well) in 96-well plates previously coated with anti-CD3 antibodies. The cells are then treated with the ranges of inhibitors to be tested (from 1000 nM to 0.05 nM, 0.1% DMSO). After 4 days of incubation, the HTRF signal is measured using a microplate reader (kexcitation = 337 nm, kemission = 620/665 nm). The ratios obtained (665/620) are normalized with respect to the positive control (cells activated by anti-CD3 and anti-CD28, 0.1% DMSO). The IC50s are calculated from a 4-parameter logistics model using the XLFit software (IDBS).

Measurement of median inhibitory concentrations (ICso) on the hERG gene and of aqueous solubility

HERG inhibition

The hERG test is used to study a gene that codes for a protein necessary for the functioning of potassium channels in heart tissue. The patch clamp method on CHO-K1 cells (cells transfected with the hERG gene and which has K + ion activity on the membranes) is used to predict in vitro the blocking of hERG (human Ether-a-go-go Related ).

The extracellular solution (control) is applied first. The cells (Chinese Hamster ovary cells expressing the Human Ether-a-go-go Related Gene) are stabilized with the extracellular solution for 5 minutes. The cells are incubated for 5 minutes with the molecules from the lowest to the highest concentration at 0.6% final DMSO.

The method of calculating the inhibition for each concentration:% inhibition = 100 x (tail current amplitude of the incubated molecule - tail current amplitude of the control vehicle). The result is expressed as an IC50 in μΜ.

Measurement of the aqueous solubility pL of a solution of the active agent at 10 mM in DMSO is diluted in 495 pL of a PBS buffer solution (pH = 7.4).

After stirring for 18 h at 20 ° C and filtration, the soluble part is assayed by UHPLC-UV against a reference standard.

The median inhibitory concentrations IC50 and the aqueous solubility for the compounds belonging to formula (I) according to the invention are presented in Table II below:

Table II

hERG IC50 pM Aqueous solubility μΜ Compound 1 > 30 80 Compound 2 ND 38 Compound 3 ND 76 Compound 4 > 30 81 Compound 5 ND 72 Compound 6 > 30 48 Compound 7 > 30 <1 Compound 8 > 30 60 Compound 9 ND 89 Compound 10 ND 95 Compound 11 ND 8 Compound 12 ND 6 Compound 13 > 30 37 Compound 14 > 30 45 Compound 15 > 30 64 Compound 16 ND 16 Compound 17 ND 1 Compound 18 > 30 6 Compound 19 > 30 21 Compound 20 11 34 Compound 21 ND ND

ND: not determined

The compounds of the invention show a selectivity with respect to the proteins of the hERG channel and a solubility in an aqueous medium measured according to the tests mentioned above.

Examples of synthesis of the compounds according to the invention

Example 1: Synthesis of compound 13: N- (1-ethyl-3-methyllH-pyrazol-5-yl) -3- (hydroxymethyl) -N-isobutyl-4- ((tetrahydro-2Hpyran-4-yl) methoxy) benzenesulfonamide

l ^st step: preparation of 5- (N- (l-ethyl-3-methyl-LH-pyrazol5-yl) sulfamoyl) -2 - ((tetrahydro-2H-pyran-4-yl) methoxy) benzoate

A solution of methyl 5- (chlorosulfonyl) -2 - ((tetrahydro-2 / 7pyran-4-yl) methoxy) benzoate (1.94 g, 5.27 mmol, 1.1 eq.), L-ethyl-3methyl -lH-pyrazol-5-amine (600 mg, 4.79 mmol, 1.0 eq.) and dimethylaminopyridine (29.3 mg, 240 qmol, 0.05 eq.) in anhydrous pyridine (12 mL) is heated at 100 ° C in the microwave for 30 minutes. The reaction is cooled to room temperature and is then concentrated under reduced pressure. Water is added and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with water and with a saturated NaCl solution and are then dried over Na2SO4, filtered and concentrated under reduced pressure.

The crude reaction product is purified by flash chromatography on silica gel (CLbCk / MeOH 100/0 to 97/3) to give 5- (2V- (ethyl-3-methyl 1-177-pyrazol-5-yl) sulfamoyl) -2 - ((tetrahydro-2JY-pyran4-yl) methoxy) methyl benzoate in the form of a white solid (936 mg, 2.16 mmol, 45%).

^Χ Η NMR (500 MHz, Chloroform-d) δ 8.26 (d, J = 2.5 Hz, 1H), 7.80 (dd, J = 8.8, 2.5 Hz, 1H), 7, 01 (d, J = 8.8 Hz, 1H), 5.60 - 5.32 (m, 1H), 4.15 - 4.00 (m, 4H), 3.95 (d, J = 6, 4 Hz, 2H), 3.90 (s, 4H), 3.47 (td, J = 11.8, 2.1 Hz, 2H), 2.15 (m and overlap s, 4H), 1.81 (dq, J = 13.1, 2.0 Hz, 2H), 1.69 - 1.46 (m, 4H), 1.37 (t, J = 7.2 Hz, 3H).

[M + H] = 43 8

2 ^nd Step: Preparation of 5- (N- (l-ethyl-3-methyl-lH-pyrazol5-yl) -N-isobutylsulfamoyl) -2 - ((tetrahydro-2H-pyran-4-yl) methoxy) benzoate methyl

To a solution of methyl 5- (A- (1-ethyl-3-methyl-1H-pyrazol-5yl) sulfamoyl) -2 - ((tetrahydro-2JY-pyran-4-yl) methoxy) benzoate (250 mg, 571 gmol, 1.0 eq.) In THF (4 mL) is added 2-methylpropan-1-ol (66 gL, 714 gmol, 1.25 eq.) Followed by triphenylphosphine (150 mg, 571 gmol, 1.0 eq.) And the mixture is cooled to 0 ° C. Di-tert-butyl azodicarboxylate (131 mg, 571 gmol, 1.0 eq.) In THF (4 mL) is added and the reaction medium is stirred at 0 ° C for 15 minutes then brought to room temperature and stirred at this temperature for 21 hours. 2-methylpropan-1-ol (66 gL, 714 gmol, 1.25 eq.) As well as triphenylphosphine (150 mg, 571 μιηοΐ, 1.0 eq.) Are added and the reaction medium is cooled to 0 ° vs. Di-tert-butyl azodicarboxylate (131 mg, 571 gmol, 1.0 eq) in THF (1 mL) is added and the reaction medium is stirred at 0 ° C for 15 minutes then brought to room temperature and stirred at this temperature for 4 hours. The reaction medium is diluted with water and ethyl acetate. The organic phase is recovered and the aqueous phase is extracted again with ethyl acetate. The combined organic phases are dried over Na ₂ SO4, filtered and concentrated under reduced pressure. The crude reaction product is purified by flash chromatography on silica gel (cHex / EtOAc 100% at 0% for 15 minutes) to obtain 5- (A- (1-ethyl-3-methyl-1 / 7pyrazol-5-yl) -A-isobutylsulfamoyl) -2 - ((tetrahydro-2Z / -pyran-4-yl) methyl methoxyjbenzoate in the form of a white solid (172 mg, 348 gmol, 61%).

^X H NMR (500 MHz, Chloroform-d) δ 8.12 (d, J = 2.4 Hz, 1H),

7.72 (dd, J = 8.8, 2.5 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 5.36 (s, 1H), 4.17 (d , J = 7.2 Hz, 2H), 4.09 - 4.00 (m, 2H), 3.96 (d, J = 6.5 Hz, 2H), 3.90 (s, 3H), 3 , 46 (dd, J = 11.8, 2.1 Hz, 1H), 3.40 (br s, 1H), 2.77 (br s, 1H), 2.20 (s, 3H), 2, 20-2.12 (m, 1H), 1.82 (d, J = 13.0 Hz, 2H), 1.54 (d, J = 7.3 Hz, 4H), 1.50 (t, J = 7.2 Hz, 3H), 1.02 (br s, 3H), 0.81 (br s, 3H).

[M + H] = 494

^Step 3: Preparation of N- (l-ethyl-3-methyl-lH-pyrazol-5-yl) -3- (hydroxymethyl) -N-isobutyl-4- ((tetrahydro-2H-pyran-4-yl) methoxy) benzenesulfonamide ( compound 13)

o.

To a solution of methyl 5- (A- (1-ethyl-3-methyl-17 / -pyrazol-5-yl) -Aisobutylsulfamoyl) -2 - ((tetrahydro-2H-pyran-4-yl) methoxy) benzoate (150 mg, 304 pmol, 1.0 eq.) In THF (3.5 mL, 0.1 M) at 0 ° C are added lithium borohydride ([2M in THF], 243 pmol, 486 pmol , 1.6 eq.) Followed by methanol (20 μL, 486 pmol, 1.6 eq.) And the reaction medium is brought to room temperature and stirred for 12 h. Lithium borohydride ([2M in THF], 243 pmol, 486 pmol, 1.6 eq.) And methanol (20 μL, 486 pmol, 1.6 eq.) Are added successively and the reaction medium is stirred at room temperature for 24 hours. The reaction medium is concentrated under reduced pressure. Water (5 mL) and ethyl acetate (15 mL) are added. The phases are separated and the aqueous phase is extracted with ethyl acetate (3 χ 15 mL). The combined organic phases are washed with a saturated NaCl solution, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude reaction product is purified by flash chromatography on silica gel (CH2Cl2 / EtOAc 100/0 to 0/100) to give N- (1-ethyl-3-methyl-1Hpyrazol-5-yl) -3- (hydroxymethyl) - N-isobutyl-4 - ((tetrahydro-2H-pyran4-yl) methoxy) benzenesulfonamide in the form of a white solid (122 mg, 262 pmol, 86%).

^X H NMR (500 MHz, Chloroform-d) δ 7.71 (d, J = 2.4 Hz, 1H), 7.57 (dd, J = 8.7, 2.4 Hz, 1H), 6, 92 (d, J = 8.7 Hz, 1H), 5.38 (s, 1H),

4.73 (d, J = 3.7 Hz, 2H), 4.22 - 4.11 (m, 2H), 4.09 - 4.00 (m, 1H), 3.94 (d, J = 6.3 Hz, 2H), 3.53 - 3.42 (m, 2H), 3.40 (s, 1H), 2.77 (s, 1H), 2.20 (s, 3H), 2, 17 - 2.04 (m, 1H), 1.76 (d, J = 12.7, 2H), 1.64 1.43 (overlap t and m, 7H), 1.01 (br s, 3H) , 0.84 (br s, 3H).

[M + H] = 466

Example 2 Synthesis of Compound 14: A-cyclobutyl-N- (lethyl-3-methyl - 1H-pyrazol-5-yl) -3- (hydroxymethyl) -4 - ((tetrahydro2H-pyran-4-yl) methoxy) benzenesulfonamide

^1st stage: preparation of N-cyclobutyl-1-ethyl-3-methyl-1Hpyrazol-5-amine

Cyclobutanone (615 qL, 8.23 mmol, 1.03 eq.) Is added to a solution of 1-ethyl-3-methyl-1H-pyrazol-5-amine (1.0 g, 7.99 mmol, 1.0 eq.) In acetic acid (13.2 mL) and the mixture is stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (2.54 g, 11.98 mmol, 1.5 eq.) Is added and the mixture is stirred at room temperature for 4 hours. The reaction medium is concentrated under reduced pressure. The residue is taken up in water and a saturated NaHCO3 solution is added. The aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with a saturated NaCl solution, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude reaction product is purified by flash chromatography on silica gel (80 g, CH2Cl2 / CH3OH 100/0 to 96/4) to give Ncyclobutyl-1-ethyl-3-methyl-1H-pyrazol-5-amine (600 mg , 3.18 mmol, 40%).

1H NMR (500 MHz, Chloroform-d) δ 5.22 (s, 1H), 3.86 (d, J =

7.2 Hz, 2H), 3.74 (m, 1H), 2.40 (ddd, J = 8.2, 3.2, 2.1 Hz, 2H), 2.17 (s, 3H), 1.92 - 1.63 (m, 4H), 1.35 (t, J = 7.2 Hz, 3H) [M + H] = 182

2 ^nd Step: Preparation of 5- (N-cyclobutyl-N- (l-ethyl-3-methyl-lH-pyrazol-5-yl) sulfamoyl) -2 - ((tetrahydro-2H-pyran-4-yl) methoxy) benzoate methyl

A solution of N-cyclobutyl-1-ethyl-3-methyl-1H-pyrazol-5amine (497 mg, 2.77 mmol, 1.0 eq.), 5- (chlorosulfonyl) -2 ((tetrahydro-2H- pyran-4-yl) methoxy) methyl benzoate (1.45 g, 4.16 mmol, 1.5 eq.) and dimethylaminopyridine (34 mg, 277 qmol, 0.1 eq.) in anhydrous pyridine (12 mL ) is heated to 100 ° C in the microwave for 30 minutes. 5- (chlorosulfonyl) -2 ((tetrahydro-2H-pyran-4-yl) methoxy) methyl benzoate (0.48 g, 1.39 mmol, 0.5 eq.) Is added and the reaction medium is heated at 100 ° C in the microwave for 30 minutes. The reaction medium is cooled to room temperature and concentrated under reduced pressure. Water and ethyl acetate are added and the phases are separated. The aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with water and with a saturated NaCl solution, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain 1.5 g of crude oil (orange oil). The crude reaction product is purified by flash chromatography on silica gel (40 g, cHex / EtOAc 9/1 to 0/1) to give 5- (Ncyclobutyl-N- (l-ethyl-3-methyl-1H-pyrazol- 5-yl) sulfamoyl) -2 ((tetrahydro-2H-pyran-4-yl) methoxy) methyl benzoate (308 mg, 626 qmol, 23%) having the appearance of a pale orange oil.

1H NMR (500 MHz, Chloroform-d) δ 8.19 (d, J = 2.5 Hz, 1H),

7.78 (dd, J = 8.8, 2.5 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 5.42 (s, 1H),

4.55 (m, 1H), 4.21 - 4.00 (overlapping signals, 6H), 3.96 (dd,

(overlap s and m, 4H), 1.80 (s, 1H), 1.61 - 1.39 (overlap of signals, 11H) [M + H] = 492

^3rd Stage: Preparation of N-cyclobutyl-N- (l-ethyl-3-méthyllH-pyrazol-5-yl) -3- (hydroxymethyl) -4 - ((tetrahydro-2H-pyran-4-yl) methoxy) benzenesulfonamide ( compound 14)

O.

To a solution of methyl 5- (N-cyclobutyl-N- (1-ethyl-3-methyl-1Hpyrazol-5-yl) sulfamoyl) -2 - ((tetrahydro-2H-pyran-4-yl) methoxy) benzoate (150 mg, 305 gmol, 1.0 eq.) In THF (3 mL) are added lithium borohydride ([2M in THF], 244 gL, 488 gmol, 1.6 eq.) Followed by methanol (20 gL, 488 gmol, 1.6 eq.) And the reaction medium is stirred for 3 h 15 min at 40 ° C. The reaction medium is brought to ambient temperature and is hydrolyzed by adding water then is concentrated under reduced pressure. The crude is taken up in water and ethyl acetate. The phases are separated and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with a saturated NaCl solution, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude reaction product is purified by flash chromatography on silica gel (12 g, CH2Cl2 / MeOH 1/0 to 95/5) to give N-cyclobutyl-N- (lethy 1-3 -methy 1- 1H-pyrazol-5 -y 1) - 3 - (hydroxy methyl) -4 - ((tetrahydro7.62 (dd, J = 8.6, 2.5 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H ), 5.45 (s, 1H),

2H-pyran-4-yl) methoxy) benzenesulfonamide in the form of a white solid (99 mg, 213 mg, 70%)

1H NMR (500 MHz, Chloroform-d) δ 7.84 - 7.73 (m, 1H),

4.73 (d, J = 6.0 Hz, 2H), 4.52 (m, 1H), 4.14 - 3.98 (m, 4H), 3.93 (dd, J = 6.4, 1.6 Hz, 2H), 3.46 (td, J = 11.9, 2.1 Hz, 2H), 2.27 - 2.05 (m, 4H), 1.87 (m, 1H), 1.83 - 1.63 (signal overlap, 4H), 1.60 (s, 2H), 1.57 - 1.39 (m, 7H).

[M + H] = 464

Claims (13)

1. Compound of formula (I), its pharmaceutically acceptable addition salts, its hydrates and / or its solvates: OH (I) Formula (I) in which: • R represents an alkyl radical, linear or branched CiC _5, a méthylcycloalkyl radical C 3 -C _5> cycloalkyl, C3-C5 or a heterocycloalkyl radical C ₃ -CE, • R2 represents a group - (X) _m (CHR ₅ ) _n Y, • m = 0 or 1, • n = 0, 1 or 2, • X represents a group -NR ₆ or a heteroatom chosen from oxygen or sulfur, • Y represents an alkyne group , substituted or not substituted by a C1-C3 alkyl group, a C1-C3 alkoxy group, a hydroxy group, a C3-C6 heterocycloalkyl group, a C5-C9 heterobicycloalkyl group, a C3-C5 cycloalkyl radical or a heteroaromatic group, • R3 and R4, identical or different, represent a hydrogen atom, a linear or branched C1-C5 alkyl radical, or • R ₃ and R4 can together form a C3-C5 cycloalkyl ring or a C3-C6 heterocycloalkyl, • R5 and Rê, identical or different, represent a hydrogen atom, a linear or branched C1-C5 alkyl radical or a C3-C5 cycloalkyl radical, • A is a pyrazole derivative chosen from the following formulas Al, A-2 and A-3: A-1 A-2 A-3 • Rg and Ru, identical or different, represent a hydrogen atom, a halogen atom, an alkyl radical, linear or branched in C1-C5, a cycloalkyl radical in C3-C5, an alkoxy radical in C1 -C5, a cyano group -CN or a group - (CF _p H _{2. P} ) _q CF _r H ₃ - _r , • p denotes 0, 1 or 2, • q denotes 0 or 1, • r denotes 1, 2 or 3, • R7 represents a hydrogen atom, an alkyl radical, linear or branched in C1-C _5j a cycloalkyl radical in C3-C5, • Rg and Ru, identical or different, represent a hydrogen atom, an atom halogen, an alkyl radical, linear or branched Ci-C _5, a cycloalkyl radical in C 3 -C _5> alkoxy C1-C5, a cyano group -CN, an amido group -C (= O) N (R ₁₃ ) (Ri4) or a group -C (Ri5) (Ri6) OH, • Rio represents a hydrogen atom, an alkyl radical, linear or branched in Ci-Cs ₍ a C ₃ -Cs cycloalkyl radical ₍ a keto group -C (= O) Ri3, an amido group -C (= O) NRi ₃ R] 4, a group -SO2R13, • Rg and Rg or Rg and Ru can together form a C ₅ -C ₇ cycloalkyl, • Rio and Ru or Rio and R _i2 can together form a heterocycloalkyl ring in C3-C6, • R13, R14, R15 and Ri6, identical or different, represent a hydrogen atom or a linear or branched C1-C3 alkyl radical, or • Ri3 and R14 can together form a heterocycloalkyl in C ₃ -C ₆ , • Ri ₅ and Ri ₆ , can together form a C ₃ C ₅ cycloalkyl, or a C ₃ -C ₆ heterocycloalkyl, • it being understood that the alkyl, alkoxy, cycloalkyl, heterocycloalkyl or heteroaromatic radicals may be optionally substituted by one or more halogen atoms, one or more alkyl radicals, C _3, one or more alkoxy radicals Ci-C _3, one or more carboxyl groups -COOH or one or more groups -C (O) alkyl-C _5. 2. Compound according to claim 1, characterized in that Ri represents a branched C1-C5 alkyl radical, preferably branched C ₃ -C ₅ , a methylcycloalkyl C ₃ -Cs radical or a cycloalkyl C ₃ -Cs radical , and more preferably R1 represents a radical chosen from isobutyl, cyclobutane, cyclopentane and methylcyclopropane. 3. Compound according to claim 1 or 2, characterized in that R2 represents a group - (X) _m (CHR5) _n Y with: • m = 1, • n = 1, • X represents a heteroatom chosen from oxygen or sulfur, and preferably is oxygen, • R ₅ represents a hydrogen atom or an alkyl radical, linear or branched, in C1-C5, and preferably a hydrogen atom, • Y represents a heterocycloalkyl group C ₃ -C ₆ , preferably an oxacyclobutane, oxacyclopentane or oxacyclohexane group, and more preferably R2 represents a group - (X) _m ( CHR5) _n Y with: • m = 1, • n = 1, • X represents an oxygen atom, • R5 represents a hydrogen atom, • Y represents an oxacyclobutane or oxacyclohexane group. 4. Compound according to any one of the preceding claims, characterized in that R3 and R ₄ , identical or different, preferably identical, represent a hydrogen atom or an alkyl radical, linear in C1-C5, or R3 and R ₄ together form a C3-C5 cycloalkyl ring, and preferably R ₃ and R ₄ , identical or different, preferably identical, represent a hydrogen atom or a methyl radical, or R3 and R ₄ together form a cycloalkyl ring in C ₃ . 5. Compound according to any one of the preceding claims, characterized in that A is a pyrazole derivative of formula A-1 in which: • R ₇ represents a hydrogen atom or an alkyl radical, linear or branched, preferably linear, in C1-C5, • Rg represent a hydrogen atom, an alkyl radical, linear or branched, preferably linear, in C1 -C5, an amido group -C (= O) N (Ri3) (Ri ₄ ) or a group -C (Ris) (Ri6) OH, • R9 represents a hydrogen atom or an alkyl radical, linear or branched, preferably linear, in C1-C5, • R13, Ri ₄ , Ris and Rie, identical or different, represent a hydrogen atom or an alkyl radical, linear or branched, preferably linear, in C1-C3, and more preferably A is a pyrazole derivative of formula A-1 in which: • R ₇ represents a hydrogen atom, a methyl radical or an ethyl radical, • Rg represent a hydrogen atom, a methyl radical, an amido group -C (= O) N (Ri3) (Ri ₄ ) or a group -C (Ri ₅ ) (Ri ₆ ) OH, with R13 and Ri ₄ representing a methyl radical and R15 and Ri6 representing a hydrogen atom, • R9 represents a hydrogen atom or a methyl radical. 6. Compound according to any one of claims 1 to 4, characterized in that A is a pyrazole derivative of formula A-2 in which R ₉ , Rio, R11, identical or different, represent a hydrogen atom or a radical alkyl, linear or branched C1-C5, preferably linear, and more preferably A is a pyrazole derivative of formula A-2 in which: • R9 and Ru, represent a hydrogen atom, • Rio represents an ethyl radical. 7. Compound according to any one of claims 1 to 4, characterized in that A is a pyrazole derivative of formula A-3 in which Rc>, Rio, R12, identical or different, represent a hydrogen atom or a radical alkyl, linear or branched C1-C5, preferably linear, and more preferably A is a pyrazole derivative of formula A-3 in which: • R9 represents a hydrogen atom or a methyl radical, • Rio represents a methyl radical or an ethyl radical, • R12 represents a hydrogen atom or a methyl radical. 8. Compound according to any one of the preceding claims, characterized in that it is chosen from the following compounds: OH ltd OH Sp Compound 5 Compound 7 Compound 9 Compound 11 Compound 13/4 \ = N Compound 6 Oh k O _t S ^z > NOT Compound 8 OH Compound 10 Compound 12 OH Oq r-, Z N t = N Compound 14 9. Compound according to claim 8, characterized in that it is chosen from compounds 6, 7, 8, 13, 14, 15, 16, 18, 19, 20 and 21. 10. Compound according to any one of claims 1 to 9 5 as a medicament. 11. Compound for its use according to any one of claims 1 to 9 in the treatment of diseases mediated by the RORyt receptor, preferably for the treatment of inflammatory disorders and / or autoimmune diseases mediated by the RORyt receptor, and especially for the treatment of acne, atopic dermatitis and / or psoriasis. 12. A pharmaceutical composition comprising, in a pharmaceutically acceptable medium, one or more compounds of formula (I) as defined according to any one of claims 1 to 9, their pharmaceutically acceptable addition salts, their hydrates and / or their solvated. 13. Pharmaceutical composition for use according to claim 12, characterized in the treatment of diseases mediated by the RORyt receptor, preferably for the treatment of inflammatory disorders and / or autoimmune diseases mediated by the RORyt receptor, and in particular for the treatment of acne, atopic dermatitis and / or psoriasis.