US2009082336A1PendingUtilityA1
mGluR1 Antagonists as Therapeutic Agents
Est. expiryJun 15, 2024(expired)· nominal 20-yr term from priority
Inventors:Julius J. MatasiDeen TulshianDuane A. BurnettWen-Lian WuPeter KorakasLisa S. SilvermanThavalakulamgara K. SasikumarLi QiangMartin S. Donalski
A61P 31/18A61P 43/00A61P 9/00A61P 9/10A61P 25/28A61P 25/06A61P 25/14A61P 25/24A61P 25/08A61P 25/04A61P 25/36A61P 27/02A61P 25/00A61P 29/02A61P 25/22A61P 25/16A61P 25/34A61P 25/18A61P 25/30A61P 25/32A61P 13/02A61P 1/08A61P 21/00A61P 21/02C07D 495/04C07D 491/14C07D 495/14C07D 471/14C09B 57/00
57
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Claims
Abstract
In its many embodiments, the present invention provides tricyclic compounds of formula I (wherein J 1 -J 4 , X, and R 1 -R 5 are as defined herein) useful as metabotropic glutamate receptor (mGluR) antagonists, particularly as selective metabotropic glutamate receptor 1 antagonists, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds and compositions to treat diseases associated with metabotropic glutamate receptor (e.g., mGluR1) such as, for example, pain, migraine, anxiety, urinary incontinence and neurodegenerative diseases such Alzheimer's disease.
Claims
exact text as granted — not AI-modified1 . A compound of formula I:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
J 1 , J 2 , J 3 and J 4 are independently N, N→O, or C(R), provided that 0-2 of J 1 , J 2 , J 3 and J 4 are N or N→O;
is a single or double bond;
R is selected from the group consisting of H, halo, —NR 6 R 7 , —OR 6 , —SR 6 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 F, —CN, —C(O)R 6 , —C(O 2 )R 6 , —OC(O)R 6 , —C(O)NR 6 R 7 , —N(R 6 )C(O)R 6 , —OS(O 2 )R 6 , —S(O 2 )R 6 , —S(O 2 )NR 6 R 7 , —N(R 6 )S(O 2 )R 6 , —N(R 6 )C(O)NR 6 R 7 , alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl optionally substituted with one or more (═O) or (═S), heterocyclyl optionally substituted with one or more (═O) or (═S), cycloalkylalkyl optionally substituted with one or more (═O) or (═S), and heterocyclylalkyl optionally substituted with one or more (═O) or (═S); wherein said alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, and heterocyclylalkyl are optionally substituted with one or more substituents independently selected from halo, alkyl optionally substituted with one or more R 11 , aryl optionally substituted with one or more R 11 , cycloalkyl optionally substituted with one or more R 11 , heteroaryl optionally substituted with one or more R 11 , heterocyclyl optionally substituted with one or more R 11 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 F, —CN, —NO 2 , —OR 6 , —SR 6 , —NR 6 R 7 , —C(O)R 6 , —C(O 2 )R 6 , —OCOR 6 , —C(O)NR 6 R 7 , —N(R 6 )C(O)R 6 , —OS(O 2 )R 6 , —S(O 2 ) R 6 , —S(O 2 )NR 6 R 7 , —N(R 6 )S(O 2 )R 6 , or —N(R 6 )C(O)NR 6 R 7 , or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy;
X is O, S, N(R 8 ), C(O), or C(R a R b );
R 1 is selected from the group consisting of H, —OR 6 , —SR 6 , —NR 6 R 7 , halo, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl optionally substituted with one or more (═O) or (═S), heterocyclyl optionally substituted with one or more (═O) or (═S), cycloalkylalkyl optionally substituted with one or more (═O) or (═S), and heterocyclylalkyl optionally substituted with one or more (═O) or (═S); wherein said alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, and heterocyclylalkyl are optionally substituted with one or more substituents independently selected from halo, alkyl optionally substituted with one or more R 11 , aryl optionally substituted with one or more R 1 ″, cycloalkyl optionally substituted with one or more R 11 , heteroaryl optionally substituted with one or more R 11 , heterocyclyl optionally substituted with one or more R 11 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 F, —CN, —NO 2 , —OR 6 , —SR 6 , —NR 6 R 7 , —C(O)R 6 , —C(O 2 )R 6 , —OC(O)R 6 , —C(O)NR 6 R 7 , —N(R 6 )C(O)R 6 , —OS(O 2 ) R 6 , —S(O 2 )R 6 , —S(O 2 )NR 6 R 7 , —N(R 6 )S(O 2 )R 6 , or —N(R 6 )C(O)NR 6 R 7 , or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy;
R 2 is selected from the group consisting of H, halo, alkyl, —N(R 12 ) 2 , —OR 12 and —SR 12 , wherein said alkyl is optionally substituted with one or more substituents independently selected from halo, hydroxy or alkoxy; or R 1 and R 2 optionally taken together form (═O) or (═S);
R 3 is selected from the group consisting of H, —NR 6 R 7 , alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl optionally substituted with one or more (═O) or (═S), heterocyclyl optionally substituted with one or more (═O) or (═S), cycloalkylalkyl optionally substituted with one or more (═O) or (═S), and heterocyclylalkyl optionally substituted with one or more (═O) or (═S); wherein said alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, and heterocyclylalkyl are optionally substituted with one or more substituents independently selected from halo, alkyl optionally substituted with one or more R 11 , aryl optionally substituted with one or more R 11 , cycloalkyl optionally substituted with one or more R 11 , heteroaryl optionally substituted with one or more R 11 , heterocyclyl optionally substituted with one or more R 11 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 F, —CN, —NO 2 , —OR 6 , —SR 6 , —NR 6 R 7 , —C(O)R 6 , —C(O 2 ) R 6 , —OC(O)R 6 , —C(O)NR 6 R 7 , —N(R 6 )C(O)R 6 , —OS(O 2 ) R 6 , —S(O 2 ) R 6 , —S(O 2 )NR 6 R 7 , —N(R 6 )S(O 2 )R 6 , or —N(R 6 )C(O)NR 6 R 7 , or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy;
R 4 is selected from the group consisting of H, —OR 6 , (═O), (═S), —SR 6 , —NR 6 R 7 , halo, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl optionally substituted with one or more (═O) or (═S), heterocyclyl optionally substituted with one or more (═O) or (═S), cycloalkylalkyl optionally substituted with one or more (═O) or (═S), and heterocyclylalkyl optionally substituted with one or more (═O) or (═S); wherein said alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, and heterocyclylalkyl are optionally substituted with one or more substituents independently selected from halo, alkyl optionally substituted with one or more R 11 , aryl optionally substituted with one or more R 11 , cycloalkyl optionally substituted with one or more R 11 , heteroaryl optionally substituted with one or more R 11 , heterocyclyl optionally substituted with one or more R 11 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 F, —CN, —NO 2 , —OR 6 , —SR 6 , —NR 6 R 7 , —C(O)R 6 , —C(O 2 )R 6 , —OC(O)R 6 , —C(O)NR 6 R 7 , —N(R 6 )C(O)R 6 , —OS(O 2 )R 6 , —S(O 2 )R 6 , —S(O 2 )NR 6 R 7 , —N(R 6 )S(O 2 )R 6 , or —N(R 6 )C(O)NR 6 R 7 , or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy; or R 3 and R 4 optionally taken together with intervening atoms form a 5-8 membered heterocyclic ring having 0-3 heteroatoms independently selected from O, N or S in addition to the intervening nitrogen;
R 5 is R 3 when is a single bond and R 5 is absent when is a double bond;
R 6 and R 7 are independently selected from the group consisting of H, alkyl, alkoxyalkyl, aryloxyalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl optionally substituted with one or more (═O) or (═S), heterocyclyl optionally substituted with one or more (═O) or (═S), cycloalkylalkyl optionally substituted with one or more (═O) or (═S), and heterocyclylalkyl optionally substituted with one or more (═O) or (═S); wherein each member of R 6 and R 7 except H is optionally substituted with one or more substituents independently selected from halo, alkyl optionally substituted with one or more R 11 , aryl optionally substituted with one or more R 11 , cycloalkyl optionally substituted with one or more R 11 , heteroaryl optionally substituted with one or more R 11 , heterocyclyl optionally substituted with one or more R 11 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 F, —CN, —NO 2 , —OR 10 , —SR 10 , —NR 9 R 10 , —C(O)R 10 , —C(O 2 )R 11 , —OC(O)R 10 , —C(O)NR 9 R 10 , —N(R 9 )C(O)R 10 , —OS(O 2 )R 11 , —S(O 2 )R 11 , —S(O 2 )NR 9 R 10 , —N(R 9 )S(O 2 )R 11 , or —N(R 9 )C(O)NR 9 R 10 , or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy; or R 6 and R 7 , when attached to the same nitrogen atom, optionally taken together with the nitrogen atom form a 3-7 membered heterocyclic ring containing 0-3 heteroatoms independently selected from O, N or S in addition to said nitrogen atom;
R a is selected from the group consisting of H, halo, alkyl, hydroxyalkyl, alkoxyalkyl, and N(R 12 ) 2 ;
R b is selected from the group consisting of H, halo, alkyl, hydroxyalkyl, and alkoxyalkyl;
R 8 is selected from the group consisting of H, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl optionally substituted with one or more (═O) or (═S), heterocyclyl optionally substituted with one or more (═O) or (═S), cycloalkylalkyl optionally substituted with one or more (═O) or (═S), and heterocyclylalkyl optionally substituted with one or more (═O) or (═S); wherein each member of R 8 except H is optionally substituted with one or more substituents independently selected from halo, alkyl optionally substituted with one or more R 11 , aryl optionally substituted with one or more R 11 , cycloalkyl optionally substituted with one or more R 11 , heteroaryl optionally substituted with one or more R 11 , heterocyclyl optionally substituted with one or more R 11 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 F, —CN, —NO 2 , —OR 10 , —SR 10 , —NR 10 R 10 , —C(O)R 10 , —C(O 2 )R 10 , —OC(O)R 10 , —C(O)NR 9 R 10 , —N(R 9 )C(O)R 10 , —OS(O 2 )R 10 , —S(O 2 )R 10 , —S(O 2 )NR 9 R 10 , —N(R 9 )S(O 2 )R 10 , or —N(R 9 )C(O)NR 9 R 10 , or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy;
R 9 is H or alkyl;
R 10 is selected from H, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl optionally substituted with one or more (═O) or (═S), heterocyclyl optionally substituted with one or more (═O) or (═S), cycloalkylalkyl optionally substituted with one or more (═O) or (═S), heterocyclylalkyl optionally substituted with one or more (═O) or (═S); wherein each member of R 11 except H is optionally substituted with one or more substituents independently selected from halo, alkyl optionally substituted with one or more R 11 , aryl optionally substituted with one or more R 11 , cycloalkyl optionally substituted with one or more R 11 , heteroaryl optionally substituted with one or more R 11 , heterocyclyl optionally substituted with one or more R 11 , —CF 3 , —OCHF 2 , —OCH 2 F, —OCF 3 , —CN, —NO 2 , —OR 12 , —SR 12 , —N(R 12 )(R 12 ), —C(O)R 12 , —C(O 2 )R 12 , —OC(O)R 12 , —C(O)N(R 12 )(R 12 ), —N(R 12 )C(O)R 12 , —OS(O 2 )R 12 , —S(O 2 )R 12 , —S(O 2 )N(R 12 )(R 12 ), —N(R 12 )S(O 2 )R 12 , or —N(R 12 )C(O)N(R 12 )(R 12 ), or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy; or R 9 and R 10 , when attached to the same nitrogen atom, optionally taken together with the attached nitrogen atom form a 3-7 membered heterocyclic ring containing 0-3 heteroatoms independently selected from O, N or S in addition to the attached nitrogen; and two R 12 s attached to the same nitrogen atom optionally taken together with the attached nitrogen atom form a 3-7 membered heterocyclic ring having 0-3 heteroatoms independently selected from O, N or S in addition to the attached nitrogen;
R 11 is halo, —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 F, —CN, —NO 2 , —OR 12 , —SR 12 , —N(R 12 )(R 12 ), —C(O)R 12 , —C(O 2 )R 12 , —OC(O)R 12 , —C(O)N(R 12 )(R 12 ), —N(R 12 )C(O)R 12 , —OS(O 2 )R 12 , —S(O 2 )R 12 , —S(O 2 )N(R 12 ) (R 12 ), —N(R 12 )S(O 2 ) R 12 , or —N(R 12 )C(O)N(R 12 )(R 12 ); and
R 12 is H or alkyl; with at least one of the following provisos 1-11:
proviso 1: when is a double bond; R 5 is absent; R 1 and R 2 taken together are (═O); X is O, S or NR 12 ; then R 3 is not H;
proviso 2: when is a double bond; R 5 is absent; R 1 and R 2 taken together are (═O); then
either (a) J 1 , J 2 , J 3 and J 4 are each C(H);
X is S or O;
R 3 is 3-(3-hydroxypiperidin-2-yl)-2-oxo-propyl; and
R 4 is not H;
or (b) J 1 , J 2 , J 3 and J 4 are each C(H);
X is NH;
R 3 is C 1 -C 3 alkyl or NH 2 ; and
R 4 is not H, —(CH 2 ) 4 —N-(optionally substituted piperazine) or —S—(CH 2 ) 3 —N-(optionally substituted piperazine);
or (c) J 1 , J 2 , J 3 and J 4 are each C(H);
X is NH,
R 3 is —NH 2 , —(CH 2 ) 2-3 —OH, —(CH 2 ) 2-3 -halo or —(CH 2 ) 2-3 —N-(optionally substituted piperazine); and
R 4 is not H or C 1 -C 3 alkyl;
or (d)(i) J 1 is N, J 2 and J 3 are each C(H), and J 4 is C(N(CH 3 ) 2 );
X is S;
R 4 is H; and
R 3 is not benzyl, phenyl, p-chlorophenyl, p-methylphenyl, or p-methoxyphenyl;
or (d)(ii) J 1 is N, J 2 is C(CH 3 ) or C(NH 2 ), J 3 is C(H), C(NO 2 ) or C(C(O)CH 3 ) and J 4 is C(CH 3 ) or C (optionally substituted phenyl);
X is S;
R 4 is H or CH 3 ; and
R 3 is not benzyl, phenyl, p-chlorophenyl, p-methylphenyl, p-methoxyphenyl, or 2-methyl-4-nitrophenyl;
or (e) J 1 is N and J 2 , J 3 and J 4 are each C(R 13 ), wherein R 13 is H, CF 3 , C 1 -C 3 alkyl, —CONH(C 1 -C 6 alkyl), —CO 2 Et, optionally substituted phenyl or benzyl;
X is O or S;
R 4 is H, halo, —NR 5 R 7 , C 1 -C 4 alkyl, or phenyl; and
R 3 is not —NH 2 , —NH(phenyl), or C 1 -C 4 alkyl optionally substituted with halo, OH, pyridyl, —NR 6 R 7 , CO 2 R 2 , COR 12 , —S—(CH 2 ) 2-3 OH, —SH, or —S(CH 2 ) 2-3 CO 2 R 12 ;
or (f) J 4 is N and J 1 , J 2 and J 3 are each C(R 12 );
X is S;
R 3 is C 1 -C 4 alkyl, NH 2 , or NH-(phenyl); and
R 4 is not H, C 1 -C 4 alkyl, or NH 2 ;
or (g) J 1 and J 2 are each N and J 3 and J 4 are each C(phenyl) or C(2-furanyl);
X is S;
R 3 is NH 2 , optionally substituted phenyl, or C 1 -C 4 alkyl optionally substituted with CN or C(O)-phenyl; and
R 4 is not H, methyl, or —NR 6 R 7 ;
or (h) J 2 is C(R) and J 4 is C(H);
X is S;
R 4 is H, C 1 -C 3 alkyl, NH 2 , N(CH 3 ) 2 , NH-(phenyl); and
J 1 and J 3 are not both N;
proviso 3: when is a double bond; R 5 is absent; R 1 and R 2 taken together are (═S); J 1 is N; J 2 is C(H), C(CH 3 ) or C(phenyl); J 3 is C(H), and J 4 is C(CH 3 ) or C(N(CH 3 ) 2 ); X is S; and R 4 is H or CH 3 ; then R 3 is not H, NH 2 , phenyl, halo substituted phenyl, or C 1 -C 6 alkyl optionally substituted with N(C 1 -C 3 alkyl) 2 or OH;
proviso 4: when is a double bond; R 5 is absent; R 1 is —CH 2 CO 2 Et or —CH 2 CN; R 2 is H; J 1 and J 2 are N and J 3 and J 4 are C(phenyl); X is S; and R 3 is phenyl or p-fluorophenyl; then R 4 is not —NR 6 R 7 ;
proviso 5: when is a single bond; R 4 is (═O); and R 1 and R 2 taken together are (═O); then
either (a) X is O, S or N(R 8 ); and
R 3 is not alkyl substituted with N-3a,4-dihydrobenzopyrano[3,4-c]pyrrolidine or N-3a,4-dihydrobenzopyrano[3,4-c]piperidine, N-1,2,3,4,4a,5-hexahydropyrazino[2,1-c][1,4]benzoxazine, or N-(2-phenyl)pyrrolidine, wherein said benzo or phenyl is optionally substituted;
or (b) J 1 , J 2 , J 3 and J 4 are each C(R 14 ), wherein R 14 is H, halo, alkoxy, NO 2 , NHSO 2 -alkyl, or NH 2 ;
X is O, S, N(H), N(CH 3 ) or N-(optionally substituted benzyl); and
R 3 and R 5 are not both H, OH or alkyl;
or (c) J 1 , J 2 , J 3 and J 4 are each C(H) or C(halo);
X is S, N(CH 3 ) or N(benzyl);
R 5 is H or halo substituted benzyl; and R 3 is not —CH 2 CO 2 R 12 ; or
R 5 is H or —CH 2 CO 2 R 12 and R 3 is not benzyl or halo substituted benzyl;
or (d) J 1 , J 2 , J 3 and J 4 are each C(H);
X is NH, N(CH 3 ) or S;
R 5 is H or CH 3 ; and
R 3 is not —(CH 2 ) 2-3 —N-(optionally substituted piperazine), —(CH 2 ) 2-3 —N(C 1 -C 3 alkyl) 2 , —(CH 2 ) 2-3 —N-pyrrolidine, —(CH 2 ) 2-3 —N-piperidine, or —(CH 2 ) 2-3 —N-morpholine;
or (e) J 1 is N and J 2 , J 3 and J 4 are each C(R);
X is S;
R 5 is H; and
R 3 is not NH 2 , optionally substituted phenyl, —(CH 2 ) 2 NH(CH 2 ) 2 NH 2 , alkyl optionally substituted with halo, hydroxy or amino;
or (f) J 1 , J 2 and J 3 are each CH and J 4 is N;
X is S;
R 5 is H; and
R 3 is not alkyl substituted with N-1,3,3a,4,5,9b-hexahydro-2H-benzo[e]isoindole wherein benzo is optionally substituted;
or (g) J 1 and J 2 are each N and J 3 and J 4 are each C(2-furanyl);
X is S;
R 3 is phenyl; and
R 5 is not H;
or (h) J 1 and J 4 are each N and J 2 and J 3 are each C(H);
X is S;
R 3 and R 5 are not both H;
proviso 6: when is a single bond; R 4 is (═O); R 1 is optionally substituted phenyl; R 2 is H; and X is CO; then R 3 and R 5 are not both H;
proviso 7: when is a single bond; R 1 and R 2 taken together are (═O); J 1 and J 2 are each N and J 3 and J 4 are each C(phenyl); X is S; and R 4 is optionally substituted phenyl; then R 3 and R 5 are not both H;
proviso 8: when is a single bond; R 4 is (═S); R 1 and R 2 taken together are (═O) or (═S); X is S; R 5 is H; and (i) J 1 and J 3 are N or (ii) J 1 is N, J 2 is C(R 15 ), J 3 is C(R 16 ) or N, and J 4 is C(CH 3 ) or C (optionally substituted phenyl), wherein R 15 is CH 3 , NH 2 , phenyl or 2-thienyl and R 16 is H, —CN, —C(O)CH 3 or —CO 2 Et; then R 3 is not H or phenyl;
proviso 9: when J 1 , J 2 , J 3 and J 4 are each C(H); R 1 and R 2 taken together are (═O); X is NH or S; and R 4 is (═S) or —SR 6 ; then R 3 is not —NH 2 ;
proviso 10: when J 1 is N, J 3 is C(H), J 4 is C(CH 3 ) or C(phenyl) and J 2 is C(CH 3 ), C (optionally substituted phenyl) or C(2-thienyl); X is S; and R 4 is H, (═S) or —SR 6 ; then R 3 is not NH 2 , C 1 -C 4 alkyl, —CH 2 CO 2 Et, or optionally substituted phenyl; and
proviso 11: when J 1 , J 2 , J 3 and J 4 are each C(H); and R 3 and R 4 form a ring with the intervening atoms; then X is not NH or S.
2 . The compound of claim 1 , wherein X is O, S, or NR 3 .
3 . The compound of claim 2 , wherein at least one of J 1 -J 4 is N or N→O.
4 . The compound of claim 3 , wherein one of J 1 -J 4 is N or N→O, and R 1 is selected from the group consisting of H, —OR 6 , —SR 6 , halo, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl optionally substituted with one or more (═O) or (═S), heterocyclyl optionally substituted with one or more (═O) or (═S), cycloalkylalkyl optionally substituted with one or more (═O) or (═S), and heterocyclylalkyl optionally substituted with one or more (═O) or (═S); wherein said alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, and heterocyclylalkyl are optionally substituted with one or more substituents independently selected from halo, alkyl optionally substituted with one or more R 11 , aryl optionally substituted with one or more R 11 , cycloalkyl optionally substituted with one or more R 11 , heteroaryl optionally substituted with one or more R 11 , heterocyclyl optionally substituted with one or more R 11 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 F, —CN, —NO 2 , —OR 6 , —SR 6 , —NR 6 R 7 , —C(O)R 6 , —C(O 2 ) R 6 , —OCOR 6 , —C(O)NR 6 R 7 , —N(R 6 )C(O)R 6 , —OS(O 2 ) R 6 , —S(O 2 ) R 6 , —S(O 2 )NR 6 R 7 , —N(R 6 )S(O 2 )R 6 , or —N(R 6 )C(O)NR 6 R 7 , or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy.
5 . The compound of claim 1 , wherein R 1 and R 2 are taken together to form (═O) or (═S).
6 . The compound of claim 1 represented by formula Ia:
7 . The compound of claim 6 , wherein X is O or S.
8 . The compound of claim 6 , wherein X is S.
9 . The compound of claim 7 , wherein J 1 is N or N→O and J 2 , J 3 and J 4 are each C(R).
10 . The compound of claim 7 , wherein J 2 is N or NO and J 1 , J 3 and J 4 are each C(R).
11 . The compound of claim 7 , wherein J 3 is N or NO and J 1 , J 2 and J 4 are each C(R).
12 . The compound of claim 7 , wherein J 4 is N or N→O and J 1 , J 2 and J 3 are each C(R).
13 . The compound of claim 7 , wherein J 1 and J 3 are each N and J 2 and J 4 are each C(R).
14 . The compound of claim 7 , wherein J 2 and J 3 are C(H) or C(halo).
15 . The compound of any one of claims 6 , wherein R 4 is H.
16 . The compound of claim 15 , wherein R is H, halo, alkyl, alkoxy, cycloalkyl, heteroaryl, —OSO 2 R 6 , or —NR 6 R 7 wherein R 6 and R 7 optionally taken together with the nitrogen atom form a 4-7 membered heterocyclic ring having 0-1 heteroatoms independently selected from O or N in addition to said nitrogen atom.
17 . The compound of claim 16 , wherein R is H, —N(C 1 -C 6 alkyl) 2 , —NH(C 1 -C 6 alkyl), halo, —C 1 -C 6 alkoxy, —OSO 2 CF 3 , —NH—(C 3 -C 6 cycloalkyl), —NH-phenyl, N-piperidinyl, N-morpholinyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, N-pyrrolyl, 114-pyrazolyl, N-piperazinyl, or N-pyrrolidinyl optionally substituted with hydroxy or (═O).
18 . The compound of claim 17 , wherein the (C 1 -C 6 alkyl) of said —NH(C 1 -C 6 alkyl) is optionally substituted with —OH or —CF 3 .
19 . The compound of claim 6 , wherein R 3 is alkyl, alkoxyalkyl, cycloalkyl, heteroaryl, heteroaralkyl, cycloalkylalkyl, aralkyl, aryl, heterocyclyl or heterocyclylalkyl; wherein each member of R 3 is optionally substituted with one or more substituents independently selected from halo, —CN, —OR 12 , alkyl, alkoxy, —OCF 3 , —OCHF 2 , amino, alkylamino, dialkylamino, hydroxyalkyl, —NR 12 C(O)R 12 , —C(O)N(R 12 ) 2 , cyanoalkyl, —CO 2 R 12 , —CF 3 , or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy; and said heterocyclyl is additionally and optionally substituted by (═O).
20 . The compound of claim 19 , wherein R 3 is C 1 -C 6 alkyl, C 3 -C 7 monocyclic cycloalkyl, 9-membered cycloalkylaryl, 9-membered cycloalkenylaryl, 6-membered monocyclic heteroaryl or heterocyclyl, 9- to 10-membered bicyclic heteroaryl or heterocyclyl, C 6 cycloalkyl(C 1 -C 6 )alkyl, ar(C 1 -C 6 )alkyl, or aryl; wherein said aryl is optionally substituted with one or more substituents independently selected from halo, —CN, —OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —OCF 3 , —OCHF 2 , amino, C 1 -C 6 alkylamino, di(C 1 -C 6 )alkylamino, hydroxy(C 1 -C 6 )alkyl, or two adjacent substituents of said aryl are linked to form a methylenedioxy or ethylenedioxy.
21 . The compound of claim 20 , wherein R 3 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, α-phenethyl, pyridyl, n-butyl, indolyl, benzothiazolyl, benzoimidazolyl, benzooxazolyl, cyclohexylmethyl, pyrano, indanyl, indenyl, phenyl, or 3,4-dihydrobenzo[1,4]oxazinyl; wherein said phenyl is optionally substituted with halo, —CN, —OMe, —OCF 3 , —OCHF 2 , —NMe 2 , —OH, —CH 2 OH, methyl, ethyl or two adjacent substituents of said phenyl are linked to form a methylenedioxy or ethylenedioxy; and said 3,4-dihydrobenzo[1,4]oxazinyl is optionally substituted with (═O).
22 . The compound of claim 20 , wherein said aryl or phenyl is p-substituted.
23 . The compound of claim 1 , wherein the compound is selected from the group consisting of those set forth below or a pharmaceutically acceptable salt or solvate thereof
Cpd
Structure
7A
7F
7G
7H
7I
7J
7K
7L
7M
7N
7O
7P
7Q
7R
7S
7T
7U
7V
7W
7X
7Y
7Z
7AA
7AB
7AC
7AD
7AE
7AF
7AG
7AH
7AI
7AJ
7AK
7AL
7AM
7AN
7AO
7AP
7AQ
7AR
7AS
7AT
7AU
7AV
7AW
7AX
7AY
7AZ
7BA
7BB
7BC
7BD
7BE
7BF
7BG
7BH
7BI
7BJ
7BK
7BL
7BM
7BN
7BO
7BP
7BQ
7BR
7BS
7BT
7BU
7BV
7BW
7BX
7BY
7BZ
7CA
7CB
7CC
7CD
7CE
7CF
7CG
7CH
7CI
7CJ
7CK
7CL
7CM
7CN
7CO
7CP
7CQ
7CR
7CS
7CT
7CU
7CV
7CW
7CX
7CY
7CZ
7DA
7DB
7DC
7DD
7DE
7DF
7DG
7DH
7DI
7DJ
7DK
7DL
7DM
7DN
7DO
7DP
7DQ
7DR
7DS
7DT
7DU
7DV
7DW
7DX
7DY
7DZ
7EA
7EB
7EC
11
12A
12B
13
14
15A
15B
15C
15D
15E
15F
15G
15H
15I
15J
15K
15L
15M
15N
15O
15P
15Q
15R
15S
15T
15U
15V
15W
15X
15Y
15Z
15AA
15AB
15AC
15AD
15AE
15AF
15AG
15AH
15AI
15AJ
15AK
19
25A
25B
25C
25D
26A
26C
27A
27B
27C
28A
28B
28C
28D
28E
28F
28G
28H
28I
28J
28K
28L
28M
28N
28O
28P
28Q
28R
28S
28T
28U
28V
28W
28X
28Y
28Z
28AA
28AB
28AC
28AD
28AE
28AF
28AG
28AH
28AI
28AJ
28AK
28AL
28AM
28AN
28AO
28AP
28AQ
28AR
28AS
28AT
28AU
28AV
28AW
28AX
28AY
28AZ
28BA
28BB
28BC
29A
29B
29C
29D
30A
30B
30C
37A
37B
37C
37D
37E
37F
37G
37H
40
41
42
43
44
45
46
47A
47B
48
49
50
51
52
53
54
55
57
58
59A
59B
59C
60A
60B
60C
60D
60E
60F
60G
60H
60I
60J
60L
61A
61B
62
63
64
65A
65B
65C
65D
65E
66A
66B
66C
66D
66E
71A
72A
72B
72C
72D
72E
72F
72G
72H
72I
73A
73B
73C
73D
73E
73F
73G
76
77
78
80
83
84
85
87A
87B
87C
95A
95B
95C
95D
95E
95F
95G
95H
95I
95J
95K
95L
95M
95N
95O
95P
95Q
95R
95S
95T
95U
95V
95W
95X
95Y
95Z
95AA
95AB
95AC
95AD
95AE
95AF
95AG
95AH
95AI
95AJ
95AK
95AL
95AM
95AN
103A
103B
103C
103D
103E
103F
104
105
106
113A
113B
113C
113D
113E
113F
113G
113H
113I
113J
113K
113L
113M
113N
115
116
116A
116B
116C
116D
116E
116F
116G
117
117A
117B
118
131A
131B
131C
131D
131E
131F
131G
134A
134B
134C
134D
134E
134F
134G
134H
134I
135A
136
137A
137B
138
144A
147A
149
150
151
152
24 . The compound of claim 23 , wherein the compound is selected from the group consisting of 7A, 7B, 7D, 7G, 7H, 7K, 7L, 7Q, 7W, 7X, 7Y, 7Z, 7AA, 7AC, 7AJ, 7AK, 7AM, 7AP, 7AS, 7AV, 7AX, 7AY, 7BF, 7BG, 7BI, 7BJ, 7BL, 7BM, 7BN, 7BO, 7BS, 7BW, 7BY, 7BZ, 7CA, 7CB, 7CC, 7CD, 7CE, 7CF, 7CG, 7CK, 7CM, 7CQ, 7CR, 7CT, 7CU, 7CV, 7CY, 7CZ, 7 DB, 7DC, 7DE, 7DF, 7DG, 7DH, 7DI, 7DJ, 7DK, 7□L, 7DO, 7DQ, 7DR, 7DU, 7DV, 7DW, 7DX, 7DZ, 7EA, 15C, 15O, 15Y, 15Z, 15AA, 15AB, 15AG, 28I, 28P, 28S, 28X, 28Y, 28Z, 28AA, 28AB, 28AC, 28AE, 28AI, 28AK, 28AL, 28AN, 28AO, 28AP, 28AR, 28AS, 28AT, 28AU, 28AV, 28AW, 28AZ, 28BB, 28BC, 37E, 37F, 45, 46, 51, 58, 60A, 60B, 60C, 60D, 60E, 60G, 66A, 66D, 71A, 72A, 72B, 72C, 72G, 72H, 72I, 95A, 95B, 96C, 95D, 95E, 95F, 95G, 95H, 95I, 95K, 95L, 95N, 95O, 95P, 95O, 95R, 95S, 95T, 95U, 95W, 95X, 95Y, 95Z, 95AA, 95AC, 95AD, 113A, 113B, 113D, 113E, 113F, 113G, 113H, 113I, 113K, 116D, 131A, 131B, 131C, 131D, 131E, 131G, 136, 137A, 137B, 138, 148, 151, and 152, or a pharmaceutically acceptable salt or solvate thereof.
25 . The compound of claim 24 , selected from the group consisting of 7A, 7B, 7H, 7L, 7Q, 7AC, 7AP, 7AS, 7BI, 7BJ, 7BL, 7BM, 7BS, 7BY, 7CC, 7CE, 7CG, 7CQ, 7CR, 7CT, 7CU, 7CV, 7CY, 7DG, 7DH, 7DK, 7□L, 7DR, 7DU, 7DV, 7DW, 15Q, 15Z, 15AA, 15AG, 28X, 28Y, 28Z, 28AA, 28AE, 28AI, 28AK, 28AL, 37E, 37F, 60A, 60D, 60E, 71A, 72G, 72H, 95A, 95B, 95C, 95E, 95F, 95G, 95H, 95K, 95L, 95P, 95Q, 95S, 95T, 95Z, 95AA, 95AC, 131C, 131 D, 131 E, 136, 148, and 152, or a pharmaceutically acceptable salt or solvate thereof.
26 . A pharmaceutical composition comprising at least one compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable carrier, adjuvant or vehicle.
27 . The pharmaceutical composition of claim 26 , further comprising one or more additional therapeutic agents.
28 . The pharmaceutical composition of claim 27 , wherein said additional therapeutic agents are selected from the group consisting of therapeutic agents suitable for pain management, anti-anxiety agents, anti-migraine agents, and therapeutic agents suitable for treating urinary incontinence.
29 . A method of selectively antagonizing metabotropic glutamate receptor 1 (mGluR1) activity in a cell in need thereof, comprising contacting said cell with a therapeutically effective amount of at least one compound of formula I:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
J 1 , J 2 , J 3 and J 4 are independently N or C(R), provided that 0-2 of J 1 , J 2 , J 3 and J 4 are N;
is a single or double bond;
R is selected from the group consisting of H, halo, —NR 6 R 7 , —OR 6 , —SR 6 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 F, —CN, —C(O)R 6 , —C(O 2 )R 6 , —OC(O)R 6 , —C(O)NR 6 R 7 , —N(R 6 )C(O)R 6 , —OS(O 2 )R 6 , —S(O 2 )R 6 , —S(O 2 )NR 6 R 7 , —N(R 6 )S(O 2 )R 6 , —N(R 6 )C(O)NR 6 R 7 , alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl optionally substituted with one or more (═O) or (═S), heterocyclyl optionally substituted with one or more (═O) or (═S), cycloalkylalkyl optionally substituted with one or more (═O) or (═S), and heterocyclylalkyl optionally substituted with one or more (═O) or (═S); wherein said alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, and heterocyclylalkyl are optionally substituted with one or more substituents independently selected from halo, alkyl optionally substituted with one or more R 11 , aryl optionally substituted with one or more R 11 , cycloalkyl optionally substituted with one or more R 11 , heteroaryl optionally substituted with one or more R 11 , heterocyclyl optionally substituted with one or more R 11 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 F, —CN, —NO 2 , —OR 6 , —SR 6 , —NR 6 R 7 , —C(O)R 6 , —C(O 2 )R 6 , —OCOR 6 , —C(O) r NR 6 R 7 , —N(R 6 )C(O)R 6 , —OS(O 2 )R 6 , —S(O 2 )R 6 , —S(O 2 )NR 6 R 7 , —N(R 6 )S(O 2 )R 6 , or —N(R 6 )C(O)NR 6 R 7 , or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy;
X is O, S, N(R 8 ), C(O), or C(R a R b );
R 1 is selected from the group consisting of H, —OR 6 , —SR 6 , —NR 6 R 7 , halo, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl optionally substituted with one or more (═O) or (═S), heterocyclyl optionally substituted with one or more (═O) or (═S), cycloalkylalkyl optionally substituted with one or more (═O) or (═S), and heterocyclylalkyl optionally substituted with one or more (═O) or (═S); wherein said alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, and heterocyclylalkyl are optionally substituted with one or more substituents independently selected from halo, alkyl optionally substituted with one or more R 11 , aryl optionally substituted with one or more R 11 , cycloalkyl optionally substituted with one or more R 11 , heteroaryl optionally substituted with one or more R 11 , heterocyclyl optionally substituted with one or more R 11 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 F, —CN, —NO 2 , —OR 6 , —SR 6 , —NR 6 R 7 , —C(O)R 6 , —C(O 2 )R 6 , —OC(O)R 6 , —C(O)NR 6 R 7 , —N(R 6 )C(O)R 6 , —OS(O 2 )R 6 , —S(O 2 )R 6 , —S(O 2 )NR 6 R 7 , —N(R 6 )S(O 2 )R 6 , or —N(R 6 )C(O)NR 6 R 7 , or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy;
R 2 is selected from the group consisting of H, halo, alkyl, —N(R 12 ) 2 , —OR 12 and —SR 12 , wherein said alkyl is optionally substituted with one or more substituents independently selected from halo, hydroxy or alkoxy; or R 1 and R 2 optionally taken together form (═O) or (═S);
R 3 is selected from the group consisting of H, —NR 6 R 7 , alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl optionally substituted with one or more (═O) or (═S), heterocyclyl optionally substituted with one or more (═O) or (═S), cycloalkylalkyl optionally substituted with one or more (═O) or (═S), and heterocyclylalkyl optionally substituted with one or more (═O) or (═S); wherein said alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, and heterocyclylalkyl are optionally substituted with one or more substituents independently selected from halo, alkyl optionally substituted with one or more R 11 , aryl optionally substituted with one or more R 11 , cycloalkyl optionally substituted with one or more R 11 , heteroaryl optionally substituted with one or more R 11 , heterocyclyl optionally substituted with one or more R 11 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 F, —CN, —NO 2 , —OR 6 , —SR 6 , —NR 6 R 7 , —C(O)R 6 , —C(O 2 )R 6 , —OC(O)R 6 , —C(O)NR 6 R 7 , —N(R 6 )C(O)R 6 , —OS(O 2 )R 6 , —S(O 2 )R 6 , —S(O 2 )NR 6 R 7 , —N(R 6 )S(O 2 )R 6 , or —N(R 6 )C(O)NR 6 R 7 , or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy;
R 4 is selected from the group consisting of H, —OR 6 , (═O), (═S), —SR 6 , —NR 6 R 7 , halo, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl optionally substituted with one or more (═O) or (═S), heterocyclyl optionally substituted with one or more (═O) or (═S), cycloalkylalkyl optionally substituted with one or more (═O) or (═S), and heterocyclylalkyl optionally substituted with one or more (═O) or (═S); wherein said alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, and heterocyclylalkyl are optionally substituted with one or more substituents independently selected from halo, alkyl optionally substituted with one or more R 11 , aryl optionally substituted with one or more R 11 , cycloalkyl optionally substituted with one or more R 11 , heteroaryl optionally substituted with one or more R 11 , heterocyclyl optionally substituted with one or more R 11 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 F, —CN, —NO 2 , —OR 6 , —SR 6 , —NR 6 R 7 , —C(O)R 6 , —C(O 2 )R 6 , —OC(O)R 6 , —C(O)NR 6 R 7 , —N(R 6 )C(O)R 6 , —OS(O 2 )R 6 , —S(O 2 )R 6 , —S(O 2 )NR 6 R 7 , —N(R 6 )S(O 2 )R 6 , or —N(R 6 )C(O)NR 6 R 7 , or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy; or R 3 and R 4 optionally taken together with intervening atoms form a 5-8 membered heterocyclic ring having 0-3 heteroatoms independently selected from O, N or S in addition to the intervening nitrogen;
R 5 is R 3 when is a single bond and R 5 is absent when is a double bond;
R 6 and R 7 are independently selected from the group consisting of H, alkyl, alkoxyalkyl, aryloxyalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl optionally substituted with one or more (═O) or (═S), heterocyclyl optionally substituted with one or more (═O) or (═S), cycloalkylalkyl optionally substituted with one or more (═O) or (═S), and heterocyclylalkyl optionally substituted with one or more (═O) or (═S); wherein each member of R 6 and R 7 except H is optionally substituted with one or more substituents independently selected from halo, alkyl optionally substituted with one or more R 11 , aryl optionally substituted with one or more R 11 , cycloalkyl optionally substituted with one or more R 11 , heteroaryl optionally substituted with one or more R 11 , heterocyclyl optionally substituted with one or more R 11 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 F, —CN, —NO 2 , —OR 10 , —SR 10 , —NR 9 R 10 , —C(O)R 10 , —C(O 2 )R 10 , —OC(O)R 10 , —C(O)NR 9 R 10 , —N(R 9 )C(O)R 10 , —OS(O 2 )R 10 , —S(O 2 )R 10 , —S(O 2 )NR 9 R 10 , —N(R 9 )S(O 2 )R 10 , or —N(R 9 )C(O)NR 9 R 10 , or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy; or R 6 and R 7 , when attached to the same nitrogen atom, optionally taken together with the nitrogen atom form a 3-7 membered heterocyclic ring containing 0-3 heteroatoms independently selected from O, N or S in addition to said nitrogen atom;
R a is selected from the group consisting of H, halo, alkyl, hydroxyalkyl, alkoxyalkyl, and N(R 12 ) 2 ;
R b is selected from the group consisting of H, halo, alkyl, hydroxyalkyl, and alkoxyalkyl;
R 8 is selected from the group consisting of H, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl optionally substituted with one or more (═O) or (═S), heterocyclyl optionally substituted with one or more (═O) or (═S), cycloalkylalkyl optionally substituted with one or more (═O) or (═S), and heterocyclylalkyl optionally substituted with one or more (═O) or (═S); wherein each member of R 8 except H is optionally substituted with one or more substituents independently selected from halo, alkyl optionally substituted with one or more R 11 , aryl optionally substituted with one or more R 11 , cycloalkyl optionally substituted with one or more R 11 , heteroaryl optionally substituted with one or more R 11 , heterocyclyl optionally substituted with one or more R 11 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 F, —CN, —NO 2 , —OR 10 , —SR 10 , —NR 10 R 10 , —C(O)R 10 , —C(O 2 )R 10 , —OC(O)R 10 , —C(O)NR 9 R 10 , —N(R 9 )C(O)R 10 , —OS(O 2 )R 10 , —S(O 2 )R 10 , —S(O 2 )NR 9 R 10 , —N(R 9 )S(O 2 )R 10 , or —N(R 9 )C(O)NR 9 R 10 , or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy;
R 9 is H or alkyl;
R 10 is selected from H, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl optionally substituted with one or more (═O) or (═S), heterocyclyl optionally substituted with one or more (═O) or (═S), cycloalkylalkyl optionally substituted with one or more (═O) or (═S), heterocyclylalkyl optionally substituted with one or more (═O) or (═S); wherein each member of R 11 except H is optionally substituted with one or more substituents independently selected from halo, alkyl optionally substituted with one or more R 11 , aryl optionally substituted with one or more R 11 , cycloalkyl optionally substituted with one or more R 11 , heteroaryl optionally substituted with one or more R 11 , heterocyclyl optionally substituted with one or more R 11 , —CF 3 , —OCHF 2 , —OCH 2 F, —OCF 3 , —CN, —NO 2 , —OR 12 , —SR 12 , —N(R 12 )(R 12 ), —C(O)R 12 , —C(O 2 )R 12 , —OC(O)R 12 , —C(O)N(R 12 )(R 12 ), —N(R 12 )C(O)R 12 , —OS(O 2 )R 12 , —S(O 2 )R 12 , —S(O 2 )N(R 12 )(R 12 ), —N(R 12 )S(O 2 )R 12 , or —N(R 12 )C(O)N(R 12 )(R 12 ), or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy; or R 9 and R 10 , when attached to the same nitrogen atom, optionally taken together with the attached nitrogen atom form a 3-7 membered heterocyclic ring containing 0-3 heteroatoms independently selected from O, N or S in addition to the attached nitrogen; and two R 12 s attached to the same nitrogen atom optionally taken together with the attached nitrogen atom form a 3-7 membered heterocyclic ring having 0-3 heteroatoms independently selected from O, N or S in addition to the attached nitrogen;
R 11 is halo, —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 F, —CN, —NO 2 , —OR 2 , —SR 12 , —N(R 12 )(R 12 ), —C(O)R 12 , —C(O 2 )R 12 , —OC(O)R 12 , —C(O)N(R 12 )(R 12 ), —N(R 12 )C(O)R 12 , —OS(O 2 )R 12 , —S(O 2 )R 12 , —S(O 2 )N(R 12 )(R 12 ), —N(R 12 )S(O 2 )R 12 , or —N(R 12 )C(O)N(R 12 )(R 12 ); and
R 12 is H or alkyl.
30 . A method of treating a disease or condition associated with metabotropic glutamate receptor 1 (mGluR1) function in a mammal in need of such treatment, comprising administering a therapeutically effective amount of at least one compound of formula I:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
J 1 , J 2 , J 3 and J 4 are independently N or C(R), provided that 0-2 of J 1 , J 2 , J 3 and J 4 are N;
is a single or double bond;
R is selected from the group consisting of H, halo, —NR 6 R 7 , —OR 6 , —SR 6 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 F, —CN, —C(O)R 6 , —C(O 2 )R 6 , —OC(O)R 6 , —C(O)NR 6 R 7 , —N(R 6 )C(O)R 6 , —OS(O 2 )R 6 , —S(O 2 )R 6 , —S(O 2 )NR 6 R 7 , —N(R 6 )S(O 2 )R 6 , —N(R 6 )C(O)NR 6 R 7 , alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl optionally substituted with one or more (═O) or (═S), heterocyclyl optionally substituted with one or more (═O) or (═S), cycloalkylalkyl optionally substituted with one or more (═O) or (═S), and heterocyclylalkyl optionally substituted with one or more (═O) or (═S); wherein said alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, and heterocyclylalkyl are optionally substituted with one or more substituents independently selected from halo, alkyl optionally substituted with one or more R 11 , aryl optionally substituted with one or more R 11 , cycloalkyl optionally substituted with one or more R 11 , heteroaryl optionally substituted with one or more R 11 , heterocyclyl optionally substituted with one or more R 11 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 F, —CN, —NO 2 , —OR 6 , —SR 6 , —NR 6 R 7 , —C(O)R 6 , —C(O 2 )R 6 , —OCOR 6 , —C(O)NR 6 R 7 , —N(R 6 )C(O)R 6 , —OS(O 2 )R 6 , —S(O 2 )R 6 , —S(O 2 )NR 6 R 7 , —N(R 6 )S(O 2 )R 6 , or —N(R 6 )C(O)NR 6 R 7 , or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy;
X is O, S, N(R 8 ), C(O), or C(R a R b );
R 1 is selected from the group consisting of H, —OR 6 , —SR 6 , —NR 6 R 7 , halo, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl optionally substituted with one or more (═O) or (═S), heterocyclyl optionally substituted with one or more (═O) or (═S), cycloalkylalkyl optionally substituted with one or more (═O) or (═S), and heterocyclylalkyl optionally substituted with one or more (═O) or (═S); wherein said alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, and heterocyclylalkyl are optionally substituted with one or more substituents independently selected from halo, alkyl optionally substituted with one or more R 11 , aryl optionally substituted with one or more R 11 , cycloalkyl optionally substituted with one or more R 11 , heteroaryl optionally substituted with one or more R 11 , heterocyclyl optionally substituted with one or more R 11 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 F, —CN, —NO 2 , —OR 6 , —SR 6 , —NR 6 R 7 , —C(O)R 6 , —C(O 2 )R 6 , —OC(O)R 6 , —C(O)NR 6 R 7 , —N(R 6 )C(O)R 6 , —OS(O 2 )R 6 , —S(O 2 )R 6 , —S(O 2 )NR 6 R 7 , —N(R 6 )S(O 2 )R 6 , or —N(R 6 )C(O)NR 6 R 7 , or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy;
R 2 is selected from the group consisting of H, halo, alkyl, —N(R 12 ) 2 , —OR 12 and —SR 12 , wherein said alkyl is optionally substituted with one or more substituents independently selected from halo, hydroxy or alkoxy; or R 1 and R 2 optionally taken together form (═O) or (═S);
R 3 is selected from the group consisting of H, —NR 6 R 7 , alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl optionally substituted with one or more (═O) or (═S), heterocyclyl optionally substituted with one or more (═O) or (═S), cycloalkylalkyl optionally substituted with one or more (═O) or (═S), and heterocyclylalkyl optionally substituted with one or more (═O) or (═S); wherein said alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, and heterocyclylalkyl are optionally substituted with one or more substituents independently selected from halo, alkyl optionally substituted with one or more R 11 , aryl optionally substituted with one or more R 11 , cycloalkyl optionally substituted with one or more R 11 , heteroaryl optionally substituted with one or more R 11 , heterocyclyl optionally substituted with one or more R 11 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 F, —CN, —NO 2 , —OR 6 , —SR 6 , —NR 6 R 7 , —C(O)R 6 , —C(O 2 )R 6 , —OC(O)R 6 , —C(O)NR 6 R 7 , —N(R 6 )C(O)R 6 , —OS(O 2 )R 6 , —S(O 2 )R 6 , —S(O 2 )NR 6 R 7 , —N(R 6 )S(O 2 )R 6 , or —N(R 6 )C(O)NR 6 R 7 , or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy;
R 4 is selected from the group consisting of H, —OR 6 , (═O), (═S), —SR 6 , —NR 6 R 7 , halo, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl optionally substituted with one or more (═O) or (═S), heterocyclyl optionally substituted with one or more (═O) or (═S), cycloalkylalkyl optionally substituted with one or more (═O) or (═S), and heterocyclylalkyl optionally substituted with one or more (═O) or (═S); wherein said alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, and heterocyclylalkyl are optionally substituted with one or more substituents independently selected from halo, alkyl optionally substituted with one or more R 11 , aryl optionally substituted with one or more R 11 , cycloalkyl optionally substituted with one or more R 11 , heteroaryl optionally substituted with one or more R 11 , heterocyclyl optionally substituted with one or more R 11 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 F, —CN, —NO 2 , —OR 6 , —SR 6 , —N1R 6 R 7 , —C(O)R 6 , —C(O 2 )R 6 , —OC(O)R 6 , —C(O)NR 6 R 7 , —N(R 6 )C(O)R 6 , —OS(O 2 )R 6 , —S(O 2 )R 6 , —S(O 2 )NR 6 R 7 , —N(R 6 )S(O 2 )R 6 , or —N(R 6 )C(O)NR 6 R 7 , or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy; or R 3 and R 4 optionally taken together with intervening atoms form a 5-8 membered heterocyclic ring having 0-3 heteroatoms independently selected from O, N or S in addition to the intervening nitrogen;
R 5 is R 3 when is a single bond and R 5 is absent when is a double bond;
R 6 and R 7 are independently selected from the group consisting of H, alkyl, alkoxyalkyl, aryloxyalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl optionally substituted with one or more (═O) or (═S), heterocyclyl optionally substituted with one or more (═O) or (═S), cycloalkylalkyl optionally substituted with one or more (═O) or (═S), and heterocyclylalkyl optionally substituted with one or more (═O) or (═S); wherein each member of R 6 and R 7 except H is optionally substituted with one or more substituents independently selected from halo, alkyl optionally substituted with one or more R 11 , aryl optionally substituted with one or more R 11 , cycloalkyl optionally substituted with one or more R 11 , heteroaryl optionally substituted with one or more R 11 , heterocyclyl optionally substituted with one or more R 11 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 F, —CN, —NO 2 , —OR 10 , —SR 10 , —NR 9 R 10 , —C(O)R 10 , —C(O 2 )R 11 , —OC(O)R 10 , —C(O)NR 9 R 10 , —N(R 9 )C(O)R 10 , —OS(O 2 )R 10 , —S(O 2 )R 10 , —S(O 2 )NR 9 R 10 , —N(R 9 )S(O 2 )R 10 , or —N(R 9 )C(O)NR 9 R 10 , or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy; or R 6 and R 7 , when attached to the same nitrogen atom, optionally taken together with the nitrogen atom form a 3-7 membered heterocyclic ring containing 0-3 heteroatoms independently selected from O, N or S in addition to said nitrogen atom;
R a is selected from the group consisting of H, halo, alkyl, hydroxyalkyl, alkoxyalkyl, and N(R 12 ) 2 ; R b is selected from the group consisting of H, halo, alkyl, hydroxyalkyl, and alkoxyalkyl; R 8 is selected from the group consisting of H, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl optionally substituted with one or more (═O) or (═S), heterocyclyl optionally substituted with one or more (═O) or (═S), cycloalkylalkyl optionally substituted with one or more (═O) or (═S), and heterocyclylalkyl optionally substituted with one or more (═O) or (═S); wherein each member of R 3 except H is optionally substituted with one or more substituents independently selected from halo, alkyl optionally substituted with one or more R 11 , aryl optionally substituted with one or more R 11 , cycloalkyl optionally substituted with one or more R 11 , heteroaryl optionally substituted with one or more R 11 , heterocyclyl optionally substituted with one or more R 11 , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 F, —CN, —NO 2 , —OR 10 , —SR 10 , —NR 10 R 10 , —C(O)R 10 , —C(O 2 )R 10 , —OC(O)R 10 , —C(O)NR 9 R 10 , —N(R 9 )C(O)R 10 , —OS(O 2 )R 10 , —S(O 2 )R 10 , —S(O 2 )NR 9 R 10 , —N(R 9 )S(O 2 )R 10 , or —N(R 9 )C(O)NR 9 R 10 , or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy;
R 9 is H or alkyl; R 10 is selected from H, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl optionally substituted with one or more (═O) or (═S), heterocyclyl optionally substituted with one or more (═O) or (═S), cycloalkylalkyl optionally substituted with one or more (═O) or (═S), heterocyclylalkyl optionally substituted with one or more (═O) or (═S); wherein each member of R 11 except H is optionally substituted with one or more substituents independently selected from halo, alkyl optionally substituted with one or more R 11 , aryl optionally substituted with one or more R 11 , cycloalkyl optionally substituted with one or more R 11 , heteroaryl optionally substituted with one or more R 11 , heterocyclyl optionally substituted with one or more R 11 , —CF 3 , —OCHF 2 , —OCH 2 F, —OCF 3 , —CN, —NO 2 , —OR 2 , —SR 2 , —N(R 12 )(R 12 ), —C(O)R 12 , —C(O 2 )R 12 , —OC(O)R 12 , —C(O)N(R 12 )(R 12 ), —N(R 12 )C(O)R 12 , —OS(O 2 )R 12 , —S(O 2 )R 12 , —S(O 2 )N(R 12 )(R 12 ), —N(R 12 )S(O 2 )R 12 , or —N(R 12 )C(O)N(R 12 )(R 12 ), or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy; or R 9 and R 11 , when attached to the same nitrogen atom, optionally taken together with the attached nitrogen atom form a 3-7 membered heterocyclic ring containing 0-3 heteroatoms independently selected from O, N or S in addition to the attached nitrogen; and two R 12 s attached to the same nitrogen atom optionally taken together with the attached nitrogen atom form a 3-7 membered heterocyclic ring having 0-3 heteroatoms independently selected from O, N or S in addition to the attached nitrogen;
R 11 is halo, —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 F, —CN, —NO 2 , —OR 2 , —SR 12 , —N(R 12 )(R 12 ), —C(O)R 12 , —C(O 2 )R 12 , —OC(O)R 12 , —C(O)N(R 12 )(R 12 ), —N(R 12 )C(O)R 12 , —OS(O 2 )R 12 , —S(O 2 )R 12 , —S(O 2 )N(R 12 )(R 12 ), —N(R 12 )S(O 2 )R 12 , or —N(R 12 )C(O)N(R 12 ) (R 12 ); and R 12 is H or alkyl.
31 . The method of claim 30 , wherein said disease or condition is pain.
32 . The method of claim 30 , wherein said disease or condition is neuropathic pain.
33 . The method of claim 30 , wherein said disease or condition is allodynia.
34 . The method of claim 30 , wherein said disease or condition is hyperalgesia.
35 . The method of claim 30 , wherein said disease or condition is pain associated with inflammation or an inflammatory disease.
36 . The method of claim 30 , further comprising administering one or more additional therapeutic agent(s) suitable for pain management.
37 . The method of claim 36 , wherein said additional therapeutic agent is an opioid analgesic.
38 . The method of claim 36 , wherein said additional therapeutic agent is a non-opioid analgesic.
39 . The method of claim 30 , wherein said disease or condition is selected from the group consisting of muscle spasms, convulsions, spasticity, migraine, psychoses, urinary incontinence, anxiety and related disorders, emesis, brain edema, tardive dyskinesia, depression, drug tolerance and withdrawal, and smoking cessation.
40 . The method of claim 39 , wherein said disease or condition is anxiety.
41 . The method of claim 40 , further comprising administering one or more additional anti-anxiety agent(s).
42 . The method of claim 37 , wherein said disease or condition is migraine.
43 . The method of claim 40 , further comprising administering one or more additional anti-migraine agent(s).
44 . The method of claim 39 , wherein said disease or condition is urinary incontinence.
45 . The method of claim 44 , further comprising administering one or more additional therapeutic agent(s) suitable for treating urinary incontinence.
46 . The method of claim 30 , wherein said disease or condition is selected from the group consisting of cerebral deficits subsequent to cardiac bypass surgery or grafting, cerebral ischemia, stroke, spinal cord injuries, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis (ALS), AIDS-induced dementia, inherited ataxias, ocular damage and retinopathy, cognitive disorders, and idiopathic or drug-induced Parkinson's.
47 . The method of claim 46 , further comprising administering one or more additional therapeutic agent(s).
48 . The method of claims 30 , wherein said compound of formula I is represented by formula Ia:
49 . The method of claim 48 , wherein X is O or S.
50 . The method of claim 49 , wherein X is S.
51 . The method of claim 48 , wherein J 1 is N or NO, J 2 , J 3 and J 4 are each C(R).
52 . The method of claim 49 , wherein J 2 is N or NO and J 1 , J 3 and J 4 are each C(R).
53 . The method of claim 49 , wherein J 3 is N or NO and J 1 , J 2 and J 4 are each C(R).
54 . The method of claim 49 , wherein J 4 is N or NO and J 1 , J 2 and J 3 are each C(R).
55 . The method of claim 49 , wherein J 1 and J 4 are each N and J 2 and J 3 are each C(R).
56 . The method of claim 49 , wherein J 2 and J 3 are C(H) or C(halo).
57 . The method of any one of claims 48 , wherein R 4 is H.
58 . The method of claim 57 , wherein R is H, halo, alkyl, alkoxy, cycloalkyl, heteroaryl, —OSO 2 R 6 , or —NR 6 R 7 wherein R 6 and R 7 optionally taken together with the nitrogen atom form a 4-7 membered heterocyclic ring having 0-1 heteroatoms independently selected from O or N in addition to said nitrogen atom.
59 . The method of claim 58 , wherein R is H, —N(C 1 -C 6 alkyl) 2 , —NH(C 1 -C 6 alkyl), halo, —C 1 -C 6 alkoxy, —OSO 2 CF 3 , —NH—(C 3 -C 6 cycloalkyl), —NH-phenyl, N-piperidinyl, N-morpholinyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, N-pyrrolyl, N-pyrazolyl, N-piperazinyl, or N-pyrrolidinyl optionally substituted with hydroxy or (═O).
60 . The method of claim 57 , wherein R 3 is alkyl, alkoxyalkyl, cycloalkyl, heteroaryl, heteroaralkyl, cycloalkylalkyl, aralkyl, aryl, heterocyclyl or heterocyclylalkyl; wherein each member of R 3 is optionally substituted with one or more substituents independently selected from halo, —CN, —OR 12 , alkyl, alkoxy, —OCF 3 , —OCHF 2 , amino, alkylamino, dialkylamino, hydroxyalkyl, —NR 12 C(O)R 12 , —C(O)N(R 12 ) 2 , cyanoalkyl, —CO 2 R 12 , —CF 3 , or two adjacent substituents are linked to form a methylenedioxy or ethylenedioxy; and said heterocyclyl is additionally and optionally substituted by (═O).
61 . The method of claim 60 , wherein R 3 is C 1 -C 6 alkyl, C 3 -C 7 monocyclic cycloalkyl, 9-membered cycloalkylaryl, 9-membered cycloalkenylaryl, 6-membered monocyclic heteroaryl or heterocyclyl, 9- to 10-membered bicyclic heteroaryl or heterocyclyl, C 6 cycloalkyl(C 1 -C 6 )alkyl, ar(C 1 -C 6 )alkyl, or aryl; wherein said aryl is optionally substituted with one or more substituents independently selected from halo, —CN, —OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —OCF 3 , —OCHF 2 , amino, C 1 -C 6 alkylamino, di(C 1 -C 6 )alkylamino, hydroxy(C 1 -C 6 )alkyl, or two adjacent substituents of said aryl are linked to form a methylenedioxy or ethylenedioxy.
62 . The method of claim 61 , wherein R 3 is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, α-phenethyl, pyridyl, n-butyl, indolyl, benzothiazolyl, benzoimidazolyl, benzooxazolyl, cyclohexylmethyl, pyrano, indanyl, indenyl, phenyl, or 3,4-dihydrobenzo[1,4]oxazinyl; wherein said phenyl is optionally substituted with halo, —CN, —OMe, —OCF 3 , —OCHF 2 , —NMe 2 , —OH, —CH 2 OH, methyl, ethyl or two adjacent substituents of said phenyl are linked to form a methylenedioxy or ethylenedioxy; and said 3,4-dihydrobenzo[1,4]oxazinyl is optionally substituted with (═O).
63 . The method of claim 61 , wherein said aryl or phenyl is p-substituted.
64 . The method of claim 48 , wherein said compound is selected from the group consisting of
Cpd
Structure
7A
7B
7D
7G
7H
7K
7L
7Q
7W
7X
7Y
7Z
7AA
7AC
7AJ
7AK
7AM
7AP
7AS
7AV
7AX
7AY
7BF
7BG
7BI
7BJ
7BL
7BM
7BN
7BO
7BS
7BW
7BY
7BZ
7CA
7CB
7CC
7CD
7CE
7CF
7CG
7CK
7CM
7CQ
7CR
7CT
7CU
7CV
7CY
7CZ
7DB
7DC
7DE
7DF
7DG
7DH
7DI
7DJ
7DK
7DL
7DO
7DQ
7DR
7DU
7DV
7DW
7DX
7DZ
7EA
15C
15Q
15Y
15Z
15AA
15AB
15AG
28I
28P
28S
28X
28Y
28Z
28AA
28AB
28AC
28AE
28AI
28AK
28AL
28AN
28AO
28AP
28AR
28AS
28AT
28AU
28AV
28AW
28AZ
28BB
28BC
37E
37F
45
46
51
58
60A
60B
60C
60D
60E
60G
66A
66D
71A
72A
72B
72C
72G
72H
72I
95A
95B
95C
95D
95E
95F
95G
95H
95I
95K
95L
95N
95O
95P
95Q
95R
95S
95W
95X
95Y
95Z
95AA
95AC
95AD
113A
113B
113D
113E
113F
113G
113H
113I
113K
116D
131A
131B
131C
131D
131E
131G
136
137A
137B
138
148
151
152
or a pharmaceutically acceptable salt or solvate thereof.
65 . The method of claim 64 , wherein said compound is selected from the group consisting of 7A, 7B, 7H, 7L, 7Q, 7AC, 7AP, 7AS, 7BI, 7BJ, 7BL, 7BM, 7BS, 7BY, 7CC, 7CE, 7CG, 7CQ, 7CR, 7CT, 7CU, 7CV, 7CY, 7DG, 7DH, 7DK, 7□L, 7DR, 7DU, 7DV, 7DW, 15Q, 15Z, 15AA, 15AG, 28X, 28Y, 28Z, 28AA, 28AE, 28AI, 28AK, 28AL, 37E, 37F, 60A, 60D, 60E, 71A, 72G, 72H, 95A, 95B, 95C, 95E, 95F, 95G, 95H, 95K, 95L, 95P, 95Q, 95S, 95T, 95Z, 95AA, 95AC, 131C, 131D, 131E, 136, 148, and 152, or a pharmaceutically acceptable salt or solvate thereof.Join the waitlist — get patent alerts
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