Substituted 5-aminothieno[2,3-C]pyridazine-6-carboxamide analogs as positive allosteric modulators of the muscarinic acetylcholine receptor M4

Patent metadata

Field	Value
Publication number	US-9868746-B2
Application number	US-201615283508-A
Country	US
Kind code	B2
Filing date	Oct 3, 2016
Priority date	Feb 23, 2012
Publication date	Jan 16, 2018
Grant date	Jan 16, 2018

Abstract

In one aspect, the invention relates to substituted 5-aminothieno[2,3-c]pyridazine-6-carboxamide analogs, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the muscarinic acetylcholine receptor M 4 (mAChR M 4 ); synthesis methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

First claim

What is claimed is:

1. A compound having a structure represented by a formula:

wherein:
each of R 3a and R 3b is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C3-C9 cycloalkyl, C2-C7 heterocycloalkyl, (C1-C8 alkyl)(C3-C9 cycloalkyl), and —(C1-C8 alkyl)-(C2-C7 heterocycloalkyl);
wherein R 3a and R 3b are optionally covalently bonded and, together with the intermediate nitrogen, form a 3- to 7-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH 2 , —OH, —CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, and C1-C6 dialkylamino;
m is an integer from 1 to 3;
Ar 1 is selected from phenyl and heterocyclyl, and Ar 1 is substituted with 0-2 groups selected from halogen, —NH 2 , —OH, —CN, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, C1-C8 dialkylamino, and —S(O) n R 5 ;
n is an integer from 0 to 2; and
R 5 , when present, is selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 polyhaloalkyl;
or a pharmaceutically acceptable salt, solvate, or polymorph thereof.

2. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any claim 1 , or pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, and a pharmaceutically acceptable carrier.

3. The compound of claim 1 , wherein each of R 3a and R 3b is independently selected from hydrogen and methyl.

4. The compound of claim 1 , wherein each of R 3a and R 3b is hydrogen.

5. The compound of claim 1 , wherein Ar 1 is phenyl substituted with 0-2 groups independently selected from halogen, —NH 2 , —OH, —CN, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, C1-C8 dialkylamino, and —S(O) n R 5 .

6. The compound of claim 5 , wherein Ar 1 is phenyl substituted with 0-2 groups independently selected from —F, —Cl, —NH 2 , —OH, —CN, methyl, —CHF 2 , and —CF 3 .

7. The compound of claim 1 , wherein Ar 1 is heterocyclyl substituted with 0-2 groups independently selected from halogen, —NH 2 , —OH, —CN, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, C1-C8 dialkylamino, and —S(O) n R 5 .

8. The compound of claim 1 , wherein Ar 1 has a structure represented by a formula selected from:

wherein:
each of R 6a , R 6b , R 6c , R 6d , and R 6e , when present, is independently selected from hydrogen, halogen, —NH 2 , —OH, —CN, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, C1-C8 dialkylamino, and —S(O) n R 5 ;
each of R 7a , R 7b , R 7c , and R 7d , when present, is independently selected from hydrogen, halogen, —NH 2 , —OH, —CN, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, C1-C8 dialkylamino, and —S(O) n R 5 ; and
R 8 , when present, is selected from hydrogen and C1-C8 alkyl.

Assignees

• Univ Vanderbilt

Inventors

• Lindsley Craig W
• Conn P Jeffrey
• Wood Michael R
• Melancon Bruce J
• Tarr James C
• Salovich James M
• Poslusney Michael S

Classifications

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07F7/1804

  Compounds having Si-O-C linkages (Si-O-acyl linkages C07F7/1896) · CPC title

• C07D409/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D495/04 Primary

  Ortho-condensed systems · CPC title