# US 2014/0194462 A1 · Alpha-7 Nicotinic Acetylcholine Receptor Allosteric Modulators, Their Derivatives and Uses Thereof

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- Number: US 2014/0194462 A1
- Document ID: US20140194462A1
- Status: Published application
- Kind: A1
- Application number: 14/048,957
- Filed: 2013-10-08
- Published: 2014-07-10
- Earliest claimed: 2009-01-15
- Assignees: Anvyl LLC
- Applicants: Anvyl LLC
- Inventors: Richard Kanner
- Web page: https://patentgrep.com/patent/US20140194462A1

## CPC

- C07D 495/04: Ortho-condensed systems
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- C07D 471/04: Ortho-condensed systems
- C07D 491/052: the oxygen-containing ring being six-membered
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present application is related to compounds represented by Formula I, which are novel allosteric modulators of α7nAChR. The application also discloses the treatment of disorders that are responsive to modulation of acetylcholine action on α7nAChR in a mammal by administering an effective amount of a compound of Formula I.

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

A compound according to claim 1, wherein R2 is hydrogen, C1-6 alkyl, C1-6 haloalkyl or C1-6 cycloalkyl, wherein each of said C1-6 alkyl and C1-6 haloalkyl is optionally substituted with one or more R9 and said C1-6 cycloalkyl is optionally substituted with 1-5 R10, and pharmaceutically acceptable salts thereof.

### Claim 3 (depends on 1)

A compound according to claim 1, wherein R3 is aryl or heteroaryl, wherein each of said aryl and heteroaryl is optionally substituted with 1-5 R10, and pharmaceutically acceptable salts thereof.

### Claim 4 (depends on 3)

A compound according to claim 3, wherein
R3 is
and n is 0-5, and pharmaceutically acceptable salts thereof.

### Claim 5 (depends on 1)

A compound according to claim 1, wherein R4 is hydrogen, and pharmaceutically acceptable salts thereof.

### Claim 6 (depends on 5)

A compound according to claim 5, wherein R5 is C1-6 alkyl optionally substituted with one or more R9, and pharmaceutically acceptable salts thereof.

### Claim 7 (depends on 1)

A compound according to claim 1, wherein R9 is aryl, heteroaryl or cycloalkyl, and pharmaceutically acceptable salts thereof.

### Claim 8 (depends on 1)

A compound according to claim 1, wherein R10 is halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy or cycloalkyloxy, and pharmaceutically acceptable salts thereof.

### Claim 9 (depends on 1)

A compound according to claim 1, wherein R7 and R8 are independently hydrogen, C1-6 alkyl, C1-6 haloalkyl or C1-6 cycloalkyl, and pharmaceutically acceptable salts thereof.

### Claim 10

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.

### Claim 11 (depends on 10)

A pharmaceutical composition according to claim 10, wherein
R3 is
and n is 0-5, and pharmaceutically acceptable salts thereof.

### Claim 12

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.

### Claim 13 (depends on 12)

A method according to claim 12, wherein R3 is
and n is 0-5, and pharmaceutically acceptable salts thereof.

### Claim 14 (depends on 12)

A method according to claim 12, wherein said disorder is a cognitive disorder related to learning or memory.

### Claim 15 (depends on 14)

A method according to claim 14, wherein said cognitive disorder is mild cognitive impairment, age related cognitive decline, senile dementia or Alzheimer's disease.

### Claim 16 (depends on 13)

A method according to claim 13, wherein said disorder is a cognitive disorder related to learning or memory.

### Claim 17 (depends on 16)

A method according to claim 16, wherein said cognitive disorder is mild cognitive impairment, age related cognitive decline, senile dementia or Alzheimer's disease.

### Claim 18

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.

### Claim 19 (depends on 18)

A method according to claim 18, wherein R3 is
and n is 0-5, and pharmaceutically acceptable salts thereof.