S-imino-S-oxo-iminothiazine compounds as BACE inhibitors, compositions, and their use

Patent metadata

Field	Value
Publication number	US-9422255-B2
Application number	US-201414774199-A
Country	US
Kind code	B2
Filing date	Mar 11, 2014
Priority date	Mar 15, 2013
Publication date	Aug 23, 2016
Grant date	Aug 23, 2016

Abstract

In its many embodiments, the present invention provides certain S-imino-S-oxo iminothiazine compounds, including compounds Formula (I): or a tautomers and/or stereoisomers thereof, and pharmaceutically acceptable salts of said compounds, said tautomeros and said stereoisomers, wherein R N , R 1A , R 1B , R 2 , R 3 , R 4 , ring A, R A , m, L 1 -, and R L are as defined herein. The novel compounds of the invention are useful as BACE inhibitors and may be useful for the treatment and prevention of various pathologies related thereto. Pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other active agents), and methods for their preparation and use, including for the possible treatment of Alzheimer's disease, are also disclosed.

First claim

We claim:

1. A compound, or a pharmaceutically acceptable salt thereof, said compound having the structural Formula (I):

or a tautomer thereof having the structural Formula (I′):

or pharmaceutically acceptable salt thereof, wherein:
R N is selected from the group consisting of alkyl, haloalkyl, heteroalkyl, and —(C 1-6 alkyl)-cycloalkyl, wherein said heteroalkyl is optionally substituted with halogen;
R 1A is independently selected from the group consisting of: H, halogen, alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl,
wherein each said alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl of R 1A is optionally unsubstituted or substituted with one or more halogen;
R 1B is selected from the group consisting of H, halogen, alkyl, and heteroalkyl, wherein said alkyl and heteroalkyl of R 1B are each optionally unsubstituted or substituted with one or more halogen;
or, alternatively, R 1B is a moiety having the formula:

wherein k is 0 or 1;
-L C - (when present) is a divalent moiety selected from the group consisting of lower alkyl and lower heteroalkyl, wherein each said lower alkyl and lower heteroalkyl is optionally substituted with one or more halogen;
ring C (when present) is selected from the group consisting of aryl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycloalkyl, monocyclic heterocycloalkenyl, and a multicyclic group;
n is 0 or more; and
each R C (when present) is independently selected from the group consisting of:
halogen, oxo, —OH, —CN, —SF 5 , —OSF 5 , —Si(R 5C ) 3 , —N(R 6C ) 2 , —NR 7C C(O)R 6C , —NR 7C S(O) 2 R 6C , —NR 7C S(O) 2 N(R 6C ) 2 , —NR 7C C(O)N(R 6C ) 2 , —NR 7C C(O)OR 6C , —C(O)R 6C , —C(O) 2 R 6C , —C(O)N(R 6C ) 2 , —S(O)R 6C , —S(O) 2 R 6C , —S(O) 2 N(R 6C ) 2 , —OR 6C , —SR 6C , alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl,
wherein said alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl, of R C are each optionally independently unsubstituted or substituted with one or more groups independently selected from R 8 ;
R 2 is selected from the group consisting of H, halogen, alkyl, heteroalkyl, cycloalkyl, and -alkyl-cycloalkyl, wherein each said alkyl, heteroalkyl, cycloalkyl, and -alkyl-cycloalkyl is optionally substituted with one or more halogen;
R 3 is selected from the group consisting of H, halogen, alkyl, heteroalkyl, cycloalkyl, and -alkyl-cycloalkyl, wherein each said alkyl, heteroalkyl, cycloalkyl, and -alkyl-cycloalkyl is optionally substituted with one or more halogen;
R 4 is selected from the group consisting of H, alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl, wherein each said alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl is optionally substituted with one or more halogen;
ring A is selected from the group consisting of aryl, monocyclic heteroaryl, and a multicyclic group;
m is 0 or more;
each R A (when present) is independently selected from the group consisting of:
halogen, oxo, —OH, —CN, —SF 5 , —OSF 5 , —Si(R 5A ) 3 , —N(R 6A ) 2 , —OR 6A , —SR 6A , alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl,
wherein said alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl of R A are each optionally independently unsubstituted or substituted with one or more groups independently selected from R 8 ;
-L 1 - is a divalent moiety selected from the group consisting of —NHC(O)— and —C(O)NH—;
R L is selected from the group consisting of alkyl and heteroalkyl, wherein said alkyl and heteroalkyl of R L are each optionally unsubstituted or substituted with one or more halogen;
or, alternatively, R L is a moiety having the formula

wherein q is 0 or 1;
-L B - (when present) is a divalent moiety selected from the group consisting of lower alkyl and lower heteroalkyl, wherein each said lower alkyl and lower heteroalkyl is optionally substituted with one or more halogen;
ring B is selected from the group consisting of aryl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycloalkyl, monocyclic heterocycloalkenyl, and a multicyclic group;
p is 0 or more; and
each R B (when present) is independently selected from the group consisting of:
halogen, oxo, —OH, —CN, —SF 5 , —OSF 5 , —Si(R 5B ) 3 , —N(R 6B ) 2 , —NR 7B C(O)R 6B , —NR 7B S(O) 2 R 6B , —NR 7B S(O) 2 N(R 6B ) 2 , —NR 7B C(O)N(R 6B ) 2 , —NR 7B C(O)OR 6B , —C(O)R 6B , —C(O)OR 6B , —C(O)N(R 6B ) 2 , —S(O)R 6B , —S(O) 2 R 6B , —S(O) 2 N(R 6B ) 2 , —OR 6B , —SR 6B , alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl,
wherein said alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl, of R B are each optionally independently unsubstituted or substituted with one or more groups independently selected from R 9 ;
each R 5A , R 5B , and R 5C (when present) is independently selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl,
wherein each said alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl of R 5A , R 5B , and R 5C is unsubstituted or substituted with one or more halogen;
each R 6A and R 6C (when present) is independently selected from the group consisting of H, alkyl, -alkyl-OH, alkenyl, alkynyl, heteroalkyl, -heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl
wherein each said alkyl, -alkyl-OH, alkenyl, alkynyl, heteroalkyl, -heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl of R 6A and R 6C is unsubstituted or substituted with one or more groups independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, haloalkyl, alkoxy, heteroalkoxy, and haloalkoxy;
each R 6B (when present) is independently selected from the group consisting of H, alkyl, -alkyl-OH, alkenyl, alkynyl, heteroalkyl, -heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl,
wherein each said alkyl, -alkyl-OH, alkenyl, alkynyl, heteroalkyl, -heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl of R 6B is unsubstituted or substituted with one or more groups independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, haloalkyl, alkoxy, heteroalkoxy, and haloalkoxy;
each R 7B , and R 7C (when present) is independently selected from the group consisting of H, alkyl, heteroalkyl, cycloalky

Assignees

• Merck Sharp & Dohme

Inventors

• Khan Tanweer A
• Scott Jack D
• Cumming Jared N

Classifications

• C07D279/12 Primary

  not condensed with other rings · CPC title

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title

• 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