Substituted thieno[2,3-b]pyridine-2-carboxamide analogs as positive allosteric modulators of the muscarinic acetylcholine receptor m4

Patent metadata

Field	Value
Publication number	US-2016200733-A1
Application number	US-201414913258-A
Country	US
Kind code	A1
Filing date	Aug 22, 2014
Priority date	Aug 23, 2013
Publication date	Jul 14, 2016
Grant date	—

Abstract

In one aspect, the invention relates to substituted thieno[2,3-b]pyridine-2-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 1a and R 1c is independently selected from —F, —Cl, —Br, —OH, C1-C6 alkoxy, C1-C6 monoalkylamino, and C1-C6 dialkylamino;
wherein R 1b is selected from hydrogen, halogen, —OH, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 monoalkylamino, and C1-C6 dialkylamino;
or wherein R 1b and R 1c are optionally covalently bonded and, together with the intermediate atoms, comprise a 3- to 7-membered cycle and substituted with 0, 1 or 2 groups independently selected from halogen, —NH 2 , —OH, —CN, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 monoalkylamino, and C1-C6 dialkylamino;
wherein R 3 is selected from hydrogen, halogen, —OH, —CN, 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 ;
wherein m is an integer selected from 0, 1, and 2;
wherein each of R 10a and R 10b , when present, is independently selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 polyhaloalkyl;
wherein R 11 , when present, is selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 polyhaloalkyl;
wherein each of R 12a and R 12b , when present, is independently selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 polyhaloalkyl;
wherein R 15 , when present, is selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 polyhaloalkyl;
wherein each Ar 1 , when present, is independently selected from phenyl, naphthyl, and heteroaryl, and wherein each Ar 1 is independently 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 each q is an integer independently selected from 0, 1, and 2;
wherein each R 16 , when present, is selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 polyhaloalkyl;

wherein each Cy 1 , when present, is independently selected from C3-C9 cycloalkyl and C2-C7 heterocycloalkyl, and wherein each Cy 1 is independently 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 ; and
wherein when Cy 1 is a C2-C7 heterocycloalkyl, the Cy 1 group is bonded to the thieno ring via a carbon-carbon bond;

wherein each of R 4a and R 4b is independently selected from hydrogen, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C3-C8 hydroxyalkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR 40 R 41 , —(C1-C6 alkyl)-NR 40 (C═O)R 41 , —(C1-C6 alkyl)-NR 40 (C═O)OR 41 , —(C1-C6 monohaloalkyl)-NR 40 (C═O)OR 41 , —(C1-C6 polyhaloalkyl)-NR 40 (C═O)OR 41 , —(C1-C8 alkyl)-Cy 2 , Cy 2 , —(C1-C8 alkyl)-Ar 2 , —(C2-C8 alkynyl)-Ar 2 , and Ar 2 ;
wherein R 4a and R 4b are not simultaneously hydrogen;
wherein each R 40 , when present, is independently selected from hydrogen and C1-C8 alkyl;
wherein each R 41 , when present, is independently selected from hydrogen, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, —(C1-C8 alkyl)-Cy 2 , Cy 2 , —(C1-C8 alkyl)-Ar 2 , and Ar 2 ;
wherein each Ar 2 , when present, is independently selected from phenyl, naphthyl, and heteroaryl, and wherein each Ar 2 is independently 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) t 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) t R 55 , —NR 50 (C1-C6 alkyl)-S(O) t NR 53 R 54 , —NR 50 (C═O)R 55 , —NR 50 (C═O)OR 55 , —NR 50 S(O) t R 55 , —(C1-C6 alkyl)-(C═O)R 55 , —(C1-C6 alkyl)-(C═O)OR 55 , —(C1-C6 alkyl)-S(O) t R 55 , —(C1-C6 alkyl)-S(O) t NR 53 R 54 , —(C═O)R 55 , —(C═O)OR 55 , —S(O) t R 55 , —S(O) t NR 53 R 54 , —(C1-C8 alkyl)-Ar 20 , Ar 20 , —(C1-C8 alkyl)-Cy 20 , Cy 20 , and R 57 ;
wherein each t is an integer independently selected from 0, 1 and 2;
wherein each Ar 20 , when present, is independently selected from phenyl, naphthyl, and heteroaryl, and wherein each Ar 20 is independently substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NH 2 , —OH, —CN, —S(O) y R 56 , C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, and C1-C8 dialkylamino;
wherein each y is an integer independently selected from 0, 1, and 2;

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

wherein 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 heterocycloalkyl, —(C1-C6)-Ar 22 , and Ar 22 ;
wherein each Ar 22 , when present, is independently selected from phenyl, naphthyl, and heteroaryl, and 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;

wherein 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 heterocycloalkyl, —(C1-C6)-Ar 23 , and Ar 23 ;
wherein each Ar 23 , when present, is independently selected from phenyl, naphthyl, and heteroaryl, and 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;

wherein 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;

wherein each Cy 2 , when present, is independently selected from C3-C9 cycloalkyl and C2-C7 heterocycloalkyl, and wherein each Cy 2 is independently substituted with 0, 1, 2, or

Assignees

• Univ Vanderbilt

Inventors

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

Classifications

• C07D495/04 Primary

  Ortho-condensed systems · CPC title