C5-C6-carbocyclic fused iminothiadiazine dioxides as BACE inhibitors, compositions, and their use

Patent metadata

Field	Value
Publication number	US-10329291-B2
Application number	US-201615780651-A
Country	US
Kind code	B2
Filing date	Nov 29, 2016
Priority date	Dec 4, 2015
Publication date	Jun 25, 2019
Grant date	Jun 25, 2019

Abstract

In its many embodiments, the present invention provides certain C5-C6-carbocyclic fused iminothiazine dioxide compounds, including compounds Formula (I): and tautomers thereof, and pharmaceutically acceptable salts of said compounds and said tautomers, wherein R 1 , ring A, R A , m, -L 1 -, ring B, R B , n, q, ring C, R C , and p 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

What is claimed is:

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:
ring C is a 3-, 4-, 5-, or 6-membered fused cycloalkyl group;
p is 1, 2, 3, or 4, provided that the value of p does not exceed the number of substitutable hydrogen atoms on ring C;
each R C is independently selected from the group consisting of H, F, —OH, oxo, lower alkyl, lower cycloalkyl, —O-(lower alkyl) and —O-(lower cycloalkyl),
wherein each said lower alkyl and lower cycloalkyl are optionally substituted with one or more fluorine, and
wherein 1 to 2 non-adjacent, non-terminal carbon atoms in each said lower alkyl are optionally independently replaced with —O—, —NH—, —N-(lower alkyl)-, —S—, —S(O)—, or —S(O) 2 —;

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

ring A is selected from the group consisting of aryl and heteroaryl;
m is 0, 1, 2, or 3, provided 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, —CN, —OH, oxo, —NH-(lower alkyl), —NHC(O)-(lower alkyl), lower alkyl, -(lower alkyl)-(lower cycloalkyl), and —O-(lower alkyl),
wherein each said lower alkyl and lower cycloalkyl are optionally substituted with one or more fluorine, and
wherein 1 to 2 non-adjacent, non-terminal carbon atoms in each said lower alkyl are optionally independently replaced with —O—, —NH—, —N-(lower alkyl), —S—, —S(O)—, or —S(O) 2 —;

q is 0 or 1;
-L 1 -, when present, represents a bond or a divalent moiety selected from the group consisting of —C(O)NH—, —CH 2 C(O)NH—, —NH—, —CH(CH 3 )NH—, —CH 2 NH—, —O—, and —CH 2 O—;
ring B, when present, is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
n is 0, 1, 2, or 3, provided that the value of n does not exceed the number of substitutable hydrogen atoms on ring B; and
each R B , when present, is independently selected from the group consisting of halogen, —CN, —OH, oxo, lower alkyl, lower cycloalkyl, -(lower alkyl)-(lower cycloalkyl), —O-(lower alkyl), —O-(lower cycloalkyl), —O-(lower alkyl)-(lower cycloalkyl), —C≡CH, —C≡C—CH 3 , —OCH 2 —C≡C—H, and —OCH 2 —C≡C—CH 3 ,
wherein each said lower alkyl and lower cycloalkyl are optionally substituted with one or more fluorine, and
wherein 1 to 2 non-adjacent, non-terminal carbon atoms in each said lower alkyl are optionally independently replaced with —O—, —NH—, —N-(lower alkyl)-, —S—, —S(O)—, or —S(O) 2 —.

2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, said compound having the structural Formula (II):

or a tautomer thereof having the structural Formula (II′):

3. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, said compound having the structural Formula (III):

or a tautomer thereof having the structural Formula (III′):

4. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, said compound having the structural Formula (IV):

or a tautomer thereof having the structural Formula (IV′):

5. A compound of any of claims 1 to 4 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
p is 1 or 2, provided that the value of p does not exceed total number of valences on ring C; and each R C is independently selected from the group consisting of H, F, —OCH 3 , and oxo.

6. A compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
R 1 is methyl.

7. A compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
q =1;
-L 1 - is —C(O)NH—;
ring A is selected from the group consisting of phenyl and pyridinyl;
m is 0, 1, 2, or 3;
each R A , when present, is independently selected from the group consisting of fluoro, chloro, methyl, and —CHF 2 .
ring B is selected from the group consisting of phenyl, pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl;
n is 0, 1, 2, or 3; and
each R B (when present) is independently selected from the group consisting of fluoro, chloro, bromo, —CN, —OH, methyl, ethyl, cyclopropyl, —CH 2 OCH 3 , —C≡CH, —C≡C—CH 3 , —CF 3 , —CHF 2 , —CH 2 F, —OCH 2 —C≡C—H, —OCH 2 —C≡C—CH 3 , —OCH 3 , —OCF 3 , —OCHF 2 , —OCH 2 F, —OCH 2 CF 3 , —OCH 2 CHF 2 , and —OCH 2 CH 2 F.

8. A compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
q =1;
-L 1 - is —NH—;
ring A is selected from the group consisting of phenyl and pyridinyl;
m is 0, 1, 2, or 3;
each R A (when present) is independently selected from the group consisting of fluoro, chloro, methyl, and —CHF 2 ;
ring B is selected from the group consisting of pyridinyl, pyrazinyl, dihydrocyclopentapyridinyl, dihydroindenyl, naphthyridinyl, pteridinyl, pyridopyrazinyl, pyridopyrimidinyl, and tetrahydroquinolinyl;
n is 0, 1, 2, or 3; and

each R B (when present) is independently selected from the group consisting of fluoro, chloro, bromo, —CN, —CF 3 , —CHF 2 , —OCH 3 , —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , and —OCH 2 CHF 2 .

9. A compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
q =1;
-L 1 - is —O—;
ring A is selected from the group consisting of phenyl and pyridinyl;
m is 0, 1, 2, or 3;
each R A (when present) is independently selected from the group consisting of fluoro, chloro, methyl, and —CHF 2 ;
ring B is selected from the group consisting of pyrazinyl, pyridinyl, and pyrimidinyl;
n is 0, 1, or 2; and

each R B group (when present) is independently selected from the group consisting of fluoro, —CN, —CF 3 and —OMe.

10. A compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
q =0;
ring A is selected from the group consisting of phenyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazinyl, thiazolyl, and thienyl;
m is 0, 1, 2, 3, or 4, provided that the value of m does not exceed the number of available substitutable hydrogen atoms on ring A; and
each R A (when present) is independently selected from the group consisting

Assignees

• Merck Sharp & Dohme

Inventors

• Scott Jack D
• Blizzard Timothy A
• Walsh Shawn P
• Cumming Jared N

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

• C07D285/20

  condensed with carbocyclic rings or ring systems · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D417/12

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