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

Patent metadata

Field	Value
Publication number	US-9957269-B2
Application number	US-201515509984-A
Country	US
Kind code	B2
Filing date	Sep 8, 2015
Priority date	Sep 12, 2014
Publication date	May 1, 2018
Grant date	May 1, 2018

Abstract

In its many embodiments, the present invention provides certain C-6 spirocarbocyclic iminothiadiazine compounds, including compounds Formula (I): or a tautomer thereof, and pharmaceutically acceptable salts of said compounds and said tautomers, wherein R 1A , R 1B , R 2A , R 2B , R 2 , R 3 , R N , ring A, R A , m, ring B, R B , and n 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 N is selected from the group consisting of alkyl and -alkyl-cycloalkyl,
wherein said alkyl and said -alkyl-cycloalkyl are optionally unsubstituted or substituted with one or more halogen,
and wherein each of 1 or 2 non-adjacent, non-terminal carbon atoms in said alkyl is optionally independently replaced with —O—, —NH—, —N(alkyl)-, —S—, —S(O)—, or —S(O) 2 —;

R 1A and R 1B are each independently selected from the group consisting of H, halogen, alkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl,
wherein each said alkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl of R 1A and R 1B is optionally independently unsubstituted or substituted with one or more halogen,
and wherein 1 or 2 non-adjacent, non-terminal carbon atoms in said alkyl is optionally independently replaced with —O—, —NH—, —N(alkyl)-, —S—, —S(O)—, or —S(O) 2 —;

R 2A and R 2B are each independently selected from the group consisting of H, halogen, alkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloaklyl,
wherein each said alkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloaklyl of R 2A and R 2B is optionally independently substituted with one or more halogen,
and wherein 1 or 2 non-adjacent, non-terminal carbon atoms in said alkyl is optionally independently replaced with —O—, —NH—, —N(alkyl)-, —S—, —S(O)—, or —S(O) 2 —;

R 3 is selected from the group consisting of H, alkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl,
wherein each said alkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl is optionally substituted with one or more halogen,
and wherein 1 or 2 non-adjacent, non-terminal carbon atoms in said alkyl is optionally independently replaced with —O—, —NH—, —N(alkyl)-, —S—, —S(O)—, or —S(O) 2 —;

ring A is selected from the group consisting of aryl and heteroaryl;
m is 0 or more, with the proviso that the value of m does not exceed the number of substitutable hydrogen atoms on ring A;
each R A (when present) is independently selected from the group consisting of halogen, oxo, —OH, —CN, alkyl, —O-alkyl, and cycloalkyl,
wherein said alkyl, —O-alkyl, and cycloalkyl are each optionally independently unsubstituted or substituted with one or more halogen, and
wherein 1 or 2 non-adjacent, non-terminal carbon atoms in said alkyl and said —O-alkyl, are optionally independently replaced with —O—, —NH—, —N(alkyl)-, —S—, —S(O)—, or —S(O) 2 —;

ring B is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
n is 0 or more, with the proviso that the value of n does not exceed the number of substitutable hydrogen atoms on ring B;
each R B (when present) is independently selected from the group consisting of halogen, oxo, —CN, —SF 5 , —OSF 5 , —OR 4B , —SR 4B , alkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, and heteroaryl,
wherein said alkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, and heteroaryl of R B are each optionally independently unsubstituted or substituted with one or more groups independently selected from R 5 , and wherein 1 or 2 non-adjacent, non-terminal carbon atoms of said alkyl are optionally independently replaced with —O—, —NH—, —N(alkyl)-, —S—, —S(O)—, or —S(O) 2 —;

each R 4B is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl,
wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl of R 4B is unsubstituted or optionally substituted with one or more fluorine,
and wherein 1 or 2 non-adjacent, non-terminal carbon atoms in said alkyl are optionally independently replaced with —O—, —NH—, —N(alkyl)-, —S—, —S(O)—, or —S(O) 2 —; and

each R 5 (when present) is independently selected from the group consisting of halogen, —OH, —CN, alkyl, —O-alkyl, cycloalkyl, -alkyl-cycloalkyl, —O-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl,
wherein each said alkyl, —O-alkyl, cycloalkyl, -alkyl-cycloalkyl, —O-cycloalkyl, -heterocycloalkyl, and -alkyl-heterocycloalkyl are optionally substituted with one or more fluorine,
and wherein 1 or 2 non-adjacent, non-terminal carbon atoms in said alkyl are optionally independently replaced with —O—, —NH—, —N(alkyl)-, —S—, —S(O)—, or —S(O) 2 —.

2. A compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
R N is selected from the group consisting of methyl, ethyl, —CH 2 -cyclopropyl, and —CH 2 CH 2 OCH 3 ;
R 1A is selected from the group consisting of H, fluorine, methyl, ethyl, cyclopropyl, —CH 2 -cyclopropyl, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , and —CH 2 OCH 3 ; and
R 1B is selected from the group consisting of H, fluorine, methyl, ethyl, cyclopropyl, —CH 2 -cyclopropyl, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , 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 N is methyl;
R 1A is selected from the group consisting of methyl, cyclopropyl, and —CHF 2 ;
R 1B is methyl;
R 2A is selected from the group consisting of H, fluorine, and methyl;
R 2B is H; and
R 3 is methyl.

4. A compound of claim 3 , 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, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazinyl, thiazolyl, and thienyl;
m is 0, 1, 2, or 3; and
each R A (when present) is independently selected from the group consisting of fluoro, chloro, bromo, —CN, —OCH 3 , —CH 2 OCH 3 , methyl, ethyl, cyclopropyl, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , and —OCHF 2 .

5. A compound of claim 4 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
ring B is selected from the group consisting of cyclopentyl, cyclohexyl, imidazopyrazinyl, imidazopyridinyl, imidazopyrimidinyl, morpholino, phenyl, piperidinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, naphthyridinyl, pteridinyl, pyrazinopyridazinyl pyridopyrazinyl, pyridopyridazinyl, and pyridopyrimidinyl;
each R B (when present) is independently selected from the group consisting of fluoro, chloro, bromo, —CN, —OH, —CH 3 , —CHF 2 , —CH 2 F, —OCH 3 , —OCH 2 —C≡C—H, —OCH 2 —C≡C—CH 3 ; and
n is 0, 1, 2, or 3, with the proviso that the value of n does not exceed the number of substitutable hydrogen atoms on ring B.

6. A compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, said compound selected from the group consisting of:

7. A pharmaceutical composition comprising a compou

Assignees

• Merck Sharp & Dohme

Inventors

• Cumming Jared N
• Scott Jack D

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

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D417/12

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