# US 10,246,440 B2 · Indazole sulfonamide derivatives as inverse agonists of retinoid-related orphan receptor gamma (ROR γ (T))

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- Number: US 10,246,440 B2
- Document ID: US10246440B2
- Status: Granted
- Kind: B2
- Application number: 15/537,678
- Filed: 2015-12-18
- Published: 2017-11-30
- Granted: 2019-04-02
- Earliest claimed: 2014-12-19
- Assignees: Galderma Research & Development
- Applicants: Galderma Research & Development
- Inventors: Branislav Musicki; Gilles Ouvry; Etienne Thoreau; Claire Bouix-Peter
- Web page: https://patentgrep.com/patent/US10246440B2

## CPC

- C07D 413/06: linked by a carbon chain containing only aliphatic carbon atoms
- A61P 17/04: Antipruritics
- A61P 17/06: Antipsoriatics
- A61P 17/10: Anti-acne agents
- C07D 209/34: in position 2
- C07D 215/36: Sulfur atoms (C07D215/24 takes precedence)
- C07D 231/56: Benzopyrazoles; Hydrogenated benzopyrazoles
- C07D 235/26: Oxygen atoms
- C07D 307/79: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 401/14: containing three or more hetero rings
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D 407/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 417/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 471/10: Spiro-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Indazole sulfonamide derivatives of formula (I), the pharmaceutically acceptable addition salts thereof, the hydrates and/or solvates thereof, and the use of same as inverse agonists of retinoid-related orphan receptor gamma RORγt are described. Pharmaceutical compositions including such compounds, as well as the use thereof for the topical and/or oral treatment of RORγt receptor-mediated inflammatory diseases, in particular acne, psoriasis and/or atopic dermatitis are also described.

## Claims

### Claim 1

A method of treating acne, atopic dermatitis and/or psoriasis comprising administering a pharmaceutical composition comprising at least one compound of formula (I), a pharmaceutically acceptable salt thereof, a hydrate thereof and/or a solvate thereof:
wherein in formula (I):
L represents a single bond or a methylene group CH2,
X represents a cyclic radical chosen from the radicals X1 and X2 below:
one or two of the elements Y1, Y2, Y3, Y4 and Y5 represent(s) a nitrogen atom and the other elements correspond to a group —CR2, or each of the elements Y1, Y2, Y3, Y4 and Y5 corresponds to a group —CR2,
each of the elements Q1, Q2 and Q3 corresponds to an identical or different —CR2a group,
R1 represents a linear or branched C3-C5 alkyl radical, optionally substituted with a hydroxyl group and/or a halogen atom, a C3-C5 cycloalkyl radical, a linear or branched C2-C5 alkenyl radical, a —CH2—(C3-C5)cycloalkyl radical, a C4-C5 heterocycloalkyl radical, a —CH2—(C4-C5)heterocycloalkyl radical,
R2 represents a hydrogen atom or a halogen atom, a linear or branched C1-C5 alkyl radical, a linear or branched C2-C4 alkenyl radical, a C1-C4 alkoxy radical, a cyano group —CN, a radical —C(═O)R′2 with R′2 denoting a C1-C3 alkoxy radical, a —CF3 radical; said alkyl, alkenyl and alkoxy radicals optionally being substituted with one or more halogen atoms,
R2a represents a hydrogen atom or a halogen atom, a linear or branched C1-C5 alkyl radical, a linear or branched C2-C4 alkenyl radical, a C1-C4 alkoxy radical, a —CN group, a hydroxyl group —OH, a group —CH(R3a)OH, a carboxylic group —COOH, a carbamoyl group —CONR2cR2d, an amido group —NR2cCOR2d, a group —SO2R2c, a group —SOR2c, a group —S(═O)(═NH—R2c), said alkyl, alkenyl and alkoxy radicals optionally being substituted with one or more halogen atoms,
R2c and R2d, which are identical or different, represent a hydrogen atom or a linear or branched C1-C5 alkyl radical;
R3a represents a hydrogen atom or a linear or branched C1-C5 alkyl radical,
R3 represents a hydrogen atom, a halogen atom, a group (CHR6)n—(Z)o—(CHR′6)p—R7 or a group CH═R7,
n, o and p, which are identical or different, represent zero or a natural integer ranging from 1 to 3,
Z represents a divalent group selected from the group consisting of a methylene group —CH2—, an amino group —NH— and an oxygen atom —O—,
R6 and R′6, which are identical or different, represent a hydrogen atom, a methyl group —CH3, a group —OH, a hydroxymethyl group, or a carboxylic function-COOH,
R7 represents:
a hydrogen or a halogen atom,
a group COOR′7 with R′7 denoting (C1)alkyl(C6)heterocycle,
a heterocycloalkyl radical, wherein the heterocycloalkyl radical is optionally substituted with one or more halogen atoms, one or more linear or branched C1-C3 alkyl groups, one or more —OH groups, one or more carbonyl functions, one or more linear or branched C1-C4 hydroxyalkyl groups, one or more amino groups, one or more groups —C(═O)R7a, one or more groups S(═O)2R7a; R7a representing a linear or branched C1-C3 alkyl radical, a linear or branched C1-C3 alkoxy radical, or an amino radical N(R8a)(R8b),
a C3-C6 cycloalkyl radical, wherein the cycloalkyl radical is optionally substituted with one or more methyl radicals, one or more halogen atoms, a cyano group —CN or one or more groups —COR13; R13 denoting a linear or branched C1-C3 alkoxy radical, or a hydroxyl group,
an aromatic radical, wherein the aromatic radical is optionally substituted with one or more halogen atoms, one or more linear or branched C1-C3 alkyl groups optionally substituted with one or more halogen atoms, one or more C1-C3 alkoxy groups, one or more amino groups —NR11R12, one or more groups —COR11, one or more groups —COOR11, one or more amido groups —CONR11R12, one or more groups —SOR11, one or more groups —SO2R11, one or more groups —NHCOR11, one or more groups —NHCOOR11, one or more groups —SO2NR11R12 or one or more —CN groups; R11 and R12, which are identical or different, representing a hydrogen atom, a hydroxyl radical —OH, a linear or branched C1-C3 alkyl radical optionally substituted with one or more halogen atoms;
a heteroaromatic radical, wherein the heteroaromatic radical is optionally substituted with one or more halogen atoms, one or more linear or branched C1-C3 alkyl groups optionally substituted with one or more halogen atoms, one or more C1-C3 alkoxy groups, one or more amino groups —NR11R12, one or more groups —COR11, one or more groups —COOR11, one or more amido groups —CONR11R12, one or more groups —SOR11, one or more groups —SO2R11, one or more groups —NHCOR11, one or more groups —NHCOOR11, one or more groups —SO2NR11R12 or one or more —CN groups; R11 and R12, which are identical or different, representing a hydrogen atom, a hydroxyl radical —OH, a linear or branched C1-C3 alkyl radical optionally substituted with one or more halogen atoms;
R5 represents a hydrogen atom or a halogen atom, a linear or branched C1-C3 alkyl radical optionally substituted with one or more halogen atoms; an amino radical —NH2, a C4-C5 heterocyclic radical, an OCH2—(C4-C5) heterocyclic radical, a radical CH2R′7a with R′7a denoting a methoxy radical, a hydroxyl group —OH, a —CH2COOH group, a group —CH(R5b)OH, a carboxylic group —COOH, a —CN group, a thioxo function,
R5b represents a hydrogen atom, a linear or branched C1-C3 alkyl radical optionally substituted with one or more carboxylic functions; a cyclopropyl radical,
R8a and R8b, which are identical or different, denote a hydrogen atom, a linear or branched C1-C3 alkyl radical or a cyclopropyl radical; and
wherein the compound of formula (I) inhibit activity of a RORγt receptor.

### Claim 2 (depends on 1)

The method as defined by claim 1, wherein R7 represents a heterocyclic radical selected from the group consisting of:
in which:
R7a represents a linear or branched C1-C3 alkyl radical, a linear or branched C1-C3 alkoxy radical or an amino radical N(R8a)(R8b),
R8a and R8b, which may be identical or different, denote a hydrogen atom, a linear or branched C1-C3 alkyl radical or a cyclopropyl radical,
R8 and R9, which are identical or different, represent a hydrogen atom, a linear or branched C1-C3 alkyl radical, a hydroxyl group —OH, a carbonyl function ═O, a C1 hydroxyalkyl radical (—CH2OH), an amino group NH2,
R8 and R9 can form, together with the carbon atoms to which they are attached, a 5- to 7-membered carbocyclic ring.

### Claim 3 (depends on 1)

The method as defined by claim 1, wherein R7 represents an aromatic or heteroaromatic radical selected from the group consisting of:
in which:
R10 represents a hydrogen atom or a halogen atom, one linear or branched C1-C3 alkyl group optionally substituted with one or more halogen atoms, one C1-C3 alkoxy group, one amino group —NR11R12, one group —COR11, one group —COOR11, one amido group —CONR11R12, one group —SOR11, one group —SO2R11, one group —NHCOR11, one group —NHCOOR11, one group —SO2NR11R12 or one —CN group; R11 and R12, which are identical or different, representing a hydrogen atom or a linear or branched C1-C3 alkyl radical optionally substituted with one or more halogen atoms,
m denotes zero or a natural integer ranging from 1 to 3.

### Claim 4 (depends on 1)

The method as defined by claim 1, wherein the compound, the pharmaceutically acceptable salt thereof, the hydrate thereof and/or the solvate thereof has a structure of formula (II):
wherein in formula (II) R1, R3, R5 and Y1 to Y5 have the same meanings as in formula (I).

### Claim 5 (depends on 1)

The method as defined by claim 1, wherein the compound has the structure of formula (III), and also the pharmaceutically acceptable addition salts thereof, hydrates thereof and/or solvates thereof:
in which formula (III) R1, R3, R5 and Y1 to Y5 have the same meanings as in formula (I).

### Claim 6 (depends on 1)

The method as defined by claim 1, wherein the compound is selected from the group consisting of:

### Claim 7 (depends on 1)

The method as defined by claim 1, wherein the method comprises administering an effective amount of the compound for the treatment of acne to an individual subject in need thereof.

### Claim 8 (depends on 1)

The method as defined by claim 1, wherein the method comprises administering an effective amount of the compound for treating psoriasis to an individual subject in need thereof.