Azabenzimidazoles and their use as AMPA receptor modulators

Patent metadata

Field	Value
Publication number	US-11312712-B2
Application number	US-201615569299-A
Country	US
Kind code	B2
Filing date	Apr 28, 2016
Priority date	Apr 29, 2015
Publication date	Apr 26, 2022
Grant date	Apr 26, 2022

Abstract

Provided herein are compounds of Formula (I), and pharmaceutically acceptable salts, N-oxides, or solvates thereof,Also provided herein are pharmaceutical compositions comprising compounds of Formula (I) and methods of using compounds of Formula (I).

First claim

What is claimed:

1. A compound of Formula (I):

Wherein
X is N;
R 1 is a member selected from the group consisting of:
—C 1-5 alkyl, —C 1-5 haloalkyl, —C 1-5 alkoxy, —C 3-8 cycloalkyl or phenyl, wherein the —C 3-8 cycloalkyl and phenyl are each independently optionally substituted with 1-3 substituents selected from the group consisting of: halo, —C 1-5 alkyl, —C 1-5 haloalkyl, —C 1-5 haloalkoxy, —OH, and —C(═O)OC 1-5 alkyl;

R 2 is selected from the group consisting of:

R 3 is selected from the group consisting of: H, —C 1-5 alkyl or —C 1-5 haloalkyl;
R 4 is selected from the group consisting of: H, halo, —CH 3 , and —CF 3 ;
R 5 is selected from the group consisting of: H, —OH, —C 1-5 alkyl, —C 1-5 alkoxy, —C 1-5 haloalkyl, —C 1-5 haloalkoxy, —NR 5a R 5b , azetidinyl, and morpholinyl; each R 5a and R 5b are independently selected from the group consisting of: —C 1-5 alkyl, and —C 1-5 haloalkyl;
and
R 7 is H;
or pharmaceutically acceptable salts, N-oxides, or solvates thereof.

2. A compound of claim 1 , wherein the compound is: 5-[2,5-Bis(trifluoromethyl)imidazo[4,5-b]pyridin-3-yl]indolin-2-one, and pharmaceutically acceptable salts, N-oxides or solvates thereof.

3. A compound of claim 1 , wherein the compound is: 2-(Difluoromethyl)-3-(1H-indazol-5-yl)-5-(trifluoromethyl)imidazo[4,5-b]pyridine, and pharmaceutically acceptable salts, N-oxides or solvates thereof.

4. A compound of claim 1 , wherein the compound is: 3-(1H-Indazol-5-yl)-2-isopropyl-5-(trifluoromethyl)imidazo[4,5-b]pyridine, and pharmaceutically acceptable salts, N-oxides or solvates thereof.

5. A compound of claim 1 , wherein the compound is: 6-[2,5-Bis(trifluoromethyl)imidazo[4,5-b]pyridin-3-yl]-3H-1,3-benzothiazol-2-one, and pharmaceutically acceptable salts, N-oxides or solvates thereof.

6. A compound of claim 1 , wherein the compound is: 5-(Difluoromethyl)-3-(1H-indazol-5-yl)-2-(trifluoromethyl)imidazo[4,5-b]pyridine; and pharmaceutically acceptable salts, N-oxides or solvates thereof.

7. A pharmaceutical composition comprising an effective amount of at least one compound of claim 6 and at least one pharmaceutically acceptable excipient.

8. A pharmaceutical composition comprising:
(A) an effective amount of at least one compound of Formula (I):

wherein
X is N;
R 1 is a member selected from the group consisting of:
—C 1-5 alkyl, —C 1-5 haloalkyl, —C 1-5 alkoxy, —C 3-8 cycloalkyl or phenyl, wherein the —C 3-8 cycloalkyl and phenyl are each independently optionally substituted with 1-3 substituents selected from the group consisting of: halo, —C 1-5 alkyl, —C 1-5 haloalkyl, —C 1-5 haloalkoxy, —OH, and —C(═)OC 1-5 alkyl;

R 2 is selected from the group consisting of:

R 3 is selected from the group consisting of: H, —C 1-5 alkyl, or —C 1-5 haloalkyl;
R 4 is selected from the group consisting of: H, halo, —CH 3, and —CF 3 ;
R 5 is selected from the group consisting of: H, —OH, —C 1-5 alkyl, —C 1-5 alkoxy, —C 1-5 haloalkyl, —C 1-5 haloalkoxy, —NR 5a R 5b , azetidinyl, and morpholinyl; each R 5a and R 5b are independently selected from the group consisting of: —C 1-5 alkyl, and —C 1-5 haloalkyl; and
R 7 is H;
or pharmaceutically acceptable salts, N-oxides or solvates of compounds of Formula (I) and (B) at least one pharmaceutically acceptable excipient.

9. A method of inhibiting TARP γ2 dependent AMPA receptor activity in a subject suffering from or diagnosed with a disease, disorder, or medical condition comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula (I):

wherein
X is N;
R 1 is a member selected from the group consisting of:
—C 1-5 alkyl, —C 1-5 haloalkyl, —C 1-5 alkoxy, —C 3-8 cycloalkyl or phenyl, wherein the -C 3-8 cycloalkyl and phenyl are each independently optionally substituted with 1-3 substituents selected from the group consisting of: halo, —C 1-5 alkyl, —C 1-5 haloalkyl, —C 1-5 haloalkoxy, —OH, and —C(═)OC 1-5 alkyl;

R 2 is selected from the group consisting of:

R 3 is selected from the group consisting of: H, —C 1-5 alkyl, or —C 1-5 haloalkyl;
R 4 is selected from the group consisting of: H, halo, —CH 3, and —CF 3 ;
R 5 is selected from the group consisting of: H, —OH, —C 1-5 alkyl, —C 1-5 alkoxy, —C 1-5 haloalkyl, —C 1-5 haloalkoxy, —NR 5a R 5b , azetidinyl, and morpholinyl; each R 5a and R 5b are independently selected from the group consisting of: —C 1-5 alkyl, and —C 1-5 haloalkyl; and
R 7 is H; or
pharmaceutically acceptable salts, N-oxides or solvates of compounds of Formula (I).

10. The method of claim 9 , wherein the disease, disorder, or medical condition is selected from cerebral ischemia, head injury, spinal cord injury, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's chorea, AIDS nervous disturbance, epilepsy, mental disorder, mobility disturbance, pain, spasticity, nervous disturbance by toxin in food, various neurodegenerative diseases, various mental diseases, chronic pain, migraine, cancer pain, diabetic neuropathy, encephalitis, acute disseminated encephalomyelitis, acute demyelinating polyneuropathy, Guillain Barre syndrome, chronic inflammatory demyelinating polyneuropathy, multiple sclerosis, Marchifava-Bignami disease, central pontine myelinolysis, Devic syndrome, Balo disease, HV- or HTLV-myelopathy, progressive multifocal leucoencephalopathy, a secondary demyelinating disorder, CNS lupus erythematodes, polyarteritis nodosa, Sjogren syndrome, sarcoidosis, isolated cerebral vasculitis, schizophrenia, prodromal schizophrenia, cognitive disorder, depression, anxiety disorders, anxious depression, and bipolar disorder.

11. The method of claim 9 , wherein the disease, disorder or condition is depression, post traumatic stress disorder, epilepsy, schizophrenia, prodromal schizophrenia, or a cognitive disorder.

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Ameriks Michael K
• Berry Cynthia G B
• Chen Gang
• Ravula Suchitra
• Savall Bradley M
• Swanson Devin M
• Wu Dongpei
• Zhang Wei

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07C2601/16

  the ring being unsaturated · CPC title

• C07D471/14

  Ortho-condensed systems · CPC title

• C07C2601/14

  The ring being saturated · CPC title

• C07C2601/02

  with a three-membered ring · CPC title