Tricyclic substituted thiadiazine dioxide compounds as BACE inhibitors, compositions and their use

Patent metadata

Field	Value
Publication number	US-9422277-B2
Application number	US-201314433296-A
Country	US
Kind code	B2
Filing date	Oct 14, 2013
Priority date	Oct 17, 2012
Publication date	Aug 23, 2016
Grant date	Aug 23, 2016

Abstract

In its many embodiments, the present invention provides certain iminothiazine dioxide compounds, including compounds Formula (I): and tautomers and stereoisomers thereof, and pharmaceutically acceptable salts of said compounds, said tautomeros and said stereoisomers, wherein the middle ring (referred to herein as “ring B”) of the tricyclic substituent is an optionally substituted 5-membered ring, and each of the remaining variables shown in the formula 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 Alzheimer's disease, are also disclosed.

First claim

We claim:

1. A compound, or a stereoisomer of said compound, or a pharmaceutically acceptable salt of said compound or said stereoisomer, 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, lower alkyl, and cyclopropyl;
ring A is selected from the group consisting of aryl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycloalkyl, monocyclic heterocycloalkenyl, and a multicyclic group;
each R 2A (when present) is independently selected from the group consisting of: halo, oxo, —OH, —CN, —SF 5 , —OSF 5 , —NO 2 , —Si(R 5 ) 3 , —N(R 6 ) 2 , —OR 6 , —SR 6 , alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl,
wherein said alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl of R 2A are each optionally unsubstituted or substituted with one or more groups independently selected from R 8 ;
m is 0 or more;
ring B is selected from the group consisting of a 5-membered heteroaryl, a 5-membered heterocycloalkyl, a 5-membered heterocycloalkenyl ring, a 5-membered cycloalkyl ring, and a 5-membered cycloalkenyl ring, wherein each said ring comprises from 1 to 4 ring heteroatoms independently selected from the group consisting of N, N-oxide, O, S, S(O), and S(O) 2 ;
each R 2B (when present) is independently selected from the group consisting of halo, —CN, alkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, heteroalkyl, haloalkyl —O-alkyl, —O-cycloalkyl, —O-alkyl-cycloalkyl, —O-heteroalkyl, and —O-haloalkyl;
n is 0 or more;
ring C is selected from the group consisting of aryl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycloalkyl, monocyclic heterocycloalkenyl, and a multicyclic group;
each R 2C (when present) is independently selected from the group consisting of: halo, oxo, —OH, —CN, —SF 5 , —OSF 5 , —Si(R 5 ) 3 , —N(R 6 ) 2 , —NR 7 C(O)R 6 , —NR 7 S(O) 2 R 12 , —NR 7 S(O) 2 N(R 6 ) 2 , —NR 7 C(O)N(R 6 ) 2 , —NR 7 C(O)OR 6 , —C(O)R 6 , —C(O) 2 R 6 , —C(O)N(R 6 ) 2 , —S(O)R 12 , —S(O) 2 R 12 , —S(O) 2 N(R 6 ) 2 , —OR 6 , —SR 6 , alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, aryl, -alkyl-aryl, heteroaryl, -alkyl-heteroaryl, heterocycloalkyl, and -alkyl-heterocycloalkyl,
wherein said alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, aryl, -alkyl-aryl, heteroaryl, -alkyl-heteroaryl, heterocycloalkyl, and -alkyl-heterocycloalkyl of R 2C are each optionally unsubstituted or substituted with one or more groups independently selected from R 8 ;
p is 0 or more;
R 4 is selected from the group consisting of lower alkyl and lower haloalkyl;
each R 5 (when present) is independently selected from the group consisting of alkyl, heteroalkyl, haloalkyl, cycloalkyl, and -alkyl-cycloalkyl;
each R 6 (when present) is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl,
wherein each said alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl of R 6 is unsubstituted or substituted with one or more groups independently selected from halo, —CN, —OH, lower alkyl, cycloalkyl, lower heteroalkyl, lower haloalkyl, lower —O-alkyl, lower —O-heteroalkyl, and lower —O-haloalkyl;
each R 7 (when present) is independently selected from the group consisting of H, alkyl, heteroalkyl, haloalkyl, cycloalkyl, -alkyl-cycloalkyl, aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl,
wherein each said cycloalkyl, -alkyl-cycloalkyl, aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl of R 7 is unsubstituted or substituted with one or more groups independently selected from halo, —CN, lower alkyl, cycloalkyl, lower heteroalkyl, lower haloalkyl, lower —O-alkyl, lower —O-heteroalkyl, and lower —O-haloalkyl;
each R 8 (when present) is independently selected from the group consisting of halo, oxo, —OH, —CN, —SF 5 , —OSF 5 , alkyl, —O-alkyl, haloalkyl, haloalkoxy, —C(O)OR 11 , cycloalkyl, -alkyl-cycloalkyl, —O-cycloalkyl, —O-alkyl-cycloalkyl, —O-benzyl, heteroalkyl, —O-heteroalkyl, and -alkyl-OH;
R 9 is selected from the group consisting of H, halo, alkyl, cycloalkyl, haloalkyl, and heteroalkyl;
R 10 is selected from the group consisting of H, halo, alkyl, cycloalkyl, haloalkyl, and heteroalkyl;
R 11 (when present) is selected from the group consisting of H, lower alkyl, lower heteroalkyl, cycloalkyl, and -alkyl-cycloalkyl; and
each R 12 (when present) is independently selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl,
wherein each said alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl of R 12 is unsubstituted or substituted with one or more groups independently selected from halo, —CN, —OH, lower alkyl, cycloalkyl, lower heteroalkyl, lower haloalkyl, lower —O-alkyl, lower —O-heteroalkyl, and lower —O-haloalkyl.

2. A compound of claim 1 , or a tautomer thereof, or a stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of said compound, said tautomer, or said stereoisomer, wherein:
R 4 is selected from the group consisting of —CH 3 and —CHF 2 ; and
one of R 9 and R 10 is H and the other is selected from the group consisting of H, halo, lower alkyl, cycloalkyl, lower haloalkyl, and lower heteroalkyl.

3. A compound of claim 2 , or a tautomer thereof, or a stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of said compound, said tautomer, or said stereoisomer, wherein:
ring B is selected from the group consisting of pyrrolyl, imidazolyl, oxadiazolyl, triazolyl, isoxazolyl, oxazolyl, thienyl, pyrazolyl, furanyl, tetrazolyl, thiazolyl, and isothiazolyl.

4. A compound of claim 3 , or a tautomer thereof, or a stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of said compound, said tautomer, or said stereoisomer, wherein:
n is 0 or more; and
each R 2B (when present) is independently selected from the group consisting of halo, —CN, methyl, ethyl, propyl, cyclopropyl, —CH 2 -cyclopropyl, —OCH 3 , —CH 2 OCH 3 , —CHF 2 , —CH 2 F, —CF 3 , —OCF 3 , and —OCHF 2 .

5. A compound of claim 4 , or a tautomer thereof, or a stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of said compound, said tautomer, or said stereoisomer, wherein:
ring A is selected from the group consisting of phenyl, pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridazinyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyrrolyl, quinazolinyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzois

Assignees

• Merck Sharp & Dohme

Inventors

• Gilbert Eric J
• Cumming Jared N
• Stamford Andrew W
• Yu Younong
• Scott Jack D
• Iserloh Ulrich

Classifications

• A61P25/16

  Anti-Parkinson drugs · 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

• A61K31/549

  having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide · CPC title

• C07D417/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D417/14 Primary

  containing three or more hetero rings · CPC title