Azacyclyl-substituted arylthienopyrimidinones, process for their preparation and their use as medicaments
View Patent ↗The invention relates to azacyclyl-substituted arylthienopyrimidinones and their derivatives, of the Formula (I); and their physiologically tolerated salts and physiologically functional derivatives, their preparation, medicaments comprising at least one azacyclyl-substituted arylthienopyrimidinone according to Formula (I) or its derivative, and the use of the azacyclyl-substituted arylthienopyrimidinones according to Formula (I) and their derivatives as MCH antagonists.
1. A compound of formula I
wherein:
R 1 , R 1 ′, R 1 ″ and R 1 ′″ are independently of one another H, F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, O—(C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, S—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, O—(C 3 -C 8 )-cycloalkyl, (C 3 -C 8 )-cycloalkenyl, (C 2 -C 6 )-alkynyl, (C 0 -C 8 )-alkylene-aryl, O—(C 0 -C 8 )-alkylene-aryl, S-aryl, N(R 3 )(R 4 ), SO 2 —CH 3 , COOH, COO—(C 1 -C 6 )-alkyl, CON(R 5 )(R 6 ), N(R 7 )CO(R 8 ), N(R 9 )SO 2 (R 10 ), CO(R 11 ), or (C(R 12 )(R 13 )) x —O(R 14 );
R 3 , R 4 , R 5 , R 6 , R 7 and R 9 are
independently of one another H, or (C 1 -C 8 )-alkyl,
or
R 3 and R 4 , or R 5 and R 6 ,
independently of one another taken together with the nitrogen atom to which they are bonded form a 5-6 membered ring which optionally comprises one additional heteroatom selected from the group consisting of NH, N—(C 1 -C 6 )-alkyl, oxygen and sulfur;
R 8 , R 10 and R 11 are
independently of one another H, or (C 1 -C 8 )-alkyl;
R 12 and R 13 are
independently of one another H, or (C 1 -C 8 )-alkyl;
R 14 is H, (C 1 -C 6 )-alkyl, or aryl;
x is 0, 1, 2, 3, 4, 5, or 6;
R 2 is H, F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, O—(C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, S—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, O—(C 3 -C 8 )-cycloalkyl, (C 3 -C 8 )-cycloalkenyl, (C 2 -C 6 )-alkynyl, (C 0 -C 8 )-alkylene-aryl, O—(C 0 -C 8 )-alkylene-aryl, S-aryl, N(R 15 )(R 16 ), SO 2 —CH 3 , COOH, COO—(C 1 -C 6 )-alkyl, CON(R 17 )(R 18 ), N(R 19 ) CO(R 20 ), N(R 21 )SO 2 (R 22 ), CO(R 23 ), or (C(R 24 )(R 25 )) x′ —O(R 26 );
R 15 , R 16 , R 17 , R 18 , R 19 and R 21 are
independently of one another H, (C 1 -C 8 )-alkyl,
or
R 15 and R 16 , or R 17 and R 18 ,
independently of one another taken together with the nitrogen atom to which they are bonded form a 5-6 membered ring which optionally comprises one additional heteroatom selected from the group consisting of NH, N—(C 1 -C 6 )-alkyl, oxygen and sulfur;
R 20 , R 22 and R 23 are
independently of one another H, or (C 1 -C 8 )-alkyl;
R 24 and R 25 are
independently of one another H, or (C 1 -C 8 )-alkyl;
R 26 is H, (C 1 -C 6 )-alkyl, or aryl;
x′ is 0, 1, 2, 3, 4, 5, or 6;
R 27 is H, or (C 1 -C 6 )-alkyl;
X is S;
A is a bond or a linker having 1 to 8 members, where the members are selected from the group consisting of O, S, SO 2 , N(R 31 ), CO, C(R 32 )(R 33 ), C(R 34 )═C(R 34 ′), cyclopropylene, and C≡C, wherein the linker contains no O—CO or CO—O groups;
R 31 , R 34 and R 34 ′ are
independently of one another H, or (C 1 -C 8 )-alkyl;
R 32 and R 33 are
independently of one another H, (C 1 -C 6 )-alkyl, OH, or O—(C 1 -C 6 )-alkyl;
B is N(R 35 )(R 36 ), hydroxy-(C 1 -C 4 )-alkyl, (C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 2 -C 8 )-alkenyl, (C 2 -C 8 )-alkynyl, or a 3 to 10-membered mono-, bi-, tri- or spirocyclic nonaromatic ring which optionally comprises 0 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, where the ring system is also optionally substituted one or more times by F, Cl, Br, CF 3 , NO 2 , CN, (C 1 -C 6 )-alkyl, O—(C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl, oxo, CO(R 37 ), CON(R 38 )(R 39 ), hydroxy, COO(R 40 ), N(R 41 )CO(C 1 -C 6 )-alkyl, N(R 42 )(R 43 ), SO 2 CH 3 , SCF 3 or S—(C 1 -C 6 )-alkyl, and the ring system may be linked to A by ═C(R 43 ′);
R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 and R 43 ′ are
independently of one another H, or (C 1 -C 8 )-alkyl,
or
R 38 and R 39 , or R 42 and R 43 , are
independently of one another taken together with the nitrogen atom to which they are bonded form a 5-6 membered ring which optionally comprises one additional heteroatom selected from the group of NH, N—(C 1 -C 6 )-alkyl, oxygen and sulfur;
Q is mono-, bi-, tri- or spirocyclic saturated or partly unsaturated ring structure having one nitrogen atom and 1-3 further heteroatoms selected from the group of N, O and S, where the rings of the structure may be spiro-linked, fused or bridged, and where the ring system is optionally substituted one or more times by F, OH, CF 3 , CN, OCF 3 , oxo, O—(C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, CO(R 44 ), (C(R 45 )(R 46 )) o —R 47 , CO(C(R 45 )(R 46 )) p —R 48 , where Q comprises in total at least two N atoms;
R 44 is H, or (C 1 -C 8 )-alkyl;
R 45 , and R 46 are
independently of one another H, (C 1 -C 8 )-alkyl, OH, (C 3 -C 8 )-cycloalkyl, or (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl;
o and p are independently of one another 0, 1, 2, 3, 4, 5, or 6;
R 47 , and R 48 are
independently of one another OH, F, O—(C 1 -C 8 )-alkyl, CON(R 49 )(R 50 ), N(R 51 )CO(R 52 ), N(R 53 )(R 54 ), CO 2 (R 55 ), SO 2 Me, CN, or a 3-10 membered ring system having 0 to 3 heteroatoms selected from the group consisting of N, O and S, and the 3-10 membered ring system is optionally substituted one or more times by F, Cl, Br, CF 3 , (C 1 -C 8 )-alkyl, O—(C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, CO(R 56 ), oxo, or OH;
R 49 , R 50 , R 51 , R 52 , R 55 and R 56 are
independently of one another H, or (C 1 -C 8 )-alkyl,
or
R 49 and R 50
taken together with the nitrogen atom to which they are bonded form a 5-6 membered ring which optionally comprises one additional heteroatom selected from the group consisting of NH, N—(C 1 -C 6 )-alkyl, oxygen and sulfur;
R 53 and R 54 are
independently of one another H, (C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 3 -C 8 )-alkenyl, (C 3 -C 8 )-alkynyl, CO(R 57 ), (C(R 58 )(R 59 )) q —R 60 , CO(C(R 61 )(R 62 )) r —R 63 , or CO—O(C 1 -C 8 )-alkyl, or R 53 and R 54 taken together with the nitrogen atom to which they are bonded form a 4 to 10-membered mono-, bi- or spirocyclic ring which optionally comprises 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, and is optionally substituted one or more times by F, Cl, Br, CF 3 , CN, O—(C 1 -C 8 )-alkyl, (C 1 -C 6 )-alkyl, CO(R 64 ), oxo, OH, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl, CON(R 65 )(R 66 ), N(R 67 )CO(R 68 ), N(R 69 )(R 70 ), CO 2 (R 71 ), or SO 2 (C 1 -C 6 )-alkyl;
R 58 and R 59 are
independently of one another H, (C 1 -C 6 )-alkyl, or OH;
R 57 , R 61 , R 62 , R 64 , R 65 , R 66 , R 67 , R 68 , R 69 , R 70 and R 71 are
independently of one another H, or (C 1 -C 6 )-alkyl,
or
R 69 and R 70
taken together with the nitrogen atom to which they are bonded form a 5-6 membered ring which optionally comprises one additional heteroatom from the group consisting of NH, N—(C 1 -C 6 )-alkyl, oxygen and sulfur;
q and r are independently of one another 0, 1, 2, 3, 4, 5, or 6;
R 60 and R 63 are
independently of one another OH, F, O—(C 1 -C 6 )-alkyl, CN, COO(R 78 ), N(R 74 )CO(C 1 -C 6 )-alkyl, N(R 76 )(R 77 ), CON(R 72 )(R 73 ), SO 2 (C 1 -C 6 )-alkyl, or a 3-12 membered mono-, bi- or spirocyclic ring which optionally comprises one or more heteroatoms from the group consisting of N, O and S, and the 3-12 membered ring is optionally substituted by F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , oxo, O—(C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, S—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, O—(C 3 -C 8 )-cycloalkyl, (C 3 -C 8 )-cycloalkenyl, O—(C 3 -C 8 )-cycloalkenyl, (C 2 -C 6 )-alkynyl, N(R 76 )(R 77 ), COO(R 78 ), SO 2 (C 1 -C 6 )-alkyl or COOH; and
R 72 , R 73 , R 74 , R 76 , R 77 and R 78 are
independently of one another H, or (C 1 -C 8 )-alkyl,
or
R 72 and R 73 , or R 76 and R 77 ,
independently of one another taken together with the nitrogen atom to which they are bonded form a 5-6 membered ring which optionally comprises one additional heteroatom selected from the group consisting of NH, N—(C 1 -C 6 )-alkyl, oxygen and sulfur;
or a pharmaceutical acceptable salt thereof.
2. The compound according to claim 1 , wherein:
B is hydroxy-(C 1 -C 4 )-alkyl, (C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 2 -C 8 )-alkenyl, (C 2 -C 8 )-alkynyl, or a 3 to 10-membered mono-, bi- or spirocyclic nonaromatic ring which optionally comprises 0 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, wherein the ring system is optionally substituted by F, Cl, Br, CF 3 , NO 2 , CN, (C 1 -C 6 )-alkyl, O—(C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl, oxo, CO(R 37 ), CON(R 38 )(R 39 ), hydroxy, COO(R 40 ), N(R 41 )CO(C 1 -C 6 )-alkyl, N(R 42 )(R 43 ) or SO 2 CH 3 , and the ring system may be linked to A by ═C(R 43 ′);
or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 1 , wherein:
B is hydroxy-(C 1 -C 4 )-alkyl, (C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, a 3 to 10-membered mono-, bi- or spirocyclic nonaromatic ring which optionally comprises 0 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, wherein the ring system is optionally substituted by F, Cl, Br, CF 3 , NO 2 , CN, (C 1 -C 6 )-alkyl, O—(C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl, oxo, CO(R 37 ), CON(R 38 )(R 39 ), hydroxy, COO(R 40 ), N(R 41 )CO(C 1 -C 6 )-alkyl, N(R 42 )(R 43 ) or SO 2 CH 3 ;
or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 1 , wherein:
B is (C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, or a 3 to 10-membered mono-, bi- or spirocyclic nonaromatic ring which optionally comprises 0 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, wherein the ring system is optionally substituted by F, Cl, CF 3 , (C 1 -C 6 )-alkyl, O—(C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl, oxo, CO(R 37 ), hydroxy, N(R 41 )CO(C 1 -C 6 )-alkyl, or SO 2 CH 3 ;
or a pharmaceutically acceptable salt thereof.
5. The compound according to Formula I:
wherein:
R 1 , R 1 ′, R 1 ″ and R 1 ′″ are
independently of one another H, F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, O—(C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, S—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, O—(C 3 -C 8 )-cycloalkyl, (C 3 -C 8 )-cycloalkenyl, (C 2 -C 6 )-alkynyl, (C 0 -C 8 )-alkylene-aryl, O—(C 0 -C 8 )-alkylene-aryl, S-aryl, N(R 3 )(R 4 ), SO 2 —CH 3 , COOH, COO—(C 1 -C 6 )-alkyl, CON(R 5 )(R 6 ), N(R 7 )CO(R 8 ), N(R 9 )SO 2 (R 10 ), CO(R 11 ), or (C(R 12 )(R 13 )) x —O(R 14 );
R 3 , R 4 , R 5 , R 6 , R 7 and R 9 are
independently of one another H, or (C 1 -C 8 )-alkyl,
or
R 3 and R 4 , or R 5 and R 6 ,
independently of one another taken together with the nitrogen atom to which they are bonded form a 5-6 membered ring which optionally comprises one additional heteroatom selected from the group consisting of NH, N—(C 1 -C 6 )-alkyl, oxygen and sulfur;
R 8 , R 10 and R 11 are
independently of one another H, or (C 1 -C 8 )-alkyl;
R 12 and R 13 are
independently of one another H, or (C 1 -C 8 )-alkyl;
R 14 is H, (C 1 -C 6 )-alkyl, or aryl;
x is 0, 1, 2, 3, 4, 5, or 6;
R 2 is H, F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, S—(C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, O—(C 3 -C 8 )-cycloalkyl, (C 3 -C 8 )-cycloalkenyl, (C 2 -C 6 )-alkynyl, (C 0 -C 8 )-alkylene-aryl, O—(C 0 -C 8 )-alkylene-aryl, S-aryl, N(R 15 )(R 16 ), SO 2 —CH 3 , COOH, COO—(C 1 -C 6 )-alkyl, CON(R 17 )(R 18 ), N(R 19 ) CO(R 20 ), N(R 21 )SO 2 (R 22 ), CO(R 23 ), or (C(R 24 )(R 25 )) x′ —O(R 26 );
R 15 , R 16 , R 17 , R 18 , R 19 and R 21 are
independently of one another H, (C 1 -C 8 )-alkyl,
or
R 15 and R 16 , or R 17 and R 18 ,
independently of one another taken together with the nitrogen atom to which they are bonded form a 5-6 membered ring which optionally comprises one additional heteroatom selected from the group consisting of NH, N—(C 1 -C 6 )-alkyl, oxygen and sulfur;
R 20 , R 22 and R 23 are
independently of one another H, or (C 1 -C 8 )-alkyl;
R 24 and R 25 are
independently of one another H, or (C 1 -C 8 )-alkyl;
R 26 is H, (C 1 -C 6 )-alkyl, or aryl;
x′ is 0, 1, 2, 3, 4, 5, or 6;
R 27 is H, or (C 1 -C 6 )-alkyl;
X is S;
A is a bond or a linker having 1 to 8 members, where the members are selected from the group consisting of O, S, SO 2 , N(R 31 ), CO, C(R 32 )(R 33 ), C(R 34 )═C(R 34 ′), cyclopropylene, and C≡C, wherein the linker contains no O—CO or CO—O groups;
R 31 , R 34 and R 34 ′ are
independently of one another H, or (C 1 -C 8 )-alkyl;
R 32 and R 33 are
independently of one another H, (C 1 -C 6 )-alkyl, OH, or O—(C 1 -C 6 )-alkyl;
B is N(R 35 )(R 36 ), hydroxy-(C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 2 -C 8 )-alkenyl, (C 2 -C 8 )-alkynyl, or a 3 to 10-membered mono-, bi-, tri- or spirocyclic nonaromatic ring which optionally comprises 0 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, where the ring system is also optionally substituted one or more times by F, Cl, Br, CF 3 , NO 2 , CN, (C 1 -C 6 )-alkyl, O—(C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl, oxo, CO(R 37 ), CON(R 38 )(R 39 ), hydroxy, COO(R 40 ), N(R 41 )CO(C 1 -C 6 )-alkyl, N(R 42 )(R 43 ), SO 2 CH 3 , SCF 3 or S—(C 1 -C 6 )-alkyl, and the ring system may be linked to A by ═C(R 43 ′);
R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 and R 43 ′ are
independently of one another H, or (C 1 -C 8 )-alkyl,
or
R 38 and R 39 , or R 42 and R 43 , are
independently of one another taken together with the nitrogen atom to which they are bonded form a 5-6 membered ring which optionally comprises one additional heteroatom selected from the group of NH, N—(C 1 -C 6 )-alkyl, oxygen and sulfur;
Q is a group of formula:
wherein the ring D is a saturated monocyclic 5-7-membered azacycle which comprises a moiety N(R 53 ) or C(R 45 )((CH 2 ) o —N(R 53 )(R 54 )); or a saturated 6-11 membered azabicycle or spirocycle which comprises a moiety N(R 53 ) or C(R 45 )((CH 2 ) o —N(R 53 )(R 54 ));
wherein
each of the ring positions capable of substitution is optionally substituted one or more times by F, OH, oxo, (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl;
R 45 is H, or (C 1 -C 6 )-alkyl; R 53 and R 54 are
independently of one another H, (C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 3 -C 8 )-alkenyl, (C 3 -C 8 )-alkynyl, CO(R 57 ), (C(R 58 )(R 59 )) q —R 60 , CO(C(R 61 )(R 62 )) r —R 63 , or CO—O(C 1 -C 8 )-alkyl, or R 53 and R 54 taken together with the nitrogen atom to which they are bonded form a 4 to 10-membered mono-, bi- or spirocyclic ring which optionally comprises 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, and is optionally substituted one or more times by F, Cl, Br, CF 3 , CN, O—(C 1 -C 8 )-alkyl, (C 1 -C 6 )-alkyl, CO(R 64 ), oxo, OH, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl, CON(R 65 )(R 66 ), N(R 67 )CO(R 68 ), N(R 69 )(R 70 ), CO 2 (R 71 ), or SO 2 (C 1 -C 6 )-alkyl;
R 58 and R 59 are independently of one another H, (C 1 -C 6 )-alkyl, or OH;
R 57 , R 61 , R 62 , R 64 , R 65 , R 66 , R 67 , R 68 , R 69 , R 70 and R 71 are
independently of one another H, or (C 1 -C 6 )-alkyl,
q and r are independently of one another 0, 1, 2, 3, 4, 5, or 6;
R 60 and R 63 are
independently of one another OH, F, O—(C 1 -C 6 )-alkyl, CN, COO(R 78 ), N(R 74 )CO(C 1 -C 6 )-alkyl, N(R 76 )(R 77 ), CON(R 72 )(R 73 ), SO 2 (C 1 -C 6 )-alkyl, or a 3-12 membered mono-, bi- or spirocyclic ring which optionally comprises one or more heteroatoms from the group consisting of N, 0 and S, and the 3-12 membered ring is optionally substituted by F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , oxo, O—(C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, S—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, O—(C 3 -C 8 )-cycloalkyl, (C 3 -C 8 )-cycloalkenyl, O—(C 3 -C 8 )-cycloalkenyl, (C 2 -C 6 )-alkynyl, N(R 76 )(R 77 ), COO(R 78 ), SO 2 (C 1 -C 6 )-alkyl or COOH; and
R 72 , R 73 , R 74 , R 76 , R 77 and R 78 are
independently of one another H, or (C 1 -C 8 )-alkyl,
or
R 72 and R 73 , or R 76 and R 77 ,
independently of one another taken together with the nitrogen atom to which they are bonded form a 5-6 membered ring which optionally comprises one additional heteroatom selected from the group consisting of NH, N—(C 1 -C 6 )-alkyl, oxygen and sulfur;
and
o is 0, 1, 2, 3, 4, 5, or 6; q and r are independently of one another 0, 1, 2, 3, 4, 5, or 6;
or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 5 , wherein Q is
each of the ring positions capable of substitution is optionally substituted one or more times by F, OH, oxo, (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl;
or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 5 , wherein Q is
each of the ring positions capable of substitution is optionally substituted one or more times by F, OH, oxo, (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, or (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl;
or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 5 , wherein Q is
each of the ring positions capable of substitution is optionally substituted one or more times by F, OH, oxo, (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, or (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl;
or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 5 , wherein Q is
each of the ring positions capable of substitution is optionally substituted one or more times by F, OH, oxo, (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl;
or a pharmaceutically acceptable salt thereof.
10. The compound according to claim 5 , wherein Q is
each of the ring positions capable of substitution is optionally substituted one or more times by F, OH, oxo, (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl;
or a pharmaceutically acceptable salt thereof.
11. The compound according to claim 1 , wherein:
R 53 is H, (C 1 -C 8 )-alkyl, (C(R 58 )(R 59 )) q —R 60 , (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 3 -C 8 )-alkenyl, (C 3 -C 8 )-alkynyl, CO—O(C 1 -C 8 )-alkyl, or CO(C(R 61 )(R 62 )) r N(R 76 )(R 77 ), R 54 is (C 1 -C 8 )-alkyl, (C(R 58 )(R 59 )) q —R 60 , (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 3 -C 8 )-alkenyl, or (C 3 -C 8 )-alkynyl,
or
R 53 and R 54 taken together with the nitrogen atom to which they are bonded form a 4 to 10-membered mono-, bi- or spirocyclic ring which optionally comprises 1 to 3 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, wherein the heterocyclic ring system is optionally substituted by F, Cl, Br, CF 3 , (C 1 -C 6 )-alkyl, O—(C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl, oxo, CO(R 64 ), CON(R 65 )(R 66 ), hydroxy, COO(R 71 ), N(R 67 )CO(C 1 -C 6 )-alkyl, N(R 69 )(R 70 ) or SO 2 (C 1 -C 6 )-alkyl;
or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 1 , wherein:
R 53 and R 54 independently of one another are (C 1 -C 8 )-alkyl, (C(R 58 )(R 59 )) q —R 60 , or (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, or
R 53 and R 54 taken together with the nitrogen atom to which they are bonded form a 4 to 10-membered mono-, bi- or spirocyclic ring which optionally comprises 1 to 2 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, wherein the heterocyclic ring system is optionally substituted by F, Cl, Br, CF 3 , (C 1 -C 6 )-alkyl, O—(C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl, oxo, CO(R 64 ), hydroxy, N(R 67 )CO(C 1 -C 6 )-alkyl, or SO 2 (C 1 -C 6 )-alkyl;
or a pharmaceutically acceptable salt thereof.
13. The compound according to claim 1 , wherein:
R 60 , and R 63 are independently of one another OH, F, O—(C 1 -C 6 )-alkyl, N(R 74 )CO(C 1 -C 6 )-alkyl, SO 2 (C 1 -C 6 )-alkyl, or a 3-12 membered mono-, bi- or spirocyclic ring which optionally comprises one or more heteroatoms from the group consisting of N, O and S, and the 3-12 membered ring is optionally substituted by F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , oxo, O—(C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, N(R 76 )(R 77 ) or SO 2 (C 1 -C 6 )-alkyl;
or a pharmaceutically acceptable salt thereof.
14. The compound according to claim 1 , wherein:
A is a bond or a linker having 1 to 6 members, where the members are selected from the group consisting of O, SO 2 , N(R 31 ), CO, C(R 32 )(R 33 ), C(R 34 )═C(R 34 ′), and C≡C,
R 31 , R 34 and R 34 ′ are
independently of one another H, or (C 1 -C 8 )-alkyl; and
R 32 , and R 33 are
independently of one another H, (C 1 -C 6 )-alkyl, OH, or O—(C 1 -C 6 )-alkyl;
or a pharmaceutically acceptable salt thereof.
15. The compound according to claim 1 , wherein:
R 2 is H, F, Cl, O—(C 1 -C 6 )-alkyl, or (C 1 -C 6 )-alkyl;
or a pharmaceutically acceptable salt thereof.
16. The compound according to claim 5 , wherein:
R 1 , R 1 ′, R 1 ′ and R 1 ′″ are
independently of one another H, F, Cl, OH, CN, O—(C 1 -C 6 )-alkyl, or (C 1 -C 6 )-alkyl;
R 2 is H;
R 27 is H, or (C 1 -C 6 )-alkyl;
X is S;
A is a bond or a linker having 1 to 5 members, where the members are selected from the group consisting of O, N(R 31 ), CO, C(R 32 )(R 33 ), C(R 34 )═C(R 34 ′), and C≡C, wherein the linker contains no O—CO or CO—O groups;
R 31 , R 34 and R 34 ′ are independently of one another H, or (C 1 -C 8 )-alkyl;
R 32 , and R 33 are independently of one another H, (C 1 -C 8 )-alkyl, OH, or O—(C 1 -C 6 )-alkyl;
B is hydroxy-(C 1 -C 8 )-alkyl, (C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 2 -C 8 )-alkenyl, (C 2 -C 8 )-alkynyl, or a 3 to 7-membered monocyclic nonaromatic ring which optionally comprises 0 to 2 heteroatoms selected from the group consisting of oxygen and nitrogen, wherein the ring system is optionally substituted by F, Cl, Br, CF 3 , (C 1 -C 6 )-alkyl, O—(C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl, oxo, CO(R 37 ), or hydroxy;
R 37 is H, (C 1 -C 8 )-alkyl;
Q is a group selected from
R 53 and R 54 are
independently of one another H, (C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 3 -C 8 )-alkenyl, (C 3 -C 8 )-alkynyl, CO(R 57 ), (C(R 58 )(R 59 )) q —R 60 , CO(C(R 61 )(R 62 )) r —R 63 , or CO—O(C 1 -C 8 )-alkyl, or
R 53 and R 54 taken together with the nitrogen atom to which they are bonded form a 4 to 10-membered mono-, bi- or spirocyclic ring which optionally comprises 0 to 2 additional heteroatoms selected from the group consisting of N, O and S, and is optionally substituted one or more times by F, Cl, Br, CF 3 , (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl, oxo, CO(R 64 ), hydroxy, N(R 67 )CO(C 1 -C 6 )-alkyl or SO 2 (C 1 -C 6 )-alkyl;
R 58 and R 59 are
independently of one another H, (C 1 -C 6 )-alkyl, or OH;
R 57 , R 61 , R 62 , R 64 and R 67 are
independently of one another H, or (C 1 -C 6 )-alkyl;
q and r are independently of one another 0, 1, or 2;
R 60 and R 63 are
independently of one another OH, F, O—(C 1 -C 6 )-alkyl, N(R 74 )CO(C 1 -C 6 )-alkyl, N(R 76 )(R 77 ), CON(R 72 )(R 73 ), SO 2 (C 1 -C 6 )-alkyl, or a 3-12 membered mono-, bi- or spirocyclic ring which optionally comprises one to three heteroatoms from the group consisting of N, O and S, and the 3-12 membered ring is optionally substituted by F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , oxo, O—(C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, N(R 76 )(R 77 ) and SO 2 (C 1 -C 6 )-alkyl; and
R 72 , R 73 , R 74 , R 76 and R 77 are
independently of one another H, or (C 1 -C 8 )-alkyl;
or a pharmaceutically acceptable salt thereof.
17. The compound according to claim 5 , wherein:
R 1 , R 1 ′, R 1 ″ and R 1 ′″ are
independently of one another H, F, Cl, O-methyl, or methyl;
R 2 is H;
R 27 is H;
X is S;
A is a bond or an moiety selected from the group consisting of O, CH 2 , CO, O—CH 2 , CHOH, CH 2 —CH 2 , CH═CH, C(CH 3 )═CH, C≡C, CH 2 —O, N(CH 3 )CO, NH—CO, CH 2 —O—CH 2 , O—CH═CH, C(OH)(CH 3 )—CH 2 —CH 2 , and C(OH)(CH 3 )—C≡C; and
B is hydroxy-(C 1 -C 4 )-alkyl, (C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 2 -C 8 )-alkenyl, (C 2 -C 8 )-alkynyl, or a 3-6 membered nonaromatic monocyclic ring selected from the group consisting of:
where the 3-6 membered nonaromatic monocyclic ring is optionally substituted by methyl, ethyl, OH, or oxo;
or a pharmaceutically acceptable salt thereof.
18. A process for preparing the compound according to claim 1 , wherein R 27 is H, comprising:
i) reacting an aromatic ortho-amino carboxylic ester of formula (II) with dimethylformamide dimethyl acetal to give corresponding aminal of formula (III):
ii) reacting the aminal of formula (III) with a substituted primary aromatic amine of formula (IV)
19. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable carrier.
20. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and at least one additional active ingredient which has beneficial effect on metabolic disturbance.
21. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and at least one antidiabetic active ingredient.
22. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and at least one lipid modulator.
23. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and at least one antiobesity active ingredient.
24. A pharmaceutical composition comprising the compound according to claim 5 or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable carrier.
25. A pharmaceutical composition comprising the compound according to claim 5 or a pharmaceutically acceptable salt thereof, and at least one additional active ingredient which has beneficial effect on metabolic disturbance.
26. A pharmaceutical composition comprising the compound according to claim 5 or a pharmaceutically acceptable salt thereof, and at least one antidiabetic active ingredient.
27. A pharmaceutical composition comprising the compound according to claim 5 or a pharmaceutically acceptable salt thereof, and at least one lipid modulator.
28. A pharmaceutical composition comprising the compound according to claim 5 or a pharmaceutically acceptable salt thereof, and at least one antiobesity active ingredient.