US 12,331,043 B2 · Benzofuran, benzothiophene, and indole analogs that inhibit the formation of tau oligomers and their method of use

Abstract

Novel benzofurans, benzothiophenes and indoles useful as inhibitors of tau oligomer formation, useful for the treatment of neurodegenerative diseases and related conditions are disclosed. The invention also relates to the pharmaceutically acceptable salts of said compounds, processes for the preparation of said compounds, intermediates used in the preparation of said compounds, and pharmaceutical compositions containing said compounds. The invention further relates to methods of use of said compounds, salts of said compounds, and said compositions in treating neurodegenerative diseases and related conditions.

A compound selected from the group consisting of:

compounds of formula (I),
Including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein R1a and R1d are each independently selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy;
R1b and R1c are selected from the group consisting of hydrogen, halogen, optionally substituted aryl and optionally substituted heteroaryl;
When R1b is hydrogen, R1c is not hydrogen;
When R1c is hydrogen, R1b is not hydrogen;
R2 is selected from the group consisting of C1-6 alkyl, C3-7 branched alkyl, C1-6 alkylaryl, optionally substituted aryl and optionally substituted heteroaryl;
X is selected from the group consisting of oxygen, sulfur, NH, and NR5;
Wherein R5 is C1-6 alkyl;
Y is selected from the group consisting of
and optionally substituted 2-benzimidazole;
Wherein R6 is selected from the group consisting of hydrogen, OH, OR7c, optionally substituted C1-6 alkyl, NR3aR3b, optionally substituted aryl, and optionally substituted heteroaryl;
R3a and R3b are independently selected from the group consisting of hydrogen and C1-6 alkyl;
R3a and R3b are taken together with the atom to which they are bound to form a three to six membered saturated ring optionally substituted with a group selected from OH, C1-6 alkyl, NR8aR8b optionally including a member selected from the group consisting of O, NR8, and S;
R8 is selected from the group consisting of hydrogen, C1-6 alkyl, and CO (C1-6alkyl);
R8a and R8b are independently selected from hydrogen and C1-6 alkyl;
R7a is selected from the group consisting of hydrogen and C1-6 alkyl;
R7b is selected from the group consisting of C1-6 alkyl, aryl, and heteroaryl;
and R7c is selected from the group consisting of C1-6 alkyl and C3-7 branched alkyl;
compounds having formula (II):
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein R1a, R1b, R1c, R1d, R2, and Y are as defined for formula I;
compounds having formula (III):
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein R1a, R1b, R1c, R1d, R2, and Y are as defined for formula I;
compounds having formula (IV):
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein R1a, R1b, R1c, R1d, R2, and Y are as defined for formula I;
compounds having formula (V):
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein R1a, R1b, R1c, R1d, R2, R5 and Y are as defined for formula I;
compounds having formula (V):
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein R1a, R1b, R1c, R1d, R2, R6, and X are as defined for formula I;
compounds having formula (VI):
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein R1a, R1b, R1c, R1d, R2, R7a, R7b and X are as defined for formula I;
compounds having formula (VII):
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein R1a, R1b, R1c, R1d, R2 and X are as defined for formula I;
compounds having formula (IX):
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein R1b, R1c, R2, X and Y are as defined for formula I;
compounds having formula (X):
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein R1b, R1c, R2, and Y are as defined for formula I;
compounds having formula (XI):
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein R1b, R1c, R2, and Y are as defined for formula I;
compounds having formula (XII):
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein R1b, R1c, R2, and Y are as defined for formula I;
compounds having formula (XIII):
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein R1b, R1c, X and Y are as defined for formula I;
R9a, R9b, and R9c are independently selected from the group consisting of hydrogen, halogen, and C1-6 alkyl;
and X1 is selected from the group consisting of oxygen and sulfur;
compounds having formula (XIV):
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein R1c, R2, X and Y are as defined for formula I;
A1, A2, A3, A4, and A5 are selected from the group consisting of nitrogen and CR10;
No more than two of A1, A2, A3, A4, and A5 may be nitrogen;
R10 is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, halogen, hydroxy, and NHSO2R11;
and R11 is independently selected from the group consisting of hydrogen and C1-6 alkyl;
compounds having formula (XIVa):
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein R1b, R2, X and Y are as defined for formula I;
A6, A7, A8, A9, and A10 are selected from the group consisting of nitrogen and CR10;
No more than two of A6, A7, A8, A9, and A10 may be nitrogen;
R10 is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, halogen, hydroxy, and NHSO2R11;
and R11 is independently selected from the group consisting of hydrogen and C1-6 alkyl;
compounds having formula (XIVb):
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein R2, X and Y are as defined for formula I;
A1, A2, A3, A4, A5, A6, A7, A8, A9, and A10 are selected from the group consisting of nitrogen and CR10;
No more than two of A1, A2, A3, A4, and A5 may be nitrogen;
No more than two of A6, A7, A8, A9, and A10 may be nitrogen;
R10 is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, halogen, hydroxy, and NHSO2R11;
and R11 is independently selected from the group consisting of hydrogen and C1-6 alkyl;
compounds having formula (XV):
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein R1c, R2 and Y are as defined for formula I;
A1, A2, A3, A4, and A5 are selected from the group consisting of nitrogen and CR10;
No more than two of A1, A2, A3, A4, and A5 may be nitrogen;
R10 is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, halogen, hydroxy, and NHSO2R11;
and R11 is independently selected from the group consisting of hydrogen and C1-6 alkyl;
compounds having formula (XVa):
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein R1b, R2 and Y are as defined for formula I;
A6, A7, A8, A9, and A10 are selected from the group consisting of nitrogen and CR10;
No more than two of A6, A7, A8, A9, and A10 may be nitrogen;
R10 is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, halogen, hydroxy, and NHSO2R11;
and R11 is independently selected from the group consisting of hydrogen and C1-6 alkyl;
compounds having formula (XVb):
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein R2 and Y are as defined for formula I;
A1, A2, A3, A4, A5, A6, A7, A8, A9, and A10 are selected from the group consisting of nitrogen and CR10;
No more than two of A1, A2, A3, A4, and A5 may be nitrogen;
No more than two of A6, A7, A8, A9, and A10 may be nitrogen;
R10 is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, halogen, hydroxy, and NHSO2R11;
and R11 is independently selected from the group consisting of hydrogen and C1-6 alkyl;
compounds having formula (XVI):
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein R1c, R2 and Y are as defined for formula I;
A1, A2, A3, A4, and A5 are selected from the group consisting of nitrogen and CR10;
No more than one of A1, A2, A3, A4, and A5 may be nitrogen;
R10 is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, halogen, hydroxy, and NHSO2R11;
and R11 is independently selected from the group consisting of hydrogen and C1-6 alkyl;
compounds having formula (XVIa):
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein R1b, R2 and Y are as defined for formula I;
A6, A7, A8, A9, and A10 are selected from the group consisting of nitrogen and CR10;
No more than two of A6, A7, A8, A9, and A10 may be nitrogen;
R10 is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, halogen, hydroxy, and NHSO2R11;
and R11 is independently selected from the group consisting of hydrogen and C1-6 alkyl;
compounds having formula (XVIb):
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein R2 and Y are as defined for formula I;
A1, A2, A3, A4, A5, A6, A7, A8, A9, and A10 are selected from the group consisting of nitrogen and CR10;
No more than two of A1, A2, A3, A4, and A5 may be nitrogen;
No more than two of A6, A7, A8, A9, and A10 may be nitrogen;
R10 is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, halogen, hydroxy, and NHSO2R11;
and R11 is independently selected from the group consisting of hydrogen and C1-6 alkyl;
compounds having formula (XVII):
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein R1c, R2 and Y are as defined for formula I;
A1, A2, A3, A4, and A5 are selected from the group consisting of nitrogen and CR10;
No more than one of A1, A2, A3, A4, and A5 may be nitrogen;
R10 is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, halogen, hydroxy, and NHSO2R11;
and R11 is independently selected from the group consisting of hydrogen and C1-6 alkyl;
compounds having formula (XVIIa):
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein R2, R1b and Y are as defined for formula I;
A6, A7, A8, A9, and A10 are selected from the group consisting of nitrogen and CR10;
No more than two of A6, A7, A8, A9, and A10 may be nitrogen;
R10 is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, halogen, hydroxy, and NHSO2R11;
and R11 is independently selected from the group consisting of hydrogen and C1-6 alkyl;
compounds having formula (XVIIb):
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein R2 and Y are as defined for formula I;
A1, A2, A3, A4, A5, A6, A7, A8, A9, and A10 are selected from the group consisting of nitrogen and CR10;
No more than two of A1, A2, A3, A4, and A5 may be nitrogen;
No more than two of A6, A7, A8, A9, and A10 may be nitrogen;
R10 is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, halogen, hydroxy, and NHSO2R11;
and R11 is independently selected from the group consisting of hydrogen and C1-6 alkyl;
compounds having formula (XVIII):
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein R1c, R2, R5 and Y are as defined for formula I;
A1, A2, A3, A4, and A5 are selected from the group consisting of nitrogen and CR10;
No more than one of A1, A2, A3, A4, and A5 may be nitrogen;
R10 is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, halogen, hydroxy, and NHSO2R11;
and R11 is independently selected from the group consisting of hydrogen and C1-6 alkyl;
compounds having formula (XVIIIa):
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein R1b, R2, R5 and Y are as defined for formula I;
A6, A7, A8, A9, and A10 are selected from the group consisting of nitrogen and CR10;
No more than two of A6, A7, A8, A9, and A10 may be nitrogen;
R10 is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, halogen, hydroxy, and NHSO2R11;
and R11 is independently selected from the group consisting of hydrogen and C1-6 alkyl;
compounds having formula (XVIIIb):
including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein R2, R5 and Y are as defined for formula I;
A1, A2, A3, A4, A5, A6, A7, A8, A9, and A10 are selected from the group consisting of nitrogen and CR10;
no more than two of A1, A2, A3, A4, and A5 may be nitrogen;
no more than two of A6, A7, A8, A9, and A10 may be nitrogen;
R10 is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, halogen, hydroxy, and NHSO2R11;
and R11 is independently selected from the group consisting of hydrogen and C1-6 alkyl, and
wherein the compound is in a pharmaceutically acceptable carrier.

137 more elements

Benzofuran, benzothiophene, and indole analogs that inhibit the formation of tau oligomers and their method of use

Life of this patent

Benzofuran, benzothiophene, and indole analogs that inhibit the formation of tau oligomers and their method of use

Life of this patent

Abstract

Claims5