Alpha-7 Nicotinic Acetylcholine Receptor Allosteric Modulators, Their Derivatives and Uses Thereof

A pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier and a compound of Formula I:

• or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, wherein:
• X is O or S;
• R2 is hydrogen, halogen, nitrile, nitro or —C(═O)R9;
• or
• R2 is C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, or C1-8 haloalkyl, wherein each of said alkyl, alkenyl, alkynyl, and haloalkyl is optionally substituted with one or more R9;
• or
• R2 is aryl, carbon-attached heteroaryl, cycloalkyl, cycloalkenyl, carbon-attached heterocycloalkyl or carbon-attached heterocycloalkenyl, wherein said heterocycloalkyl is optionally fused with a phenyl or a 5-6 membered heteroaryl having 1-3 heteroatoms, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein each of said aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl is optionally substituted with 1-5 R10;
• R3 is aryl, heteroaryl, heterocycloalkyl or heterocycloalkenyl, wherein said heterocycloalkyl is optionally fused with a phenyl or a 5-6 membered heteroaryl having 1-3 heteroatoms, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein each of said aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl is optionally substituted with 1-5 R10;
• R4 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or C1-8 haloalkyl, wherein each of said alkyl, alkenyl, alkynyl, and haloalkyl is optionally substituted with one or more R9;
• or
• R4 is aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, wherein heterocycloalkyl is optionally fused with a phenyl or a 5-6 membered heteroaryl having 1-3 heteroatoms, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein each of said aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl is optionally substituted with 1-5 R10;
• R5 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, —C(═O)R9, —S(═O)0-2R9, —S(═O)0-2-A-R9 or A-C(═O)R9, wherein each of said alkyl, alkenyl, alkynyl, and haloalkyl is optionally substituted with one or more R9;
• or
• R5 is aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, wherein said heterocycloalkyl is optionally fused with a phenyl or a 5-6 membered heteroaryl, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein each of said aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl is optionally substituted with 1-5 R10;
• or
• R4 and R5 taken together with the nitrogen to which they are attached form a heteroaryl, a heterocycloalkyl or a heterocycloalkenyl, wherein said heterocycloalkyl is optionally fused with a phenyl or a 5-6 membered heteroaryl having 1-3 heteroatoms, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein each of said heteroaryl, heterocycloalkyl, and heterocycloalkenyl is optionally substituted with 1-5 R10;
• each of R7 and R8 is independently hydrogen, C1-8 alkyl, C1-8 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, or C1-8 haloalkoxy;
• wherein each of said alkyl, alkenyl, alkynyl, haloalkyl, and haloalkoxy is optionally substituted with one or more R9;
• or
• each of R7 and R8 is independently halogen, nitrile, nitro, hydroxyl, —C(═O)R9, —S(═O)0-2R9, —NR4R5, —O-A-R9, —S(═O)0-2-A-R9 or -A-C(═O)R9;
• or
• each of R7 and R8 is independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, wherein said heterocycloalkyl is optionally fused with a phenyl or a 5-6 membered heteroaryl having 1-3 heteroatoms, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein each of said aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl is optionally substituted with 1-5 R10;
• or
• R9 is hydroxyl, C1-6 alkoxy, C1-8 haloalkoxy, C3-6 cycloalkoxy or —NR11R12;
• or
• R9 is aryl, heteroaryl, cycloalkyl, or cycloalkenyl, wherein each of said aryl, heteroaryl, cycloalkyl and cycloalkenyl are optionally substituted with 1-5 R10;
• or
• R9 is heterocycloalkyl or heterocycloalkenyl, wherein said heterocycloalkyl is optionally fused with a phenyl or a 5-6 membered heteroaryl having 1-3 heteroatoms, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein each of said heterocycloalkyl and said heterocycloalkenyl is optionally substituted with 1-5 R10;
• R10 is nitro, nitrile, hydroxyl, halogen, C1-6 acyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cycloalkoxy, cycloalkyloxy, aryl, heteroaryl, —NR11R12, —C(═O)OR11, —C(═O)NHR11, —NHC(═O)R13, —NHS(═O)2R13, —S(═O)0-2R13, —S(═O)2NHR11, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, wherein said heterocycloalkyl is optionally fused with a phenyl or a 5-6 membered heteroaryl having 1-3 heteroatoms, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O);
• wherein each of said alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkoxy, cycloalkyloxy, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl is optionally substituted;
• each of R11 and R12 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, cycloalkyl or cycloalkenyl;
• wherein each of said alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl and cycloalkenyl is optionally substituted with one or more R9;
• R13 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl or C4-6 cycloalkenyl;
• wherein each of said alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl and cycloalkenyl is optionally substituted;
• and
• A is C1-8 alkyl, C2-8 alkenyl or C1-8 haloalkyl.

A method for treating a disorder selected from the group consisting of a neurodegenerative disease, senile dementia, schizophrenia, Alzheimer's disease, learning deficit, cognition deficit, memory loss, Lewy Body dementia, attention-deficit disorder, attention deficit hyperactivity disorder, anxiety, mania, manic depression, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, brain inflammation, Tourette's syndrome, pain, inflammation, septic shock, ulcerative colitis, and irritable bowel comprising administering to a patient in need of such treatment an effective amount of a pharmaceutical composition comprising a compound of Formula I:

• or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, wherein:
• X is O or S;
• R2 is hydrogen, halogen, nitrile, nitro or —C(═O)R9;
• or
• R2 is C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, or C1-8 haloalkyl, wherein each of said alkyl, alkenyl, alkynyl, and haloalkyl is optionally substituted with one or more R9;
• or
• R2 is aryl, carbon-attached heteroaryl, cycloalkyl, cycloalkenyl, carbon-attached heterocycloalkyl or carbon-attached heterocycloalkenyl, wherein said heterocycloalkyl is optionally fused with a phenyl or a 5-6 membered heteroaryl having 1-3 heteroatoms, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein each of said aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl is optionally substituted with 1-5 R10;
• R3 is aryl, heteroaryl, heterocycloalkyl or heterocycloalkenyl, wherein said heterocycloalkyl is optionally fused with a phenyl or a 5-6 membered heteroaryl having 1-3 heteroatoms, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein each of said aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl is optionally substituted with 1-5 R10;
• R4 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or C1-8 haloalkyl, wherein each of said alkyl, alkenyl, alkynyl, and haloalkyl is optionally substituted with one or more R9;
• or
• R4 is aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, wherein heterocycloalkyl is optionally fused with a phenyl or a 5-6 membered heteroaryl having 1-3 heteroatoms, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein each of said aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl is optionally substituted with 1-5 R10;
• R5 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, —C(═O)R9, —S(═O)0-2R9, —S(═O)0-2-A-R9 or A-C(═O)R9, wherein each of said alkyl, alkenyl, alkynyl, and haloalkyl is optionally substituted with one or more R9;
• or
• R5 is aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, wherein said heterocycloalkyl is optionally fused with a phenyl or a 5-6 membered heteroaryl, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein each of said aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl is optionally substituted with 1-5 R10;
• or
• R4 and R5 taken together with the nitrogen to which they are attached form a heteroaryl, a heterocycloalkyl or a heterocycloalkenyl, wherein said heterocycloalkyl is optionally fused with a phenyl or a 5-6 membered heteroaryl having 1-3 heteroatoms, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein each of said heteroaryl, heterocycloalkyl, and heterocycloalkenyl is optionally substituted with 1-5 R10;
• each of R7 and R8 is independently hydrogen, C1-8 alkyl, C1-8 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, or C1-8 haloalkoxy;
• wherein each of said alkyl, alkenyl, alkynyl, haloalkyl, and haloalkoxy is optionally substituted with one or more R9;
• or
• each of R7 and R8 is independently halogen, nitrile, nitro, hydroxyl, —C(═O)R9, —S(═O)0-2R9, —NR4R5, —O-A-R9, —S(═O)0-2-A-R9 or -A-C(═O)R9;
• or
• each of R7 and R8 is independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, wherein said heterocycloalkyl is optionally fused with a phenyl or a 5-6 membered heteroaryl having 1-3 heteroatoms, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein each of said aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl is optionally substituted with 1-5 R10;
• or
• R9 is hydroxyl, C1-6 alkoxy, C1-8 haloalkoxy, C3-6 cycloalkoxy or —NR11R12;
• or
• R9 is aryl, heteroaryl, cycloalkyl, or cycloalkenyl, wherein each of said aryl, heteroaryl, cycloalkyl and cycloalkenyl are optionally substituted with 1-5 R10;
• or
• R9 is heterocycloalkyl or heterocycloalkenyl, wherein said heterocycloalkyl is optionally fused with a phenyl or a 5-6 membered heteroaryl having 1-3 heteroatoms, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein each of said heterocycloalkyl and said heterocycloalkenyl is optionally substituted with 1-5 R10;
• R10 is nitro, nitrile, hydroxyl, halogen, C1-6 acyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cycloalkoxy, cycloalkyloxy, aryl, heteroaryl, —NR11R12, —C(═O)OR11, —C(═O)NHR11, —NHC(═O)R13, —NHS(═O)2R13, —S(═O)0-2R13, —S(═O)2NHR11, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, wherein said heterocycloalkyl is optionally fused with a phenyl or a 5-6 membered heteroaryl having 1-3 heteroatoms, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O);
• wherein each of said alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkoxy, cycloalkyloxy, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl is optionally substituted;
• each of R11 and R12 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, cycloalkyl or cycloalkenyl;
• wherein each of said alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl and cycloalkenyl is optionally substituted with one or more R9;
• R13 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl or C4-6 cycloalkenyl;
• wherein each of said alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl and cycloalkenyl is optionally substituted;
• and
• A is C1-8 alkyl, C2-8 alkenyl or C1-8 haloalkyl.

A method for modulating α7nAChR comprising administering to a patient in need of such modulation an effective amount of a pharmaceutical composition comprising a compound of Formula I:

• or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, wherein:
• X is O or S;
• R2 is hydrogen, halogen, nitrile, nitro or —C(═O)R9;
• or
• R2 is C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, or C1-8 haloalkyl, wherein each of said alkyl, alkenyl, alkynyl, and haloalkyl is optionally substituted with one or more R9;
• or
• R2 is aryl, carbon-attached heteroaryl, cycloalkyl, cycloalkenyl, carbon-attached heterocycloalkyl or carbon-attached heterocycloalkenyl, wherein said heterocycloalkyl is optionally fused with a phenyl or a 5-6 membered heteroaryl having 1-3 heteroatoms, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein each of said aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl is optionally substituted with 1-5 R10;
• R3 is aryl, heteroaryl, heterocycloalkyl or heterocycloalkenyl, wherein said heterocycloalkyl is optionally fused with a phenyl or a 5-6 membered heteroaryl having 1-3 heteroatoms, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein each of said aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl is optionally substituted with 1-5 R10;
• R4 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or C1-8 haloalkyl, wherein each of said alkyl, alkenyl, alkynyl, and haloalkyl is optionally substituted with one or more R9;
• or
• R4 is aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, wherein heterocycloalkyl is optionally fused with a phenyl or a 5-6 membered heteroaryl having 1-3 heteroatoms, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein each of said aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl is optionally substituted with 1-5 R10;
• R5 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, —C(═O)R9, —S(═O)0-2R9, —S(═O)0-2-A-R9 or A-C(═O)R9, wherein each of said alkyl, alkenyl, alkynyl, and haloalkyl is optionally substituted with one or more R9;
• or
• R5 is aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, wherein said heterocycloalkyl is optionally fused with a phenyl or a 5-6 membered heteroaryl, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein each of said aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl is optionally substituted with 1-5 R10;
• or
• R4 and R5 taken together with the nitrogen to which they are attached form a heteroaryl, a heterocycloalkyl or a heterocycloalkenyl, wherein said heterocycloalkyl is optionally fused with a phenyl or a 5-6 membered heteroaryl having 1-3 heteroatoms, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein each of said heteroaryl, heterocycloalkyl, and heterocycloalkenyl is optionally substituted with 1-5 R10;
• each of R7 and R8 is independently hydrogen, C1-8 alkyl, C1-8 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, or C1-8 haloalkoxy;
• wherein each of said alkyl, alkenyl, alkynyl, haloalkyl, and haloalkoxy is optionally substituted with one or more R9;
• or
• each of R7 and R8 is independently halogen, nitrile, nitro, hydroxyl, —C(═O)R9, —S(═O)0-2R9, —NR4R5, —O-A-R9, —S(═O)0-2-A-R9 or -A-C(═O)R9;
• or
• each of R7 and R8 is independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, wherein said heterocycloalkyl is optionally fused with a phenyl or a 5-6 membered heteroaryl having 1-3 heteroatoms, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein each of said aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl is optionally substituted with 1-5 R10;
• or
• R9 is hydroxyl, C1-6 alkoxy, C1-8 haloalkoxy, C3-6 cycloalkoxy or —NR11R12;
• or
• R9 is aryl, heteroaryl, cycloalkyl, or cycloalkenyl, wherein each of said aryl, heteroaryl, cycloalkyl and cycloalkenyl are optionally substituted with 1-5 R10;
• or
• R9 is heterocycloalkyl or heterocycloalkenyl, wherein said heterocycloalkyl is optionally fused with a phenyl or a 5-6 membered heteroaryl having 1-3 heteroatoms, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O), wherein each of said heterocycloalkyl and said heterocycloalkenyl is optionally substituted with 1-5 R10;
• R10 is nitro, nitrile, hydroxyl, halogen, C1-6 acyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cycloalkoxy, cycloalkyloxy, aryl, heteroaryl, —NR11R12;
• C(═O)NHR11, —C(═O)NHR11, —NHC(═O)R13, —NHS(═O)2R13;
• —S(═O)0-2R13;
• —S(═O)2NHR11, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, wherein said heterocycloalkyl is optionally fused with a phenyl or a 5-6 membered heteroaryl having 1-3 heteroatoms, wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(═O);
• wherein each of said alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkoxy, cycloalkyloxy, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl is optionally substituted;
• each of R11 and R12 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, cycloalkyl or cycloalkenyl;
• wherein each of said alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl and cycloalkenyl is optionally substituted with one or more R9;
• R13 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl or C4-6 cycloalkenyl;
• wherein each of said alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl and cycloalkenyl is optionally substituted;
• and
• A is C1-8 alkyl, C2-8 alkenyl or C1-8 haloalkyl.