Granted Patent B2

US 8,759,535 · App. 13/028,406 · Granted Jun 24, 2014

Abstract

Claims (274)

1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof,

wherein

one of X 1 , X 2 , X 3 , and X 4 is

 and the remaining members of X 1 , X 2 , X 3 , and X 4 are independently N or

G is hydrogen, —C 1-8 alkyl, —C 3-10 cycloalkyl, —C 1-6 alkylene-C 3-10 cycloaklyl, heterocyclyl, —C 1-6 alkylene-C 3-10 heterocyclyl, phenyl, heteroaryl, or NR h R k , where the alkyl, alkylene, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from R c ;

L is —CH 2 —C(O)N(R 6 )—, —C(O)N(R 6 )—, —C(O)—O—, —SO 2 —, —C(O)—, heteroarylene optionally substituted one or more times with substituents independently selected from R x , or heterocyclylene optionally substituted one or more times with substituents independently selected from R x ; or the group -L-G is -cyano;

R 1 is hydrogen, R a , phenyl, or heteroaryl, where the phenyl and heteroaryl groups are optionally substituted one or more times with substituents independently selected from R x ;

R 2 is R b ;

R 3 is hydrogen, —C 1-6 alkyl, or —C 1-6 alkylene-C 3-10 cycloaklyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from R z ;

R 4 is —C 1-6 alkyl or —C 1-6 alkylene-C 3-10 cycloaklyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from R y ;

R 6 is hydrogen, —C 1-6 alkyl, —C 1-6 alkylene-C 3-10 cycloaklyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from R x ;

R a is

a) -halogen,

b) —C 1-6 alkyl,

c) —C 3-10 cycloalkyl,

d) -heterocyclyl,

e) -cyano,

f) —CF 3 ,

g) —OCF 3 ,

h) —O—R d ,

i) —S(O) w —R d ,

j) —S(O) 2 O—R d ,

k) —NR d R e ,

l) —C(O)—R d ,

m) —C(O)—O—R d ,

n) —OC(O)—R d ,

o) —C(O)NR d R e ,

p) —C(O)-heterocyclyl,

q) —NR d C(O)R e ,

r) —OC(O)NR d R e ,

s) —NR d C(O)OR d , or

t) —NR d C(O)NR d R e ,

where the alkyl, cycloalkyl, and heterocyclyl groups are optionally substituted one or more times with substituents independently selected from R y ;

R b is

a) -halogen,

b) —C 1-6 alkyl,

c) —C 3-10 cycloalkyl,

d) -heterocyclyl,

e) -phenyl,

f) -heteroaryl,

g) -cyano,

h) —CF 3 ,

i) —OCF 3 ,

j) —O—R f ,

k) —S(O) w —R f ,

l) —S(O) 2 O—R f ,

m) —NR f R g ,

n) —C(O)—R f ,

o) —C(O)—O—R f ,

p) —OC(O)—R f ,

q) —C(O)NR f R g ,

r) —C(O)-heterocyclyl,

s) —NR f C(O)R g ,

t) —OC(O)NR f R g ,

u) —NR f C(O)OR f , or

v) —NR f C(O)NR f R g ,

where the alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from R z ;

R c is

a) -halogen,

b) —C 1-6 alkyl,

c) —C 3-10 cycloalkyl,

d) -heterocyclyl,

e) -cyano,

f) —CF 3 ,

g) —OCF 3 ,

h) —O—R h ,

i) —S(O) w —R h ,

j) —S(O) 2 O—R h ,

k) —NR h R k ,

l) —C(O)—R h ,

m) —C(O)—O—R h ,

n) —OC(O)—R h ,

o) —C(O)NR h R k ,

p) —C(O)-heterocyclyl,

q) —NR h C(O)R k ,

r) —OC(O)NR h R k ,

s) —NR h C(O)OR k ,

t) —NR h C(O)NR h R k ,

u) —NR h S(O) w R k ,

v) -phenyl,

w) -heteroaryl, or

x) —O—(C 1-4 alkylene)-O—(C 1-4 alkylene)-N(R h )C(O)—OR k ,

where the alkylene, alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from R x ;

R d and R e are independently hydrogen, C 1-6 alkyl, or C 3-10 cycloalkyl, where the alkyl and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from R y ; or, if R d and R e are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from R y ;

R f and R g are independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, phenyl, or heteroaryl, where the alkyl, cycloalkyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from R z ; or, if R f and R g are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from R z ;

R h and R k are independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, heterocyclyl, phenyl, or heteroaryl, where the alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from R x ; or, if R h and R k are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from R x ;

R y is

a) -halogen,

b) —NH 2 ,

c) -cyano,

d) -carboxy,

e) -hydroxy,

f) -thiol,

g) —CF 3 ,

h) —OCF 3 ,

i) —C(O)—NH 2 ,

j) —S(O) 2 —NH 2 ,

k) oxo,

l) —C 1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

m) -heterocyclyl optionally substituted one or more times with one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

n) —C 3-10 cycloalkyl optionally substituted one or more times with one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

o) —O—C 1-6 alkyl optionally substituted one or more times with one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

p) —O—C 3-10 cycloalkyl optionally substituted one or more times with one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

q) —NH—C 1-6 alkyl optionally substituted one or more times with one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

r) —N(C 1-6 alkyl) 2 optionally substituted one or more times with one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

s) —C(O)—C 1-6 alkyl, optionally substituted one or more times with one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

t) —C(O)—O—C 1-6 alkyl, optionally substituted one or more times one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

u) —S—C 1-6 alkyl, optionally substituted one or more times with one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

v) —S(O) 2 —C 1-6 alkyl, optionally substituted one or more times one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

w) —C(O)—NH—C 1-6 alkyl, optionally substituted one or more times one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

x) —C(O)—N(C 1-6 alkyl) 2 , optionally substituted one or more times one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

y) —S(O) 2—NH—C 1-6 alkyl, optionally substituted one or more times one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

z) —S(O) 2 —N(C 1-6 alkyl) 2 , optionally substituted one or more times one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

aa) —NH—C(O)—C 1-6 alkyl, optionally substituted one or more times one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 , or

bb) —NH—S(O) 2 —C 1-6 alkyl, optionally substituted one or more times one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ;

R x is

a) —R y

b) -phenyl, optionally substituted one or more times with one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

c) -heteroaryl, optionally substituted one or more times with one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C 1-6 alkyl, —NH 2 , —NH—C 1-6 alkyl, and —N(C 1-6 alkyl) 2 ,

d) —O-phenyl,

e) —O-heteroaryl,

f) —C(O)-phenyl,

g) —C(O)-heteroaryl,

h) —C(O)—O-phenyl, or

i) —C(O)—O-heteroaryl;

R z is

a) —R y

b) -phenyl,

c) -heteroaryl;

d) —O-phenyl,

e) —O-heteroaryl,

f) —C(O)-phenyl,

g) —C(O)-heteroaryl,

h) —C(O)—O-phenyl, or

i) —C(O)—O-heteroaryl;

v is an integer from 0 to 4, and

w is an integer from 0 to 2.

2. The compound of claim 1 , wherein: G is hydrogen, —C 1-8 alkyl, —C 3-10 cycloalkyl, —C 1-6 alkylene-C 3-10 cycloaklyl, heterocyclyl, —C 1-6 alkylene-C 3-10 heterocyclyl, or —NR h R k , where the alkyl, alkylene, cycloalkyl, and heterocyclyl groups are optionally substituted one or more times with substituents independently selected from R c ;

L is —C(O)N(R 6 )—, —C(O)—O—, —SO 2 —, or —C(O)—;

R 1 is hydrogen or R a ;

R c is

a) -halogen,

b) —C 1-6 alkyl,

c) —C 3-10 cycloalkyl,

d) -heterocyclyl,

e) -cyano,

f) —CF 3 ,

g) —OCF 3 ,

h) —O—R h ,

i) —S(O) w —R h ,

j) —S(O) 2 O—R h ,

k) —NR h R k ,

l) —C(O)—R h ,

m) —C(O)—O—R h ,

n) —OC(O)—R h ,

o) —C(O)NR h R k ,

p) —C(O)-heterocyclyl,

q) —NR h C(O)R k ,

r) —OC(O)NR h R k ,

s) —NR h C(O)OR k ,

t) —NR h C(O)NR h R k ,

u) —NR h S(O) w R k , or

v) —O—(C 1-4 alkylene)—O—(C 1-4 alkylene)—N(R h )C(O)—OR k ,

where the alkylene, alkyl, cycloalkyl, or heterocyclyl groups are optionally substituted one or more times with substituents independently selected from R x ;

R h and R k are independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, or heterocyclyl, where the alkyl, cycloalkyl, and heterocyclyl groups are optionally substituted one or more times with substituents independently selected from R x ; or, if R h and R k are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from R x ;

R x is R y .

3. The compound of claim 2 , wherein R 3 is hydrogen.

4. The compound of claim 3 , wherein X 3 is

and X 1 , X 2 , and X 4 are each

5. The compound of claim 4 , wherein v is 1 and R 2 is attached at the 6-position of the benzothiazole ring.

6. The compound of claim 4 , wherein R 2 is fluoro, chloro, —CF 3 , or —OCF 3 .

7. The compound of claim 4 , wherein R 1 is hydrogen.

8. The compound of claim 4 , wherein R 4 is methyl.

9. The compound of claim 4 , wherein L is —C(O)NH—.

10. The compound of claim 4 , wherein G is C 1-8 alkyl optionally substituted one or more times with substituents independently selected from R c .

11. The compound of claim 10 , wherein G is C 1-8 alkyl optionally substituted once by —C(O)NR h R k .

12. The compound of claim 11 , wherein G is —CH 2 —C(O)NR h R k .

13. The compound of claim 10 , wherein G is C 1-8 alkyl optionally substituted once by —O—R h .

14. The compound of claim 13 , wherein G is —(CH 2 ) 2 —OR h .

15. The compound of claim 4 , wherein G is C 3-10 cycloalkyl optionally substituted one or more times with substituents independently selected from R c .

16. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or diluent.

17. The pharmaceutical composition of claim 16 , where the pharmaceutical composition further comprises a medically effective active ingredient selected from the group consisting of an Nrf2 activator, an antioxidant, a detoxification agent, an anti-inflammatory agent, and an antidiabetic agent, where the antidiabetic agent is optionally metformin.

18. A method of increasing the activity of or the amount of HMOX-1 in a human subject comprising: administering to a human subject a compound of claim 1 .

19. A method of increasing Nrf2 dependent gene transcription in a human subject comprising: administering to a human subject a compound of claim 1 .

20. A method of reducing the amount of ROS in a human subject comprising:

administering to a human subject a compound of claim 1 .

21. A compound of claim 1 , wherein the compound is selected from the group consisting of:

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid (2-ethoxy-ethyl)-amide;

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid (2-hydroxy-ethyl)-amide;

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid (2-methoxy-2-methyl-propyl)-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid (2-methoxy-ethyl)-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid (2-hydroxy-ethyl)-amide;

2-(6Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5carboxylic acid (2-methoxy-ethyl)-amide;

6-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ethylamide;

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide;

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid [2-(2-fluoro-ethoxy)-ethyl]-amide;

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid ((S)-2-hydroxy-propyl)-amide;

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid ((R)-2-hydroxy-propyl)-amide;

2-(6Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5carboxylic acid (2-ethoxy-ethyl)-amide;

1-Ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid (2-ethoxy-ethyl)-amide;

1-(2-Methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid (2-ethoxy-ethyl)-amide;

2-(6Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5carboxylic acid (2-fluoro-ethyl)-amide;

2-(6Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5carboxylic acid (2-methoxy-ethyl)-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid ((R)-2-hydroxy-propyl)-amide

2-(6Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid [2-(2-methoxy-ethoxy)-ethyl]-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid [2-(2-methoxy-ethoxy)-ethyl]-amide; and

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid [2-(2-dimethylamino-ethoxy)-ethyl]amide;

or a pharmaceutically acceptable salt thereof.

22. A compound of claim 1 , wherein the compound is selected from the group consisting of:

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5carboxylic acid [2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid (2-morpholin-4-yl-ethyl)-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid (3-morpholin-4-yl-3-oxo-propyl)-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid [2-((R)-3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]amide;

2-(6Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5carboxylic acid [2-((R)-3-methoxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;

2-(6Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5carboxylic acid [2-((S)-3-methoxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid [2-((S)-3-methoxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid [2-((R)-3-dimethylamino-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid [2-((S)-3-dimethylamino-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid (2-morpholin-4-yl-2-oxo-ethyl)-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid [2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid [2-((R)-3-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid [2-((S)-3-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide;

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid [2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide;

2-(6Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5carboxylic acid [2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid ((S)-1-methyl-2-morpholin-4-yl-2-oxo-ethyl)-amide; and

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid [(R)-1-methyl-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]amide;

or a pharmaceutically acceptable salt thereof.

23. A compound of claim 1 , wherein the compound is selected from the group consisting of:

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid dimethylcarbamoylmethyl-amide;

2-(6Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5carboxylic acid dimethylcarbamoylmethyl-amide;

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5carboxylic acid (2-dimethylcarbamoyl-ethyl)-amide;

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid ((S)-1-dimethylcarbamoyl-ethyl)amide;

2-(6Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5carboxylic acid (2-dimethylcarbamoyl-ethyl)-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid (2-dimethylcarbamoyl-ethyl)-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid methylcarbamoylmethyl-amide;

2-(6Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5carboxylic acid ((S)-1-dimethylcarbamoyl-ethyl)-amide;

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid ((S)-1-dimethylcarbamoyl-ethyl)amide; and

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid ((R)-1-dimethylcarbamoyl-ethyl)-amide;

or a pharmaceutically acceptable salt thereof.

24. A compound of claim 1 , wherein the compound is selected from the group consisting of:

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5carboxylic acid (2-ethanesulfonyl-ethyl)-amide; and

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5carboxylic acid (3-methanesulfonyl-propyl)-amide;

or a pharmaceutically acceptable salt thereof.

25. A compound, wherein the compound is

3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid dimethylcarbamoylmethyl-amide or a pharmaceutically acceptable salt thereof.

26. The compound of claim 25 , wherein the compound is 3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6carboxylic acid dimethylcarbamoylmethyl-amide.

27. A compound, wherein the compound is

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid (2-methoxy-ethyl)-amide or a pharmaceutically acceptable salt thereof.

28. The compound of claim 27 , wherein the compound is 1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid (2-methoxy-ethyl)-amide.

29. A compound, wherein the compound is

3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (2-methoxy-ethyl)-amide or a pharmaceutically acceptable salt thereof.

30. The compound of claim 29 , wherein the compound is 3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6carboxylic acid (2-methoxy-ethyl)-amide.

31. A compound, wherein the compound is 1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide or a pharmaceutically acceptable salt thereof.

32. The compound of claim 31 , wherein the compound is 1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide.

33. A compound, wherein the compound is

6-Methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-morpholin-4-yl-ethyl)-amide or a pharmaceutically acceptable salt thereof.

34. The compound of claim 33 , wherein the compound is 6-Methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5carboxylic acid (2-morpholin-4-yl-ethyl)-amide.

35. A compound, wherein the compound is

3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (2-morpholin-4-yl-ethyl)-amide or a pharmaceutically acceptable salt thereof.

36. The compound of claim 35 , wherein the compound is 3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (2-morpholin-4-yl-ethyl)-amide.

37. A compound, wherein the compound is 1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzimidazole-5carboxylic acid dimethylcarbamoylmethyl-amide or a pharmaceutically acceptable salt thereof.

38. The compound of claim 37 , wherein the compound is 1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzimidazole-5Carboxylic acid dimethylcarbamoylmethyl-amide.

39. A pharmaceutical composition comprising a compound of claim 21 and a pharmaceutically acceptable carrier.

40. A pharmaceutical composition comprising a compound of claim 22 and a pharmaceutically acceptable carrier.

41. A pharmaceutical composition comprising a compound of claim 23 and a pharmaceutically acceptable carrier.

42. A pharmaceutical composition comprising a compound of claim 24 and a pharmaceutically acceptable carrier.

43. A pharmaceutical composition comprising a compound of claim 25 and a pharmaceutically acceptable carrier.

44. A pharmaceutical composition comprising a compound of claim 27 and a pharmaceutically acceptable carrier.

45. A pharmaceutical composition comprising a compound of claim 29 and a pharmaceutically acceptable carrier.

46. A pharmaceutical composition comprising a compound of claim 31 and a pharmaceutically acceptable carrier.

47. A pharmaceutical composition comprising a compound of claim 33 and a pharmaceutically acceptable carrier.

48. A pharmaceutical composition comprising a compound of claim 35 and a pharmaceutically acceptable carrier.

49. A pharmaceutical composition comprising a compound of claim 37 and a pharmaceutically acceptable carrier.

Assignments (11)