IP Library Granted Patent US 11,649,230
Granted Patent B2
US 11,649,230 · App. 17/399,338 · Granted May 16, 2023

Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof

Inventors: Adnan M. M. Mjalli (Oak Ridge, NC); Dharma Rao Polisetti (High Point, NC); Jareer Nabeel Kassis (Colfax, NC); Matthew J. Kostura (Hillsborough, NC); Mustafa Guzel (Jamestown, NC); Otis Clinton Attucks (Winston-Salem, NC); Robert Carl Andrews (Jamestown, NC); Samuel Victory (Winston-Salem, NC); Suparna Gupta (Waverly, IA)
Assignee: VTV THERAPEUTICS LLC
C07D417/12A61K31/4168A61K31/4188A61K31/428A61K31/437A61P1/16C07D235/30C07D417/14C07D471/04C07D513/04
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Quick Facts
Patent No.
US 11,649,230
App. No.
17/399,338
Granted
May 16, 2023
Kind
B2
Abstract

Substituted fused imidazole derivatives, methods of their preparation, pharmaceutical compositions comprising a substituted fused imidazole derivative, and methods of use in treating renal diseases are provided. The substituted fused imidazole derivatives may control the activity or the amount or both the activity and the amount of heme-oxygenase.

Claims (253)

1. A method of treating a disease comprising administering to a human subject a compound,

wherein the disease is an inflammatory disease; and

wherein the compound is 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 cycloalkyl, 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 cycloalkyl, 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 cycloalkyl, 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 cycloalkyl, 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 method of claim 1 , wherein the inflammatory disease is selected from the group consisting of: asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, inflammatory bowel syndrome, Crohn's disease, celiac disease, scleroderma, systemic lupus erythematosus, and rheumatoid arthritis.

3. The method of claim 1 ,

wherein R 4 is -methyl, -ethyl, -isopropyl, -isobutyl, —CH 2 CH 2 —OCH 3 , —CH 2 CH 2 —F, —CH 2 CH 2 —NH 2 , or —CH 2 CH 2 —NH—CH 3 ; and

wherein R 3 is hydrogen.

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

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

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

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

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

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

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

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

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

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

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

15. The method of claim 1 , wherein the compound is selected from the group consisting of:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

or a pharmaceutically acceptable salt thereof.

16. The method of claim 1 , wherein the compound is selected from the group consisting of:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

or a pharmaceutically acceptable salt thereof.

17. The method of claim 1 , wherein the compound is selected from the group consisting of:

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

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

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

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

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

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

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

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

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

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

or a pharmaceutically acceptable salt thereof.

18. The method of claim 1 , wherein the compound is selected from the group consisting of:

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

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

or a pharmaceutically acceptable salt thereof.

19. The method of claim 1 , 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.

20. The method of claim 1 , wherein the compound is

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

or a pharmaceutically acceptable salt thereof.

21. The method of claim 1 , 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.

22. The method of claim 1 , wherein the compound is

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

or a pharmaceutically acceptable salt thereof.

23. The method of claim 1 , 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.

24. The method of claim 1 , 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.

25. A method of treating a disease comprising administering to a human subject a compound,

wherein the disease is an inflammatory disease; and

wherein the compound is a compound of Formula (I) or a pharmaceutically acceptable salt thereof

wherein

X 3 is

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

R 1 is hydrogen, —OCH 3 , or —F,

v is an integer from 0 to 2,

R 2 is —Cl, —F, —CF 3 , or —OCF 3 ,

R 4 is -methyl, -ethyl, -isopropyl, or -isobutyl,

L is —C(O)N(R 6 )—,

R 6 is hydrogen, and

G is —H, -methyl, -ethyl, -n-propyl, -isopropyl, -isobutyl, —CH 2 Y 3 , —CH 2 CH 2 Y 3 , —CH 2 CH 2 CH 2 Y 3 , —CH(CH 3 )CH 2 Y 3 , —CH 2 CH(Y 3 )CH 3 , —CH(Y 3 )CH 3 , —CH 2 C(Y 3 )(CH 3 ) 2 , or —C(Y 3 )(CH 3 ) 2 ,

where

Y 3 is -cyclopropyl, —CF 3 , —OCF 3 , —OCH 3 , —OCH 2 CH 3 , —F, —OH, —O(CH 2 ) 2 —OH, —O(CH 2 ) 2 —F, —SCH 3 , —S(O) 2 —CH 3 , —SCH 2 CH 3 , —S(O) 2 CH 2 CH 3 , —NH—CH 3 , —NH—CH 2 CH 3 , —N(CH 3 ) 2 , —NH—C(O)—CH 3 , —NH—C(O)—CH 2 CH 3 , or C(O)—Y 4 , where

Y 4 is —OH, —OCH 3 , —OCH 2 CH 3 , —OC(CH 3 ) 3 , —NH 2 , —NH—CH 3 , —NH—CH 2 CH 3 , —N(CH 3 ) 2 , or —N(CH 2 CH 3 ) 2 .

26. The method of claim 25 , wherein the inflammatory disease is selected from the group consisting of: asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, inflammatory bowel syndrome, Crohn's disease, celiac disease, scleroderma, systemic lupus erythematosus, and rheumatoid arthritis.

27. A method of treating a disease comprising administering to a human subject a compound, wherein the disease is an inflammatory disease, and wherein the compound is

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide or a pharmaceutically acceptable salt thereof.

28. The method of claim 27 , wherein the renal disease is selected from the group consisting of: inflammatory disease is selected from the group consisting of: asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, inflammatory bowel syndrome, Crohn's disease, celiac disease, scleroderma, systemic lupus erythematosus, and rheumatoid arthritis.

29. The method of claim 27 , wherein the compound is

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide.

Assignments (4)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 15, 2021
From: MJALLI, ADNAN M.M.; POLISETTI, DHARMA RAO; KASSIS, JAREER NABEEL; KOSTURA, MATTHEW J.; GUZEL, MUSTAFA; ATTUCKS, OTIS CLINTON; ANDREWS, ROBERT CARL; VICTORY, SAMUEL; GUPTA, SUPARNA
To: TRANSTECH PHARMA, INC.
Reel/Frame 058107/0325 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 15, 2021
From: TRANSTECH PHARMA, INC.
To: HIGH POINT PHARMACEUTICALS, LLC
Reel/Frame 058107/0344 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 15, 2021
From: VTVX HOLDINGS II LLC
To: VTV THERAPEUTICS LLC
Reel/Frame 058107/0463 →
CHANGE OF NAME Recorded Nov 15, 2021
From: HIGH POINT PHARMACEUTICALS, LLC
To: VTVX HOLDINGS II LLC
Reel/Frame 058300/0422 →
Continuity (8)
Division 17028226 · Sep 22, 2020
Division 16739493 · Jan 10, 2020
Division 16292524 · Mar 5, 2019
Division 16007532 · Jun 13, 2018
Division 14215873 · Mar 17, 2014
Continuation 13028406 · Feb 16, 2011
Provisional Application 61305724 · Feb 18, 2010
Related Publication 20220169641A1 · Jun 2, 2022