Trifluoromethyl alcohols as modulators of RORγt

Patent metadata

Field	Value
Publication number	US-9850236-B2
Application number	US-201514927499-A
Country	US
Kind code	B2
Filing date	Oct 30, 2015
Priority date	Oct 30, 2014
Publication date	Dec 26, 2017
Grant date	Dec 26, 2017

Abstract

The present invention comprises compounds of Formula I.

wherein:

X, A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , and R 3 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.

First claim

What is claimed is:

1. A compound of Formula I:

wherein
X is CH, CR 1 , or N;
A 1 is C (1-2) alkyl;
A 2 is cyclobutyl, or C (1-4) alkyl, wherein said C (1-4) alkyl is optionally substituted with OCH 3 or up to three fluorine atoms;
or A 1 and A 2 are taken together with their attached nitrogen to form a ring selected the group consisting of azetidinyl, piperidinyl, pyrrolidinyl,

wherein said ring is optionally substituted with up to three substituents independently selected from the group consisting of F, CF 3 , CH 3 , —CN, and CH 2 OH;
R 1 is Cl, C(CH 3 ) 3 , CH 2 CH 3 , OCF 3 , CF 3 , OCH(CH 3 ) 2 , CHF 2 , OCHF 2 , OCH 3 , F, CH 3 , or —CN;
R 2 is H, F, or Cl;
or R 1 and R 2 may be taken together with their attached phenyl to form a naphthalenyl, or quinolinyl group;

R 3 is CF 3 , or CH 2 CH 3 ;
A 3 is H
A 4 is H, C (1-5) alkyl,

wherein said C (1-5) alkyl is optionally substituted with one to two substituents independently selected from COOH, CONH 2 , —CN, and OH;
or A 3 and A 4 may be taken together with their attached nitrogen to make a ring selected from the group consisting of

and pharmaceutically acceptable salts thereof.

2. The compound of claim 1 wherein:
R 1 is Cl, C(CH 3 ) 3 , CH 2 CH 3 , OCF 3 , CF 3 , OCH(CH 3 ) 2 , CHF 2 , OCHF 2 , OCH 3 , F, or CH 3 ;
A 4 is H, C (1-5) alkyl,

wherein said C (1-5) alkyl is optionally substituted with one to two substituents independently selected from CONH 2 , —CN, and OH;
and pharmaceutically acceptable salts thereof.

3. The compound of claim 2 , of Formula II:

and pharmaceutically acceptable salts thereof.

4. The compound of claim 2 selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

5. The compound of claim 3 selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

6. The compound of claim 1 selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

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

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

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

10. 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 claim 1 .

11. The method of claim 10 , wherein the disease is psoriasis.

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

13. The method of claim 10 , wherein the inflammatory bowel disease is ulcerative colitis.

14. The method of claim 10 , wherein the inflammatory bowel disease is Crohn's disease.

15. The method of claim 10 , wherein the disease is multiple sclerosis.

16. The method of claim 10 , wherein the disease is neutrophilic asthma.

17. The method of claim 10 , wherein the disease is steroid resistant asthma.

18. The method of claim 10 , wherein the disease is psoriatic arthritis.

19. The method of claim 10 , wherein the disease is ankylosing spondylitis.

20. The method of claim 10 , wherein the disease is systemic lupus erythematosus.

21. The method of cl

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Goldberg Steven
• Venkatesan Hariharan
• Tanis Virginia
• Kinzel Olaf
• Gege Christian
• Steeneck Christoph
• Kleymann Gerald
• Hoffmann Thomas
• Fourie Anne M
• Xue Xiaohua

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title