US 12,331,043 B2
Benzofuran, benzothiophene, and indole analogs that inhibit the formation of tau oligomers and their method of use
Eliot J. Davidowitz, West Hempstead, NY (US); James G. Moe, Stamford, CT (US); Allen B. Reitz, Lansdale, PA (US); Haiyan Bian, Princeton, NJ (US); Charles Gluchowski, Danville, CA (US); James Hendrix, Hillsborough, NJ (US); Albert S. Yehaskel, Great Neck, NY (US); Mark E. McDonnell, Lansdale, PA (US); and H. Marie Loughran, Perkasie, PA (US)
Assigned to Oligomerix, Inc., White Plains, NY (US)
Filed by OLIGOMERIX INC., White Plains, NY (US)
Filed on Apr. 14, 2022, as Appl. No. 17/721,178.
Application 17/721,178 is a division of application No. 16/471,424, granted, now 11,306,075, previously published as PCT/US2017/067032, filed on Dec. 18, 2017.
Claims priority of provisional application 62/436,787, filed on Dec. 20, 2016.
Prior Publication US 2024/0158379 A1, May 16, 2024
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 409/14 (2006.01); C07D 307/80 (2006.01); C07D 405/14 (2006.01)
CPC C07D 409/14 (2013.01) [C07D 307/80 (2013.01); C07D 405/14 (2013.01)] 5 Claims
 
1. A compound selected from the group consisting of:
compounds of formula (I),

OG Complex Work Unit Chemistry
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

OG Complex Work Unit Chemistry
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):

OG Complex Work Unit Chemistry
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):

OG Complex Work Unit Chemistry
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):

OG Complex Work Unit Chemistry
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):

OG Complex Work Unit Chemistry
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):

OG Complex Work Unit Chemistry
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):

OG Complex Work Unit Chemistry
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):

OG Complex Work Unit Chemistry
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):

OG Complex Work Unit Chemistry
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):

OG Complex Work Unit Chemistry
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):

OG Complex Work Unit Chemistry
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):

OG Complex Work Unit Chemistry
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):

OG Complex Work Unit Chemistry
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):

OG Complex Work Unit Chemistry
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):

OG Complex Work Unit Chemistry
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):

OG Complex Work Unit Chemistry
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):

OG Complex Work Unit Chemistry
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):

OG Complex Work Unit Chemistry
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):

OG Complex Work Unit Chemistry
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):

OG Complex Work Unit Chemistry
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):

OG Complex Work Unit Chemistry
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):

OG Complex Work Unit Chemistry
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):

OG Complex Work Unit Chemistry
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):

OG Complex Work Unit Chemistry
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):

OG Complex Work Unit Chemistry
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):

OG Complex Work Unit Chemistry
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):

OG Complex Work Unit Chemistry
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):

OG Complex Work Unit Chemistry
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.