CHROMANE, ISOCHROMANE AND DIHYDROISOBENZOFURAN DERIVATIVES AS mGluR2-NEGATIVE ALLOSTERIC MODULATORS, COMPOSITIONS, AND THEIR USE

Patent metadata

Field	Value
Publication number	US-2019247374-A1
Application number	US-201916392131-A
Country	US
Kind code	A1
Filing date	Apr 23, 2019
Priority date	Sep 27, 2016
Publication date	Aug 15, 2019
Grant date	—

Abstract

and ring B, n, R1, R2, R2A, R3, and R3A are as defined herein. The compounds of the invention are useful as mGluR2 inhibitors, or mGluR2 negative allosteric modulators (NAMs), and may be useful in methods of treating a patient for diseases or disorders in which the mGluR2-NAM receptor is involved, such as Alzheimer's disease, cognitive impairment, mild congnitive impairment, schizophrenia and other mood disorders, pain disorders and sleep disorders, by administering to the patient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. The invention is also directed to pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, (optionally in combination with one or more additional active ingredients), and a pharmaceutically acceptable carrier, and the use of the compounds and pharmaceutical compositions of the invention in the treatment of such diseases.

First claim

1 . A compound of Formula (I):

or a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer, wherein:
ring A is a moiety selected from:

wherein:
R 2 is selected from H, cyclopropyl, —(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkyl-OH, —(C 1 -C 4 )alkyl-OCH 3 , —(C 1 -C 4 )haloalkyl, —(C 1 -C 4 )alkyl-O—(C 1 -C 4 )haloalkyl, —CH(CH 3 ) 2 , —CH 2 —O—(C 1 -C 4 )haloalkyl, —CH(CH 3 )—O—(C 1 -C 4 )haloalkyl, —CH 2 —NH—(C 1 -C 4 )haloalkyl, and —CH 2 —N(CH 3 )—(C 1 -C 4 )haloalkyl,
R 2A is selected from H and methyl;
R 3 is selected from H and methyl;
R 3A is selected from H and methyl;
ring B is a moiety selected from the group consisting of phenyl, heteroaryl, —(C 5 -C 6 ) cycloalkyl, and —(C 5 -C 6 ) cycloalkenyl;
n is 0, 1, 2, or 3, provided that the value of n does not exceed the maximum number of substitutable hydrogen atoms on ring B; and
each R 1 (when present) is independently selected from the group consisting of halogen, —CN, —OH, —(C 1 -C 6 ) alkyl, —O—(C 1 -C 6 ) alkyl, —(C 1 -C 6 ) haloalkyl, —O—(C 1 -C 6 ) haloalkyl, cyclopropyl, cyclobutyl, —NH 2 , —NH(C 1 -C 6 )alkyl, —N(C 1 -C 6 alkyl) 2 , —C(O)O(C 1 -C 6 ) alkyl, and phenyl.

2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
ring A is the moiety:

and Formula (I) takes the form of Formula (IA):

3 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein
R 2 is selected from H, cyclopropyl, —CH 3 , —CH(CH 3 ) 2 , —CH 2 —OH, —CH 2 —OCH 3 , —CF 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 —O—CH 2 F, —CH 2 —O—CHF 2 , —CH(CH 3 )—O—CH 2 F, —CH(CH 3 )—O—CHF 2 , —CH 2 —NH—CH 2 CF 3 , and —CH 2 —N(CH 3 )—CH 2 CF 3 ; R 2A is selected from H and methyl; R 3 is selected from H and methyl; and R 3A is selected from H and methyl.

4 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein
R 2 and R 2A are both methyl; and R 3 and R 3A are both H.

5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
ring A is the moiety:

and Formula (I) takes the form of Formula (IB):

6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
ring A is the moiety:

and Formula (I) takes the form of Formula (IC):

7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof,
wherein ring A is the moiety:

and Formula (I) takes the form of Formula (ID):

8 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
ring B is a moiety selected from the group consisting of phenyl, cyclopentyl, cyclohexyl, pyridinyl, pyrimidinyl, pyrazolyl, thienyl, thiazolyl, thiadiazolyl, isoxazolyl, oxadiazolyl and oxazolyl; n is 0, 1, 2, or 3, provided that the value of n does not exceed the maximum number of substitutable hydrogen atoms on ring B; and each R 1 (when present) is independently selected from the group consisting of halogen, —CN, —OH, —(C 1 -C 6 ) alkyl, —O—(C 1 -C 6 ) alkyl, —(C 1 -C 6 ) haloalkyl, —O—(C 1 -C 6 ) haloalkyl, cyclopropyl, cyclobutyl, —NH 2 , —NH(C 1 -C 6 )alkyl, —N(C 1 -C 6 alkyl) 2 , —C(O)O(C 1 -C 6 ) alkyl, and phenyl.

9 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
ring B is a moiety selected from the group consisting of: phenyl, pyrazolyl, pyridinyl, thienyl, isoxazolyl, oxadiazolyl and oxazolyl; n is 0, 1, or 2; and each R 1 (when present) is independently selected from the group consisting of fluoro, chloro, —CH 3 , and —CHCF 2 .

10 . The compound of claim 1 , having the Formula (IA-1):

or a steroisomer thereof or a pharmaceutically acceptable salt of said compound or said stereoisomer, wherein:
R 2 is selected from H, cyclopropyl, —CH 3 , —CH(CH 3 ) 2 , —CH 2 —OH, —CH 2 —OCH 3 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 —O—CH 2 F, —CH 2 —O—CHF 2 , —CH(CH 3 )—O—CH 2 F, —CH(CH 3 )—O—CHF 2 , —CH 2 —NH—CH 2 CF 3 , and —CH 2 —N(CH 3 )—CH 2 CF 3 ;
R 2A is selected from H and CH 3 ;
R 3 is selected from H and CH 3 ; and
R 3A is selected from H and CH 3 .

11 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, said compound selected from the group consisting of:

12 - 25 . (canceled)

26 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

27 . (canceled)

28 . A method of treating Alzheimer's disease, mild cognitive impairment, schizophrenia, mood disorder, or sleep disorder, said method comprising administering an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof to a person in need thereof.

29 . (canceled)

30 . (canceled)

Assignees

• Merck Sharp & Dohme

Inventors

• Sebhat Iyassu K
• Arasappan Ashok
• Hoyt Scott B
• Wilkening Robert R
• Demong Duane

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

• A61P25/24

  Antidepressants · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title