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

Patent metadata

Field	Value
Publication number	US-9637498-B2
Application number	US-201414913266-A
Country	US
Kind code	B2
Filing date	Aug 22, 2014
Priority date	Aug 23, 2013
Publication date	May 2, 2017
Grant date	May 2, 2017

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 M4 (mAChR M4); 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
R 1 is selected from hydrogen, halogen, —OH, —CN, —NH 2 , —CF 3 , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, and C1-C6 dialkylamino;
R 2 is selected from hydrogen, halogen, —OH, —CN, —NH 2 , —CF 3 , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, and C1-C6 dialkylamino;
R 3 is selected from hydrogen, halogen, —OH, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxy, —CR 10a R 10b OR 11 , —CR 10a R 10b NR 12a R 12b , —S(O) m R 15 , —(C1-C6 alkyl)-Ar 1 , —(C1-C8 alkyl)-Cy 1 , Ar 1 , and Cy 1 ;
m is an integer selected from 0, 1, and 2;
R 10a and R 10b , when present, are each independently selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 polyhaloalkyl;
R 11 , when present, is selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 polyhaloalkyl;
R 12a and R 12b , when present, are each independently selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 polyhaloalkyl;
R 15 , when present, is selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 polyhaloalkyl;
Ar 1 , when present, is selected from phenyl, naphthyl, and monocyclic heteroaryl, wherein Ar 1 is substituted with 0, 1, 2, or 3 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) q R 16 ;
each q is an integer independently selected from 0, 1, and 2;
each R 16 , when present, is selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 polyhaloalkyl;

Cy 1 , when present, is selected from C3-C9 cycloalkyl and C2-C7 monocyclic heterocycloalkyl, wherein Cy 1 is substituted with 0, 1, 2, or 3 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) q R 16 ;
wherein when Cy 1 is a C2-C7 monocyclic heterocycloalkyl, the Cy 1 group is bonded to the thieno ring via a carbon-carbon bond;

R 4a is selected from hydrogen, C1-C8 alkyl, C1-C8 monohaloalkyl, and C1-C8 polyhaloalkyl;
R 4b is selected from —(C1-C8 alkyl)-Cy 2 , Cy 2 , —(C1-C8 alkyl)-Ar 2 , —(C2-C8 alkynyl)-Ar 2 , and Ar 2 ;
Ar 2 , when present, is selected from phenyl, naphthyl, and monocyclic heteroaryl, wherein Ar 2 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH 2 , —OH, —CN, —N 3 , —SF 5 , C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, C1-C8 dialkylamino, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR 51 R 52 , —(C1-C6 alkyl)-NR 50 (C═O)R 55 , —(C1-C6 alkyl)-NR 50 (C═O)OR 55 , —(C1-C6 alkyl)-NR 50 S(O) n R 55 , —NR 50 (C1-C6 alkyl)-(C═O)R 55 , —NR 50 (C1-C6 alkyl)-(C═O)OR 55 , —NR 50 (C1-C6 alkyl)-S(O) n R 55 , —NR 50 (C1-C6 alkyl)-S(O) n NR 53 R 54 , —NR 50 (C═O)R 55 , —NR 50 (C═O)OR 55 , —NR 50 S(O) n R 55 , —(C1-C6 alkyl)-(C═O)R 55 , —(C1-C6 alkyl)-(C═O)OR 55 , —(C1-C6 alkyl)-S(O) n R 55 , —(C1-C6 alkyl)-S(O) n NR 53 R 54 , —(C═O)R 55 , —(C═O)OR 55 , —S(O)—R 55 , —S(O)—NR 53 R 54 , —(C1-C8 alkyl)-Ar 20 , Ar 20 , —(C1-C8 alkyl)-Cy 20 , Cy 20 , and R 57 ;
each n is an integer independently selected from 0, 1, and 2;
each Ar 20 , when present, is independently selected from phenyl, naphthyl, and monocyclic heteroaryl, wherein each Ar 20 is independently substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH 2 , —OH, —CN, —S(O) i R 56 , C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, and C1-C8 dialkylamino;
each j is an integer independently selected from 0, 1, and 2;

each Cy 20 , when present, is independently selected from C3-C9 cycloalkyl and C2-C7 monocyclic heterocycloalkyl, wherein each Cy 20 is independently substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH 2 , —OH, —CN, —S(O) i R 56 , C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, and C1-C8 dialkylamino;
each R 50 , when present, is independently selected from hydrogen and C1-C8 alkyl;
each R 51 , when present, is independently selected from hydrogen and C1-C8 alkyl;
each R 52 , when present, is independently selected from hydrogen and C1-C8 alkyl;
each R 53 , when present, is independently selected from hydrogen and C1-C8 alkyl;
wherein each R 54 , when present, is independently selected from hydrogen, C1-C8 alkyl, C3-C9 cycloalkyl, C2-C7 monocyclic heterocycloalkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, —(C1-C6)-Ar 21 , and Ar 21 ;
each Ar 21 , when present, is independently selected from phenyl, naphthyl, and monocyclic heteroaryl, wherein each Ar 21 is independently substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH 2 , —OH, —CN, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, and C1-C8 dialkylamino;

each R 55 , when present, is independently selected from hydrogen, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C3-C9 cycloalkyl, C2-C7 monocyclic heterocycloalkyl, —(C1-C6)-Ar 22 , and Ar 22 ;
each Ar 22 , when present, is independently selected from phenyl, naphthyl, and monocyclic heteroaryl, wherein each Ar 22 is independently substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH 2 , —OH, —CN, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, and C1-C8 dialkylamino;

each R 56 , when present, is independently selected from hydrogen, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C3-C9 cycloalkyl, C2-C7 monocyclic heterocycloalkyl, —(C1-C6)-Ar 23 , and Ar 23 ;
each Ar 23 , when present, is independently selected from phenyl, naphthyl, and monocyclic heteroaryl, wherein each Ar 23 is independently substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH 2 , —OH, —CN, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, and C1-C8 dialkylamino;

each R 57 , when present, is independently selected from C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monoalkylamino, or C1-C4 dialkylamino substituted with 1 or 2 groups selected from —F, —CH 3 , —CF 3 , —OH, —NH 2 , and —CN;
Cy 2 , when present, is selected from C3-C9 cycloalkyl and C2-C7 monocyclic heterocycloalkyl, wherein each Cy 2 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH 2 , —OH, —CN, —N 3 , —SF 5 , C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, C1-C8 dialkylamino, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR 51 R 52 , —(C1-C6 alkyl)-NR 50 (C═O)R 55 , —(C1-C6 alkyl)-NR 50 (C═O)OR 55 , —(C1-C6 alkyl)-NR 50 S(O) n R 55 , —NR 50 (C1-C6 alkyl)-(C═O)R 55 , —NR 50 (C1-C6 alkyl)-(C═O)OR 55 , —NR 50 (C1-C6 alkyl)-S(O) n R 55 , —NR 50 (C1-C6 alkyl)-S(O) n NR 53 R 54 , —NR 50 (C═O)R 55 , —NR 50 (C═O)OR 55 , —NR 50 S(O) n R 55 , —(C1-C6 alkyl)-(C═O)R 55 , —(C1-C6 alkyl)-(C═O)OR 55 , —(C1-C6 alkyl)-S(O) n R 55 , —(C1-C6 alkyl)-S(O) n NR 53 R 54 , —(C═O)R 55 , —(C═O)OR 55 , —S(O)—R 55 , —S(O)—NR 53 R 54 , —(C1-C8 alkyl)-Ar 20 , Ar 20 , —(C1-C8 alkyl)-Cy 20 , Cy 20 , and R 57 ;

or R 4a and R 4b are optionally covalently bonded and, together with the intermediate nitrogen, form a 3- to 8 membered monocyclic heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH 2 , —OH, —CN, —N 3 , —SF 5 , C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxy, C1-C8 alkylamin

Assignees

• Univ Vanderbilt

Inventors

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

Classifications

• C07D495/04 Primary

  Ortho-condensed systems · CPC title