PHENYL LINKED QUINOLINYL MODULATORS OF RORyt

• US 20150105404A1
• Filed: 10/15/2013
• Published: 04/16/2015
• Est. Priority Date: 10/15/2013
• Status: Active Grant

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Leonard, Kristi A., Barbay, Kent, Edwards, James P., Kreutter, Kevin D., Kummer, David A., Maharoof, Umar, Urbanski, Maud, Wang, Aihua, Wolin, Ronald L., Woods, Craig R., Fourie, Anne, Xue, Xiaohua, Nishimura, Rachel, Venkatesan, Hariharan, Cummings, Maxwell D.
• Granted Patent: US 9,403,816 B2
• Time in Patent Office: Days
• US Class Current: 514/256
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings

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

1. The compounds of Formula I:

2. The compounds of claim 1, wherein:

R¹ is imidazolyl, thiazolyl, pyridyl, pyrimidinyl, or phenyl;

wherein said pyridyl, and said phenyl are optionally substituted with —

CN, CF₃, F, or Cl; and

wherein said imidazolyl, and thiazolyl are optionally substituted with one or two CH₃ groups;

R² is 1-methyl-1,2,3-triazol-5-yl, N-acetyl piperidin-4-yl, N-Boc-piperidin-4-yl, N-methyl piperidin-4-yl, 1-H-piperidin-4-yl, oxazol-2-yl, 2,4-dimethyl thiazol-5-yl, 1-methyl imidazol-2-yl, 1-methyl-imidazol-5-yl, or pyridyl;

wherein said pyridyl is optionally substituted with CF₃;

R³ is H, OH;

R⁴ is H;

R⁵ is H, Cl, —

CN, C_(1-4)alkyl, OC_(1-2)alkyl, SCH₃, N(CH₃)₂, or N(CH₃)OCH₃;

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, Cl, —

CN, OCH₃, or OCF₃;

R⁷ is Cl, —

CN, CF₃, SCH₃, OCH₂CF₃, NA¹A², N(CH₃)CH₂CH₂NA¹A², OC_(1-3)alkyl, OCH₂CH₂OCH₃, OCH₂CH₂NA¹A², or OCH₂CH₂NH₂;

A¹ is H, or CH₃;

A² is OCH₃, CH₃, CH₂CH₂OH, C(O)C_(1-2)alkyl, or CH₂CH₂OCH₃;

or A¹ and A² may be taken together with their attached nitrogen to form a ring selected from the group consisting of;

3. A compound of claim 1 selected from the group consisting of:

4. A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

5. A pharmaceutical composition made by mixing a compound of claim 1 and a pharmaceutically acceptable carrier.

6. A process for making a pharmaceutical composition comprising mixing a compound of claim 1 and a pharmaceutically acceptable carrier.

7. A method for treating or ameliorating a RORγ

t mediated inflammatory syndrome, disorder or disease comprising administering to a subject in need thereof an effective amount of a compound of claim 1.

9. The method of claim 7, wherein the disease is psoriasis.

10. The method of claim 7, wherein the disease is rheumatoid arthritis.

13. The method of claim 7, wherein the disease is multiple sclerosis.

14. The method of claim 7, wherein the disease is neutrophilic asthma.

15. The method of claim 7, wherein the disease is steroid resistant asthma.

16. The method of claim 7, wherein the disease is psoriatic arthritis.

17. The method of claim 7, wherein the disease is ankylosing spondylitis.

18. The method of claim 7, wherein the disease is systemic lupus erythematosus.

19. The method of claim 7, wherein the disease is chronic obstructive pulmonary disorder.

20. 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.

8. The method of claim 8, wherein the disease is 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.

11. The method of claim 8, wherein the inflammatory bowel disease is ulcerative colitis.

12. The method of claim 8, wherein the inflammatory bowel disease is Crohn'"'"'s disease.