Pyridine derivatives as muscarinic m1 receptor positive allosteric modulators

Patent metadata

Field	Value
Publication number	US-2016016907-A1
Application number	US-201514799621-A
Country	US
Kind code	A1
Filing date	Jul 15, 2015
Priority date	Jul 18, 2014
Publication date	Jan 21, 2016
Grant date	—

Abstract

The present invention provides, in part, compounds of Formula I:

N-oxides thereof, and pharmaceutically acceptable salts of the compounds or N-oxides; processes for the preparation of; intermediates used in the preparation of; and compositions containing such compounds, N-oxides, or salts, and their uses for treating M1-mediated (or M1-associated) disorders including, e.g., Alzheimer's disease, schizophrenia (e.g., its cognitive and negative symptoms), pain, addiction, and a sleep disorder.

First claim

1 . A compound of Formula I:

or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or the N-oxide, wherein:
R 1 is selected from the group consisting of C 1-8 alkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, (C 3-10 cycloalkyl)-C 1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, (C 6-10 aryl)-C 1-4 alkyl-, (5- to 10-membered heteroaryl)-C 1-4 alkyl-, wherein each of the C 1-8 alkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, (C 3-10 cycloalkyl)-C 1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, (C 6-10 aryl)-C 1-4 alkyl-, and (5- to 10-membered heteroaryl)-C 1-4 alkyl- is optionally substituted one or more independently selected R 5 , and wherein each of the C 1-8 alkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, (C 3-10 cycloalkyl)-C 1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, (C 6-10 aryl)-C 1-4 alkyl-, and (5- to 10-membered heteroaryl)-C 1-4 alkyl- is further optionally substituted one or more oxo;
each of R 2 and R 3 is independently selected from the group consisting of H, halogen, OH, methyl, and methoxy, wherein each of the methyl and methoxy is optionally substituted with one or more substituents each independently selected from OH and halogen;
R 4 is selected from the group consisting of H, halogen, OR 6 , CN, C 1-8 alkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, (C 3-10 cycloalkyl)-C 1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, (C 6-10 aryl)-C 1-4 alkyl-, and (5- to 10-membered heteroaryl)-C 1-4 alkyl-, wherein each of the C 1-8 alkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, (C 3-10 cycloalkyl)-C 1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, (C 6-10 aryl)-C 1-4 alkyl-, and (5- to 10-membered heteroaryl)-C 1-4 alkyl- is optionally substituted with one or more independently selected R 7 , and wherein each of the C 1-8 alkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, (C 3-10 cycloalkyl)-C 1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, (C 6-10 aryl)-C 1-4 alkyl-, and (5- to 10-membered heteroaryl)-C 1-4 alkyl- is further optionally substituted one or more oxo;
T 1 is selected from the group consisting of H, halogen, N(R c ) 2 , —NR e R f , —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, (C 3-6 cycloalkyl)-C 1-2 alkyl-, and C 1-6 alkoxy, wherein each of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, (C 3-6 cycloalkyl)-C 1-2 alkyl-, and C 1-6 alkoxy of T 1 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —CN, —C(═O)C 1-4 alkyl, —C(═O)OH, —C(═O)O—C 1-4 alkyl, —C(═O)NHC 1-4 alkyl, —C(═O)N(C 1-4 alkyl) 2 , oxo, —OH, —OC(═O)—C 1-4 alkyl, —OC(═O)O—C 1-4 alkyl, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —NHC(═O)C 1-4 alkyl, —NHC(═O)OC 1-4 alkyl, —NHC(═O)NHC 1-4 alkyl, and C 1-4 alkoxy, and wherein R e and R f together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —OH, oxo, —C(═O)H, —C(═O)OH, —C(═O)—C 1-4 alkyl, —C(═O)—NH 2 , —C(═O)—N(C 1-4 alkyl) 2 , —CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxylalkyl, C 1-4 haloalkyl, and C 1-4 haloalkoxy;
T 2 is selected from the group consisting of halogen, —N(R c ) 2 , —NR e R f , —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, (C 3-6 cycloalkyl)-C 1-2 alkyl-, and C 1-6 alkoxy, wherein each of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, (C 3-6 cycloalkyl)-C 1-2 alkyl-, and C 1-6 alkoxy of T 2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —CN, —C(═O)C 1-4 alkyl, —C(═O)OH, —C(═O)O—C 1-4 alkyl, —C(═O)NHC 1-4 alkyl, —C(═O)N(C 1-4 alkyl) 2 , oxo, —OH, —OC(═O)—C 1-4 alkyl, —OC(═O)O—C 1-4 alkyl, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —NHC(═O)C 1-4 alkyl, —NHC(═O)OC 1-4 alkyl, —NHC(═O)NHC 1-4 alkyl, and C 1-4 alkoxy;
T 3 is selected from the group consisting of H, halogen, CH 3 , and C 1 fluoroalkyl;
each of X 1 , X 2 , X 3 , and X 4 is independently selected from the group consisting of CR 9 and N, provided that at most two of X 1 , X 2 , X 3 , and X 4 are N;
each R 5 is independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, —SF 5 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, a 4- to 10-membered heterocycloalkyl, —N(R a )(R b ), —N(R c )(C(═O)R d ), —O(═O)—N(R a )(R b ), —C(═O)—R d , —C(═O)—OR d , —OC(═O)—R d , —N(R c )(S(═O) 2 R d ), —S(═O) 2 —N(R a )(R b ), —SR d , and —OR d , wherein each of the C 1-6 alkyl, C 3-7 cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —CN, —OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, —N(R a )(R b ), —N(R c )(C(═O)R d ), —C(═O)—OR d , —C(═O)H, —C(═O)R d , —C(═O)N(R a )(R b ), —N(R c )(S(═O) 2 R d ), —S(═O) 2 —N(R a )(R b ), —SR d , and —OR d ;
R 6 is selected from the group consisting of H, C 1-8 alkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, (C 3-10 cycloalkyl)-C 1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, (C 6-10 aryl)-C 1-4 alkyl-, and (5- to 10-membered heteroaryl)-C 1-4 alkyl-, wherein each of the C 1-8 alkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, (C 3-10 cycloalkyl)-C 1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, (C 6-10 aryl)-C 1-4 alkyl-, and (5- to 10-membered heteroaryl)-C 1-4 alkyl- is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —CN, —C(═O)C 1-4 alkyl, —C(═O)OH, —C(═O)O—C 1-4 alkyl, —C(═O)NHC 1-4 alkyl, —C(═O)N(C 1-4 alkyl) 2 , oxo, —OH, —OC(═O)—C 1-4 alkyl, —OC(═O)O—C 1-4 alkyl, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —NHC(═O)C 1-4 alkyl, —NHC(═O)OC 1-4 alkyl, —NHC(═O)NHC 1-4 alkyl, and C 1-4 alkoxy;
each R 7 is independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, —SF 5 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, a 4- to 10-membered heterocycloalkyl, —N(R a )(R b ), —N(R c )(C(═O)R d ), —C(═O)—N(R a )(R b ), —C(═O)—R d , —C(═O)—OR d , —OC(═O)—R d , —N(R c )(S(═O) 2 R d ), —S(═O) 2 —N(R a )(R b ), —SR d , and —OR d , wherein each of eth C 1-6 alkyl, C 3-7 cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —CN, —OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, —N(R a )(R b ), —N(R c )(C(═O)R d ), —C(═O)—OR d , —C(═O)H, —C(═O)R d , —C(═O)N(R a )(R b ), —N(R c )(S(═O) 2 R d ), —S(═O) 2 —N(R a )(R b ), —SR d , and —OR d ;
each R 9 is independently selected from the group consisting of H, halogen, —OH, —NO 2 , —CN, —SF 5 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-6 cycloalkyl-C 1-2 alkyl-, 4- to 10-membered heterocycloalkyl, —N(R a )(R b ), —N(R c )(C(═O)R d ), —C(═O)—N(R a )(R b ), —C(═O)—R d , —C(═O)—OR d , —OC(═O)—R d , —N(R c )(S(═O) 2 R d ), —S(═O) 2 —N(R a )(R b ), —SR d , and OR d , where

Assignees

• Pfizer

Inventors

• Brodney Michael Aaron
• Davoren Jennifer Elizabeth
• Garnsey Michelle Renee
• Zhang Lei
• O'Neil Steven Victor

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

• C07D213/81 Primary

  Amides; Imides · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D401/06

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

• A61P25/00

  Drugs for disorders of the nervous system · CPC title