Novel Compounds for the Treatment of Diseases Associated with Amyloid or Amyloid-like Proteins

A method of treating or preventing a disease or condition associated with an amyloid and/or amyloid-like protein comprising administering to a subject in need of such treatment an effective amount of a compound of formula (I):

• A-L1-B (I)
• and all stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof;
• wherein
• A is selected from:
• L1 is:
• B is selected from:
• wherein
• for each occurrence R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, CN, CF3, CONR4R5, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl can be optionally substituted, or wherein R1 and R2 when taken together can form a 5- to 8-membered ring containing carbon atoms and optionally one or more heteroatoms selected from O, S, or N or optionally one or more heteroatom-containing moieties, wherein the heteroatom includes but is not limited to N, O and/or S, and wherein the 5- to 8-membered ring may be substituted by NR20R21;
• for each occurrence R3 is each independently selected from the group consisting of:
• hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl can be optionally substituted;
• for each occurrence Ra is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, S(O)tNR4R5, S(O)tR4, C(O)OR4, C(O)R4, and C(O)NR4R5;
• for each occurrence Rb is independently selected from the group consisting of hydrogen, alkyl, and haloalkyl;
• for each occurrence R4, R5, R20 and R21 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl can be optionally substituted, or wherein R20 and R21 when taken together with the nitrogen to which they are attached can form a 3- to 8-membered ring containing carbon atoms and optionally one or more further heteroatoms selected from O, S, or N or optionally one or more heteroatom-containing moieties, wherein the heteroatom includes but is not limited to N, O and/or S, and wherein the 3- to 8-membered ring may be optionally substituted;
• for each occurrence X and Y are each independently selected from the group consisting of CR3 and N;
• and
• t is 1 or 2.

A test kit for detection and/or diagnosis of an amyloid-associated disease or condition comprising a compound of formula (I):

• A-L1-B (I)
• and all stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof;
• wherein
• A is selected from:
• L1 is:
• B is selected from:
• wherein
• for each occurrence R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, CN, CF3, CONR4R5, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl can be optionally substituted, or wherein R1 and R2 when taken together can form a 5- to 8-membered ring containing carbon atoms and optionally one or more heteroatoms selected from O, S, or N or optionally one or more heteroatom-containing moieties, wherein the heteroatom includes but is not limited to N, O and/or S, and wherein the 5- to 8-membered ring may be substituted by NR20R21;
• for each occurrence R3 is each independently selected from the group consisting of:
• hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl can be optionally substituted;
• for each occurrence Ra is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, S(O)tNR4R5, S(O)tR4, C(O)OR4, C(O)R4, and C(O)NR4R5;
• for each occurrence Rb is independently selected from the group consisting of hydrogen, alkyl, and haloalkyl;
• for each occurrence R4, R5, R20 and R21 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl can be optionally substituted, or wherein R20 and R21 when taken together with the nitrogen to which they are attached can form a 3- to 8-membered ring containing carbon atoms and optionally one or more further heteroatoms selected from O, S, or N or optionally one or more heteroatom-containing moieties, wherein the heteroatom includes but is not limited to N, O and/or S, and wherein the 3- to 8-membered ring may be optionally substituted;
• for each occurrence X and Y are each independently selected from the group consisting of CR3 and N;
• and
• t is 1 or 2.

A method of treating or preventing an ocular disease or condition associated with a pathological abnormality or change in a tissue of a visual system, comprising administering to a subject in need of such treatment an effective amount of a compound of formula (I):

• A-L1-B (I)
• and all stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof;
• wherein
• A is selected from:
• L1 is:
• B is selected from:
• wherein
• for each occurrence R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, CN, CF3, CONR4R5, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl can be optionally substituted, or wherein R1 and R2 when taken together can form a 5- to 8-membered ring containing carbon atoms and optionally one or more heteroatoms selected from O, S, or N or optionally one or more heteroatom-containing moieties, wherein the heteroatom includes but is not limited to N, O and/or S, and wherein the 5- to 8-membered ring may be substituted by NR20R21;
• for each occurrence R3 is each independently selected from the group consisting of:
• hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl can be optionally substituted;
• for each occurrence Ra is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, S(O)tNR4R5, S(O)tR4, C(O)OR4, C(O)R4, and C(O)NR4R5;
• for each occurrence Rb is independently selected from the group consisting of hydrogen, alkyl, and haloalkyl;
• for each occurrence R4, R5, R20 and R21 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl can be optionally substituted, or wherein R20 and R21 when taken together with the nitrogen to which they are attached can form a 3- to 8-membered ring containing carbon atoms and optionally one or more further heteroatoms selected from O, S, or N or optionally one or more heteroatom-containing moieties, wherein the heteroatom includes but is not limited to N, O and/or S, and wherein the 3- to 8-membered ring may be optionally substituted;
• for each occurrence X and Y are each independently selected from the group consisting of CR3 and N;
• and
• t is 1 or 2.

A method for inhibiting Aβ1-42 aggregation, Tau aggregation or alpha-synuclein aggregation comprising administering to a subject in need of such treatment an effective amount of a compound of formula (I):

• A-L1-B (I)
• and all stereoisomers, racemic mixtures, pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof;
• wherein
• A is selected from:
• L1 is:
• B is selected from:
• wherein
• for each occurrence R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, CN, CF3, CONR4R5, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl can be optionally substituted, or wherein R1 and R2 when taken together can form a 5- to 8-membered ring containing carbon atoms and optionally one or more heteroatoms selected from O, S, or N or optionally one or more heteroatom-containing moieties, wherein the heteroatom includes but is not limited to N, O and/or S, and wherein the 5- to 8-membered ring may be substituted by NR20R21;
• for each occurrence R3 is each independently selected from the group consisting of:
• hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl can be optionally substituted;
• for each occurrence Ra is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, S(O)tNR4R5, S(O)tR4, C(O)OR4, C(O)R4, and C(O)NR4R5;
• for each occurrence Rb is independently selected from the group consisting of hydrogen, alkyl, and haloalkyl;
• for each occurrence R4, R5, R20 and R21 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl can be optionally substituted, or wherein R20 and R21 when taken together with the nitrogen to which they are attached can form a 3- to 8-membered ring containing carbon atoms and optionally one or more further heteroatoms selected from O, S, or N or optionally one or more heteroatom-containing moieties, wherein the heteroatom includes but is not limited to N, O and/or S, and wherein the 3- to 8-membered ring may be optionally substituted;
• for each occurrence X and Y are each independently selected from the group consisting of CR3 and N;
• and
• t is 1 or 2.