US2012196897A1PendingUtilityA1
New compounds
Est. expiryMar 5, 2029(~2.7 yrs left)· nominal 20-yr term from priority
Inventors:Roland PfauKirsten ArndtHenri DoodsKlaus KlinderRaimund KuelzerDimitrijs LubriksJuergen MackBenjamin PelcmanHenning PriepkeRobert RoennDirk StenkampEdgars Suna
A61P 29/00A61P 25/04A61P 11/00C07D 409/12C07D 401/12C07D 235/30C07D 405/12C07D 403/12
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Claims
Abstract
The present invention relates to compounds of general formula I in which A, L, M, Q 2 , Q 3 , Q 4 , R 1 , R 5 , R a , R b , R c , W, X, Y, Z 1 , Z 2 , Z 3 are defined in the description, the salts thereof, particularly the physiologically acceptable salts thereof. The compounds are of potential utility in the treatment and/or prevention of inflammatory diseases and associated conditions, in particular, in the treatment and/or prevention of pain. The invention also relates to the use of such compounds as medicaments, to pharmaceutical compositions containing them, and to their preparation.
Claims
exact text as granted — not AI-modified1 . A compound of formula I:
one of X and Y represents —N(R 6 )—; and
the other represents —N═;
one of Z 1 , Z 2 and Z 3 independently represents —C(R 7 )═ or —N═; and
the other two of Z 1 , Z 2 and Z 3 represent —C(R 7 )═;
Q 2 , Q 3 and Q 4 respectively represent —C(R 2 )═, —C(R 3 )═ and —C(R 4 )═;
or any one or two of Q 2 , Q 3 or Q 4 may alternatively and independently represent —N═;
R 1 represents halo, OH, —CN;
C 1-3 alkyl, C 2-6 alkynyl, OC 1-3 alkyl, which latter three groups are optionally substituted by one or more substituents selected from fluoro, —CN, ═O, OH, —OCH 3 , —OCF 3 ;
R 2 , R 3 and R 4 independently represent hydrogen, halo, —CN;
C 1-3 alkyl, OC 1-3 alkyl, which latter two groups are optionally substituted by one or more substituents selected from fluoro, —CN, ═O, OH, —OCH 3 , —OCF 3 ;
R a , R b independently represent hydrogen, C 1-3 alkyl,
or both together with the carbon atom which they are bound to, form a C 3-7 cycloalkylene ring, or a 4-6 membered heterocycloalkylene ring;
R c represents hydrogen or C 1-3 alkyl;
W represents —C(O)—, —S(O)—, —S(O) 2 —, —C(O)O—, or
—C(O)NR d —, which groups are bound to the nitrogen of the —NR c — moiety via carbon or sulfur atom;
R d represents hydrogen or C 1-3 alkyl;
M represents C 1-7 , alkyl, C 3-7 cycloalkyl, both of which groups are optionally substituted by one or more groups selected from fluoro, —OH, —CN, —NH 2 , —NH(C 1-3 alkyl), N(C 1-3 alkyl) 2 , —OC 1-3 alkyl,
—SC 1-3 alkyl, aryl, heteroaryl [which latter two groups can be substituted by one or more substituents selected from halo, OH,
—CN, C 1-3 alkyl, OC 1-3 alkyl (which latter two alkyl groups are optionally substituted by one or more fluoro atoms)],
C 1-7 alkyl, C 2-7 alkynyl, C 3-7 cycloalkyl-C 0-2 alkyl, 4-7 membered heterocycloalkyl-C 0-2 alkyl (which latter alkyl, alkynyl, heterocycloalkyl or cycloalkyl groups are optionally substituted by one or more substituents selected from fluoro, —CN, ═O, —NH 2 ,
—NH(C 1-3 alkyl), —N(C 1-3 alkyl) 2 , —OH, —OC 1-3 alkyl);
or
aryl, heteroaryl, 4-7 membered heterocycloalkyl, all of which groups are optionally substituted by one or more substituents selected from
halo, —OH, —CN, —NH 2 , —NH(C 1-3 alkyl), —N(C 1-3 alkyl) 2 , —OC 1-3 alkyl,
—SC 1-3 alkyl, aryl, heteroaryl [which latter two groups can be substituted by one or more substituents selected from halo, OH,
—CN, C 1-3 alkyl, —OC 1-3 alkyl (which latter two alkyl groups are optionally substituted by one or more fluoro atoms)], C 1-7 alkyl, C 2-7 alkynyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl (which latter alkyl, alkynyl, heterocycloalkyl or cycloalkyl groups are optionally substituted by one or more substituents selected from fluoro, —CN, ═O, —NH 2 , —NH(C 1-3 alkyl), N(C 1-3 alkyl) 2 , —OH,
—OC 1-3 alkyl)];
R 5 represents hydrogen; or C 1-3 alkyl;
R 6 represents hydrogen; C 1-5 alkyl, C 3-6 alkynyl, 4-7 membered heterocycloalkyl-C 0-2 alkyl or C 3-7 cycloalkyl-C 0-2 alkyl (which latter four groups are optionally substituted by one or more substituents selected from fluoro, —CN, ═O, C 1-3 alkyl, —OH, —OC 1-3 alkyl, —NH 2 ,
—NH(C 1-3 alkyl), N(C 1-3 alkyl) 2 );
each R 7 independently represents hydrogen, halo, —CN,
C 1-7 alkyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 1-5 alkyl-O—, C 3-7 cycloalkyl-
C 0-2 alkyl-O—, 4-7 membered heterocycloalkyl-C 0-2 alkyl-O—, (in which latter six groups the alkyl, alkynyl, cycloalkyl or heterocycloalkyl fragments are optionally substituted by one or more substituents selected from fluoro, —CN, ═O, OH, —OC 1-3 alkyl, —NH 2 , —NH—C 1-3 alkyl, N(C 1-3 alkyl) 2 or by one or more C 1-3 alkyl groups, which can be optionally substituted by one or more fluoro atoms);
or
aryl or heteroaryl, which latter two groups can be substituted by one or more substituents selected from halo, OH, —CN, C 1-3 alkyl,
—OC 1-3 alkyl (in which latter two groups the alkyl fragments are optionally substituted by one or more fluoro atoms);
L represents —C(O)N(R 8 )—, —N(R 8 )C(O)—, —S(O) 2 N(R 8 )—, —N(R 8 )S(O) 2 —,
N(R 8 )C(O)N(R 8 )—, —OC(O)N(R 8 )— or —N(R 8 )C(O)O—;
A represents hydrogen, C 1-8 alkyl, C 3-8 alkynyl, aryl, heteroaryl, aryl-C 1-3 alkyl-, C 3-8 cycloalkyl-C 0-3 alkyl-, 4-7 membered heterocycloalkyl-C 0-3 alkyl-, heteroaryl-C 1-3 alkyl-, in which groups the alkyl-, alkynyl-, cycloalkyl- and heterocycloalkyl-fragments are optionally substituted by one or more substituents selected from R 9a and the aryl and heteroaryl fragments are optionally substituted by one or more substituents selected from R 9b ;
or
A-L- together represent one of the following groups
in which
V represents a bond, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, wherein in each of the latter alkylene groups one methylene [—(CH 2 )—] unit can optionally be replaced by an oxygen atom, a —NH— or —N(C 1-3 alkyl)- group and each methylene unit can optionally and independently be substituted by one or two of the following groups: fluoro, —CN, ═O,
—NH 2 , —NH(C 1-3 alkyl), N(C 1-3 alkyl) 2 , —OH, —OC 1-3 alkyl);
each R 8 independently represents hydrogen, or C 1-3 alkyl;
each R 9a independently represents fluoro, —OH,
—CN, ═O, —NH 2 , —NH(C 1-3 alkyl), —N(C 1-3 alkyl) 2 , —OC 1-6 alkyl, C 1-6 alkyl, (in which latter four groups the alkyl, fragments are optionally substituted by one or more substituents selected from fluoro, —CN, ═O, —NH 2 , —NH(C 1-3 alkyl), N(C 1-3 alkyl) 2 , —OH, —OC 1-3 alkyl) or aryl, heteroaryl [which latter two groups can be substituted by one or more substituents selected from halo, OH, —CN, C 1-3 alkyl, OC 1-3 alkyl (which latter two alkyl groups are optionally substituted by one or more fluoro atoms)];
each R 9b represents independently halo, —OH, —CN, —NH 2 , —NH(C 1-3 alkyl),
—N(C 1-3 alkyl) 2 , —OC 1-3 alkyl, —SO 1-3 alkyl,
aryl, heteroaryl [which latter two groups can be substituted by one or more substituents selected from halo, OH, —CN, C 1-3 alkyl, OC 1-3 alkyl (which latter two alkyl groups are optionally substituted by one or more fluoro atoms)], C 1-7 alkyl, C 2-7 alkynyl, C 3-7 cycloalkyl,
4-7 membered heterocycloalkyl (which latter alkyl, alkynyl, heterocycloalkyl or cycloalkyl groups are optionally substituted by one or more substituents selected from fluoro, —CN, ═O, —NH 2 ,
—NH(C 1-3 alkyl), N(C 1-3 alkyl) 2 , —OH, OC 1-3 alkyl);
or a salt thereof.
2 . A compound according to claim 1 having formula Ia:
in which A, L, M, Q 2 , Q 3 , Q 4 , R 1 , R 6 , R a , R b , R c , W, Z 1 , Z 2 , Z 3 have the same meaning as defined in claim 1 ,
or a salt thereof.
3 . A compound according to claim 1 having formula Ib:
in which A, L, M, Q 2 , Q 3 , Q 4 , R 1 , R 6 , R 7 , R a , R b , R c , W have the same meaning as defined in claim 1 ,
or a salt thereof.
4 . A compound according to claim 1 having formula Ic:
in which A, L, M, R 1 , R 2 , R 3 , R 4 , R 6 , R a , R b , R c , W, Z 1 , Z 2 , Z 3 have the same meaning as defined in claim 1 ,
or a salt thereof.
5 . A compound according to claim 1 having formula Id:
in which A, L, M, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R a , R b , R c , W have the same meaning as defined in claim 1 ,
or a salt thereof.
6 . A compound according to claim 1 , wherein
W represents —C(O)—, —S(O) 2 —, which groups are bound to the nitrogen of the —NR c — moiety via carbon or sulfur atom; or a salt thereof.
7 . A compound according to claim 1 , wherein
M represents C 1-7 alkyl, C 3-7 cycloalkyl, both of which groups are optionally substituted by one or more groups selected from: fluoro, —OH, —CN, —NH 2 , —OC 1-3 alkyl, —SC 1-3 alkyl, aryl [which latter aryl group can be substituted by one or more substituents selected from halo, OH, —CN, C 1-3 alkyl, OC 1-3 alkyl (which latter two alkyl groups are optionally substituted by one or more fluoro atoms)],
C 1-7 alkyl, C 3-7 cycloalkyl-C 0-2 -alkyl (which latter alkyl and cycloalkyl groups are optionally substituted by one or more substituents selected from fluoro, —CN, ═O, —NH 2 , —NH(C 1-3 alkyl), —N(C 1-3 alkyl) 2 ,
—OH, —OC 1-3 alkyl);
or
aryl, heteroaryl, 4-7 membered heterocycloalkyl, all of which groups are optionally substituted by one or more substituents selected from halo, —CN,
—OC 1-3 alkyl, C 1-7 alkyl, C 3-7 cycloalkyl, (which latter alkyl and cycloalkyl groups are optionally substituted by one or more substituents selected from fluoro, —CN, —OC 1-3 alkyl);
or a salt thereof.
8 . A compound according to claim 1 , wherein
R 6 represents hydrogen; C 1-5 alkyl, C 3-5 cycloalkyl-C 0-1 alkyl, which latter two groups are optionally substituted by one or more substituents selected from fluoro, —OCH 3 , —NH(C 1-3 alkyl), N(C 1-3 alkyl) 2 ; or a salt thereof.
9 . A compound according to claim 1 , wherein
R 2 , R 3 and R 4 independently represent hydrogen, fluoro, chloro- or —CH 3 optionally substituted by one or more fluorine atoms; or a salt thereof.
10 . A compound according to claim 1 , wherein
L represents —C(O)NH— or —S(O) 2 NH—, which groups are bound to the
9-membered fused heteroaromatic scaffold via the carbon or sulfur atom, respectively;
or a salt thereof.
11 . A compound according to claim 1 , wherein
each R 7 represents hydrogen, halo, C 1-5 alkyl-O—, C 3-5 cycloalkyl-C 0-2 alkyl-O—, 4-5-membered heterocycloalkyl-C 0-2 alkyl-O— (in which latter three groups the alkyl, cycloalkyl or heterocycloalkyl fragments are optionally substituted by one or more substituents selected from fluoro, —OC 1-3 alkyl or by one or more C 1-3 alkyl groups, which can be optionally substituted by one or more fluoro atoms); or a salt thereof.
12 . A compound according to claim 1 , wherein
A represents hydrogen, O 1-6 alkyl, C 3-6 alkynyl, phenyl, 5-6-membered heteroaryl,
C 3-6 cycloalkyl-C 0-2 alkyl-, 4-6-membered heterocycloalkyl-C 0-2 alkyl, phenyl-C 1-3 alkyl-, 5-6-membered heteroaryl-C 1-3 alkyl in which groups the alkyl-, alkynyl-, cycloalkyl- and heterocycloalkyl-fragments are optionally substituted by one or two substituents selected from R 9a and the phenyl, thienyl and pyridyl fragments are optionally substituted by one or two substituents selected from R 9b ;
each R 9a independently represents fluoro, phenyl, C 1-2 alkyl, —OC 1-4 alkyl which latter two groups are optionally substituted by one to three fluoro atoms; each R 9b represents independently fluoro, chloro, bromo, C 1-2 alkyl, —OC 1-2 alkyl which latter two groups are optionally substituted by one or more fluoro; or a salt thereof.
13 . A compound according to claim 1 , wherein
M represents C 1-6 alkyl, C 3-6 cycloalkyl, 4-6-membered heterocycloalkyl, all of which groups are optionally substituted by one or more groups selected from fluoro, —OH, —CN, —NH 2 , phenyl, —CF 3 , O 1-2 alkyl,
C 3-5 cycloalkyl-C 0-1 alkyl;
or phenyl, 5-6-membered heteroaryl both of which are optionally substituted by one or more substituents independently selected from fluoro, chloro, methyl, —CF 3 , —OCH 3 ;
or a salt thereof.
14 . A compound according to claim 1 , having formula Ie:
in which
A represents hydrogen, C 1-6 alkyl, phenylpropargyl, phenyl, C 3-6 cycloalkyl-C 0-2 alkyl-, tetrahydrofuranyl-C 0-2 alkyl, pyrrolidinyl-
C 0-2 alkyl, piperidin-C 0-2 alkyl, pyridyl-C 1-2 alkyl-, in which groups the alkyl-, alkynyl-, cycloalkyl- and heterocycloalkyl fragments are optionally substituted by one or more substituents selected from R 9a and the phenyl and pyridyl fragments are optionally substituted by one or more substituents selected from R 9b ;
each R 9a independently represents fluoro, C 1-2 alkyl, —OC 1-4 alkyl in which latter two groups the alkyl fragments are optionally substituted by one or more fluoro atoms;
each R 9b represents independently fluoro, chloro, bromo,
L represents —C(O)NH— or —S(O) 2 NH—, which groups are bound to the 9-membered fused heteroaromatic scaffold via the carbon or sulfur atom, respectively;
W represents —C(O)—, —S(O) 2 —;
M represents C 1-4 alkyl, C 3-6 cycloalkyl which latter two groups are optionally substituted by one or more groups selected from fluoro,
—OH, —CN, —NH 2 , phenyl, CF 3 , C 1-2 alkyl, cyclopropyl-methyl;
or
represents oxetanyl or tetrahydrofuranyl, both of which groups are optionally substituted by a CH 3 -group;
or phenyl, thienyl both of which are optionally substituted by one or two substituents independently selected from fluoro or chloro,
R 1 represents fluoro, chloro, bromo, CH 3 , CH 2 F, CHF 2 , CF 3 , —OCH 3 ;
R 4 represents hydrogen or fluoro;
R 6 represents hydrogen, C 1-3 alkyl, C 3-5 cycloalkyl-C 0-1 alkyl, which latter two groups are optionally substituted by one or more substituents selected from fluoro, —OCH 3 , —NH(C 1-3 alkyl), N(C 1-3 alkyl) 2 ;
R 7-Z2 represents hydrogen, halo, —OC 1-5 alkyl, in which latter group the alkyl is optionally substituted by one or more fluoro atoms;
R 7-Z1 and R 7-Z3 independently represent hydrogen or fluoro;
or a salt thereof.
15 . A compound according to claim 1 , selected from the following Examples 1 to 100:
Example
Structure
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or a pharmaceutically acceptable salt of any of the above Examples 1 to 100.
16 . A pharmaceutical composition comprising at least one compound according to claim 1 and a pharmaceutically acceptable adjuvant, diluent or carrier.
17 . A method for treating or preventing an inflammatory disease or associated condition in a patient comprising administering to said patient a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
18 . A method according to claim 17 , wherein the condition to be treated or to prevented is pain.Cited by (0)
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