US2010204160A1PendingUtilityA1
Substituted 1,2-ethylenediamines, methods for preparing them and uses thereof
Est. expiryMar 30, 2025(expired)· nominal 20-yr term from priority
Inventors:Christian EickmeierStefan PetersKlaus FuchsNiklas HeineSandra HandschuhCornelia Dorner-CiossekKlaus KlinderMarcus Kostka
A61P 9/00A61P 43/00A61P 35/04A61P 9/10A61P 35/00A61P 25/00A61P 3/10A61P 25/28A61P 1/18C07K 5/06191C07K 5/0812C07K 5/0821A61P 21/00C07K 5/06026C07K 5/0808C07K 5/06034
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Claims
Abstract
The present invention relates to substituted 1,2-ethylenediamines of general formula (I) wherein the groups R 1 to R 15 , A, B, L, i as well as X 1 -X 4 are defined as in the specification and claims and the use thereof for the treatment of Alzheimer's disease (AD) and similar diseases.
Claims
exact text as granted — not AI-modified1 - 41 . (canceled)
42 . A method for treating or preventing a disease or condition associated with an abnormal processing of Amyloid Precursor Protein (APP) or aggregation of Abeta peptide, comprising administering to a patient in need thereof a compound of formula (I)
wherein:
A is aryl or heteroaryl, optionally substituted by one or more fluorine atoms;
L are each independently hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, carboxy, formyl, cyano, nitro, F 3 C, HF 2 C, FH 2 C, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 1-6 -alkyl-S, C 1-6 -alkyl-S—C 1-3 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkenyl, C 3-7 -cycloalkyl-C 1-6 -alkyl, C 3-7 -cycloalkyl-C 2-6 -alkenyl, C 3-7 -cycloalkyl-C 2-6 -alkynyl, C 3-7 -cycloalkenyl-C 1-6 -alkyl, C 3-7 -cycloalkenyl-C 2-6 -alkenyl, C 3-7 -cycloalkenyl-C 2-6 -alkynyl, aryl, aryl-C 1-6 -alkyl, aryl-C 2-6 -alkenyl, aryl-C 2-6 -alkynyl, heterocyclyl, heterocyclyl-C 1-6 -alkyl, heterocyclyl-C 2-6 -alkenyl, heterocyclyl-C 2-6 -alkynyl, heteroaryl, heteroaryl-C 1-6 -alkyl, heteroaryl-C 2-6 -alkenyl, heteroaryl-C 2-6 -alkynyl, R 15 —O, R 15 —O—C 1-3 -alkyl, (R 14 ) 2 N, (R 14 ) 2 N—CO, R 14 —CO—(R 14 )N, (R 14 ) 2 N—CO—(R 14 )N, R 14 —SO 2 —(R 14 )N, (R 14 ) 2 N—SO 2 or R 14 —SO 2 , wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, F 3 C, HF 2 C, FH 2 C, hydroxy-C 1-6 -alkyl, C 1-3 -alkyl, C 1-6 -alkoxy, (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl, (R 14 ) 2 N—CO and HOSO 2 —;
i is 0, 1, 2 or 3;
B is a C 1-4 -alkylene bridge, optionally substituted by one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, cyano, nitro, F 3 C, HF 2 C, FH 2 C, C 1-4 -alkyl, C 1-6 -alkyl-S—C 1-3 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, aryl, aryl-C 1-3 -alkyl, heteroaryl, heteroaryl-C 1-3 -alkyl, R 15 —O, (R 14 ) 2 N—SO 2 , (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl, (R 14 ) 2 N—CO R 14 —SO 2 , R 14 —CO—(R 14 )N, R 14 —SO 2 (R 14 )N, (R 14 ) 2 N—SO 2 , R 14 —CO— and R 14 —SO—, wherein
two C 1-4 -alkyl groups bound to the same carbon atom of the C 1-4 -alkylene bridge may be joined together to form a C 3-7 -cycloalkyl group, and
each of the above-mentioned groups and the C 3-7 -cycloalkyl group formed from the C 1-4 -alkyl groups are optionally substituted independently of one another by one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, F 3 C, HF 2 C, FH 2 C, C 1-3 -alkyl, C 1-3 -alkoxy, R 15 —O—C 1-3 -alkyl, R 14 —CO(R 14 )N, R 14 —SO 2 (R 14 )N, (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl, (R 14 ) 2 N—CO, (R 14 ) 2 N—SO 2 — and HOSO 2 —, and
wherein when B is a C 3-4 -alkylene bridge, the CH 2 group of the C 3-4 -alkylene bridge, which is bound to the group A, is optionally replaced by —O—;
R 1 is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-6 -alkyl, C 3-7 -cycloalkyl-C 2-6 -alkenyl, C 3-7 -cycloalkyl-C 2-6 -alkynyl, C 3-7 -cycloalkenyl, C 3-7 -cycloalkenyl-C 1-6 -alkyl, C 3-7 -cycloalkenyl-C 2-6 -alkenyl, C 3-7 -cycloalkenyl-C 2-6 -alkynyl, aryl, aryl-C 1-6 -alkyl, aryl-C 2-6 -alkenyl, aryl-C 2-6 -alkynyl, heterocyclyl, heterocyclyl-C 1-6 -alkyl, heterocyclyl-C 2-6 -alkenyl, heterocyclyl-C 2-6 -alkynyl, heteroaryl, heteroaryl-C 1-6 -alkyl, heteroaryl-C 2-6 -alkenyl or heteroaryl-C 2-6 -alkynyl,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, F 3 C, HF 2 C, FH 2 C, C 1-3 -alkyl, C 1-3 -alkoxy, hydroxy-C 1-6 -alkyl, (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl, (R 14 ) 2 N—CO—(R 14 ) 2 N—SO 2 , R 14 —CO—(R 14 )N, R 14 —SO 2 —(R 14 )N and HOSO 2 —;
X 1 , is nitrogen or C(R 10 );
X 2 , X 3 , X 4 are each independently nitrogen or C(R 11 ),
with the proviso that 0, 1, 2 or 3 of the groups X 1 , X 2 , X 3 and X 4 are nitrogen;
R 2 is C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, R 15 —O—C 1-3 -alkyl, C 1-6 -alkyl-S—C 1-3 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 2-6 -alkynyl, C 3-7 -cycloalkenyl, C 3-7 -cycloalkenyl-C 1-6 -alkyl, C 3-7 -cycloalkenyl-C 2-6 -alkenyl, C 3-7 -cycloalkenyl-C 2-6 -alkynyl, heterocyclyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, heterocyclyl-C 1-3 -alkyl, C 3-7 -cycloalkyl-C 2-3 -alkenyl, heterocyclyl-C 2-3 -alkenyl, heterocyclyl-C 2-3 -alkynyl, aryl, heteroaryl, aryl-C 1-3 -alkyl, heteroaryl-C 1-3 -alkyl, aryl-C 2-3 -alkenyl, aryl-C 2-3 -alkynyl, heteroaryl-C 2-3 -alkenyl or heteroaryl-C 2-3 -alkynyl,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from fluorine, chlorine, bromine, iodine, F 3 C, HF 2 C, FH 2 C, hydroxy, oxo, carboxy, formyl, cyano, nitro, (R 14 ) 2 N, HOSO 2 —, C 1-3 -alkyl, C 1-6 -alkyl-S—C 1-3 -alkyl, (R 14 ) 2 N—SO 2 —, R 14 —CO—R 14 )N, R 14 —SO 2 —(R 14 )N, (R 14 ) 2 N—C 1-3 -alkyl, (R 14 ) 2 N—CO, R 15 —O and R 15 —O—C 1-3 -alkyl;
R 3 , R 4 are each independently hydrogen, C 1-6 -alkyl, fluorine, F 3 C, HF 2 C, or FH 2 C;
R 5 , R 7 are each independently hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl, heterocyclyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, C 3-7 -cycloalkyl-C 2-6 -alkynyl, heterocyclyl-C 1-3 -alkyl, C 3-7 -cycloalkyl-C 2-4 -alkenyl, heterocyclyl-C 2-4 -alkenyl, heterocyclyl-C 2-4 -alkynyl, C 3-7 -cycloalkenyl, C 3-7 -cycloalkenyl-C 1-6 -alkyl, C 3-7 -cycloalkenyl-C 2-6 -alkenyl, C 3-7 -cycloalkenyl-C 2-6 -alkynyl, aryl, heteroaryl, aryl-C 1-3 -alkyl, heteroaryl-C 1-3 -alkyl, aryl-C 2-3 -alkenyl, heteroaryl-C 2-3 -alkenyl, aryl-C 2-3 -alkynyl or heteroaryl-C 2-3 -alkynyl,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C 1-3 -alkyl, R 15 —O, C 1-3 -alkyl-S, aryl, heteroaryl, heteroaryl-C 1-3 -alkyl, aryl-C 1-6 -alkyl, R 14 —CO—(R 14 )N, R 14 —SO 2 —(R 14 )N, (R 14 ) 2 N—SO 2 —, (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl, (R 14 ) 2 N—CO and HOSO 2 —;
R 6 , R 9 are each independently hydrogen, C 1-6 -alkyl, C 1-6 -alkoxy-C 1-3 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, C 2-6 -alkenyl, heterocyclyl-C 1-3 -alkyl, heteroaryl, heteroaryl-C 1-3 -alkyl or C 2-6 -alkynyl,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, cyano, C 1-3 -alkyl, C 1-6 -alkoxy- and (R 14 ) 2 N;
R 8 is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, C 3-7 -cycloalkyl-C 2-4 -alkenyl, C 3-7 -cycloalkyl-C 2-4 -alkynyl, C 3-7 -cycloalkenyl, C 3-7 -cycloalkenyl-C 1-6 -alkyl, C 3-7 -cycloalkenyl-C 2-6 -alkenyl, C 3-7 -cycloalkenyl-C 2-6 -alkynyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, heterocyclyl-C 2-4 -alkenyl, heterocyclyl-C 2-4 -alkynyl, aryl, aryl-C 1-3 -alkyl, aryl-C 2-4 -alkenyl, aryl-C 2-4 -alkynyl, heteroaryl, heteroaryl-C 1-3 -alkyl, heteroaryl-C 2-4 -alkenyl or heteroaryl-C 2-4 -alkynyl,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C 1-3 -alkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, R 15 —O, R 15 —O—C 1-3 -alkyl, R 15 —S, R 15 —S—C 1-3 -alkyl, aryl, heteroaryl, heteroaryl-C 1-3 -alkyl, aryl-C 1-6 -alkyl, (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl, (R 14 ) 2 N—CO (R 14 ) 2 N—CO—N(R 14 )—, (R 14 ) 2 N—SO 2 — and HOSO 2 —;
R 10 is hydrogen, fluorine, chlorine, bromine, iodine, cyano, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-6 -alkyl, C 3-7 -cycloalkyl-C 2-6 -alkynyl, heterocyclyl, heterocyclyl-C 1-6 -alkyl, heterocyclyl-C 2-6 -alkenyl, heterocyclyl-C 2-6 -alkynyl, C 3-7 -cycloalkyl-C 2-6 -alkenyl, heterocyclyl-C 2-4 -alkenyl, C 3-7 -cycloalkenyl, C 3-7 -cycloalkenyl-C 1-6 -alkyl, C 3-7 -cycloalkenyl-C 2-6 -alkenyl, C 3-7 -cycloalkenyl-C 2-6 -alkynyl, aryl, aryl-C 1-6 -alkyl, heteroaryl, heteroaryl-C 1-6 -alkyl, aryl-C 2-6 -alkenyl, heteroaryl-C 2-6 -alkenyl, aryl-C 2-6 -alkynyl or heteroaryl-C 2-6 -alkynyl, R 15 —O, R 15 —O—C 1-3 -alkyl, R 12 —SO 2 —(R 13 )N or R 12 —CO—(R 13 )N
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 1-6 -alkyl-S, C 1-6 -alkyl-S—C 1-3 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-6 -alkyl, aryl, aryl-C 1-6 -alkyl, heterocyclyl, heterocyclyl-C 1-6 -alkyl, heteroaryl, heteroaryl-C 1-6 -alkyl, R 15 —O, R 15 —O—CO, R 15 —CO, R 15 —O—CO—(R 14 )N, (R 14 ) 2 N—CO—O, R 15 —O—C 1-3 -alkyl, (R 14 ) 2 N, (R 14 ) 2 N—CO, R 14 —CO—(R 14 )N, (R 14 ) 2 N—CO—(R 14 )N, (R 14 ) 2 N—SO 2 —, (R 14 ) 2 N—SO 2 —(R 14 )N, R 14 —SO 2 —, F 3 C, HF 2 C, FH 2 C, F 3 C—O, HF 2 C—O, FH 2 C—O and R 14 —SO 2 —(R 14 )N;
R 11 are each independently hydrogen, fluorine, chlorine, bromine, iodine, R 15 —O, (R 14 ) 2 N or C 1-3 -alkyl,
wherein the C 1-3 -alkyl group is optionally substituted by one or more fluorine atoms;
R 12 is C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl-C 2-6 -alkenyl, aryl-C 2-3 -alkenyl, heteroaryl-C 2-4 -alkenyl, heterocyclyl-C 2-4 -alkenyl, aryl-C 2-3 -alkynyl, C 3-7 -cycloalkyl-C 2-4 -alkynyl, heterocyclyl-C 2-4 -alkynyl-heteroaryl-C 2-3 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 2-6 -alkyl, heterocyclyl, heterocyclyl-C 1-4 -alkyl, C 3-7 -cycloalkenyl, C 3-7 -cycloalkenyl-C 1-6 -alkyl, C 3-7 -cycloalkenyl-C 2-6 -alkenyl, C 3-7 -cycloalkenyl-C 2-6 -alkynyl, aryl, aryl-C 1-4 -alkyl, heteroaryl, heteroaryl-C 1-3 -alkyl or (R 14 ) 2 N,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C 1-3 -alkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, R 15 —O, R 15 —O—C 1-3 -alkyl, R 14 —CO(R 14 )N, R 14 —SO 2 (R 14 )N, (R 14 ) 2 N—SO 2 —R 14 —SO 2 —, R 14 —SO, R 14 —S, (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl and (R 14 ) 2 N—CO;
R 13 is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, aryl, aryl-C 1-3 -alkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, heterocyclyl-C 2-3 -alkenyl, heterocyclyl-C 2-3 -alkynyl, heteroaryl, heteroaryl-C 2-3 -alkenyl, heteroaryl-C 2-3 -alkynyl or heteroaryl-C 1-3 -alkyl,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C 1-3 -alkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, R 15 —O, R 15 —O—C 1-3 -alkyl, (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl and R 14 CO;
or
R 12 and R 13 together form a C 2-6 -alkylene bridge, so that with the inclusion of the nitrogen atom linked to R 13 and the SO 2 — or CO group linked to R 12 , a heterocyclic ring is formed,
wherein one or two CH 2 groups of the C 2-6 -alkylene bridge are optionally replaced independently of one another by O, S, SO, SO 2 or N(R 14 ) in such a way that in each case two O or S atoms or an O and an S atom are not joined together directly, and the C atoms of the above-mentioned C 2-6 -alkylene bridge are optionally substituted by one or more groups selected from fluorine, chlorine, bromine, hydroxy, carboxy, formyl, cyano, F 3 C, HF 2 C, FH 2 C, C 1-6 -alkyl, C 1-6 -alkoxy, oxo and nitro;
R 14 are each independently hydrogen, C 1-6 -alkyl, C 1-6 -alkoxy-C 1-3 -alkyl, C 3-6 -cyclyoalkyl, C 3-6 -cyclyoalkyl-C 1-3 -alkyl, aryl or aryl-C 1-3 -alkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, heteroaryl or heteroaryl-C 1-3 -alkyl, wherein
two C 1-6 -alkyl groups bound to the same nitrogen atom together may form a C 2-6 -alkylene bridge, so that with the inclusion of the nitrogen atom bound to the groups R 14 a heterocyclic ring is formed,
wherein a CH 2 group of the C 2-6 -alkylene bridge may be replaced by O, S or N(R 14 ), and
the above-mentioned groups and the heterocyclic ring are optionally substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C 1-3 -alkyl, hydroxy-C 1-3 -alkyl, C 1-3 -alkoxy, (R 15 ) 2 N—CO or (R 15 ) 2 N and
R 15 are each independently hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cyclyoalkyl-C 1-3 -alkyl, aryl, aryl-C 1-3 -alkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, heteroaryl or heteroaryl-C 1-3 -alkyl,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C 1-3 -alkyl- and C 1-3 -alkoxy;
or a tautomer, diastereomer, enantiomer, mixture or salt thereof.
43 . A method for treating or preventing diseases or conditions influenced by inhibiting the β-secretase activity, comprising administering to a patient in need thereof a compound of formula (I)
wherein:
A is aryl or heteroaryl, optionally substituted by one or more fluorine atoms;
L are each independently hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, carboxy, formyl, cyano, nitro, F 3 C, HF 2 C, FH 2 C, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 1-6 -alkyl-S, C 1-6 -alkyl-S-—C 1-3 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkenyl, C 3-7 -cycloalkyl-C 1-6 -alkyl, C 3-7 -cycloalkyl-C 2-6 -alkenyl, C 3-7 -cycloalkyl-C 2-6 -alkynyl, C 3-7 -cycloalkenyl-C 1-6 -alkyl, C 3-7 -cycloalkenyl-C 2-6 -alkenyl, C 3-7 -cycloalkenyl-C 2-6 -alkynyl, aryl, aryl-C 1-6 -alkyl, aryl-C 2-6 -alkenyl, aryl-C 2-6 -alkynyl, heterocyclyl, heterocyclyl-C 1-6 -alkyl, heterocyclyl-C 2-6 -alkenyl, heterocyclyl-C 2-6 -alkynyl, heteroaryl, heteroaryl-C 1-6 -alkyl, heteroaryl-C 2-6 -alkenyl, heteroaryl-C 2-6 -alkynyl, R 15 —O, R 15 —O—C 1-3 -alkyl, (R 14 ) 2 N, (R 14 ) 2 N—CO, R 14 —CO—(R 14 )N, (R 14 ) 2 N—CO—(R 14 )N, R 14 —SO 2 —(R 14 )N, (R 14 ) 2 N—SO 2 or R 14 —SO 2 , wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, F 3 C, HF 2 C, FH 2 C, hydroxy-C 1-6 -alkyl, C 1-3 -alkyl, C 1-6 -alkoxy, (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl, (R 14 ) 2 N—CO and HOSO 2 —;
i is 0, 1, 2 or 3;
B is a C 1-4 -alkylene bridge, optionally substituted by one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, cyano, nitro, F 3 C, HF 2 C, FH 2 C, C 1-4 -alkyl, C 1-6 -alkyl-S—C 1-3 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, aryl, aryl-C 1-3 -alkyl, heteroaryl, heteroaryl-C 1-3 -alkyl, R 15 —O, (R 14 ) 2 N—SO 2 , (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl, (R 14 ) 2 N—CO, R 14 —SO 2 , R 14 —CO—(R 14 )N, R 14 —SO 2 (R 14 )N, (R 14 ) 2 N—SO 2 , R 14 —CO— and R 14 —SO—, wherein
two C 1-4 -alkyl groups bound to the same carbon atom of the C 1-4 -alkylene bridge may be joined together to form a C 3-7 -cycloalkyl group, and
each of the above-mentioned groups and the C 3-7 -cycloalkyl group formed from the C 1-4 -alkyl groups are optionally substituted independently of one another by one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, F 3 C, HF 2 C, FH 2 C, C 1-3 -alkyl, C 1-3 -alkoxy, R 15 —O—C 1-3 -alkyl, R 14 —CO(R 14 )N, R 14 —SO 2 (R 14 )N, (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl, (R 14 ) 2 N—CO, (R 14 ) 2 N—SO 2 — and HOSO 2 — and
wherein when B is a C 3-4 -alkylene bridge, the CH 2 group of the C 3-4 -alkylene bridge, which is bound to the group A, is optionally replaced by —O—;
R 1 is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-6 -alkyl, C 3-7 -cycloalkyl-C 2-6 -alkenyl, C 3-7 -cycloalkyl-C 2-6 -alkynyl, C 3-7 -cycloalkenyl, C 3-7 -cycloalkenyl-C 1-6 -alkyl, C 3-7 -cycloalkenyl-C 2-6 -alkenyl, C 3-7 -cycloalkenyl-C 2-6 -alkynyl, aryl, aryl-C 1-6 -alkyl, aryl-C 2-6 -alkenyl, aryl-C 2-6 -alkynyl, heterocyclyl, heterocyclyl-C 1-6 -alkyl, heterocyclyl-C 2-6 -alkenyl, heterocyclyl-C 2-6 -alkynyl, heteroaryl, heteroaryl-C 1-6 -alkyl, heteroaryl-C 2-6 -alkenyl or heteroaryl-C 2-6 -alkynyl,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, F 3 C, HF 2 C, FH 2 C, C 1-3 -alkyl, C 1-3 -alkoxy, hydroxy-C 1-6 -alkyl, (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl, (R 14 ) 2 N—CO—(R 14 ) 2 N—SO 2 , R 14 —CO—(R 14 )N, R 14 —SO 2 —(R 14 )N and HOSO 2 —;
X 1 , is nitrogen or C(R 10 ),
X 2 , X 3 , X 4 are each independently nitrogen or C(R 11 ),
with the proviso that 0, 1, 2 or 3 of the groups X 1 , X 2 , X 3 and X 4 are nitrogen;
R 2 is C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, R 15 —O—C 1-3 -alkyl, C 1-6 -alkyl-S—C 1-3 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 2-6 -alkynyl, C 3-7 -cycloalkenyl, C 3-7 -cycloalkenyl-C 1-6 -alkyl, C 3-7 -cycloalkenyl-C 2-6 -alkenyl, C 3-7 -cycloalkenyl-C 2-6 -alkynyl, heterocyclyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, heterocyclyl-C 1-3 -alkyl, C 3-7 -cycloalkyl-C 2-3 -alkenyl, heterocyclyl-C 2-3 -alkenyl, heterocyclyl-C 2-3 -alkynyl, aryl, heteroaryl, aryl-C 1-3 -alkyl, heteroaryl-C 1-3 -alkyl, aryl-C 2-3 -alkenyl, aryl-C 2-3 -alkynyl, heteroaryl-C 2-3 -alkenyl or heteroaryl-C 2-3 -alkynyl,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from fluorine, chlorine, bromine, iodine, F 3 C, HF 2 C, FH 2 C, hydroxy, oxo, carboxy, formyl, cyano, nitro, (R 14 ) 2 N, HOSO 2 —, C 1-3 -alkyl, C 1-6 -alkyl-S—C 1-3 -alkyl, (R 14 ) 2 N—SO 2 —, R 14 —CO—(R 14 )N, R 14 —SO 2 —(R 14 )N, (R 14 ) 2 N—C 1-3 -alkyl, (R 14 ) 2 N—CO, R 15 —O and R 15 —O—C 1-3 -alkyl;
R 3 , R 4 are each independently hydrogen, C 1-6 -alkyl, fluorine, F 3 C, HF 2 C or FH 2 C;
R 5 , R 7 are each independently hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl, heterocyclyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, C 3-7 -cycloalkyl-C 2-6 -alkynyl, heterocyclyl-C 1-3 -alkyl, C 3-7 -cycloalkyl-C 2-4 -alkenyl, heterocyclyl-C 2-4 -alkenyl, heterocyclyl-C 2-4 -alkynyl, C 3-7 -cycloalkenyl, C 3-7 -cycloalkenyl-C 1-6 -alkyl, C 3-7 -cycloalkenyl-C 2-6 -alkenyl, C 3-7 -cycloalkenyl-C 2-6 -alkynyl, aryl, heteroaryl, aryl-C 1-3 -alkyl, heteroaryl-C 1-3 -alkyl, aryl-C 2-3 -alkenyl, heteroaryl-C 2-3 -alkenyl, aryl-C 2-3 -alkynyl or heteroaryl-C 2-3 -alkynyl,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C 1-3 -alkyl, R 15 —O, C 1-3 -alkyl-S, aryl, heteroaryl, heteroaryl-C 1-3 -alkyl, aryl-C 1-6 -alkyl, R 14 —CO—(R 14 )N, R 14 —SO 2 —(R 14 )N, (R 14 ) 2 N—SO 2 —, (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl, (R 14 ) 2 N—CO and HOSO 2 —;
R 6 , R 9 are each independently hydrogen, C 1-6 -alkyl, C 1-6 -alkoxy-C 1-3 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, C 2-6 -alkenyl, heterocyclyl-C 1-3 -alkyl, heteroaryl, heteroaryl-C 1-3 -alkyl or C 2-6 -alkynyl,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, cyano, C 1-3 -alkyl, C 1-6 -alkoxy- and (R 14 ) 2 N;
R 8 is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, C 3-7 -cycloalkyl-C 2-4 -alkenyl, C 3-7 -cycloalkyl-C 2-4 -alkynyl, C 3-7 -cycloalkenyl, C 3-7 -cycloalkenyl-C 1-6 -alkyl, C 3-7 -cycloalkenyl-C 2-6 -alkenyl, C 3-7 -cycloalkenyl-C 2-6 -alkynyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, heterocyclyl-C 2-4 -alkenyl, heterocyclyl-C 2-4 -alkynyl, aryl, aryl-C 1-3 -alkyl, aryl-C 2-4 -alkenyl, aryl-C 2-4 -alkynyl, heteroaryl, heteroaryl-C 1-3 -alkyl, heteroaryl-C 2-4 -alkenyl or heteroaryl-C 2-4 -alkynyl,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C 1-3 -alkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, R 15 —O, R 15 —O—C 1-3 -alkyl, R 15 —S, R 15 —S—C 1-3 -alkyl, aryl, heteroaryl, heteroaryl-C 1-3 -alkyl, aryl-C 1-6 -alkyl, (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl, (R 14 ) 2 N—CO (R 14 ) 2 N—CO—N(R 14 )—, (R 14 ) 2 N—SO 2 — and HOSO 2 —;
R 10 is hydrogen, fluorine, chlorine, bromine, iodine, cyano, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-6 -alkyl, C 3-7 -cycloalkyl-C 2-6 -alkynyl, heterocyclyl, heterocyclyl-C 1-6 -alkyl, heterocyclyl-C 2-6 -alkenyl, heterocyclyl-C 2-6 -alkynyl, C 3-7 -cycloalkyl-C 2-6 -alkenyl, heterocyclyl-C 2-4 -alkenyl, C 3-7 -cycloalkenyl, C 3-7 -cycloalkenyl-C 1-6 -alkyl, C 3-7 -cycloalkenyl-C 2-6 -alkenyl, C 3-7 -cycloalkenyl-C 2-6 -alkynyl, aryl, aryl-C 1-6 -alkyl, heteroaryl, heteroaryl-C 1-6 -alkyl, aryl-C 2-6 -alkenyl, heteroaryl-C 2-6 -alkenyl, aryl-C 2-6 -alkynyl or heteroaryl-C 2-6 -alkynyl, R 15 —O, R 15 —O—C 1-3 -alkyl, R 12 —SO 2 —(R 13 )N or R 12 —CO—(R 13 )N
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 1-6 -alkyl-S, C 1-6 alkyl-S—C 1-3 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-6 -alkyl, aryl, aryl-C 1-6 -alkyl, heterocyclyl, heterocyclyl-C 1-6 -alkyl, heteroaryl, heteroaryl-C 1-6 -alkyl, R 15 —O, R 15 —O—CO, R 15 —CO, R 15 —O—CO—(R 14 )N, (R 14 ) 2 N—CO—O, R 15 —O—C 1-3 -alkyl, (R 14 ) 2 N, (R 14 ) 2 N—CO, R 14 —CO—(R 14 )N, (R 14 ) 2 N—CO—(R 14 )N, (R 14 ) 2 N—SO 2 —, (R 14 ) 2 N—SO 2 —(R 14 )N, R 14 —SO 2 —, F 3 C, HF 2 C, FH 2 C, F 3 C—O, HF 2 C−O, FH 2 C—O and R 14 —SO 2 —(R 14 )N;
R 11 are each independently hydrogen, fluorine, chlorine, bromine, iodine, R 15 —O, (R 14 ) 2 N or C 1-3 -alkyl,
wherein the C 1-3 -alkyl group is optionally substituted by one or more fluorine atoms;
R 12 is C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl-C 2-6 -alkenyl, aryl-C 2-3 -alkenyl, heteroaryl-C 2-4 -alkenyl, heterocyclyl-C 2-4 -alkenyl, aryl-C 2-3 -alkynyl, C 3-7 -cycloalkyl-C 2-4 -alkynyl, heterocyclyl-C 2-4 -alkynyl-heteroaryl-C 2-3 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-6 -alkyl, heterocyclyl, heterocyclyl-C 1-4 -alkyl, C 3-7 -cycloalkenyl, C 3-7 -cycloalkenyl-C 1-6 -alkyl, C 3-7 -cycloalkenyl-C 2-6 -alkenyl, C 3-7 -cycloalkenyl-C 2-6 -alkynyl, aryl, aryl-C 1-4 -alkyl, heteroaryl, heteroaryl-C 1-3 -alkyl or (R 14 ) 2 N,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C 1-3 -alkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, R 15 —O, R 15 —O—C 1-3 -alkyl, R 14 —CO(R 14 )N, R 14 —SO 2 (R 14 )N, (R 14 ) 2 N—SO 2 —, R—SO 2 —, R 14 —SO, R 14 —S, (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl and (R 14 ) 2 N—CO;
R 13 is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, aryl, aryl-C 1-3 -alkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, heterocyclyl-C 2-3 -alkenyl, heterocyclyl-C 2-3 -alkynyl, heteroaryl, heteroaryl-C 2-3 -alkenyl, heteroaryl-C 2-3 -alkynyl or heteroaryl-C 1-3 -alkyl,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C 1-3 -alkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, R 15 —O, R 15 —O—C 1-3 -alkyl, (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl and R 14 CO;
or
R 12 and R 13 together form a C 2-6 -alkylene bridge, so that with the inclusion of the nitrogen atom linked to R 13 and the SO 2 — or CO group linked to R 12 , a heterocyclic ring is formed,
wherein one or two CH 2 groups of the C 2-6 -alkylene bridge are optionally replaced independently of one another by O, S, SO, SO 2 or N(R 14 ) in such a way that in each case two O or S atoms or an O and an S atom are not joined together directly, and the C atoms of the above-mentioned C 2-6 -alkylene bridge are optionally substituted by one or more groups selected from fluorine, chlorine, bromine, hydroxy, carboxy, formyl, cyano, F 3 C, HF 2 C, FH 2 C, C 1-6 -alkyl, C 1-6 -alkoxy, oxo and nitro;
R 14 are each independently hydrogen, C 1-6 -alkyl, C 1-6 -alkoxy-C 1-3 -alkyl, C 3-6 -cyclyoalkyl, C 3-6 -cyclyoalkyl-C 1-3 -alkyl, aryl or aryl-C 1-3 -alkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, heteroaryl or heteroaryl-C 1-3 -alkyl, wherein
two C 1-6 -alkyl groups bound to the same nitrogen atom together may form a C 2-6 -alkylene bridge, so that with the inclusion of the nitrogen atom bound to the groups R 14 a heterocyclic ring is formed,
wherein a CH 2 group of the C 2-6 -alkylene bridge may be replaced by O, S or N(R 14 ), and
the above-mentioned groups and the heterocyclic ring are optionally substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C 1-3 -alkyl, hydroxy-C 1-3 -alkyl, C 1-3 -alkoxy, (R 15 ) 2 N—CO or (R 15 ) 2 N, and
R 15 are each independently hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cyclyoalkyl-C 1-3 -alkyl, aryl, aryl-C 1-3 -alkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, heteroaryl or hetero aryl-C 1-3 -alkyl,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C 1-3 -alkyl- and C 1-3 -alkoxy;
or a tautomer, diastereomer, enantiomer, mixture or salt thereof.
44 . A method for treating or preventing diseases or conditions influenced by inhibiting the aspartylprotease cathepsin D, comprising administering to a patient in need thereof a compound according of formula (I)
wherein:
A is aryl or heteroaryl, optionally substituted by one or more fluorine atoms;
L are each independently hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, carboxy, formyl, cyano, nitro, F 3 C, HF 2 C, FH 2 C, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 1-6 -alkyl-S, C 1-6 -alkyl-S—C 1-3 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkenyl, C 3-7 -cycloalkyl-C 1-6 -alkyl, C 3-7 -cycloalkyl-C 2-6 -alkenyl, C 3-7 -cycloalkyl-C 2-6 -alkynyl, C 3-7 -cycloalkenyl-C 1-6 -alkyl, C 3-7 -cycloalkenyl-C 2-6 -alkenyl, C 3-7 -cycloalkenyl-C 2-6 -alkynyl, aryl, aryl-C 1-6 -alkyl, aryl-C 2-6 -alkenyl, aryl-C 2-6 -alkynyl, heterocyclyl, heterocyclyl-C 1-6 -alkyl, heterocyclyl-C 2-6 -alkenyl, heterocyclyl-C 2-6 -alkynyl, heteroaryl, heteroaryl-C 1-6 -alkyl, heteroaryl-C 2-6 -alkenyl, heteroaryl-C 2-6 -alkynyl, R 15 —O, R 15 —O—C 1-3 -alkyl, (R 14 ) 2 N, (R 14 ) 2 N—CO, R 14 —CO—(R 14 )N, (R 14 ) 2 N—CO—(R 14 )N, R 14 —SO 2 —(R 14 )N, (R 14 ) 2 N—SO 2 or R 14 —SO 2 , wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, F 3 C, HF 2 C, FH 2 C, hydroxy-C 1-6 -alkyl, C 1-3 -alkyl, C 1-6 -alkoxy, (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl, (R 14 ) 2 N—CO and HOSO 2 —;
i is 0, 1, 2 or 3;
B is a C 1-4 -alkylene bridge, optionally substituted by one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, cyano, nitro, F 3 C, HF 2 C, FH 2 C, C 1-4 -alkyl, C 1-6 -alkyl-S—C 1-3 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, aryl, aryl-C 1-3 -alkyl, heteroaryl, heteroaryl-C 1-3 -alkyl, R 15 —O, (R 14 ) 2 N—SO 2 , (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl, (R 14 ) 2 N—CO, R 14 —SO 2 , R 14 —CO—(R 14 )N, R 14 —SO 2 (R 14 )N, (R 14 )N—SO 2 , R 14 —CO— and R 14 —SO—, wherein
two C 1-4 -alkyl groups bound to the same carbon atom of the C 1-4 -alkylene bridge may be joined together to form a C 3-7 -cycloalkyl group, and
each of the above-mentioned groups and the C 3-7 -cycloalkyl group formed from the C 1-4 -alkyl groups are optionally substituted independently of one another by one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, F 3 C, HF 2 C, FH 2 C, C 1-3 -alkyl, C 1-3 -alkoxy, R 15 —O—C 1-3 -alkyl, R 14 —CO(R 14 )N, R 14 —SO 2 (R 14 )N, (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl, (R 14 ) 2 N—CO, (R 14 ) 2 N—SO 2 — and HOSO 2 — and
wherein when B is a C 3-4 -alkylene bridge, the CH 2 group of the C 3-4 -alkylene bridge, which is bound to the group A, is optionally replaced by —O—;
R 1 is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-6 -alkyl, C 3-7 -cycloalkyl-C 2-6 -alkenyl, C 3-7 -cycloalkyl-C 2-6 -alkynyl, C 3-7 -cycloalkenyl, C 3-7 -cycloalkenyl-C 1-6 -alkyl, C 3-7 -cycloalkenyl-C 2-6 -alkenyl, C 3-7 -cycloalkenyl-C 2-6 -alkynyl, aryl, aryl-C 1-6 -alkyl, aryl-C 2-6 -alkenyl, aryl-C 2-6 -alkynyl, heterocyclyl, heterocyclyl-C 1-6 -alkyl, heterocyclyl-C 2-6 -alkenyl, heterocyclyl-C 2-6 -alkynyl, heteroaryl, heteroaryl-C 1-6 -alkyl, heteroaryl-C 2-6 -alkenyl or heteroaryl-C 2-6 -alkynyl,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, F 3 C, HF 2 C, FH 2 C, C 1-3 -alkyl, C 1-3 -alkoxy, hydroxy-C 1-6 -alkyl, (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl, (R 14 ) 2 N—CO—(R 14 ) 2 N—SO 2 , R 14 —CO—(R 14 )N, R 14 —SO 2 —(R 14 )N and HOSO 2 —;
X 1 , is nitrogen or C(R 10 );
X 2 , X 3 , X 4 are each independently nitrogen or C(R 11 ),
with the proviso that 0, 1, 2 or 3 of the groups X 1 , X 2 , X 3 and X 4 are nitrogen;
R 2 is C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, R 15 —O—C 1-3 -alkyl, C 1-6 -alkyl-S—C 1-3 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 2-6 -alkynyl, C 3-7 -cycloalkenyl, C 3-7 -cycloalkenyl-C 1-6 -alkyl, C 3-7 -cycloalkenyl-C 2-6 -alkenyl, C 3-7 -cycloalkenyl-C 2-6 -alkynyl, heterocyclyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, heterocyclyl-C 1-3 -alkyl, C 3-7 -cycloalkyl-C 2-3 -alkenyl, heterocyclyl-C 2-3 -alkenyl, heterocyclyl-C 2-3 -alkynyl, aryl, heteroaryl, aryl-C 1-3 -alkyl, heteroaryl-C 1-3 -alkyl, aryl-C 2-3 -alkenyl, aryl-C 2-3 -alkynyl, heteroaryl-C 2-3 -alkenyl or heteroaryl-C 2-3 -alkynyl,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from fluorine, chlorine, bromine, iodine, F 3 C, HF 2 C, FH 2 C, hydroxy, oxo, carboxy, formyl, cyano, nitro, (R 14 ) 2 N, HOSO 2 —, C 1-3 -alkyl, C 1-6 -alkyl-S—C 1-3 -alkyl, (R 14 ) 2 N—SO 2 —, R 14 —CO—(R 14 )N, R 14 —SO 2 —(R 14 )N, (R 14 ) 2 N—C 1-3 -alkyl, (R 14 ) 2 N—CO, R 15 —O and R 15 —O—C 1-3 -alkyl;
R 3 , R 4 are each independently hydrogen, C 1-6 -alkyl, fluorine, F 3 C, HF 2 C or FH 2 C;
R 5 , R 7 are each independently hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl, heterocyclyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, C 3-7 -cycloalkyl-C 2-6 -alkynyl, heterocyclyl-C 1-3 -alkyl, C 3-7 -cycloalkyl-C 2-6 -alkenyl, heterocyclyl-C 2-4 -alkenyl, heterocyclyl-C 2-4 -alkynyl, C 3-7 -cycloalkenyl, C 3-7 -cycloalkenyl-C 1-6 -alkyl, C 3-7 -cycloalkenyl-C 2-6 -alkenyl, C 3-7 -cycloalkenyl-C 2-6 -alkynyl, aryl, heteroaryl, aryl-C 1-3 -alkyl, heteroaryl-C 1-3 -alkyl, aryl-C 2-3 -alkenyl, heteroaryl-C 2-3 -alkenyl, aryl-C 2-3 -alkynyl or heteroaryl-C 2-3 -alkynyl,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C 1-3 -alkyl, R 15 —O, C 1-3 -alkyl-S, aryl, heteroaryl, heteroaryl-C 1-3 -alkyl, aryl-C 1-6 -alkyl, R 14 —CO—(R 14 )N, R 14 —SO 2 —(R 14 )N, (R 14 ) 2 N—SO 2 —, (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl, (R 14 ) 2 N—CO and HOSO 2 —;
R 6 , R 9 are each independently hydrogen, C 1-6 -alkyl, C 1-6 -alkoxy-C 1-3 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, C 2-6 -alkenyl, heterocyclyl-C 1-3 -alkyl, heteroaryl, heteroaryl-C 1-3 -alkyl or C 2-6 -alkynyl,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, cyano, C 1-3 -alkyl, C 1-6 -alkoxy- and (R 14 ) 2 N;
R 8 is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, C 3-7 -cycloalkyl-C 2-4 -alkenyl, C 3-7 -cycloalkyl-C 2-4 -alkynyl, C 3-7 -cycloalkenyl, C 3-7 -cycloalkenyl-C 1-6 -alkyl, C 3-7 -cycloalkenyl-C 2-6 -alkenyl, C 3-7 -cycloalkenyl-C 2-6 -alkynyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, heterocyclyl-C 2-4 -alkenyl, heterocyclyl-C 2-4 -alkynyl, aryl, aryl-C 1-3 -alkyl, aryl-C 2-4 -alkenyl, aryl-C 2-4 -alkynyl, heteroaryl, heteroaryl-C 1-3 -alkyl, heteroaryl-C 2-4 -alkenyl or heteroaryl-C 2-4 -alkynyl,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C 1-3 -alkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, R 15 —O, R 15 —O—C 1-3 -alkyl, R 15 —S, R 15 —S—C 1-3 -alkyl, aryl, heteroaryl, heteroaryl-C 1-3 -alkyl, aryl-C 1-6 -alkyl, (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl, (R 14 ) 2 N—CO, (R 14 ) 2 N—CO—N(R 14 )—, (R 14 ) 2 N—SO 2 — and HOSO 2 —;
R 10 is hydrogen, fluorine, chlorine, bromine, iodine, cyano, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-6 -alkyl, C 3-7 -cycloalkyl-C 2-6 -alkynyl, heterocyclyl, heterocyclyl-C 1-6 -alkyl, heterocyclyl-C 2-6 -alkenyl, heterocyclyl-C 2-6 -alkynyl, C 3-7 -cycloalkyl-C 2-6 -alkenyl, heterocyclyl-C 2-4 -alkenyl, C 3-7 -cycloalkenyl, C 3-7 -cycloalkenyl-C 1-6 -alkyl, C 3-7 -cycloalkenyl-C 2-6 -alkenyl, C 3-7 -cycloalkenyl-C 2-6 -alkynyl, aryl, aryl-C 1-6 -alkyl, heteroaryl, heteroaryl-C 1-6 -alkyl, aryl-C 2-6 -alkenyl, heteroaryl-C 2-6 -alkenyl, aryl-C 2-6 -alkynyl or heteroaryl-C 2-6 -alkynyl, R 15 —O, R 15 —O—C 1-3 -alkyl, R 12 —SO 2 —(R 13 )N or R 12 —CO—(R 13 )N
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 1-6 -alkyl-S, C 1-6 -alkyl-S—C 1-3 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-6 -alkyl, aryl, aryl-C 1-6 -alkyl, heterocyclyl, heterocyclyl-C 1-6 -alkyl, heteroaryl, heteroaryl-C 1-6 -alkyl, R 15 —O, R 15 —O—CO, R 15 —CO, R 15 —O—CO—(R 14 )N, (R 14 ) 2 N—CO—O, R 15 —O—C 1-3 -alkyl, (R 14 ) 2 N, (R 14 ) 2 N—CO, R 14 —CO—(R 14 )N, (R 14 ) 2 N—CO—(R 14 )N, (R 14 ) 2 N—SO 2 —, (R 14 ) 2 N—SO 2 —(R 14 )N, R 14 —SO 2 —, F 3 C, HF 2 C, FH 2 C, F 3 C—O, HF 2 C—O, FH 2 C—O and R 14 —SO 2 —(R 14 )N;
R 11 are each independently hydrogen, fluorine, chlorine, bromine, iodine, R 15 —O, (R 14 ) 2 N or C 1-3 -alkyl,
wherein the C 1-3 -alkyl group is optionally substituted by one or more fluorine atoms;
R 12 is C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl-C 2-6 -alkenyl, aryl-C 2-3 -alkenyl, heteroaryl-C 2-4 -alkenyl, heterocyclyl-C 2-4 -alkenyl, aryl-C 2-3 -alkynyl, C 3-7 -cycloalkyl-C 2-4 -alkynyl, heterocyclyl-C 2-4 -alkynyl-heteroaryl-C 2-3 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-6 -alkyl, heterocyclyl, heterocyclyl-C 1-4 -alkyl, C 3-7 -cycloalkenyl, C 3-7 -cycloalkenyl-C 1-6 -alkyl, C 3-7 -cycloalkenyl-C 2-6 -alkenyl, C 3-7 -cycloalkenyl-C 2-6 -alkynyl, aryl, aryl-C 1-4 -alkyl, heteroaryl, heteroaryl-C 1-3 -alkyl or (R 14 ) 2 N,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C 1-3 -alkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, R 15 —O, R 15 —O—C 1-3 -alkyl, R 14 —CO(R 14 )N, R 14 —SO 2 (R 14 )N, (R 14 ) 2 N—SO 2 —, R 14 —SO 2 —, R 14 —SO, R 14 —S, (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl and (R 14 ) 2 N—CO;
R 13 is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, aryl, aryl-C 1-3 -alkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, heterocyclyl-C 2-3 -alkenyl, heterocyclyl-C 2-3 -alkynyl, heteroaryl, heteroaryl-C 2-3 -alkenyl, heteroaryl-C 2-3 -alkynyl or heteroaryl-C 1-3 -alkyl,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C 1-3 -alkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, R 15 —O, R 15 —O—C 1-3 -alkyl, (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl and R 14 CO;
or
R 12 and R 13 together form a C 2-6 -alkylene bridge, so that with the inclusion of the nitrogen atom linked to R 13 and the SO 2 — or CO group linked to R 12 , a heterocyclic ring is formed,
wherein one or two CH 2 groups of the C 2-6 -alkylene bridge are optionally replaced independently of one another by O, S, SO, SO 2 or N(R 14 ) in such a way that in each case two O or S atoms or an O and an S atom are not joined together directly, and the C atoms of the above-mentioned C 2-6 -alkylene bridge are optionally substituted by one or more groups selected from fluorine, chlorine, bromine, hydroxy, carboxy, formyl, cyano, F 3 C, HF 2 C, FH 2 C, C 1-6 -alkyl, C 1-6 -alkoxy, oxo and nitro;
R 14 are each independently hydrogen, C 1-6 -alkyl, C 1-6 -alkoxy-C 1-3 -alkyl, C 3-6 -cyclyoalkyl, C 3-6 -cyclyoalkyl-C 1-3 -alkyl, aryl or aryl-C 1-3 -alkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, heteroaryl or heteroaryl-C 1-3 -alkyl, wherein
two C 1-6 -alkyl groups bound to the same nitrogen atom together may form a C 2-6 -alkylene bridge, so that with the inclusion of the nitrogen atom bound to the groups R 14 a heterocyclic ring is formed,
wherein a CH 2 group of the C 2-6 -alkylene bridge may be replaced by O, S or N(R 14 ), and
the above-mentioned groups and the heterocyclic ring are optionally substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C 1-3 -alkyl, hydroxy-C 1-3 -alkyl, C 1-3 -alkoxy, (R 15 ) 2 N—CO or (R 15 ) 2 N and
R 15 are each independently hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cyclyoalkyl-C 1-3 -alkyl, aryl, aryl-C 1-3 -alkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, heteroaryl or heteroaryl-C 1-3 -alkyl,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C 1-3 -alkyl- and C 1-3 -alkoxy;
or a tautomer, diastereomer, enantiomer, mixture or salt thereof.
45 . The method according to claim 44 wherein the disease or condition is the metastasisation of tumour cells.
46 . The method according to claim 43 wherein the disease or condition is selected from the group consisting of Alzheimer's disease (AD), MCI (“mild cognitive impairment”), trisomy 21 (Down's syndrome), cerebral amyloid angiopathy, degenerative dementias, hereditary cerebral haemorrhage with amyloidosis, Dutch type (HCHWA-D), Alzheimer's dementia with Lewy bodies, trauma, stroke, pancreatitis, Inclusion Body Myositis (IBM), and other peripheral amyloidoses, diabetes or arteriosclerosis.
47 . The method according to claim 46 wherein the disease or condition is Alzheimer's disease (AD).
48 . A method for inhibiting β-secretase activity, comprising contacting β-secretase with an effective inhibitory amount of a compound of formula (I)
wherein:
A is aryl or heteroaryl, optionally substituted by one or more fluorine atoms;
L are each independently hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, carboxy, formyl, cyano, nitro, F 3 C, HF 2 C, FH 2 C, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 1-6 -alkyl-S, C 1-6 -alkyl-S—C 1-3 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkenyl, C 3-7 -cycloalkyl-C 1-6 -alkyl, C 3-7 -cycloalkyl-C 2-6 -alkenyl, C 3-7 -cycloalkyl-C 2-6 -alkynyl, C 3-7 -cycloalkenyl-C 1-6 -alkyl, C 3-7 -cycloalkenyl-C 2-6 -alkenyl, C 3-7 -cycloalkenyl-C 2-6 -alkynyl, aryl, aryl-C 1-6 -alkyl, aryl-C 2-6 -alkenyl, aryl-C 2-6 -alkynyl, heterocyclyl, heterocyclyl-C 1-6 -alkyl, heterocyclyl-C 2-6 -alkenyl, heterocyclyl-C 2-6 -alkynyl, heteroaryl, heteroaryl-C 1-6 -alkyl, heteroaryl-C 2-6 -alkenyl, heteroaryl-C 2-6 -alkynyl, R 15 —O, R 15 —O—C 1-3 -alkyl, (R 14 ) 2 N, (R 14 ) 2 N—CO, R 14 —CO—(R 14 )N, (R 14 ) 2 N—CO—(R 14 )N, R 14 —SO 2 —(R 14 )N, (R 14 ) 2 N—SO 2 or R 14 —SO 2 , wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, F 3 C, HF 2 C, FH 2 C, hydroxy-C 1-6 -alkyl, C 1-3 -alkyl, (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl, (R 14 ) 2 N—CO and HOSO 2 —;
i is 0, 1, 2 or 3;
B is a C 1-4 -alkylene bridge, optionally substituted by one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, cyano, nitro, F 3 C, HF 2 C, FH 2 C, C 1-4 -alkyl, C 1-6 -alkyl-S—C 1-3 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 alkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, aryl, aryl-C 1-3 -alkyl, heteroaryl, heteroaryl-C 1-3 -alkyl, R 15 —O, (R 14 ) 2 N—SO 2 , (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl, (R 14 ) 2 N—CO, R 14 SO 2 , R 14 —CO—(R 14 )N, R 14 SO 2 (R 14 )N, (R 14 ) 2 N—SO 2 , R 14 —CO— and R 14 —SO—, wherein
two C 1-4 -alkyl groups bound to the same carbon atom of the C 1-4 -alkylene bridge may be joined together to form a C 3-7 -cycloalkyl group, and
each of the above-mentioned groups and the C 3-7 -cycloalkyl group formed from the C 1-4 -alkyl groups are optionally substituted independently of one another by one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, F 3 C, HF 2 C, FH 2 C, C 1-3 -alkyl, R 15 —O—C 1-3 -alkyl, R 14 —CO(R 14 )N, R 14 —SO 2 (R 14 )N, (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl, (R 14 ) 2 N—CO, (R 14 ) 2 N—SO 2 — and HOSO 2 — and
wherein when B is a C 3-4 -alkylene bridge, the CH 2 group of the C 3-4 -alkylene bridge, which is bound to the group A, is optionally replaced by —O—;
R 1 is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-6 -alkyl, C 3-7 -cycloalkyl-C 2-6 -alkenyl, C 3-7 -cycloalkyl-C 2-6 -alkynyl, C 3-7 -cycloalkenyl, C 3-7 -cycloalkenyl-C 1-6 -alkyl, C 3-7 -cycloalkenyl-C 2-6 -alkenyl, C 3-7 -cycloalkenyl-C 2-6 -alkynyl, aryl, aryl-C 1-6 -alkyl, aryl-C 2-6 -alkenyl, aryl-C 2-6 -alkynyl, heterocyclyl, heterocyclyl-C 1-6 -alkyl, heterocyclyl-C 2-6 -alkenyl, heterocyclyl-C 2-6 -alkynyl, heteroaryl, heteroaryl-C 1-6 -alkyl, heteroaryl-C 2-6 -alkenyl or heteroaryl-C 2-6 -alkynyl,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, F 3 C, HF 2 C, FH 2 C, C 1-3 -alkyl, C 1-3 -alkoxy, hydroxy-C 1-6 -alkyl, (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl, (R 14 ) 2 N—CO—(R 14 ) 2 N—SO 2 , R 14 —CO—(R 14 )N, R 14 —SO 2 —(R 14 )N and HOSO 2 —;
X 1 , is nitrogen or C(R 10 );
X 2 , X 3 , X 4 are each independently nitrogen or C(R 11 ),
with the proviso that 0, 1, 2 or 3 of the groups X 1 , X 2 , X 3 and X 4 are nitrogen;
R 2 is C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, R 15 —O—C 1-3 -alkyl, C 1-6 -alkyl-S—C 1-3 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 2-6 -alkynyl, C 3-7 -cycloalkenyl, C 3-7 -cycloalkenyl-C 1-6 -alkyl, C 3-7 -cycloalkenyl-C 2-6 -alkenyl, C 3-7 -cycloalkenyl-C 2-6 -alkynyl, heterocyclyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, heterocyclyl-C 1-3 -alkyl, C 3-7 -cycloalkyl-C 2-3 -alkenyl, heterocyclyl-C 2-3 -alkenyl, heterocyclyl-C 2-3 -alkynyl, aryl, heteroaryl, aryl-C 1-3 -alkyl, heteroaryl-C 1-3 -alkyl, aryl-C 2-3 -alkenyl, aryl-C 2-3 -alkynyl, heteroaryl-C 2-3 -alkenyl or heteroaryl-C 2-3 -alkynyl,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from fluorine, chlorine, bromine, iodine, F 3 C, HF 2 C, FH 2 C, hydroxy, oxo, carboxy, formyl, cyano, nitro, (R 14 ) 2 N, HOSO 2 —, C 1-3 -alkyl, C 1-6 -alkyl-S—C 1-3 -alkyl, (R 14 ) 2 N—SO 2 —, R 14 —CO—(R 14 )N, R 14 —SO 2 —(R 14 )N, (R 14 ) 2 N—C 1-3 -alkyl, (R 14 ) 2 N—CO, R 15 —O and R 15 —O—C 1-3 -alkyl;
R 3 , R 4 are each independently hydrogen, C 1-6 -alkyl, fluorine, F 3 C, HF 2 C or FH 2 C;
R 5 , R 7 are each independently hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl, heterocyclyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, C 3-7 -cycloalkyl-C 2-6 -alkynyl, heterocyclyl-C 1-3 -alkyl, C 3-7 -cycloalkyl-C 2-4 -alkenyl, heterocyclyl-C 2-4 -alkenyl, heterocyclyl-C 2-4 -alkynyl, C 3-7 -cycloalkenyl, C 3-7 -cycloalkenyl-C 1-6 -alkyl, C 3-7 -cycloalkenyl-C 2-6 -alkenyl, C 3-7 -cycloalkenyl-C 2-6 -alkynyl, aryl, heteroaryl, aryl-C 1-3 -alkyl, heteroaryl-C 1-3 -alkyl, aryl-C 2-3 -alkenyl, heteroaryl-C 2-3 -alkenyl, aryl-C 2-3 -alkynyl or heteroaryl-C 2-3 -alkynyl,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C 1-3 -alkyl, R 15 —O, C 1-3 -alkyl-S, aryl, heteroaryl, heteroaryl-C 1-3 -alkyl, aryl-C 1-6 -alkyl, R 14 —CO—(R 14 )N, R 14 —SO 2 —(R 14 )N, (R 14 ) 2 N—SO 2 —, (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl, (R 14 ) 2 N—CO and HOSO 2 —;
R 6 , R 9 are each independently hydrogen, C 1-6 -alkyl, C 1-6 -alkoxy-C 1-3 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, C 2-6 -alkenyl, heterocyclyl-C 1-3 -alkyl, heteroaryl, heteroaryl-C 1-3 -alkyl or C 2-6 -alkynyl,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, cyano, C 1-3 -alkyl, C 1-6 -alkoxy- and (R 14 ) 2 N;
R 8 is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, C 3-7 -cycloalkyl-C 2-4 -alkenyl, C 3-7 -cycloalkyl-C 2-4 -alkynyl, C 3-7 -cycloalkenyl, C 3-7 -cycloalkenyl-C 1-6 -alkyl, C 3-7 -cycloalkenyl-C 2-6 -alkenyl, C 3-7 -cycloalkenyl-C 2-6 -alkynyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, heterocyclyl-C 2-4 -alkenyl, heterocyclyl-C 2-4 -alkynyl, aryl, aryl-C 1-3 -alkyl, aryl-C 2-4 -alkenyl, aryl-C 2-4 -alkynyl, heteroaryl, heteroaryl-C 1-3 -alkyl, heteroaryl-C 2-4 -alkenyl or heteroaryl-C 2-4 -alkynyl,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C 1-3 -alkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, R 15 —O, R 15 —O—C 1-3 -alkyl, R 15 —S, R 15 —S—C 1-3 -alkyl, aryl, heteroaryl, heteroaryl-C 1-3 -alkyl, aryl-C 1-6 -alkyl, (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl, (R 14 ) 2 N—CO (R 14 ) 2 N—CO—N(R 14 )—, (R 14 ) 2 N—SO 2 — and HOSO 2 —;
R 10 is hydrogen, fluorine, chlorine, bromine, iodine, cyano, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-6 -alkyl, C 3-7 -cycloalkyl-C 2-6 -alkynyl, heterocyclyl, heterocyclyl-C 1-6 -alkyl, heterocyclyl-C 2-6 -alkenyl, heterocyclyl-C 2-6 -alkynyl, C 3-7 -cycloalkyl-C 2-6 -alkenyl, heterocyclyl-C 2-4 -alkenyl, C 3-7 -cycloalkenyl, C 3-7 -cycloalkenyl-C 1-6 -alkyl, C 3-7 -cycloalkenyl-C 2-6 -alkenyl, C 3-7 -cycloalkenyl-C 2-6 -alkynyl, aryl, aryl-C 1-6 -alkyl, heteroaryl, heteroaryl-C 1-6 -alkyl, aryl-C 2-6 -alkenyl, heteroaryl-C 2-6 -alkenyl, aryl-C 2-6 -alkynyl or heteroaryl-C 2-6 -alkynyl, R 15 —O, R 15 —O—C 1-3 -alkyl, R 12 —SO 2 —(R 13 )N or R 12 —CO—(R 13 )N
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 1-6 -alkyl-S, C 1-6 -alkyl-S—C 1-3 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-6 -alkyl, aryl, aryl-C 1-6 -alkyl, heterocyclyl, heterocyclyl-C 1-6 -alkyl, heteroaryl, heteroaryl-C 1-6 -alkyl, R 15 —O, R 15 —O—CO, R 15 —CO, R 15 —O—CO—(R 14 )N, (R 14 ) 2 N—CO—O, R 15 —O—C 1-3 -alkyl, (R 14 ) 2 N, (R 14 ) 2 N—CO, R 14 —CO—(R 14 )N, (R 14 ) 2 N—CO—(R 14 )N, (R 14 ) 2 N—SO 2 —, (R 14 ) 2 N—SO 2 —(R 14 )N, R 14 —SO 2 —, F 3 C, HF 2 C, FH 2 C, F 3 C—O, HF 2 C—O, FH 2 C—O and R 14 —SO 2 —(R 14 )N;
R 11 are each independently hydrogen, fluorine, chlorine, bromine, iodine, R 15 —O, (R 14 ) 2 N or C 1-3 -alkyl,
wherein the C 1-3 -alkyl group is optionally substituted by one or more fluorine atoms;
R 12 is C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl-C 2-6 -alkenyl, aryl-C 2-3 -alkenyl, heteroaryl-C 2-4 -alkenyl, heterocyclyl-C 2-4 -alkenyl, aryl-C 2-3 -alkynyl, C 3-7 -cycloalkyl-C 2-4 -alkynyl, heterocyclyl-C 2-4 -alkynyl-heteroaryl-C 2-3 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-6 -alkyl, heterocyclyl, heterocyclyl-C 1-4 -alkyl, C 3-7 -cycloalkenyl, C 3-7 -cycloalkenyl-C 1-6 -alkyl, C 3-7 -cycloalkenyl-C 2-6 -alkenyl, C 3-7 -cycloalkenyl-C 2-6 -alkynyl, aryl, aryl-C 1-4 -alkyl, heteroaryl, heteroaryl-C 1-3 -alkyl or (R 14 ) 2 N,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C 1-3 -alkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, R 15 —O, R 15 —O—C 1-3 -alkyl, R 14 —CO(R 14 )N, R 14 —SO 2 (R 14 )N, (R 14 ) 2 N—SO 2 —, R 14 —SO 2 —, R 14 —SO, R 14 —S, (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl and (R 14 ) 2 N—CO;
R 13 is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, aryl, aryl-C 1-3 -alkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, heterocyclyl-C 2-3 -alkenyl, heterocyclyl-C 2-3 -alkynyl, heteroaryl, heteroaryl-C 2-3 -alkenyl, heteroaryl-C 2-3 -alkynyl or heteroaryl-C 1-3 -alkyl,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C 1-3 -alkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, R 15 —O, R 15 —O—C 1-3 -alkyl, (R 14 ) 2 N, (R 14 ) 2 N—C 1-3 -alkyl and R 14 CO;
or
R 12 and R 13 together form a C 2-6 -alkylene bridge, so that with the inclusion of the nitrogen atom linked to R 13 and the SO 2 — or CO group linked to R 12 , a heterocyclic ring is formed,
wherein one or two CH 2 groups of the C 2-6 -alkylene bridge are optionally replaced independently of one another by O, S, SO, SO 2 or N(R 14 ) in such a way that in each case two O or S atoms or an O and an S atom are not joined together directly, and the C atoms of the above-mentioned C 2-6 -alkylene bridge are optionally substituted by one or more groups selected from fluorine, chlorine, bromine, hydroxy, carboxy, formyl, cyano, F 3 C, HF 2 C, FH 2 C, C 1-6 -alkyl, C 1-6 -alkoxy, oxo and nitro;
R 14 are each independently hydrogen, C 1-6 -alkyl, C 1-6 -alkoxy-C 1-3 -alkyl, C 3-6 -cyclyoalkyl, C 3-6 -cyclyoalkyl-C 1-3 -alkyl, aryl or aryl-C 1-3 -alkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, heteroaryl or heteroaryl-C 1-3 -alkyl, wherein
two C 1-6 -alkyl groups bound to the same nitrogen atom together may form a C 2-6 -alkylene bridge, so that with the inclusion of the nitrogen atom bound to the groups R 14 a heterocyclic ring is formed,
wherein a CH 2 group of the C 2-6 -alkylene bridge may be replaced by O, S or N(R 14 ), and
the above-mentioned groups and the heterocyclic ring are optionally substituted independently of one another by one or more groups selected from among fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C 1-3 -alkyl, hydroxy-C 1-3 -alkyl, C 1-3 -alkoxy, (R 15 ) 2 N—CO or (R 15 ) 2 N and
R 15 are each independently hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cyclyoalkyl-C 1-3 -alkyl, aryl, aryl-C 1-3 -alkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl, heteroaryl or heteroaryl-C 1-3 -alkyl,
wherein the above-mentioned groups are optionally substituted independently of one another by one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxy, oxo, carboxy, formyl, cyano, nitro, C 1-3 -alkyl- and C 1-3 -alkoxy;
or a tautomer, diastereomer, enantiomer, mixture or salt thereof.Join the waitlist — get patent alerts
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