Quinoline Carboxamide and Quinoline Carbonitrile Derivatives as mGluR2-Negative Allosteric Modulators, Compositions, and Their Use

Patent metadata

Field	Value
Publication number	US-2016159744-A1
Application number	US-201615047213-A
Country	US
Kind code	A1
Filing date	Feb 18, 2016
Priority date	Nov 3, 2011
Publication date	Jun 9, 2016
Grant date	—

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

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 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, —C(O)—, halogen, -cyclopropyl, —O—CH 3 , and —O—CF 3 ;
R 1 is selected from the group consisting of:
(1) heterocycloalkyl and 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) H and —(C 1 -C 6 ) alkyl;
(5) —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

(6) —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 . A compound of claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer, 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 , phenyl, —(C 3 -C 8 ) spirocycloalkyl, —(C 3 -C 8 ) cycloalkyl, —(C 1 -C 6 ) haloalkyl, and phenyl.

3 . A compound of claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer, wherein R′ 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 , phenyl, —(C 3 -C 8 ) spirocycloalkyl, —(C 3 -C 8 ) cycloalkyl, —(C 1 -C 6 ) haloalkyl, and phenyl, with the proviso that when R 1 is not unsubstituted or substituted triazolyl, substituted oxadiazolyl, substituted thiazolyl, or substituted thiadiazolyl.

4 . A compound of claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer, 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.

5 . A compound of claim 1

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

• A61P25/28

  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

• A61P25/20

  Hypnotics; Sedatives · CPC title

• A61P25/04

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

• A61P25/24

  Antidepressants · CPC title