Substituted benzimidazole and substituted benzothiazole inhibitors of transforming growth factor-β kinase and methods of use thereof
The present invention provides novel inhibitors of TAK1 having formula (I) and methods of using such compounds to treat various diseases.
1. A pharmaceutical composition comprising a compound of Formula (I):
or a tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier;
wherein
X is NR 1 ;
R 1 is H, C 1-6 alkyl, C 1-4 carbonyl, or C 1-4 carboxy, wherein the C 1-4 carbonyl is a group —C(O)R attached by an alkyl group of up to 3 carbon atoms and R is aryl, alkoxy, or amino;
R 2 is H, C 1-4 alkyl, C 1-4 alkoxy, or halogen;
R 3 is OH, C 1-4 alkoxy, NH 2 , NH(C 1-4 alkyl), or N(C 1-4 alkyl)(C 1-4 alkyl); and
R 4 is H, C 1-4 alkyl, C 1-4 alkoxy, or halogen;
wherein the C 1-4 alkyl and C 1-6 alkyl of R 1 , R 2 , and R 4 are optionally and independently substituted by halo, OH, NH 2 , NH(C 1-4 alkyl), or N(C 1-4 alkyl)(C 1-4 alkyl).
2. The pharmaceutical composition according to claim 1 , wherein the compound of Formula (I) is
or a tautomer thereof.
3. A kit comprising the pharmaceutical composition according to claim 1 , and instructions for treating a disease modulated by transforming growth factor β activated kinase 1.
4. A compound according to Formula (I):
or a tautomer or pharmaceutically acceptable salt thereof;
wherein
X is NR 1 ;
R 1 is C 1-6 alkyl, C 1-4 carbonyl, or C 1-4 carboxy, wherein the C 1-4 carbonyl is a group —C(O)R attached by an alkyl group of up to 3 carbon atoms and R is aryl, alkoxy, or amino;
R 2 is H, C 1-4 alkyl, C 1-4 alkoxy, or halogen;
R 3 is OH, C 1-4 alkoxy, NH 2 , NH(C 1-4 alkyl), or N(C 1-4 alkyl)(C 1-4 alkyl); and
R 4 is H, C 1-4 alkyl, C 1-4 alkoxy, or halogen;
wherein the C 1-4 alkyl and C 1-6 alkyl of R 1 , R 2 , and R 4 are optionally and independently substituted by halo, OH, NH 2 , NH(C 1-4 alkyl), or N(C 1-4 alkyl)(C 1-4 alkyl);
wherein the compound of Formula (I) is not
5. The compound according to claim 4 , or a tautomer or pharmaceutically acceptable salt thereof, wherein R 1 is propyl.
6. The compound according to claim 4 , or a tautomer or pharmaceutically acceptable salt thereof, wherein R 2 is OCH 3 or Br.
7. The compound according to claim 4 , or a tautomer or pharmaceutically acceptable salt thereof, wherein R 3 is OCH 3 or NHCH 3 .
8. The compound according to claim 4 , or a tautomer or pharmaceutically acceptable salt thereof, wherein R 4 is H, CH 3 , OCH 3 or Cl.
9. The compound according to claim 4 , or a tautomer or pharmaceutically acceptable salt thereof, wherein
R 1 is not propyl when R 3 is NH 2 .
10. The compound according to claim 4 , or a tautomer or pharmaceutically acceptable salt thereof, selected from the group consisting of:
Compound
X
R 2
R 3
R 4
3
—N(CH 3 )—
—H
—NH 2
—H
5
—N(CH 2 CH(CH 3 ) 2 )—
—H
—NH 2
—H
6
—N(CH 2 CH 2 OH)—
—H
—NH 2
—H
7
—N(CH 2 CO 2 CH 3 )—
—H
—NH 2
—H
8
—N(CH 2 C(O)Ph)—
—H
—NH 2
—H
9
—N(CH 2 CH 2 N(CH 3 ) 2 )—
—H
—NH 2
—H
10
—N(CH 2 CONH 2 )—
—H
—NH 2
—H
14
—N(CH 2 CH 2 CH 3 )—
—H
—OH
—H
15
—N(CH 2 CH 2 CH 3 )—
—H
—OCH 3
—H
16
—N(CH 2 CH 2 CH 3 )—
—H
—NHCH 3
—H
17
—N(CH 2 CH 2 CH 3 )—
—H
—NHCH 2 CH 3
—H
18
—N(CH 2 CH 2 CH 3 )—
—H
—NHCH 3
—CH 3
19
—N(CH 2 CH 2 CH 3 )—
—H
—NHCH 3
—OCH 3
20
—N(CH 2 CH 2 CH 3 )—
—H
—NHCH 3
—Cl
24
—N(CH 2 CH 3 )—
—H
—OCH 3
—H
25
—N(CH 2 CH 3 )—
—H
—NH 2
—H
26
—N(CH 2 CH 3 )—
—H
—OH
—H
27
—N(CH 2 CH 3 )—
—H
—NHCH 3
—H
28
—N(CH 2 (CH 2 ) 4 NH 2 )—
—H
—OCH 3
—H
29
—N(CH 2 CH 2 CH 3 )—
—H
—NH 2
4-Br
30
—N(CH 2 CH 2 CH 3 )—
—H
—NH 2
5-Br.
11. The compound according to claim 10 , or a tautomer or pharmaceutically acceptable salt thereof, selected from the group consisting of:
Compound
X
R 2
R 3
R 4
3
—N(CH 3 )—
—H
—NH 2
—H
5
—N(CH 2 CH(CH 3 ) 2 )—
—H
—NH 2
—H
6
—N(CH 2 CH 2 OH)—
—H
—NH 2
—H
7
—N(CH 2 CO 2 CH 3 )—
—H
—NH 2
—H
8
—N(CH 2 C(O)Ph)-
—H
—NH 2
—H
9
—N(CH 2 CH 2 N(CH 3 ) 2 )—
—H
—NH 2
—H
10
—N(CH 2 CONH 2 )—
—H
—NH 2
—H
14
—N(CH 2 CH 2 CH 3 )—
—H
—OH
—H
15
—N(CH 2 CH 2 CH 3 )—
—H
—OCH 3
—H
16
—N(CH 2 CH 2 CH 3 )—
—H
—NHCH 3
—H
17
—N(CH 2 CH 2 CH 3 )—
—H
—NHCH 2 CH 3
—H
18
—N(CH 2 CH 2 CH 3 )—
—H
—NHCH 3
—CH 3
19
—N(CH 2 CH 2 CH 3 )—
—H
—NHCH 3
—OCH 3
20
—N(CH 2 CH 2 CH 3 )—
—H
—NHCH 3
—Cl.
12. A pharmaceutical composition comprising the compound according to claim 4 , or a tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
13. A kit comprising the compound according to claim 4 , or a tautomer or a pharmaceutically acceptable salt thereof, and instructions for treating a disease modulated by transforming growth factor β activated kinase 1.
14. A method for modulating transforming growth factor β activated kinase 1 activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to Formula (I):
or a tautomer or pharmaceutically acceptable salt thereof;
wherein
X is NR 1 or S;
R 1 is H, C 1-6 alkyl, C 1-4 carbonyl, or C 1-4 carboxy, wherein the C 1-4 carbonyl is a group —C(O)R attached by an alkyl group of up to 3 carbon atoms and R is aryl, alkoxy, or amino;
R 2 is H, C 1-4 alkyl, C 1-4 alkoxy, or halogen;
R 3 is OH, C 1-4 alkoxy, NH 2 , NH(C 1-4 alkyl), or N(C 1-4 alkyl)(C 1-4 alkyl); and
R 4 is H, C 1-4 alkyl, C 1-4 alkoxy, or halogen;
wherein the C 1-4 alkyl and C 1-6 alkyl of R 1 , R 2 , and R 4 are optionally and independently substituted by halo, OH, NH 2 , NH(C 1-4 alkyl), or N(C 1-4 alkyl)(C 1-4 alkyl).
15. The method according to claim 14 , wherein the subject has malaria.
16. The method according to claim 14 , wherein the subject has a disease selected from the group consisting of an inflammatory condition, an autoimmune condition, and cancer.
17. The method according to claim 16 , wherein the disease is selected from the group consisting of breast cancer, colorectal cancer, leukemia, neurofibrodomas, and non-small cell lung cancer.
18. The method according to claim 16 , wherein the disease is selected from the group consisting of rheumatoid arthritis, osteoarthritis, gout, psoriatic arthritis, ankylosing spondylitis, diabetes, Sjogren's syndrome, lupus, inflammatory bowel disease, and psoriasis.
19. The method according to claim 18 , wherein the inflammatory bowel disease is selected from the group consisting of Crohn's disease and ulcerative colitis.
20. The method according to claim 14 , wherein the compound of Formula (I) is selected from the group consisting of:
Com-
pound
X
R 2
R 3
R 4
1
—N(CH 2 CH 2 CH 3 )—
—H
—NH 2
—H
2
—N(H)—
—H
—NH 2
—H
3
—N(CH 3 )—
—H
—NH 2
—H
5
—N(CH 2 CH(CH 3 ) 2 )—
—H
—NH 2
—H
6
—N(CH 2 CH 2 OH)—
—H
—NH 2
—H
7
—N(CH 2 CO 2 CH 3 )—
—H
—NH 2
—H
8
—N(CH 2 C(O)Ph)—
—H
—NH 2
—H
9
—N(CH 2 CH 2 N(CH 3 ) 2 )—
—H
—NH 2
—H
10
—N(CH 2 CONH 2 )—
—H
—NH 2
—H
11
—S—
—H
—NH 2
—H
12
—S—
—OCH 3
—NH 2
—H
13
—S—
—Br
—NH 2
—H
14
—N(CH 2 CH 2 CH 3 )—
—H
—OH
—H
15
—N(CH 2 CH 2 CH 3 )—
—H
—OCH 3
—H
16
—N(CH 2 CH 2 CH 3 )—
—H
—NHCH 3
—H
17
—N(CH 2 CH 2 CH 3 )—
—H
—NHCH 2 CH 3
—H
18
—N(CH 2 CH 2 CH 3 )—
—H
—NHCH 3
—CH 3
19
—N(CH 2 CH 2 CH 3 )—
—H
—NHCH 3
—OCH 3
20
—N(CH 2 CH 2 CH 3 )—
—H
—NHCH 3
—Cl
21
—S—
—H
—OH
—H
22
—S—
—Br
—OH
—H
23
—S—
—OCH 3
—OCH 3
—H
24
—N(CH 2 CH 3 )—
—H
—OCH 3
—H
25
—N(CH 2 CH 3 )—
—H
—NH 2
—H
26
—N(CH 2 CH 3 )—
—H
—OH
—H
27
—N(CH 2 CH 3 )—
—H
—NHCH 3
—H
28
—N(CH 2 (CH 2 ) 4 NH 2 )—
—H
—OCH 3
—H
29
—N(CH 2 CH 2 CH 3 )—
—H
—NH 2
4-Br
30
—N(CH 2 CH 2 CH 3 )—
—H
—NH 2
5-Br
or a tautomer thereof.
21. The method according to claim 14 , wherein the compound of Formula (I) is
or a tautomer thereof.