# US 10,118,895 B2 · ROR gamma (RORγ) modulators

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- Number: US 10,118,895 B2
- Document ID: US10118895B2
- Status: Granted
- Kind: B2
- Application number: 15/578,997
- Filed: 2016-06-03
- Published: 2018-05-24
- Granted: 2018-11-06
- Earliest claimed: 2015-06-05
- Assignees: Lead Pharma Holding B.V.; Sanofi
- Applicants: Lead Pharma Holding B.V.; Sanofi
- Inventors: Joseph Maria Gerardus Barbara Cals; David Machnik; Sander Bernardus Nabuurs; Jean-Francois Sabuco; Laurent Schio
- Web page: https://patentgrep.com/patent/US10118895B2

## CPC

- C07D 213/71: to which a second hetero atom is attached
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/4427: containing further heterocyclic ring systems
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/4965: Non-condensed pyrazines
- A61K 31/50: Pyridazines; Hydrogenated pyridazines
- A61K 31/505: Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 5/14: of the thyroid hormones, e.g. T3, T4
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/06: Antiasthmatics
- A61P 11/14: Antitussive agents
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 33/02: Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 213/75: Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
- C07D 237/18: Sulfur atoms
- C07D 239/38: One sulfur atom
- C07D 241/18: Oxygen or sulfur atoms
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Novel compounds according to Formula I Meta or para or a pharmaceutically acceptable salt thereof wherein: A11-A14 are N or CR11, CR12, CR13, CR14, respectively, with the proviso that no more than two of the four positions A in A11-A14 can be simultaneously N; A6, A7, A8, A9, A10 are N or CR6, CR7, CR8, CR9, CR10, respectively, with the proviso that at least one but no more than two of the five positions A in A6, A7, A8, A9, A10 is N; R1 is C(2-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, (di)C(3-6)cycloalkylamino or (di)(C(3-6)cycloalkylC(1-3)alkyl)amino; R5 is H, hydroxyethyl, methoxyethyl, C(1-6)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(1-9)heteroaryl, C(1-9)heteroarylC(1-3)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkylC(1-3)alkyl; the sulfonyl group with R1 is represented by one of R7, R8 or R9; R15 is H, C(1-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(1-9)heteroaryl, C(1-9)heteroarylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkyl-C(1-3)alkyl; and R16 is C(1-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(1-9)heteroaryl, C(1-9)heteroarylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkyl-C(1-3)alkyl.

## Claims

### Claim 1

A compound according to Formula I
Meta or para or a pharmaceutically acceptable salt thereof wherein:
A11-A14 are N or CR11, CR12, CR13, CR14, respectively, with the proviso that no more than two of the four positions A in A11-A14 can be simultaneously N;
A6, A7, A8, A9, A10 are N or CR6, CR7, CR8, CR9, CR10, respectively, with the proviso that at least one but no more than two of the five positions A in A6, A7, A8, A9, A10 is N;
R1 is C(2-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, (di)C(3-6)cycloalkylamino or (di)(C(3-6)cycloalkylC(1-3)alkyl)amino, with all carbon atoms of alkyl groups optionally substituted with one or more F and all carbon atoms of cycloalkyl groups optionally substituted with one or more F or methyl;
R2 and R3 are independently H, F, methyl, ethyl, hydroxy, methoxy or R2 and R3 together is carbonyl, all alkyl groups, if present, optionally being substituted with one or more F;
R4 is H or C(1-6)alkyl;
R5 is H, hydroxyethyl, methoxyethyl, C(1-6)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(1-9)heteroaryl, C(1-9)heteroarylC(1-3)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkylC(1-3)alkyl, all groups optionally substituted with one or more F, C(1-2)alkoxy or cyano;
the sulfonyl group with R1 is represented by one of R7, R8 or R9;
the remaining R6-R14 are independently H, halogen, amino, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-6)alkyl, all of the alkyl groups optionally being substituted with one or more F; and
R15 is H, C(1-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(1-9)heteroaryl, C(1-9)heteroarylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkyl-C(1-3)alkyl, all groups optionally substituted with one or more F, C(1-2)alkoxy or cyano;
and R16 is C(1-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(1-9)heteroaryl, C(1-9)heteroarylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkyl-C(1-3)alkyl, all groups optionally substituted with one or more F, C(1-2)alkyl, C(1-2)alkoxy or cyano.

### Claim 2 (depends on 1)

The compound according to claim 1 wherein:
A11-A14 are N or CR11, CR12, CR13, CR14, respectively, with the proviso that no more than two of the four positions A in A11-A14 can be simultaneously N;
A6, A7, A9, A10 are N or CR6, CR7, CR9, CR10, respectively, with the proviso that at least one but no more than two of the four positions A in A6, A7, A9, A10 is N;
A8 is CR8;
R1 is C(3-6)cycloalkylC(1-3)alkyl or (di)C(3-6)cycloalkylamino with all carbon atoms of alkyl groups optionally substituted with one or more F and all carbon atoms of cycloalkyl groups optionally substituted with one or more F or methyl;
R2 and R3 are independently H;
R4 is H;
R5 is H, hydroxyethyl, methoxyethyl, C(1-6)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkylC(1-3)alkyl, all groups optionally substituted with one or more F, C(1-2)alkoxy or cyano;
the sulfonyl group with R1 is represented by R8;
the remaining R6-R14 are independently H, halogen, C(1-3)alkoxy or C(1-6)alkyl, all of the alkyl groups optionally being substituted with one or more F or hydroxy; and
R15 is C(1-6)alkyl or C(3-6)cycloalkyl, all groups optionally substituted with one or more F, C(1-2)alkoxy or cyano;
and R16 is C(1-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(6-10)aryl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkyl-C(1-3)alkyl, all groups optionally substituted with one or more F, C(1-2)alkyl, C(1-2)alkoxy or cyano.

### Claim 3 (depends on 1)

The compound according to claim 1 wherein:
A11-A14 are respectively CR11, CR12, CR13, CR14;
A6, A7, A9, A10 are N or CR6, CR7, CR9, CR10, respectively, with the proviso that at least one but no more than two of the four positions A in A6, A7, A9, A10 is N;
A8 is CR8;
R1 is C(3-6)cycloalkylC(1-3)alkyl, all carbon atoms of cycloalkyl groups optionally substituted with one or more F or methyl;
R2 and R3 are independently H;
R4 is H;
R5 is H, hydroxyethyl, methoxyethyl, C(1-6)alkyl or C(2-5)heterocycloalkylC(1-3)alkyl;
the sulfonyl group with R1 is represented by R8;
the remaining R6-R14 are independently H, halogen, C(1-3)alkoxy or C(1-6)alkyl, all carbon atoms of alkyl groups optionally substituted with one hydroxy;
R15 is C(1-6)alkyl or C(3-6)cycloalkyl, all carbon atoms of the alkyl groups optionally substituted with one or more F;
and R16 is C(1-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl or C(6-10)aryl, all carbon atoms of the alkyl groups optionally substituted with one or more F.

### Claim 4 (depends on 1)

The compound according to claim 1 wherein:
A11 or A14 is N, the remaining position A being CR11 or CR14;
A12 and A13 are respectively CR12 and CR13;
A6, A7, A9, A10 are N or CR6, CR7, CR9, CR10, respectively, with the proviso that at least one but no more than two of the four positions A in A6, A7, A9, A10 is N;
A8 is CR8;
R1 is C(3-6)cycloalkylC(1-3)alkyl;
R2 and R3 are independently H;
R4 is H;
R5 is H;
the sulfonyl group with R1 is represented by R8;
the remaining R6-R14 are independently H;
R15 is C(1-6)alkyl, all carbon atoms of alkyl groups optionally substituted with one or more F;
and R16 is C(1-6)alkyl, all carbon atoms of alkyl groups optionally substituted with one or more F.

### Claim 5 (depends on 1)

The compound as defined in claim 1 which is selected from the group of:
2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)ethyl]phenyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[3-methyl-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[3-fluoro-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide;
N-[3-chloro-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[3-methoxy-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[2-methyl-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[2-fluoro-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[2-methoxy-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[5-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-2-pyridyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[1-hydroxy-1-(trifluoromethyl)butyl]phenyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[1-hydroxy-3-methyl-1-(trifluoromethyl)butyl]phenyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[1-hydroxy-4-methyl-1-(trifluoromethyl)pentyl]phenyl]acetamide;
N-[4-(1-cyclopentyl-2,2,2-trifluoro-1-hydroxy-ethyl)phenyl]-2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]acetamide;
N-[4-[1-(cyclopentylmethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]phenyl]-2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]acetamide;
N-[4-[1-(cyclohexylmethyl)-2,2,2-trifluoro-1-hydroxy-ethyl]phenyl]-2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[5-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-2-pyridyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[dicyclopropyl(hydroxy)methyl]phenyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-(2,2,2-trifluoro-1-hydroxy-1-phenyl-ethyl)phenyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[1-hydroxy-1-(trifluoromethyl)propyl]phenyl]acetamide (racemate);
(−)-2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide (levogyre enantiomer);
(+)-2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide (dextrogyre enantiomer);
2-[6-[(2-methylcyclopropyl)methylsulfonyl]-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide;
2-[6-[(2,2-difluorocyclopropyl)methylsulfonyl]-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide (racemate);
(+)-2-[6-[(2,2-difluorocyclopropyl)methylsulfonyl]-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide (dextrogyre enantiomer);
(−)-2-[6-[(2,2-difluorocyclopropyl)methylsulfonyl]-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide (levogyre enantiomer);
2-[6-(cyclopropylmethylsulfonyl)-4-methyl-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)-2-methyl-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)-5-methyl-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-(oxetan-3-ylmethoxy)-1-(trifluoromethyl)ethyl]phenyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-(2-methoxyethoxy)-1-(trifluoromethyl)ethyl]phenyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)-3-pyridyl]-N-[4-[2,2,2-trifluoro-1-(2-hydroxyethoxy)-1-(trifluoromethyl)ethyl]phenyl]acetamide;
2-[5-(cyclopropylmethylsulfonyl)-2-pyridyl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide;
2-[5-(cyclopropylmethylsulfonyl)-2-pyridyl]-N-[4-[2,2,2-trifluoro-1-isopropoxy-1-(trifluoromethyl)ethyl]phenyl]acetamide;
2-[5-(cyclopropylmethylsulfonyl)-2-pyridyl]-N-[3-methyl-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl];
2-[5-(cyclopropylmethylsulfonyl)-2-pyridyl]-N-[3-fluoro-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide;
2-[5-(cyclopropylmethylsulfonyl)-2-pyridyl]-N-[4-[dicyclopropyl(hydroxy)methyl]phenyl]acetamide;
2-[5-(cyclopropylmethylsulfonyl)-2-pyridyl]-N-[4-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)ethyl]phenyl]acetamide;
2-[5-(cyclopropylmethylsulfonyl)pyrimidin-2-yl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide;
2-[5-(cyclopropylmethylsulfonyl)pyrazin-2-yl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide;
2-[6-(cyclopropylmethylsulfonyl)pyridazin-3-yl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide;
2-[2-(cyclopropylmethylsulfonyl)pyrimidin-5-yl]-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide.

### Claim 6 (depends on 1)

A compound according to claim 1 or a pharmaceutically acceptable salt thereof for use in therapy.

### Claim 7 (depends on 1)

The compound according to claim 1 or a pharmaceutically acceptable salt thereof for the treatment of ROR γ-mediated diseases or conditions.

### Claim 8 (depends on 1)

A medicament according to claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

A pharmaceutical composition which comprises a compound of Formula I according to claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

### Claim 10 (depends on 9)

The pharmaceutical composition according to claim 9, which further comprises at least one additional therapeutically active agent.