Diazine-fused amidines as BACE inhibitors, compositions, and their use

Patent metadata

Field	Value
Publication number	US-9868738-B2
Application number	US-201515512081-A
Country	US
Kind code	B2
Filing date	Sep 14, 2015
Priority date	Sep 19, 2014
Publication date	Jan 16, 2018
Grant date	Jan 16, 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 2 , R A , ring A, R A , m, L 1 , R L , 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

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′):

wherein:
-L 1 - is a bond or the divalent moiety —C(O)NH—;
R 1A and R 1B are each independently selected from the group consisting of H, halogen, alkyl, and cycloalkyl,
wherein said alkyl and said cycloalkyl are optionally substituted with one or more fluorine, and
wherein 1 to 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 —;

R 2 is selected from the group consisting of H, alkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl,
wherein said alkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl are optionally substituted with one or more halogen, and
wherein 1 to 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 —;

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 available 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 of R A are each optionally independently unsubstituted or substituted with one or more fluorine, and
wherein 1 to 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 —;

R L is alkyl,
wherein said alkyl is optionally further substituted with one or more halogen, and
wherein 1 to 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 —;
or, alternatively, R L is a moiety having the formula

wherein
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 available substitutable hydrogen atoms on ring b; and
each R B (when present) is independently selected from the group consisting of halogen, oxo, —OH, —CN, —SF 5 , —OSF 5 , —OR 3B , —SR 3B , 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 4 , and wherein 1 to 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 —;

ring C is selected from the group consisting of pyrazinyl, pyrimidinyl, and pyridazinyl;
p is 0 or more, with the proviso that the value of p does not exceed the number of available substitutable hydrogen atoms on ring C; and
each R c (when present) is independently selected from the group consisting of alkyl and cycloalkyl,
wherein said alkyl and cycloalkyl are each optionally substituted with one to three fluorine, and
wherein 1 to 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 —;

each R 3B is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl,
wherein each said alkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl of R 3B is unsubstituted or optionally substituted with one or more fluorine, and
wherein 1 to 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 4 (when present) is independently selected from the group consisting of halogen, —OH, —CN, alkyl, alkoxy, cycloalkyl, -alkyl-cycloalkyl, —O-cycloalkyl, -heterocycloalkyl, and -alkyl-heterocycloalkyl,
wherein each said alkyl, alkoxy, cycloalkyl, -alkyl-cycloalkyl, —O—cycloalkyl, -heterocycloalkyl, and -alkyl-heterocycloalkyl are optionally substituted with one or more fluorine, and
wherein 1 to 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 1A is selected from the group consisting of H and fluorine;
R 1B is selected from the group consisting of H and fluorine; and
R 2 is selected from the group consisting of methyl and —CHF 2 .

3. A compound of claim 2 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
ring C is selected from the group consisting of pyrazine and pyrimidine;
p is 0 or 1; and
R C (when present) is independently selected from the group consisting of methyl, ethyl, —CF 3 , —CHF 2 , —CH 2 F, —CH 2 OCH 3 , and cyclopropyl.

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, with the proviso 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 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:
R L is selected from the group consisting of methyl, ethyl, —CF 3 , —CHF 2 , —CH 2 F, —CH 2 CF 3 , —CF 2 CH 3 , —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CH 2 CH 2 OCH 3 , —CH(OCH 3 )CH 3 , —CH 2 SCH 3 , —CH 2 N(CH 3 ) 2 , —CH 2 OCF 3 , and —CH 2 OCHF 2 .

6. A compound of claim 5 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
-L 1 - is a bond.

7. A compound of claim 5 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
-L 1 - is the divalent moiety —C(O)NH—.

8. A compound of claim 4 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
R L is a moiety having the formula

 wherein:
ring B is selected from the group consisting of cyclobutyl, cyclopropyl, furanyl, imidazopyridinyl, imidazopyrimidinyl, imidazothiazolyl, indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxetanyl, phenyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydrofuranyl, tetrahydr

Assignees

• Merck Sharp & Dohme
• Liu Kun
• He Shuwen
• Cumming Jared N
• Stamford Andrew W

Inventors

• Liu Kun
• He Shuwen
• Cumming Jared N
• Stamford Andrew W

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title