C5-C6-oxacyclic fused iminopyrimidinone compounds as bace inhibitors, compositions, and their use

Patent metadata

Field	Value
Publication number	US-10047098-B2
Application number	US-201515527975-A
Country	US
Kind code	B2
Filing date	Nov 20, 2015
Priority date	Nov 25, 2014
Publication date	Aug 14, 2018
Grant date	Aug 14, 2018

Abstract

In its many embodiments, the present invention provides certain C5-C6-oxacyclic fused iminopyrimidinone compounds, including compounds Formula (I): or a tautomer thereof, and pharmaceutically acceptable salts of said compounds and said tautomers, wherein R N , R 1 , R A , ring A, m, n, -L 1 -, ring B, R B , 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′):

or pharmaceutically acceptable salt thereof, wherein:
ring C is selected from the group consisting of tetrahydrofuranyl and tetrahydropyranyl, wherein 1 or 2 of the ring carbon atoms having two available substitutable hydrogen atoms of said tetrahydrofuranyl and tetrahydropyranyl rings are optionally independently replaced with a —C(R C1 R C2 )— group,
wherein R C1 and R C2 are each independently selected from the group consisting of H, halogen, —CO 2 -(lower alkyl), alkyl, cycloalkyl, -alkyl-cycloalkyl, -heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl,
wherein said alkyl, cycloalkyl, -alkyl-cycloalkyl, -heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl of R C1 and R C2 are optionally substituted with one or more R 3 , and
wherein 1 to 2 non-adjacent, non-terminal carbon atoms in each said alkyl of R C1 and R C2 are optionally independently replaced with —O—, —NH—, —N(alkyl)-, —S—, —S(O)—, or —S(O) 2 —,

or, alternatively, wherein said R C1 and R C2 of one said —C(R C1 R C2 )— group are taken together with the carbon to which they are attached form a spirocyclic ring consisting of from 3 to 6 carbon atoms, wherein 1 of said carbon atoms may be replaced with —O—, —NH—, —N(lower alkyl)-, —N(lower haloalkyl)-, —S—, —S(O)—, or —S(O) 2 —, and
wherein each of the carbon atoms of said spirocyclic ring may be optionally independently substituted with 1 to 4 fluorine, lower alkyl, lower haloalkyl, or —CH 2 O-(lower alkyl);

R N is selected from the group consisting of H, alkyl, cycloalkyl, and -alkyl-cycloalkyl,
wherein said alkyl, cycloalkyl, and -alkyl-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 1 is selected from the group consisting of H, halogen, and alkyl,
wherein said alkyl is 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 —,

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, lower alkyl, —O-(lower alkyl), lower alkenyl, —O-(lower alkenyl), and -(lower alkyl)-(lower cycloalkyl);
wherein said lower alkyl, —O-(lower alkyl), lower alkenyl, —O-(lower alkenyl), and -(lower alkyl)-(lower 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 lower alkyl and are optionally independently replaced with —O—, —NH—, —N(alkyl)-, —S—, —S(O)—, or —S(O) 2 —;
n is 0 or 1;

-L 1 - (when present) independently represents a bond or a divalent moiety selected from the group consisting of —O—, —CH 2 —O—, —CH(CH 3 )—O—, —CH(CF 3 )—O—, and —CH(CHF 2 )—O—;
ring B is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
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 B; and
each R B (when present) is independently selected from the group consisting of halogen, oxo, —OH, —CN, —SF 5 , —OSF 5 , —OR 2B , —SR 2B , 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 3 , 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 2B 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 2B 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 —;

each R 3 (when present) is independently selected from the group consisting of halogen, —OH, —CN, alkyl, -alkyl-OH, —O-alkyl, cycloalkyl, -alkyl-cycloalkyl, —O-cycloalkyl, —O-alkyl-cycloalkyl, -heterocycloalkyl, -alkyl-heterocycloalkyl, —O-heterocycloalkyl and —O-alkyl-heterocycloalkyl,
wherein each said alkyl, -alkyl-OH, —O-alkyl, cycloalkyl, -alkyl-cycloalkyl, —O-cycloalkyl, —O-alkyl-cycloalkyl, -heterocycloalkyl, -alkyl-heterocycloalkyl, —O-heterocycloalkyl and —O-alkyl-heterocycloalkyl, are optionally substituted with one or more halogen,
and wherein 1 to 2 non-adjacent, non-terminal carbon atoms in said alkyl and —O-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 methyl; and
R 1 is H.

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

4. A compound of claim 3 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
R C1 and R C2 are each independently selected from the group consisting of H, —CO 2 CH 3 , methyl, —CHF 2 , cyclopropyl, —CH 2 OCH 3 , phenyl, and isoxazoyl,
wherein each said phenyl and isoxazoyl of R C1 and R C2 is unsubstituted or substituted with one or more fluoro or methyl groups.

5. A compound of claim 4 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
n=1;
-L 1 - is —O—;
ring B is selected from the group consisting of cyclobutyl, cyclopentyl, cyclopropyl, isoquinolinyl, phenyl, piperidinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, quinolinyl, tetrahydrofuranyl, and tetrahydropyranyl;
p is 0, 1, 2, or 3, with the proviso that the value of p does not exceed the number of available substitutable hydrogen atoms on ring B; and
each R B group (when present) is independently selected from the group consisting of fluoro, chloro, —CN, —OCH 3 , —O—CH 2 -cyclopropyl, OCH 2 —C≡C—H, —OCH 2 —C≡C—CH 3 , methyl, ethyl, cyclopropyl, —CH 2 -cyclopropyl, —CH 2 OCH 3 , —C≡CH, —C≡C—CH 3 , —CF 3 , —CHF 2 , —OCF 3 , —OCHF 2 , oxadiazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, and triazolyl,
wherein each said oxadiazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, and triazolyl, is optionally substituted with one substituent from the group consisting of fluo

Assignees

• Merck Sharp & Dohme

Inventors

• Dai Xing
• Cumming Jared N
• Liu Hong
• Scott Jack D

Classifications

• C07D491/052 Primary

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• A61P25/28

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