IP Library › Granted Patent US 9,636,333
Granted Patent B2
US 9,636,333 · App. 14/821,396 · Granted May 2, 2017

Methyl/fluoro-pyridinyl-methoxy substituted pyridinone-pyridinyl compounds and fluoro-pyrimidinyl-methoxy substituted pyridinone-pyridinyl compounds

Inventors: Susan L. Hockerman (Kirkwood, MO); Joseph B. Monahan (St. Louis, MO); Shaun R. Selness (Chesterfield, MO)
Assignee: CONFLUENCE LIFE SCIENCES, INC.
A61K31/444A61K31/506A61K45/06C07D213/69C07D401/14
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Quick Facts
Patent No.
US 9,636,333
App. No.
14/821,396
Granted
May 2, 2017
Kind
B2
Abstract

The present disclosure provides methyl/fluoro-pyridinyl-methoxy substituted pyridinone-pyridinyl compounds and fluoro-pyrimidinyl-methoxy substituted pyridinone-pyridinyl compounds useful in the treatment of p38 kinase mediated diseases, such as lymphoma and auto-inflammatory disease, including rheumatoid arthritis, having the structure of Formula (I): wherein R 1 , R 2 , R 3 , R 4 , R 5 and X are as defined in the detailed description; pharmaceutical compositions comprising at least one of the compounds; and methods for treating p38 kinase mediated diseases using the compound.

Claims (137)

1. A method for treating a condition in a subject comprising:

administering to the subject a therapeutically effective amount of a p38 inhibitor of a compound of Formula I,

or a pharmaceutically acceptable salt thereof, wherein:

X is CH or N;

R 1 is selected from the group consisting of —H, C 1 -C 6 alkyl, fluoro, chloro, bromo, cyano, and —CF 3 ;

R 2 is selected from the group consisting of —H, methyl, cyano, and fluoro;

R 3 is selected from the group consisting of:

R 4 is selected from the group consisting of —H, methyl, —OH, and —OCH 3 ;

R 5 is —H or C 1 -C 3 alkyl;

m is 1 or 2;

n is 0 or 1;

p is 1; and

q is 0 or 1;

wherein the condition is amenable to inhibition of p38 and said condition is selected from the group consisting of ulcerative colitis, inflammatory bowel disease, Crohn's disease, psoriasis, systemic lupus erythematosus, multiple sclerosis, Grave's disease, myasthenia gravis, chronic inflammatory disorders, acute inflammatory disorders, auto-inflammatory disorders, bone disorders, osteoarthritis, septic shock, endotoxic shock, endotoxin-induced toxic shock, toxic shock syndrome, sepsis, atherosclerosis, diabetes, rheumatoid arthritis, osteoarthritis, arthritis, asthma, inflammatory bowel disease, ulcerative colitis, Crohn's disease, reperfusion injury, neuronal ischemia, stroke, chronic gout, graft versus host disease, allograft rejection, psoriasis, glomerulonephritis, pulmonary inflammation, lymphoma, metastatic melanoma, multiple myeloma, and chronic obstructive pulmonary disease (COPD), and fibrotic diseases.

2. The method of claim 1 , wherein the subject is a mammal selected from a canine and a human.

3. The method of claim 1 , wherein the condition is a chronic inflammatory disorder.

4. The method of claim 3 , wherein the chronic inflammatory disorder is rheumatoid arthritis.

5. The method of claim 1 , wherein the compound has the structure of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

X is CH or N;

R 1 is selected from the group consisting of —H, C 1 -C 6 alkyl, fluoro, chloro, bromo, cyano, and —CF 3 ;

R 2 is selected from the group consisting of H, methyl, cyano, and fluoro;

R 3 is

R 4 is selected from the group consisting of —H, methyl, —OH, and —OCH 3 ;

R 5 is —H or C 1 -C 3 alkyl;

m is 1 or 2; and

n is 0 or 1.

6. The method of claim 5 , wherein R 3 is selected from the group consisting of 3,5-difluoropyridin-2-yl, 3-fluoropyridin-2-yl, 5-fluoro-3-methylpyridin-2-yl, 6-fluoropyridin-2-yl, 6-fluoro-4-methylpyridin-2-yl, 3-fluoro-5-methylpyridin-2-yl, and 5-fluoropyridin-2-yl.

7. The method of claim 6 , wherein the compound has the structure of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

X is CH or N;

R 1 is chloro or bromo; and

R 2 is —H or methyl.

8. The method of claim 5 , wherein the compound is selected from the group consisting of:

3-bromo-4-((3,5-difluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;

3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;

3-bromo-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-bromo-4-((3,5-difluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;

3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;

3-bromo-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one.

9. The method of claim 6 , wherein the compound is selected from the group consisting of:

3-chloro-4-((5-fluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-chloro-4-((3-fluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-chloro-4-((5-fluoro-3-methylpyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-chloro-4-((6-fluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-chloro-4-((6-fluoro-4-methylpyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-chloro-4-((3-fluoro-5-methylpyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-bromo-4-((5-fluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-chloro-4-((5-fluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;

3-bromo-4-((5-fluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;

3-chloro-4-((5-fluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-bromo-4-((5-fluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-chloro-4-((5-fluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;

3-bromo-4-((5-fluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;

3-bromo-4-((3-fluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-chloro-4-((3-fluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;

3-bromo-4-((3-fluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;

3-chloro-4-((3-fluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-bromo-4-((3-fluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-chloro-4-((3-fluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;

3-bromo-4-((3-fluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;

3-bromo-4-((5-fluoro-3-methylpyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-chloro-4-((5-fluoro-3-methylpyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;

3-bromo-4-((5-fluoro-3-methylpyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;

3-chloro-4-((5-fluoro-3-methylpyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-bromo-4-((5-fluoro-3-methylpyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-chloro-4-((5-fluoro-3-methylpyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;

3-bromo-4-((5-fluoro-3-methylpyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;

3-bromo-4-((6-fluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H[1,4′-bipyridin]-2-one;

3-chloro-4-((6-fluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;

3-bromo-4-((6-fluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;

3-chloro-4-((6-fluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-bromo-4-((6-fluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-chloro-4-((6-fluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′2′,2″-terpyridin]-2-one;

3-bromo-4-((6-fluoropyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′2′,2″-terpyridin]-2-one;

3-bromo-4-((6-fluoro-4-methylpyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-chloro-4-((6-fluoro-4-methylpyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′2′,2″-terpyridin]-2-one;

3-bromo-4-((6-fluoro-4-methylpyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′2′,2″-terpyridin]-2-one;

3-chloro-4-((6-fluoro-4-methylpyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-bromo-4-((6-fluoro-4-methylpyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-chloro-4-((6-fluoro-4-methylpyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;

3-bromo-4-((6-fluoro-4-methylpyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;

3-bromo-4-((3-fluoro-5-methylpyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-chloro-4-((3-fluoro-5-methylpyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′2′,2″-terpyridin]-2-one;

3-bromo-4-((3-fluoro-5-methylpyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;

3-chloro-4-((3-fluoro-5-methylpyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-bromo-4-((3-fluoro-5-methylpyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-chloro-4-((3-fluoro-5-methylpyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one; and

3-bromo-4-((3-fluoro-5-methylpyridin-2-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one.

10. The method of claim 1 , wherein the compound has the structure of Formula (IV):

or a pharmaceutically acceptable salt thereof, wherein:

X is CH or N;

R 1 is selected from the group consisting of —H, C 1 -C 6 alkyl, fluoro, chloro, bromo, cyano, and —CF 3 ;

R 2 is selected from the group consisting of —H, methyl, cyano, and fluoro;

R 4 is selected from the group consisting of —H, methyl, —OH, and —OCH 3 ;

R 5 is —H or C 1 -C 3 alkyl;

m is 1 or 2; and

n is 0 or 1.

11. The method of claim 10 , wherein the compound has the structure of Formula (V):

or a pharmaceutically acceptable salt thereof, wherein:

X is CH or N;

R 1 is chloro or bromo; and

R 2 is —H or methyl.

12. The method of claim 11 , wherein the compound is selected from the group consisting of:

3-chloro-4-((4-fluoropyridin-3-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-bromo-4-((4-fluoropyridin-3-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-chloro-4-((4-fluoropyridin-3-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;

3-bromo-4-((4-fluoropyridin-3-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;

3-chloro-4-((4-fluoropyridin-3-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-bromo-4-((4-fluoropyridin-3-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-chloro-4-((4-fluoropyridin-3-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one; and

3-bromo-4-((4-fluoropyridin-3-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one.

13. The method of claim 1 , wherein the compound has the structure of Formula (VI):

or a pharmaceutically acceptable salt thereof, wherein:

X is CH or N;

R 1 is selected from the group consisting of —H, C 1 -C 6 alkyl, fluoro, chloro, bromo, cyano, and —CF 3 ;

R 2 is selected from the group consisting of —H, methyl, cyano, and fluoro;

R 4 is selected from the group consisting of —H, methyl, —OH, and —OCH 3 ;

R 5 is —H or C 1 -C 3 alkyl;

p is 1; and

q is 0 or 1.

14. The method of claim 13 , wherein the compound has the structure of Formula (VII):

or a pharmaceutically acceptable salt thereof, wherein:

X is CH or N;

R 1 is chloro or bromo; and

R 2 is —H or methyl.

15. The method of claim 14 , wherein the compound is selected from the group consisting of:

3-chloro-4-((5-fluoropyrimidin-4-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-bromo-4-((5-fluoropyrimidin-4-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-chloro-4-((5-fluoropyrimidin-4-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;

3-bromo-4-((5-fluoropyrimidin-4-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one;

3-chloro-4-((5-fluoropyrimidin-4-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-bromo-4-((5-fluoropyrimidin-4-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-5-methylpyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one;

3-chloro-4-((5-fluoropyrimidin-4-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H-[1,4′:2′,2″-terpyridin]-2-one; and

3-bromo-4-((5-fluoropyrimidin-4-yl)methoxy)-6″-(2-hydroxypropan-2-yl)-3″,5′,6-trimethyl-2H[1,4′:2′,2″-terpyridin]-2-one.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 15, 2018
From: ACLARIS LIFE SCIENCES, INC.
To: ACLARIS THERAPEUTICS, INC.
Reel/Frame 046153/0695 →
MERGER Recorded Nov 16, 2017
From: CONFLUENCE LIFE SCIENCES, INC.
To: ACLARIS LIFE SCIENCES, INC.
Reel/Frame 044477/0208 →
Continuity (3)
Continuation 14298610 · Jun 6, 2014
Provisional Application 61832736 · Jun 7, 2013
Related Publication 20150352092A1 · Dec 10, 2015