C-6 spirocarbocyclic iminothiadiazine dioxides as BACE inhibitors, compositions, and their use

Patent metadata

Field	Value
Publication number	US-9802928-B2
Application number	US-201415104658-A
Country	US
Kind code	B2
Filing date	Dec 14, 2014
Priority date	Dec 18, 2013
Publication date	Oct 31, 2017
Grant date	Oct 31, 2017

Abstract

In its many embodiments, the present invention provides certain C-6 spirocarbocyclic iminothiadiazine compounds, including compounds Formula (I): or a tautomers thereof, and pharmaceutically acceptable salts of said compounds and said tautomers, wherein R 1 , R 4 , ring A, R A , m, L 1 , and RL are as defined herein. 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:
-L 1 - is a divalent moiety selected from the group consisting of —NHC(O)— and —C(O)NH—;
R 1 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;
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 and heteroaryl;
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 ;
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, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl;
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, and -alkyl-heterocycloalkyl,
wherein each said alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl,
and -alkyl-heterocycloalkyl of R 5A and R 5B is unsubstituted or substituted with one or more halogen;
each 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 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, —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. A compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
R 1 is selected from the group consisting of H, methyl, ethyl, cyclopropyl, —CH 2 -cyclopropyl, and —CH 2 OCH 3 .

3. A compound of claim 2 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
R 4 is selected from the group consisting of methyl and —CHF 2 .

4. A compound of claim 3 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
-L 1 - is —C(O)NH—.

5. A compound of claim 4 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
ring A is selected from the group consisting of phenyl, pyridazinyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, thiazolyl, and thienyl;
m is 0, 1, or 2; and
each R A (when present) is independently selected from the group consisting of halogen, oxo, —CN, —SF 5 , —NHCH 3 , —N(CH 3 ) 2 , —OCH 3 , —OCH 2 CH 3 , —O-cyclopropyl, —O—CH 2 -cyclopropyl, —CH 2 OCH 3 , —S(CH 3 ), methyl, ethyl, cyclopropyl, —CH 2 -cyclopropyl, —CF 3 , —CHF 2

Assignees

• Merck Sharp & Dohme

Inventors

• Scott Jack D
• Cumming Jared N
• BLIZZARD Timothy
• Ellis Michael

Classifications

• C07D513/04

  Ortho-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D417/12 Primary

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

• A61P25/00

  Drugs for disorders of the nervous system · CPC title