N-substituted indoles and other heterocycles for treating brain disorders

Patent metadata

Field	Value
Publication number	US-2021332012-A1
Application number	US-202117345471-A
Country	US
Kind code	A1
Filing date	Jun 11, 2021
Priority date	Feb 27, 2019
Publication date	Oct 28, 2021
Grant date	—

Abstract

The present invention provides N-substituted indoles and other heterocycles and methods of using the compounds for treating brain disorders.

First claim

What is claimed is:

1 . A compound of Formula I:

wherein:
X is CR 3 ;
R 1a and R 1b are each independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl;
R 1c is C 1-6 alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl;
alternatively, two of R 1a , R 1b , and R 1c are combined with the atoms to which they are attached to form a C 3-12 heterocycloalkyl;
R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 1-6 haloalkyl, C 1-6 alkylamine, C 1-6 alkoxy, C 1-6 haloalkoxy, —OR 8a , —NO 2 , —CN, —C(O)R 8b , —C(O)OR 8b , —OC(O)R 8b , —OC(O)OR 8b , —N(R 8b R 8c ), —N(R 8b )C(O)R 8c , —C(O)N(R 8b R 8c ), —N(R 8b )C(O)OR 8c , —OC(O)N(R 8b R 8c ), —N(R 8b )C(O)N(R 8c R 8d ), —C(O)C(O)N(R 8b R 8c ), —S(O 2 )R 8b , —S(O) 2 N(R 8b R 8c ), C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl;
R 8a is C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl;
R 8b , R 8c and R 8d are each independently H or C 1-6 alkyl;
alternatively, one of R 1a , R 1b , or R 1c is combined with R 2 to form a C 5-12 heterocycloalkyl;
alternatively, R 2 and R 3 are combined with the atoms to which they are each attached to form a C 4-8 cycloalkyl, C 4-10 heterocycloalkyl, or C 6-12 aryl;
alternatively, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atoms to which they are each attached to form a C 4-6 cycloalkyl, C 4-6 heterocycloalkyl, C 6-12 aryl, or C 5-10 heteroaryl; and
L is C 1-6 alkylene,
or pharmaceutically acceptable salts and isomers thereof,
wherein when R 1a , R 1b and R 1c are each Me, L is methylene, X is CR 3 and R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are hydrogen, then the compound is

and
wherein the compound is other than

2 . The compound of claim 1 , selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

3 . The compound of claim 2 , which is

or a pharmaceutically acceptable salt thereof.

4 . The compound of claim 2 , which is

or a pharmaceutically acceptable salt thereof.

5 . The compound of claim 2 , which is

or a pharmaceutically acceptable salt thereof.

6 . The compound of claim 2 , which is

or a pharmaceutically acceptable salt thereof.

7 . The compound of claim 2 , which is

or a pharmaceutically acceptable salt thereof.

8 . The compound of claim 2 , which is

or a pharmaceutically acceptable salt thereof.

9 . The compound of claim 2 , which is

or a pharmaceutically acceptable salt thereof.

10 . The compound of claim 2 , which is

or a pharmaceutically acceptable salt thereof.

11 . The compound of claim 2 , which is

or a pharmaceutically acceptable salt thereof.

12 . The compound of claim 2 , which is

or a pharmaceutically acceptable salt thereof.

13 . A compound of Formula II:

wherein:
X is CR 3 ;
R 1a and R 1b are each independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl;
alternatively, R 1a and R 1b are combined with the atoms to which they are attached to form a C 3-12 heterocycloalkyl;
R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 1-6 haloalkyl, C 1-6 alkylamine, C 1-6 alkoxy, C 1-6 haloalkoxy, —OR 8a , —NO 2 , —CN, —C(O)R 8b , —C(O)OR 8b , —OC(O)R 8b , —OC(O)OR 8b , —N(R 8b R 8c ), —N(R 8b )C(O)R 8c , —C(O)N(R 8b R 8c ), —N(R 8b )C(O)OR 8c , —OC(O)N(R 8b R 8c ), —N(R 8b )C(O)N(R 8c R 8d ), —C(O)C(O)N(R 8b R 8c ), —S(O 2 )R 8b , —S(O) 2 N(R 8b R 8c ), C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl;
R 8a is C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl;
R 8b , R 8c and R 8d are each independently H or C 1-6 alkyl;
alternatively, one of R 1a or R 1b is combined with R 2 to form a C 5-12 heterocycloalkyl;
alternatively, R 2 and R 3 are combined with the atoms to which they are each attached to form a C 4-8 cycloalkyl, C 4-10 heterocycloalkyl, or C 6-12 aryl;
alternatively, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atoms to which they are each attached to form a C 4-6 cycloalkyl, C 4-6 heterocycloalkyl, C 6-12 aryl, or C 5-10 heteroaryl; and
L is C 1-6 alkylene,
or pharmaceutically acceptable salts and isomers thereof,
wherein when R 1a and R 1b are both Me, and L is methylene, then at least one of R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is not hydrogen and the compound is other than:

wherein when R 1a and R 1b are Me, L is ethylene, and X is CR 3 , then at least one of R 2 , R 3 , R 4 , R 5 , R 6 and R 7 is not hydrogen;
wherein when R 1c is hydrogen, and R 5 is Br, Cl, F, —NH 2 , —NO 2 , or C 1-3 alkoxy, then at least one of R 2 , R 3 , R 4 , R 6 , or R 7 is not hydrogen; and
wherein when R 1c is hydrogen and R 5 is F, then at least one of R 2 , R 3 , R 4 , R 6 , or R 7 is not hydrogen and R 6 is not F.

14 . The compound of claim 13 , selected from the group consisting of:

Assignees

• Univ California

Inventors

• Olson David E
• Dunlap Lee
• Wagner Florence

Classifications

• C07D403/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61P25/24

  Antidepressants · CPC title

• C07D209/30

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61P25/30

  for treating abuse or dependence · CPC title