# US 10,369,146 B2 · Phenyl linked quinolinyl modulators of RORγt

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- Number: US 10,369,146 B2
- Document ID: US10369146B2
- Status: Granted
- Kind: B2
- Application number: 15/182,231
- Filed: 2016-06-14
- Published: 2016-09-29
- Granted: 2019-08-06
- Earliest claimed: 2013-10-15
- Assignees: Janssen Pharmaceutica NV
- Applicants: Janssen Pharmaceutica NV
- Inventors: Kristi A. Leonard; Kent Barbay; James P. Edwards; Kevin D. Kreutter; David A. Kummer; Umar Maharoof; Rachel Nishimura; Maud Urbanski; Hariharan Venkatesan; Aihua Wang; Ronald L. Wolin; Craig R. Woods; Anne Fourie; Xiaohua Xue; Maxwell D. Cummings
- Web page: https://patentgrep.com/patent/US10369146B2

## CPC

- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 401/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- 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)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention comprises compounds of Formula I. wherein: R1, R2, R3, R4, R5, R6, R7, R8, and R9 are defined in the specification. The invention also comprises a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is rheumatoid arthritis or psoriasis. The invention also comprises a method of modulating RORγt activity in a mammal by administration of a therapeutically effective amount of at least one compound of claim 1.

## Claims

### Claim 1

A method for treating or ameliorating a RORγt mediated inflammatory syndrome, disorder or disease selected from the group consisting of: inflammatory bowel diseases, rheumatoid arthritis, psoriasis, chronic obstructive pulmonary disorder, psoriatic arthritis, ankylosing spondylitis, neutrophilic asthma, steroid resistant asthma, multiple sclerosis, and systemic lupus erythematosus, comprising administering to a subject in need thereof an effective amount of a compound of Formula I:
wherein:
R1 is azetidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazyl, piperidinyl, tetrahydropyranyl, phenyl, oxazolyl, isoxazolyl, thiophenyl, benzoxazolyl, or quinolinyl; wherein said piperidinyl, pyridyl, pyridyl N-oxide, imidazolyl, phenyl, thiophenyl, benzoxazolol, and pyrazolol are optionally substituted with SO2CH3, C(O)CH3, C(O)NH2, CH3, CH2CH3, CF3, Cl, F, —CN, OCH3, N(CH3)2, —(CH2)3OCH3, SCH3, OH, CO2H, CO2C(CH3)3, or OCH2OCH3; and optionally substituted with up to two additional substituents independently selected from the group consisting of Cl, OCH3, and CH3; and wherein said triazolyl, oxazolyl, isoxazol and thiazolyl are optionally substituted with one or two CH3 groups; and wherein said azetidinyl is optionally substituted with CO2C(CH3)3, C(O)NH2, CH3, SO2CH3, or C(O)CH3;
R2 is 1-methyl-1,2,3-triazolyl, pyridyl, pyridyl-N-oxide, 1-methyl pyrazol-4-yl, pyrimidin-5-yl, pyridazyl, pyrazin-2-yl, oxazolyl, isoxazolyl, N-acetyl-azetidin-3-yl, N-methylsulfonyl-azetidin-3-yl, N-Boc-azetidin-3-yl, N-methyl-azetidin-3-yl, N-acetamidyl-azetidin-3-yl, N-acetyl piperidinyl, 1-H-piperidinyl, N-Boc-piperidinyl, N—C(1-2)alkyl-piperidinyl, thiazol-5-yl, 1-methyl imidazol-2-yl, 1-(3-methoxypropyl)-imidazol-5-yl, or 1-C(1-2)alkyl imidazol-5-yl; wherein said 1-C(1-2)alkyl imidazol-5-yl is optionally substituted with up to two additional CH3 groups, or one substituent selected from the group consisting of SCH3, and Cl; and said pyridyl, and pyridyl-N-oxide are optionally substituted with up to two substituents independently selected from the group consisting of C(O)NH2, —CN, OCH3, CF3, Cl, and CH3; and said thiazol-5-yl, oxazolyl, and isoxazolyl are optionally substituted with up to two CH3 groups; and said 1-methyl pyrazol-4-yl is optionally substituted with up to two additional CH3 groups;
R3 is H, OH, OCH3, NHCH3, N(CH3)2 or NH2;
R4 is H, or F;
R5 is H, Cl, —CN, CF3, SCH3, OC(1-3)alkyl, OH, C(1-4)alkyl, N(CH3)OCH3, NH(C(1-2)alkyl), N(C(1-2)alkyl)2, NH-cyclopropyl, OCHF2, 4-hydroxy-piperidinyl, azetidin-1-yl, or fur-2-yl;
R6 is 2-chloro-thiophen-5-yl, 1-methyl-pyrazol-4-yl, phenyl, pyrimidinyl, or pyridyl, wherein said phenyl, pyrimidinyl, and pyridyl are optionally substituted with SO2CH3, NHSO2CH3, CF3, F, Cl, —CN, OCH3 or OCF3;
R7 is H Cl, —CN, C(1-4)alkyl, OCH2CF3, OCH2CH2OCH3, CF3, SCH3, SO2CH3, OCHF2, NA1A2, C(O)NHCH3, N(CH3)CH2CH2NA1A2, OCH2CH2NA1A2, OCH2CH2NH2, OC(1-3)alkyl, OCH2-(1-methyl)-imidazol-2-yl, imidazol-2-yl, fur-2-yl, pyrazol-4-yl, pyrid-3-yl, or pyrimidin-5-yl; thiophen-3-yl, 1-methyl-indazol-5-yl, 1-methyl-indazol-6-yl, phenyl, or
wherein said imidazolyl or pyrazolyl can be optionally substituted with a CH3 group;
A1 is H or C(1-4)alkyl;
A2 is C(1-4)alkyl, cyclopropyl, C(1-4)alkylOC(1-4)alkyl, C(1-4)alkylOH, C(O)C(1-2)alkyl, or OCH3; or A1 and A2 may be taken together with their attached nitrogen to form a ring selected from the group consisting of:
Ra is H, F, OCH3, or OH;
Rb is CH3, or phenyl;
R8 is H, CH3, OCH3, or F;
R9 is H, or F;
and pharmaceutically acceptable salts thereof;
provided that (4-chloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-3-yl)methanamine, (4-chlorophenyl)(2,4-dichloro-3-(2-chlorophenyl)quinolin-6-yl)(1-methyl-1H-imidazol-2-yl)methanol, (4-chloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-4-yl)methanamine, (4-chlorophenyl)(3-(2,6-dichlorophenyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol, (4-chloro-3-phenylquinolin-6-yl)(2-(dimethylamino)pyridin-4-yl)(1-methyl-1H-imidazol-2-yl)methanol, 4-(2-((4-chloro-6-((4-chlorophenyl)(hydroxy)(l-methyl-1H-imidazol-5-yl)methyl)-3-phenylquinolin-2-yl)oxy)ethyl)thiomorpholine 1,1-dioxide, 1-(2-((4-chloro-6-((4-chlorophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)-3-phenylquinolin-2-yl)oxy)ethyl)pyrrolidin-2-one, (2-chloro-4-(dimethylamino)-3-phenylquinolin-6-yl)(pyridin-2-yl)(pyridin-4-yl)methanol, (4-chloro-3-phenylquinolin-6-yl)(2-fluoropyridin-4-yl)(1-methyl-1H-imidazol-2-yl)methanol, (4-chloro-2-(1-methyl-1H-pyrazol-4-yl)-3-phenylquinolin-6-yl)(4-chlorophenyl)(pyridin-3-yl)methanol, (2,4-dichloro-3-phenylquinolin-6-yl)di(pyridin-2-yl)methanol, 6-((3-chlorophenyl)(hydroxy)(2-(trifluoromethyl)pyridin-4-yl)methyl)-3-phenylquinoline-2-carbonitrile, (2,4-dichloro-8-methyl-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-4-yl)(6-methylpyridin-3-yl)methanol, (4-chlorophenyl)(2,4-dichloro-3-(2-chlorophenyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol, (2,4-dichloro-3-phenylquinolin-6-yl)(phenyl)(pyridin-2-yl)methanol, and (2,4-dichloro-3-phenylquinolin-6-yl)(oxazol-2-yl)(phenyl)methanol are excluded from the claim.

### Claim 2 (depends on 1)

The method of claim 1, wherein the disease is psoriasis.

### Claim 3 (depends on 1)

The method of claim 1, wherein the disease is rheumatoid arthritis.

### Claim 4 (depends on 1)

The method of claim 1, wherein the inflammatory bowel disease is ulcerative colitis.

### Claim 5 (depends on 1)

The method of claim 1, wherein the inflammatory bowel disease is Crohn's disease.

### Claim 6 (depends on 1)

The method of claim 1, wherein the disease is multiple sclerosis.

### Claim 7 (depends on 1)

The method of claim 1, wherein the disease is neutrophilic asthma.

### Claim 8 (depends on 1)

The method of claim 1, wherein the disease is steroid resistant asthma.

### Claim 9 (depends on 1)

The method of claim 1, wherein the disease is psoriatic arthritis.

### Claim 10 (depends on 1)

The method of claim 1, wherein the disease is ankylosing spondylitis.

### Claim 11 (depends on 1)

The method of claim 1, wherein the disease is systemic lupus erythematosus.

### Claim 12 (depends on 1)

The method of claim 1, wherein the disease is chronic obstructive pulmonary disorder.

### Claim 13 (depends on 1)

A method of treating or ameliorating a syndrome, disorder or disease, in a subject in need thereof comprising administering to the subject an effective amount of a compound of claim 1 or composition or medicament thereof in a combination therapy with one or more anti-inflammatory agents, or immunosuppressive agents, wherein said syndrome, disorder or disease is selected from the group consisting of: rheumatoid arthritis, and psoriasis.