C2-azaspiro iminothiazine dioxides as BACE inhibitors, compositions, and their use

Patent metadata

Field	Value
Publication number	US-9453034-B2
Application number	US-201414774204-A
Country	US
Kind code	B2
Filing date	Mar 11, 2014
Priority date	Mar 15, 2013
Publication date	Sep 27, 2016
Grant date	Sep 27, 2016

Abstract

In its many embodiments, the present invention provides certain C2-azaspirosubstituted iminothiazine dioxide compounds. The novel compounds of the invention are useful as BACE inhibitors and/or 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 1A is selected from the group consisting of H, halo, alkyl, cycloalkyl, haloalkyl, and heteroalkyl;
R 1B is selected from the group consisting of H, halo, alkyl, cycloalkyl, haloalkyl, and heteroalkyl;
ring C is a moiety selected from the group consisting of

each R 2 is independently selected from the group consisting of H, -alkyl-OH, alkyl, heteroalkyl, and cycloalkyl wherein each said alkyl, heteroalkyl, and cycloalkyl of R 2 is optionally substituted with halogen;
each R 3 is independently selected from the group consisting of H, halogen, -alkyl-OH, alkyl, heteroalkyl, alkoxy, and cycloalkyl, wherein each said alkyl, heteroalkyl, alkoxy, and cycloalkyl of R 3 is optionally substituted with halogen;
R N is selected from the group consisting of: H, —C(O)R 6N , —C(O)OR 6N , —C(O)N(R 6N ) 2 , —S(O) 2 R 6N , —S(O) 2 N(R 6N ) 2 , alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl,
wherein said alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl, of R N are each optionally independently unsubstituted or substituted with one or more groups independently selected from R 9 ;
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 and R 5B (when present) is independently selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, wherein each said alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl of R 5A and R 5B is unsubstituted or substituted with one or more halogen;
each R 6N and R 6A (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 6N and R 6A 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 (when present) is independently selected from the group consisting of H, alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl, wherein each said alkyl, heteroalkyl, -heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl of R 7B is unsubstituted or substituted with one or more halogen;
each R 8 (when present) is independently selected from the group consisting of halogen, lower alkyl, lower heteroalkyl, lower alkoxy, lower cycloalkyl, and lower heterocycloalkyl, wherein each said lower alkyl, lower heteroalkyl, lower alkoxy, lower cycloalkyl, and lower heterocycloalkyl of R 8 is optionally substituted with halogen; and
each R 9 (when present) is independently selected from the group consisting of halogen, —NO 2 , —OH, —CN, —SF 5 , —OSF 5 , alkyl, -alkyl-OH, heteroalkyl, -heteroalkyl-OH, alkoxy, —O-heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, —O-cycloalkyl, —O-alkyl-cycloalkyl, -heterocycloalkyl, -alkyl-heterocycloalkyl, —O-heterocycloalkyl and —O-alkyl-heterocycloalkyl, wherein each said alkyl, -alkyl-OH, heteroalkyl, -heteroalkyl-OH, alkoxy, —O-heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, —O-cycloalkyl, —O-alkyl-cycloalkyl, -heterocycloalkyl, -alkyl-heterocycloalkyl, —O-heterocycloalkyl and —O-alkyl-heterocycloalkyl are optionally substituted with one or more halogen.

2. The compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said

Assignees

• Merck Sharp & Dohme

Inventors

• Gilbert Eric J
• Cumming Jared N
• Scott Jack D
• Wu Wen-Lian
• Burnett Duane A
• Stamford Andrew W

Classifications

• A61P25/28

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