Tricyclic heteroaryl compounds useful as IRAK4 inhibitors

Patent metadata

Field	Value
Publication number	US-12286428-B2
Application number	US-202017627915-A
Country	US
Kind code	B2
Filing date	Jul 16, 2020
Priority date	Jul 18, 2019
Publication date	Apr 29, 2025
Grant date	Apr 29, 2025

Abstract

Disclosed are compounds of Formula (I) or a salt or prodrug thereof, wherein: X 1 and X 2 are independently C or N, provided that zero or one of X 1 and X 2 is N; Ring A represented by the structure is: or; and Q, R 1 , R 2 , R 3 , R 4 , R 6 , and p are define herein. Also disclosed are methods of using such compounds as modulators of IRAK4, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing inflammatory and autoimmune diseases, or in the treatment of cancer.

First claim

What is claimed is:

1. A compound of Formula (I):

or a salt or prodrug thereof, wherein:
W is CR 5 or N;
X 1 and X 2 are independently C or N, provided that zero or one of X 1 and X 2 is N;
Ring A represented by the structure

is:

R 1 is —CN or —C(O)NH 2 ;
R 2 is hydrogen or —NH(CH 3 );
R 3 is hydrogen or F
R 4 is hydrogen, F, or —CH 3 ;
R 5 is hydrogen;
each R 6 is independently —CH 3 , —CF 3 , or —C(CH 3 ) 2 OH;
Q is

each R 7 is F, C 1-3 alkyl, or C 1-2 fluoroalkyl;
each R 8 is independently hydrogen or —CH 2 OH;
n is zero, 1, 2, or 3; and
p is zero, 1 or 2.

2. The compound according to claim 1 or a salt or prodrug thereof, wherein:
W is CR 5 .

3. The compound according to claim 1 or a salt or prodrug thereof, wherein:
W is N.

4. The compound according to claim 1 or a salt or prodrug thereof, wherein one of X 1 and X 2 is CR 5 and the other of X 1 and X 2 is N.

5. The compound according to claim 1 having the structure of Formula (II)

or a salt or prodrug thereof.

6. The compound according to claim 1 or a salt or prodrug thereof, wherein:
Ring A is:

7. The compound according to claim 1 or a salt or prodrug thereof, wherein Ring A is:

8. The compound according to claim 1 or a salt or prodrug thereof, wherein Ring A is:

9. The compound according to claim 1 or a salt or prodrug thereof, wherein:
Q is

10. The compound according to claim 1 or a salt thereof, wherein said compound is selected from:
(S)-9-((5-oxopyrrolidin-2-yl)methoxy)imidazo[1,2-a]quinoline-4-carboxamide (1);
9-(((2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl)methoxy)imidazo[1,2-a]quinoline-4-carboxamide (2);
9-(((2S,3 S)-3-ethyl-5-oxopyrrolidin-2-yl)methoxy) imidazo[1,2-a]quinoline-4-carboxamide (3);
9-(((2S,3 S,4R)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)imidazo[1,2-a]quinoline-4-carboxamide (4);
9-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)imidazo[1,2-a]quinoline-4-carboxamide (5);
9-(((2S,3 S,4S)-3-ethyl-4-fluoro-4-methyl-5-oxopyrrolidin-2-yl)methoxy) imidazo[1,2-a]quinoline-4-carboxamide (6);
(R)-9-((5-oxomorpholin-3-yl)methoxy) imidazo[1,2-a]quinoline-4-carboxamide (7);
9-(((2S,3S)-3-ethyl-4,4-difluoro-5-oxopyrrolidin-2-yl)methoxy)imidazo[1,2-a]quinoline-4-carboxamide (10);
9-(((2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl)methoxy)-2-methylimidazo[1,2-a]quinoline-4-carboxamide (11);
9-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-2-methylimidazo[1,2-a]quinoline-4-carboxamide (12);
9-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-2-(2-hydroxypropan-2-yl) imidazo[1,2-a]quinoline-4-carboxamide (13);
9-(((2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl)methoxy)-6-fluoroimidazo[1,2-a]quinoline-4-carboxamide (14);
9-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-6-fluoroimidazo[1,2-a]quinoline-4-carboxamide (15);
1-(((2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl)methoxy)imidazo[1,2-a][1,7]naphthyridine-6-carboxamide (16);
1-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)imidazo[1,2-a][1,7]naphthyridine-6-carboxamide (17);
1-(((2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl)methoxy)-8-methylimidazo[1,2-a][1,7]naphthyridine-6-carboxamide (18);
1-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-8-methylimidazo[1,2-a][1,7]naphthyridine-6-carboxamide (19);
1-(((2S,3S)-3-ethyl-4,4-difluoro-5-oxopyrrolidin-2-yl)methoxy) imidazo[1,2-a][1,7]naphthyridine-6-carboxamide (20);
1-(((2S,3S)-3-ethyl-4,4-difluoro-5-oxopyrrolidin-2-yl)methoxy)-8-methylimidazo[1,2-a][1,7]naphthyridine-6-carboxamide (21);
1-(((4R,5S)-5-ethyl-2-oxooxazolidin-4-yl)methoxy)imidazo[1,2-a][1,7]naphthyridine-6-carboxamide (22);
1-(((4S,5R)-5-ethyl-2-oxooxazolidin-4-yl) methoxy)imidazo[1,2-a][1,7]naphthyridine-6-carboxamide (23);
1-(((4S,5S)-5-ethyl-2-oxooxazolidin-4-yl)methoxy)imidazo[1,2-a][1,7]naphthyridine-6-carboxamide (24);
1-(((2R,3S)-2-ethyl-5-oxomorpholin-3-yl)methoxy)imidazo[1,2-a][1,7]naphthyridine-6-carboxamide (25);
1-(((2S,3R)-2-ethyl-5-oxomorpholin-3-yl)methoxy)imidazo[1,2-a][1,7]naphthyridine-6-carboxamide (26);
(S)-1-((2-oxoimidazolidin-4-yl)methoxy) imidazo[1,2-a][1,7]naphthyridine-6-carboxamide (27);
1-(((2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl)methoxy)-3-methylimidazo[1,2-a][1,7]naphthyridine-6-carboxamide (28);
1-(((2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl)methoxy)-3,8-dimethylimidazo[1,2-a][1,7]naphthyridine-6-carboxamide (29);
1-(((2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl)methoxy)-8-(trifluoromethyl)imidazo[1,2-a][1,7]naphthyridine-6-carboxamide (30);
1-(((2S,3 S)-3-ethyl-5-oxopyrrolidin-2-yl) methoxy)-8-(trifluoromethyl)imidazo[1,2-a][1,7]naphthyridine-6-carboxamide (31);
(1-(((2S,3S,4S)-3-ethyl-4-fluoro-1-(hydroxymethyl)-5-oxopyrrolidin-2-yl)methoxy) imidazo[1,2-a][1,7]naphthyridine-6-carboxamide (32);
1-((((3R)-3-ethyl-5-oxopyrrolidin-2-yl)methyl)amino)imidazo[1,2-a][1,7]naphthyridine-6-carboxamide (33);
10-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)pyrazolo[5,1-a]isoquinoline-5-carboxamide (34);
10-(((2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl)methoxy)pyrazolo[5,1-a]isoquinoline-5-carboxamide (35);
1-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy) pyrazolo[5,1-a][2,7]naphthyridine-6-carboxamide (36);
9-(((2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl)methoxy)-[1,2,4]triazolo[1,5-a]quinoline-4-carboxamide (37);
9-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-[1,2,4]triazolo[1,5-a]quinoline-4-carboxamide (38);
9-(((2S,3S)-3-ethyl-4,4-difluoro-5-oxopyrrolidin-2-yl)methoxy)-[1,2,4]triazolo[1,5-a]quinoline-4-carboxamide (39);
9-(((2S,3 S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-2-methyl-[1,2,4]triazolo[1,5-a]quinoline-4-carboxamide (40);
9-(((2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl)methoxy)-[1,2,4]triazolo[4,3-a]quinoline-4-carboxamide (41);
9-(((2S,3S)-3-ethyl-5-oxopyrrolidin-2-yl) methoxy)-[1,2,4]triazolo[4,3-a]quinoline-4-carboxamide (42);
9-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-[1,2,4]triazolo[4,3-a]quinoline-4-carboxamide (43);
9-(((2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl)methoxy)tetrazolo[1,5-a]quinoline-4-carboxamide (44);
9-(((2S,3 S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy) tetrazolo[1,5-a]quinoline-4-carboxamide (45);
9-(((2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl)methoxy)-[1,2,4]triazolo[1,5-a][1,7]naphthyridine-4-carboxamide (46);
9-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-[1,2,4]triazolo[1,5-a][1,7]naphthyridine-4-carboxamide (47);
9-(((2S,3S)-3-ethyl-4,4-difluoro-5-oxopyrrolidin-2-yl)methoxy)-[1,2,4]triazolo[1,5-a][1,7]naphthyridine-4-carboxamide (48);
9-(((2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl)methoxy)-2-methyl-[1,2,4]triazolo[1,5-a][1,7]naphthyridine-4-carboxamide (49);
1-(((2S,3S,4S)-3-et

Assignees

• Bristol Myers Squibb Co

Inventors

• Nair Satheesh Kesavan
• Paidi Venkatram Reddy
• Sarkunam Kandhasamy
• Sistla Ramesh Kumar
• Hynes John
• Murugesan Natesan

Classifications

• C07D491/048

  the oxygen-containing ring being five-membered · CPC title

• C07D471/14

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title