C6-spiro iminothiadiazine dioxides as BACE inhibitors, compositions, and their use

Patent metadata

Field	Value
Publication number	US-9580396-B2
Application number	US-201314653671-A
Country	US
Kind code	B2
Filing date	Dec 16, 2013
Priority date	Dec 21, 2012
Publication date	Feb 28, 2017
Grant date	Feb 28, 2017

Abstract

In its many embodiments, the present invention provides certain C5-spiro iminothiadiazine dioxide compounds, including compounds Formula (I): (structurally represented) or tautomers thereof, and pharmaceutically acceptable salts of said compounds, wherein R1, R2, R3, X, Y, s, ring A, RA, m, -L1-, 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:
R 1 is selected from the group consisting of H, alkyl, heteroalkyl, cycloalkyl, and -alkyl-cycloalkyl, wherein each said alkyl, heteroalkyl, cycloalkyl, and -alkyl-cycloalkyl, is optionally substituted with one or more halogen;
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;
s is 0 or 1;
when s is 0, then Y is absent and X is selected from the group consisting of —C(R 1X ) 2 —, —O—, —S—, —S(O)—, and —S(O) 2 —, and
when s is 1, then X is selected from the group consisting of —C(R 1X ) 2 —, —O—, —S—, —S(O)—, and —S(O) 2 —, and Y is —C(R 1Y ) 2 —,
or, alternatively, when s is 1, then X is —C(R 1X ) 2 — and Y is selected from the group consisting of —C(R 1Y ) 2 —, —O—, —S—, —S(O)—, and —S(O) 2 —;
each R 1X (when present) is independently selected from the group consisting of: H, halogen, alkyl, heteroalkyl, and cycloalkyl,
wherein said alkyl, heteroalkyl, and cycloalkyl are each optionally independently unsubstituted or substituted with one or more halogen;
each R 1Y (when present) is independently selected from the group consisting of: H, halogen, alkyl, heteroalkyl, and cycloalkyl,
wherein said alkyl, heteroalkyl, and cycloalkyl are each optionally independently unsubstituted or 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, —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 ;
n is 0 or 1;
-L 1 - represents a bond or a divalent moiety selected from the group consisting of -alkyl-, -haloalkyl-, -heteroalkyl-, -alkenyl-, -alkynyl-, —NHC(O)—, —C(O)NH—, —C(S)NH—, —NHC(S)—, —NH—, —NHS(O) 2 —, —S(O) 2 NH—, —O—CH 2 —, —CH 2 —O—, —NHCH 2 —, and —CH 2 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, 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 7 S(O) 2 R 6B , —NR 7B S(O) 2 N(NR 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 5X , R 5Y , R 5A , R 5B , and R 5C (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 5X , R 5Y , R 5A , R 5B , and R 5C is unsubstituted or substituted with one or more halogen;
each R 6X , R 6Y , 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 6X , R 6Y , 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 7X , R 7Y , R 7A , R 7B , and R 7C (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 7X , R 7Y , R 7A , R 7B , and R 7C 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-alky

Assignees

• Merck Sharp & Dohme

Inventors

• Cumming Jared N
• Scott Jr Jack D
• Stamford Andrew W
• Iserloh Ulrich
• Neelamkavil Santhosh Francis
• Shao Pengcheng Patrick
• Wilson Jonathan E

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

• C07D513/10

  Spiro-condensed systems · CPC title

• C07D285/20

  condensed with carbocyclic rings or ring systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D285/24 Primary

  with oxygen atoms directly attached to the ring sulfur atom · CPC title