CHROMANE, ISOCHROMANE AND DIHYDROISOBENZOFURAN DERIVATIVES AS mGluR2-NEGATIVE ALLOSTERIC MODULATORS, COMPOSITIONS, AND THEIR USE
The present invention provides certain substituted chromane, isochromane, and dihydroisobenzofuran compounds of formula (I): or a pharmaceutically acceptable salt thereof, wherein ring A is a moiety selected from: and ring B, n, R 1 , R 2 , R 2A , R 3 , and R 3A are as defined herein. The compounds of the invention are useful as mGuR2 inhibitors, or mGluR2 negative allosteric modulators (NAMs), and may be useful in methods of treating a patient for diseases or disorders in which the mGuR2-NAM receptor is involved, such as Alzheimer's disease, cognitive impairment, mild 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.
1 - 30 . (canceled)
31 . A pharmaceutical composition comprising:
(i) a compound having the 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;
(ii) an additional therapeutic agent; and
(iii) a pharmaceutically acceptable carrier.
32 . The composition of claim 1 , wherein the additional therapeutic agent is an acetylcholinesterase inhibitor.
33 . The composition of claim 1 , wherein the acetylcholinesterase inhibitor is donepezil.
34 . The composition of claim 1 , wherein the compound of formula (I) is selected from:
or a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer.
35 . The composition of claim 34 , wherein the additional therapeutic agent is an acetylcholinesterase inhibitor.
36 . The composition of claim 5 , wherein the acetylcholinesterase inhibitor is donepezil.
37 . 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 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.
38 . The method of claim 37 , wherein the treating is for Alzheimer's Disease.
39 . The method of claim 38 , wherein the treating is for mood disorder.
40 . The method of claim 39 , wherein the mood disorder is depression.
41 . The method of claim 38 , further comprising administration of an acetylcholinesterase inhibitor.
42 . The method of claim 41 , wherein the acetylcholinesterase inhibitor is donepezil.
43 . The method of claim 37 , wherein the compound of formula (I) is selected from:
or a stereoisomer thereof, or a pharmaceutically acceptable salt of said compound or said stereoisomer.
44 . The method of claim 43 , wherein the treating is for Alzheimer's Disease.
45 . The method of claim 43 , wherein the treating is for mood disorder.
46 . The method of claim 45 , wherein the mood disorder is depression.
47 . The method of claim 44 , further comprising administration of an acetylcholinesterase inhibitor.
48 . The method of claim 47 , wherein the acetylcholinesterase inhibitor is donepezil.