Quinoline carboxamide and quinoline carbonitrile derivatives as mGluR2-negative allosteric modulators, compositions, and their use

Patent metadata

Field	Value
Publication number	US-9636337-B2
Application number	US-201615047224-A
Country	US
Kind code	B2
Filing date	Feb 18, 2016
Priority date	Nov 3, 2011
Publication date	May 2, 2017
Grant date	May 2, 2017

Abstract

The present invention provides quinoline carboxamide and quinoline carbonitrile compounds of formula (I)

wherein ring A, R Q , -L-, R 1 , n, R 2 , and R 3 are as defined herein. The compounds of the invention are useful as non-competitive mGluR2 antagonists, or mGluR2 negative allosteric modulators (NAMs), and in methods of treating a patient (preferably a human) for diseases or disorders in which the mGluR2-NAM receptor is involved, including potentially Alzheimer's disease, cognitive 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

What is claimed is:

1. A method of treating a disease or disorder mediated by the mGluR 2 receptor, said method comprising administering to an individual in need thereof an effective amount of a compound of Formula (V):

or a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer, wherein:
ring A is a moiety selected from the group consisting of: phenyl, —(C 5 -C 6 ) cycloalkyl, —(C 5 -C 6 ) cycloalkyenl, -pyridinyl, pyrimidinyl, -pyrazolyl, -thienyl, -thiazolyl, -thiadiazolyl, and -oxazolyl;
R Q is selected from the group consisting of —CN and —C(O)NH 2 ;
-L- is a bond or a divalent moiety selected from the group consisting of:
—(C(R 1L ) 2 ) p —,

—C(O)—, —S(O)—, and —S(O) 2 —;
p is 1, 2, or 3;
each R 1L is independently selected from the group consisting of H, —CH 3 , —CF 3 , —OH, halogen, -cyclopropyl, —O—CH 3 , and —O—CF 3 ;
R 1 is selected from the group consisting of:
(1) heterocycloalkyl, heterocycloalkenyl,
wherein said heterocycloalkyl and said heterocycloalkenyl are monocyclic or multicyclic ring systems comprising from 3 to 10 ring atoms in which 1, 2, or 3 of the atoms of each said ring system is a ring heteroatom independently selected from the group consisting of N, S, S(O), S(O) 2 , and O,
and wherein each said heterocycloalkyl group and each said heterocycloalkenyl group is unsubstituted or substituted with 1 to 5 groups independently selected from the group consisting of oxo, CN, —OH, halogen, —(C 1 -C 6 ) alkyl, hydroxy-substituted —(C 1 -C 6 ) alkyl, —(C 1 -C 6 ) alkynyl, —(C 1 -C 6 ) haloalkyl, hydroxy-substituted —(C 1 -C 6 ) haloalkyl, —O—(C 1 -C 6 ) alkyl, —(C 3 -C 8 ) cycloalkyl, -alkyl-cycloalkyl, —CH(OH)cycloalkyl, phenyl, -alkyl-phenyl, monocyclic heteroaryl, -alkyl-monocyclic heteroaryl, —(C 3 -C 8 ) spirocycloalkyl, —(C 3 -C 8 ) spiroheterocycloalkyl, —C(O)H, —C(O)OH, —C(O)—(C 1 -C 6 ) alkyl, —C(O)O(C 1 -C 6 ) alkyl, —N(R 1A )C(O)—(C 1 -C 6 ) alkyl, —N(R 1A ) 2 , —C(O)N(R 1A ) 2 , —S(O) 2 H, —S(O)-phenyl, —S(O)—(C 1 -C 6 ) alkyl-phenyl, —S(O) 2 -phenyl, —S(O) 2 —(C 1 -C 6 ) alkyl-phenyl, —S(O) 2 OH, and —S(O) 2 —(C 1 -C 6 ) alkyl,
wherein each R 1A group is independently selected from the group consisting of H and —(C 1 -C 6 alkyl);
(2) heteroaryl,
wherein said heteroaryl is a monocyclic or multicyclic ring system comprising from 5 to 10 ring atoms in which from 1 to 4 of the atoms of said ring system is a ring nitrogen atom,
and wherein said heteroaryl is unsubstituted or substituted with 1 to 5 groups independently selected from the group consisting of oxo, CN, —OH, halogen, —(C 1 -C 6 ) alkyl, hydroxy-substituted —(C 1 -C 6 ) alkyl, —(C 1 -C 6 ) alkynyl, —(C 1 -C 6 ) haloalkyl, hydroxy-substituted —(C 1 -C 6 ) haloalkyl, —O—(C 1 -C 6 ) alkyl, —(C 3 -C 8 ) cycloalkyl, -alkyl-cycloalkyl, —CH(OH)cycloalkyl, phenyl, -alkyl-phenyl, monocyclic heteroaryl, -alkyl-monocyclic heteroaryl, —(C 3 -C 8 ) spirocycloalkyl, —C(O)H, —C(O)OH, —C(O)—(C 1 -C 6 ) alkyl, —C(O)O(C 1 -C 6 ) alkyl, —N(R 1B )C(O)—(C 1 -C 6 ) alkyl, —N(R 1B ) 2 , —C(O)N(R 1B ) 2 , —S(O) 2 H, —S(O)-phenyl, —S(O)—(C 1 -C 6 ) alkyl-phenyl, —S(O) 2 -phenyl, —S(O) 2 —(C 1 -C 6 ) alkyl-phenyl, —S(O) 2 OH, and —S(O) 2 —(C 1 -C 6 ) alkyl,
wherein each R 1B group is independently selected from the group consisting of H and —(C 1 -C 6 alkyl),
with the proviso that R 1 is not unsubstituted or substituted triazolyl, and with the further proviso that when R 1 is substituted oxadiazolyl, substituted thiazolyl, or substituted thiadiazolyl, then -L- is selected from the group consisting of —(C(R 1L ) 2 ) p —, and

(3) phenyl,
wherein said phenyl is unsubstituted or substituted with from 1 to 5 groups independently selected from the group consisting of oxo, CN, —OH, halogen, —(C 1 -C 6 ) alkyl, —(C 1 -C 6 ) alkynyl, —(C 1 -C 6 ) haloalkyl, —O—(C 1 -C 6 ) alkyl, —(C 3 -C 8 ) cycloalkyl, -alkyl-cycloalkyl, —CH(OH)cycloalkyl, monocyclic heteroaryl, -alkyl-monocyclic heteroaryl, —(C 3 -C 8 ) spirocycloalkyl, —C(O)H, —C(O)OH, —C(O)(C 1 -C 6 ) alkyl, —C(O)O(C 1 -C 6 ) alkyl, —N(R 1C )C(O)—(C 1 -C 6 ) alkyl, —N(R 1C ) 2 , —C(O)N(R 1C ) 2 , —S(O) 2 H, —S(O)-phenyl, —S(O)—(C 1 -C 6 ) alkyl-phenyl, —S(O) 2 -phenyl, —S(O) 2 —(C 1 -C 6 ) alkyl-phenyl, —S(O) 2 OH, and —S(O) 2 —(C 1 -C 6 ) alkyl,
wherein each R 1C group is independently selected from the group consisting of H and —(C 1 -C 6 alkyl);
(4) —CH 2 N(R 1D )R 1E , wherein:
R 1D is selected from the group consisting of H, —(C 1 -C 6 ) alkyl, and —C(O)OR 1H ; and
R 1E is selected from the group consisting of —O—(C 1 -C 6 ) alkyl, heteroalkyl, -alkyl-C(O)N(R 1H ), and —C(O)OR 1H ,
wherein each R 1H is independently selected from the group consisting of H and —(C 1 -C 6 ) alkyl; and

(5) —CH 2 N(R 1F )OR 1G , wherein:
R 1F is selected from the group consisting of H, —(C 1 -C 6 ) alkyl, and —C(O)OR 1H ,
wherein each R 1H is independently selected from the group consisting of H and —(C 1 -C 6 ) alkyl; and
R 1G is selected from the group consisting of H and —(C 1 -C 6 ) alkyl;

n is 0, 1, 2, or 3;
each R 2 (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, cyclopentyl, cyclohexyl, —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; and
R 3 is selected from the group consisting of hydrogen and fluorine.

2. The method of claim 1 , wherein said disease or disorder is selected from the group consisting of Alzheimer's disease, cognitive impairment, schizophrenia, mood disorder, pain, and sleep disorder.

3. The method of claim 1 , wherein R 1 is selected from the group consisting of heterocycloalkyl and heterocycloalkenyl,
wherein each of said heterocycloalkyl and said heterocycloalkenyl contains 1, 2, or 3 ring heteroatoms independently selected from the group consisting of N, S, S(O), S(O)2, and O,
and wherein each said heterocycloalkyl group and each said heterocycloalkenyl group is unsubstituted or substituted with 1 to 5 groups independently selected from the group consisting of oxo, —CN, —OH, —(C 1 -C 6 ) alkyl, —O—(C 1 -C 6 ) alkyl, —N(H)C(O)—(C 1 -C 6 ) alkyl, —C(O)NH 2 , —C(O)N(H)(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —(C 3 -C 8 ) spirocycloalkyl, —(C 3 -C 8 ) cycloalkyl, —(C 1 -C 6 ) haloalkyl, and phenyl.

4. The method of claim 1 , wherein R 1 is heteroaryl,
wherein said heteroaryl is mono or bicyclic and comprises from 1 to 3 ring nitrogen atoms,
and wherein said heteroaryl is unsubstituted or substituted with 1 to 5 groups independently selected from the group consisting of oxo, —CN, —OH, —(C 1 -C 6 ) alkyl, —O—(C 1 -C 6 ) alkyl, —N(H)C(O)—(C 1 -C 6 ) alkyl, —C(O)NH 2 , —C(O)N(H)(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —(C 3 -C 8 ) spirocycloalkyl, —(C 3 -C 8 ) cycloalkyl, —(C 1 -C 6 ) haloalkyl, and phenyl, with the proviso that R 1 is not unsubstituted or substituted triazolyl, substituted oxadiazolyl, substituted thiazolyl, or substituted thiadiazolyl.

5. The method of claim 1 , wherein R 1 is phenyl,
wherein said phenyl is unsubstituted or substituted with from 1 to 5 groups independently selected from the group consisting of halogen, —O—(C 1 -C 6 ) alkyl, CN, —S(O)-phenyl, —S(O) 2 -phenyl, —S(O)—(C 1 -C 6 ) alkyl-phenyl, and —S(O) 2 —(C 1 -C 6 ) alkyl-phenyl.

Assignees

• Merck Sharp & Dohme
• Merck Sharp & Dohme

Inventors

• Bungard Christopher James
• Converso Antonella
• De Leon Pablo
• Hanney Barbara
• Hartingh Timothy John
• Manikowski Jesse Josef
• Manley Peter J
• Meissner Robert
• Meng Zhaoyang
• Perkins James J
• Rudd Michael T
• Shu Youheng

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title

• 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