# US 2014/0194424 A1 · Spirolactam derivatives and uses of same

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- Number: US 2014/0194424 A1
- Document ID: US20140194424A1
- Status: Published application
- Kind: A1
- Application number: 14/103,866
- Filed: 2013-12-12
- Published: 2014-07-10
- Earliest claimed: 2009-10-28
- Assignees: H. Lundbeck A/S
- Applicants: H. Lundbeck A/S
- Inventors: Hao Zhou; Guiying Li; Dario Doller; Gil Ma
- Web page: https://patentgrep.com/patent/US20140194424A1

## CPC

- C07D 209/54: Spiro-condensed
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/22: Anxiolytics
- 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
- A61P 25/32: Alcohol-abuse
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 213/50: Ketonic radicals
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides spirolactam derivatives of formula (I): wherein R1-R7 are as defined herein; or a pharmaceutically acceptable salt thereof; and pharmaceutical compositions and uses of the same.

## Claims

### Claim at position 1

1-20. (canceled)

### Claim 21

A method of treating a disease or disorder comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein the disease or disorder is a central nervous system disease or disorder; and
wherein:
R1 and R2 are each independently aryl, heteroaryl, alkyl, cycloalkyl, ketocycloalkyl, or heterocyclyl, which is optionally mono-, di-, or tri-substituted independently with alkyl, cycloalkyl, alkoxy, hydroxy, halogen, cyano, trifluoroalkyl, amino, acyl, aryl, heteroaryl, heterocyclyl, —C(O)NHR30, —C(O)N(R30)R31—N(R30)C(O)R31, —NHR30, —N(R30)R31 or —OR30; wherein:
R30 and R31 are each independently C1-C6alkyl or C1-C6cycloalkyl that is optionally substituted with acyl, halogen, —CN, —NH2, —NH(C1-C3alkyl), —N(C1-C3alkyl)2, C1-C3alkylheterocyclyl, C1-C3alkylcarbamate, —C(O)NH(C1-C3alkyl), —C(O)N(C1-C3alkyl)2, —NHC(O)—C1-C3alkyl, —N(C1-C3alkyl)-C(O)—C1-C3alkyl, OH, or —O—C1-C6alkyl; and
each aryl, heteroaryl, heterocyclyl substituent is optionally substituted with C1-3alkyl, C3-5cycloalkyl, C1-3alkoxy, hydroxy, halogen, cyano, trifluoroalkyl, or amino;
R3, R4, R5 and R6 are each independently H, C1-3alkyl, C3-5cycloalkyl, halogen, or hydroxy;
R7 is H; or
R1 and R7 taken together with the —C(O)N— to which they are attached form a mono- or bicyclic 4- to 12-membered heterocycloalkyl or heteroaryl, which optionally contains 1-3 additional heteroatoms; or a pharmaceutically acceptable salt thereof.

### Claim 21 (depends on 20)

The method of claim 20, wherein R1 and R2 are both aryl.

### Claim 22 (depends on 20)

The method of claim 20, wherein R1 and R2 are both heteroaryl.

### Claim 23 (depends on 20)

The method of claim 20, wherein R1 is aryl and R2 is heteroaryl.

### Claim 24 (depends on 20)

The method of claim 20, wherein R1 is heteroaryl and R2 is aryl.

### Claim 25 (depends on 20)

The method of claim 20, wherein either R1 or R2 is heteroaryl

### Claim 26 (depends on 20)

The method of claim 20, wherein either R1 or R2 is aryl.

### Claim 27 (depends on 20)

The method of claim 20, wherein at least one aryl is phenyl.

### Claim 28 (depends on 20)

The method of claim 20, wherein R1 is aryl or heteroaryl and R2 is cycloalkyl, ketocycloalkyl or heterocyclyl.

### Claim 29 (depends on 20)

The method of claim 20, wherein the mono-, di-, or tri-substituents are independently selected from the group consisting of methyl, methoxy, dimethylamino-ethoxy, amino, methylamino, dimethylamino, cyano, chloro, cyano, dimethylamino, dimethylamino-ethoxy, methyl, methylamino, methoxy, fluoro, —C(O)NHCH3, phenyl, furanyl, pyrrolidinyl, thiophenyl and trifluoromethyl.

### Claim 30 (depends on 20)

The method of claim 20, wherein the phenyl is optionally substituted with fluorine.

### Claim 31 (depends on 20)

The method of claim 20, wherein the compound is selected from the group consisting of trans-Pyridine-2-carboxylic acid [2-(3-chloro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-Pyridine-2-carboxylic acid [2-(3-chloro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
trans-6-Methyl-pyridine-2-carboxylic acid [2-(3-chloro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-6-Methyl-pyridine-2-carboxylic acid [2-(3-chloro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
Pyridine-2-carboxylic acid [(5R,7R)-2-(3-chloro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
Pyridine-2-carboxylic acid [(5S,7S)-2-(3-chloro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-Pyridine-2-carboxylic acid [2-(6-methyl-pyridin-2-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
3-Chloro-N-[2-(6-methyl-pyridin-2-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-benzamide;
cis-Pyridine-2-carboxylic acid [2-(3-cyano-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-6-Methyl-pyridine-2-carboxylic acid [2-(3-cyano-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-6-Methyl-pyrazine-2-carboxylic acid [2-(3-cyano-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-6-Methyl-pyrazine-2-carboxylic acid [2-(3-chloro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-Pyrazine-2-carboxylic acid [2-(3-chloro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-1-Methyl-1H-pyrazole-3-carboxylic acid [2-(3-chloro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-N-[2-(3-Cyano-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-3-fluoro-benzamide;
cis-N-[2-(3-Cyano-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-3-chloro-benzamide;
cis-6-Methyl-pyridine-2-carboxylic acid [2-(3-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
trans-6-Methyl-pyridine-2-carboxylic acid [2-(3-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-Pyridine-2-carboxylic acid [2-(3-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
trans-Pyridine-2-carboxylic acid [2-(3-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-6-Methyl-pyrazine-2-carboxylic acid [2-(3-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
trans-6-Methyl-pyrazine-2-carboxylic acid[2-(3-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-6-Methyl-pyridine-2-carboxylic acid [2-(6-methyl-pyridin-2-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
trans-3-Fluoro-N-[2-(6-methyl-pyridin-2-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-benzamide;
Pyridine-2-carboxylic acid [(5R,7R)-2-(3-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
3-Fluoro-N-(1-oxo-2-pyridin-2-yl-2-aza-spiro[4.5]dec-7-yl)-benzamide;
cis-3-Fluoro-N-[2-(6-methyl-pyridin-2-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-benzamide;
3-Fluoro-N-[(5R,7R)-2-(6-methyl-pyridin-2-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-benzamide;
cis-Pyridine-2-carboxylic acid [2-(4-methyl-pyrimidin-2-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-Pyridine-2-carboxylic acid [2-(4-fluoro-pyridin-2-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-6-Methyl-pyridine-2-carboxylic acid [2-(5-fluoro-pyridin-2-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-6-Methyl-pyridine-2-carboxylic acid [2-(4-fluoro-pyridin-2-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-Pyridine-2-carboxylic acid [2-(5-fluoro-pyridin-2-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-6-Methyl-pyridine-2-carboxylic acid [2-(4-methyl-pyrimidin-2-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-3-Fluoro-N-[2-(5-fluoro-pyridin-2-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-benzamide;
cis-3-Fluoro-N-[2-(4-fluoro-pyridin-2-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-benzamide;
cis-3-Fluoro-N-[2-(4-methyl-pyrimidin-2-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-benzamide;
cis-3-Fluoro-N-[2-(6-methyl-pyrazin-2-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-benzamide;
cis-Pyridine-2-carboxylic acid [2-(6-methyl-pyrazin-2-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-6-Methyl-pyridine-2-carboxylic acid [2-(6-methyl-pyrazin-2-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-6-Methyl-pyridine-2-carboxylic acid [1-oxo-2-(6-trifluoromethyl-pyridin-2-yl)-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-6-Methyl-pyridine-2-carboxylic acid [2-(3,5-difluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-6-Methyl-pyridine-2-carboxylic acid [2-(6-cyano-pyridin-2-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-6-Methyl-pyridine-2-carboxylic acid [2-(4-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
6-Methyl-pyridine-2-carboxylic acid (1-oxo-2-pyridin-2-yl-2-aza-spiro[4.5]dec-7-yl)-amide;
cis-6-Methyl-pyridine-2-carboxylic acid (1-oxo-2-phenyl-2-aza-spiro[4.5]dec-7-yl)-amide;
cis-6-Methyl-pyridine-2-carboxylic acid (1-oxo-2-m-tolyl-2-aza-spiro[4.5]dec-7-yl)-amide;
cis-6-Methyl-pyridine-2-carboxylic acid [2-(4-methyl-pyridin-2-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-6-Methyl-pyridine-2-carboxylic acid [2-(5-methyl-pyridin-2-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-6-Methyl-pyridine-2-carboxylic acid [2-(3-methyl-pyridin-2-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-6-Methyl-pyridine-2-carboxylic acid [2-(2-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-6-Methyl-pyridine-2-carboxylic acid [2-(2-methyl-pyridin-4-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-N-[2-(6-Cyano-pyridin-2-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-3-fluoro-benzamide;
cis-Pyridine-2-carboxylic acid [2-(3,5-difluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-6-Methyl-pyrazine-2-carboxylic acid [2-(3,5-difluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-Pyrazine-2-carboxylic acid [2-(3,5-difluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-2-Methyl-pyrimidine-4-carboxylic acid [2-(5-fluoro-pyridin-2-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-3-Chloro-N-2-(2-methyl-pyrimidin-4-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-benzamide;
cis-2-Methyl-pyrimidine-4-carboxylic acid [2-(6-methyl-pyrazin-2-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-2-Methyl-pyrimidine-4-carboxylic acid [2-(3-cyano-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-2-Methyl-pyrimidine-4-carboxylic acid [1-oxo-2-(6-trifluoromethyl-pyridin-2-yl)-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-6-Methyl-pyridine-2-carboxylic acid [2-(2-methyl-pyrimidin-4-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-6-Methyl-pyridine-2-carboxylic acid [2-(6-methyl-pyridin-3-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-6-Methyl-pyridine-2-carboxylic acid [2-(5-fluoro-pyridin-3-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-3-Fluoro-N-[2-(2-methyl-pyrimidin-4-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-benzamide;
cis-3-Fluoro-N-[2-(2-methyl-pyridin-4-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-benzamide;
6-Methyl-pyridine-2-carboxylic acid [(5R,7R)-2-(3,5-difluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-5-Fluoro-pyridine-2-carboxylic acid [2-(3-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-2-Methyl-pyrimidine-4-carboxylic acid [2-(3-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-Pyrimidine-4-carboxylic acid [2-(3-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-6-Methyl-pyridine-2-carboxylic acid [2-(5-methyl-pyridin-3-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-6-Methyl-pyridine-2-carboxylic acid [2-(3-methoxy-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
6-Methyl-pyridine-2-carboxylic acid [(5R,7R)-2-(5-fluoro-pyridin-2-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-Pyridine-2-carboxylic acid [2-(5-fluoro-pyridin-3-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-Pyridine-2-carboxylic acid [2-(3,4-difluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-2-Methyl-pyrimidine-4-carboxylic acid [2-(3,5-difluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-N-[2-(3-Fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-isonicotinamide;
cis-N-[2-(3-Fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-2-methyl isonicotinamide;
cis-Pyrimidine-4-carboxylic acid [2-(3,5-difluoro-phenyl)-1-oxo-2-azaspiro[4.5]dec-7-yl]-amide;
6-Methyl-pyridine-2-carboxylic acid [(5R,7R)-2-(4-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
6-Methyl-pyridine-2-carboxylic acid [(5S,7S)-2-(3,5-difluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
2-Methyl-pyrimidine-4-carboxylic acid [(5R,7R)-2-(3,5-difluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-6-Methyl-pyridine-2-carboxylic acid (2-benzyl-1-oxo-2-aza-spiro[4.5]dec-7-yl)-amide;
cis-3-Methyl-N-[2-(2-methyl-pyrimidin-4-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-benzamide;
cis-3,5-Difluoro-N-[2-(2-methyl-pyrimidin-4-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-benzamide;
cis-6-Methyl-pyrazine-2-carboxylic acid {2-[6-(4-fluoro-phenyl)-pyrimidin-4-yl]-1-oxo-2-aza-spiro[4.5]dec-7-yl}-amide;
cis-6-Methyl-pyridine-2-carboxylic acid {2-[6-(4-fluoro-phenyl)-pyrimidin-4-yl]-1-oxo-2-aza-spiro[4.5]dec-7-yl}-amide;
cis-3-Fluoro-N-{2-[6-(4-fluoro-phenyl)-pyrimidin-4-yl]-1-oxo-2-aza-spiro[4.5]dec-7-yl}-benzamide;
cis-4-Fluoro-N-[2-(2-methyl-pyrimidin-4-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-benzamide;
cis-3,4-Difluoro-N-[2-(2-methyl-pyrimidin-4-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-benzamide;
cis-2-Fluoro-N-[2-(2-methyl-pyrimidin-4-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-benzamide;
cis-2-Methyl-N-[2-(2-methyl-pyrimidin-4-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-isonicotinamide;
cis-6-Hydroxymethyl-pyridine-2-carboxylic acid [2-(3-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-6-Trifluoromethyl-pyridine-2-carboxylic acid [2-(3-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
N-[(5R,7R)-2-(3-Fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-2-methyl-isonicotinamide;
cis-6-Trifluoromethyl-pyridine-2-carboxylic acid [2-(2-methyl-pyrimidin-4-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
Pyridine-2-carboxylic acid [9,9-difluoro-2-(3-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
Pyridine-2-carboxylic acid [(5R,7S)-9,9-difluoro-2-(3-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
Pyridine-2-carboxylic acid [(5S,7R)-9,9-difluoro-2-(3-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide; or
cis-2-[2-(3-Chloro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-2,3-dihydro-isoindol-1-one;
Pyridine-2-carboxylic acid [(5S,7S)-9,9-difluoro-2-(3-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
Pyridine-2-carboxylic acid [(5R,7R)-9,9-difluoro-2-(3-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
2-Methyl-pyrimidine-4-carboxylic acid [(5S,7R)-9,9-difluoro-2-(3-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
2-Methyl-pyrimidine-4-carboxylic acid [(5R,7S)-9,9-difluoro-2-(3-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
trans-2-Methyl-pyrimidine-4-carboxylic acid [2-(3,5-difluoro-phenyl)-9,9-difluoro-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-Pyridine-2-carboxylic acid [9,9-difluoro-2-(4-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-6-Methyl-pyridine-2-carboxylic acid [9,9-difluoro-2-(3-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-6-Methyl-pyridine-2-carboxylic acid [9,9-difluoro-2-(2-methyl-pyrimidin-4-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-6-Methyl-pyridine-2-carboxylic acid [9,9-difluoro-2-(5-fluoro-pyridin-2-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-Pyridine-2-carboxylic acid [2-(3,5-difluoro-phenyl)-9,9-difluoro-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-Pyridine-2-carboxylic acid [9,9-difluoro-2-(5-fluoro-pyridin-2-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-Pyridine-2-carboxylic acid [9,9-difluoro-2-(2-methyl-pyrimidin-4-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
Pyridine-2-carboxylic acid [(5S,7R)-2-(3,5-difluoro-phenyl)-9,9-difluoro-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
Pyridine-2-carboxylic acid [(5R,7S)-2-(3,5-difluoro-phenyl)-9,9-difluoro-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-2-Methyl-pyrimidine-4-carboxylic acid [2-(3,5-difluoro-phenyl)-1,9-dioxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-2-Methyl-pyrimidine-4-carboxylic acid [2-(3,5-difluoro-phenyl)-9-hydroxy-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
trans-2-Methyl-pyrimidine-4-carboxylic acid [2-(3,5-difluoro-phenyl)-9-hydroxy-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
2-Methyl-pyrimidine-4-carboxylic acid [(5R,7S,9S)-2-(3,5-difluoro-phenyl)-9-hydroxy-9-methyl-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
2-Methyl-pyrimidine-4-carboxylic acid [(5R,7S,9R)-2-(3,5-difluoro-phenyl)-9-hydroxy-9-methyl-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
N-[(5S,7R)-9,9-Difluoro-2-(2-methyl-pyrimidin-4-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-3-fluoro-benzamide;
N-[(5R,7S)-9,9-Difluoro-2-(2-methyl-pyrimidin-4-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-3-fluoro-benzamide;
trans-2-Methyl-pyrimidine-4-carboxylic acid [2-(3,5-difluoro-phenyl)-9-fluoro-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-3-Fluoro-N-[2-(3-fluoro-phenyl)-1,9-dioxo-2-aza-spiro[4.5]dec-7-yl]-benzamide;
cis-6-Methyl-pyridine-2-carboxylic acid [2-(3-fluoro-phenyl)-1,9-dioxo-2-aza-spiro[4.5]dec-7-yl]-amide;
trans-3-Fluoro-N-[2-(3-fluoro-phenyl)-9-hydroxy-1-oxo-2-aza-spiro[4.5]dec-7-yl]-benzamide;
trans-6-Methyl-pyridine-2-carboxylic acid [2-(3-fluoro-phenyl)-9-hydroxy-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
6-Methyl-pyridine-2-carboxylic acid [(5S,7R)-9,9-difluoro-2-(5-fluoro-pyridin-2-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-N-[9,9-Difluoro-2-(2-methyl-pyrimidin-4-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-3-fluoro-benzamide;
cis-2-Methyl-pyrimidine-4-carboxylic acid [9,9-difluoro-2-(3-fluoro-phenyl)-1-oxo-2-azaspiro[4.5]dec-7-yl]-amide;
cis 3-Fluoro-N-[-2-(3-methoxy-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-benzamide;
cis 3-Fluoro-N-[2-(3-hydroxy-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-benzamide;
cis-N-[(5S,7S)-2-(3-Dimethylamino-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-3-fluoro-benzamide;
cis-3-Fluoro-N-[(2-(4-methoxy-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-benzamide;
cis-3-Fluoro-N-{2-[3-(3-morpholin-4-yl-propyl)-phenyl]-1-oxo-2-aza-spiro[4.5]dec-7-yl}-benzamide;
cis-3-Fluoro-N-[2-(3-fluoro-5-methoxy-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-benzamide;
cis-3-Fluoro-N-{1-oxo-2-[3-(2-oxo-2-pyrrolidin-1-yl-ethoxy)-phenyl]-2-aza-spiro[4.5]dec-7-yl}-benzamide;
cis-Thiazole-2-carboxylic acid [2-(3-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-N-[2-(4-Dimethylamino-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-3-fluoro-benzamide;
cis-3-Fluoro-N-(1-oxo-2-thiazol-2-yl-2-aza-spiro[4.5]dec-7-yl)-benzamide;
cis-Thiazole-2-carboxylic acid [(2-(2-methyl-pyrimidin-4-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-2-Methyl-pyrimidine-4-carboxylic acid [2-(3-fluoro-5-methoxy-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-N-[2-(3-Cyano-5-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-3-fluoro-benzamide;
cis-Thiazole-2-carboxylic acid [2-(3,5-difluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-2-Methyl-thiazole-4-carboxylic acid [2-(3,5-difluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-Pentanoic acid [2-(3,5-difluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-N-[2-(3,5-Difluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-butyramide;
3-Fluoro-N-[(5R,7R)-2-(2-methyl-pyrimidin-4-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-benzamide;
3-Chloro-N-[(5R,7R)-2-(2-methyl-pyrimidin-4-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-benzamide;
cis-5-Fluoro-pyridine-2-carboxylic acid [(2-(2-methyl-pyrimidin-4-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
cis-3-Fluoro-N-[1-oxo-2-(2-trifluoromethyl-pyrimidin-4-yl)-2-aza-spiro[4.5]dec-7-yl]-benzamide;
cis-N-[2-(2,6-Dimethyl-pyrimidin-4-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-3-fluoro-benzamide;
3-Methyl-N-[(5R,7R)-2-(2-methyl-pyrimidin-4-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-benzamide;
cis-3-Fluoro-N-(2-methyl-1-oxo-2-aza-spiro[4.5]dec-7-yl)-benzamide;
cis-3-Fluoro-N-(2-ethyl-1-oxo-2-aza-spiro[4.5]dec-7-yl)-benzamide;
cis-3-Fluoro-N-(2-propyl-1-oxo-2-aza-spiro[4.5]dec-7-yl)-benzamide;
6-Methyl-pyridine-2-carboxylic acid[(5R,7R)-1-oxo-2-(2-trifluoromethyl-pyrimidin-4-yl)-2-aza-spiro[4.5]dec-7-yl]-amide;
3-Fluoro-N-[2-(1-methyl-piperidin-4-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-benzamide;
3-Fluoro-N-[2-(1-methyl-1H-pyrazol-3-yl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-benzamide; and
2-Methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid [(5R,7R)-2-(3,5-difluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]amide; or a pharmaceutically acceptable salt thereof.

### Claim 32 (depends on 1)

The method of claim 1, wherein the compound is selected from the group consisting of Pyridine-2-carboxylic acid [9-fluoro-2-(3-fluoro-phenyl)-9-methyl-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
2-Methyl-pyrimidine-4-carboxylic acid [2-(3,5-difluoro-phenyl)-9-fluoro-9-methyl-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
2-Methyl-pyrimidine-4-carboxylic acid [9-fluoro-2-(4-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
Pyridine-2-carboxylic acid [8,8-difluoro-2-(3-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
Pyridine-2-carboxylic acid [8-fluoro-2-(3-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
Pyridine-2-carboxylic acid [2-(3-fluoro-phenyl)-8-hydroxy-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
Pyridine-2-carboxylic acid [8-fluoro-2-(3-fluoro-phenyl)-8-methyl-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
Pyridine-2-carboxylic acid [2-(3-fluoro-phenyl)-8-hydroxy-8-methyl-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
2-Methyl-pyrimidine-4-carboxylic acid [2-(3,5-difluoro-phenyl)-8,8-difluoro-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
2-Methyl-pyrimidine-4-carboxylic acid [2-(3,5-difluoro-phenyl)-8-fluoro-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
2-Methyl-pyrimidine-4-carboxylic acid [2-(3,5-difluoro-phenyl)-8-fluoro-8-methyl-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
2-Methyl-pyrimidine-4-carboxylic acid [2-(3,5-difluoro-phenyl)-8-hydroxy-8-methyl-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
2-Methyl-pyrimidine-4-carboxylic acid [2-(3,5-difluoro-phenyl)-8-hydroxy-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
2-Methyl-pyrimidine-4-carboxylic acid [8,8-difluoro-2-(4-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
2-Methyl-pyrimidine-4-carboxylic acid [8-fluoro-2-(4-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
2-Methyl-pyrimidine-4-carboxylic acid [8-fluoro-2-(4-fluoro-phenyl)-8-methyl-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
2-Methyl-pyrimidine-4-carboxylic acid [2-(4-fluoro-phenyl)-8-hydroxy-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
2-Methyl-pyrimidine-4-carboxylic acid [2-(4-fluoro-phenyl)-8-hydroxy-8-methyl-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
Pyridine-2-carboxylic acid [4,4-difluoro-2-(3-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
Pyridine-2-carboxylic acid [4-fluoro-2-(3-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
Pyridine-2-carboxylic acid [2-(3-fluoro-phenyl)-4-hydroxy-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
Pyridine-2-carboxylic acid [4-fluoro-2-(3-fluoro-phenyl)-4-methyl-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
Pyridine-2-carboxylic acid [2-(3-fluoro-phenyl)-4-hydroxy-4-methyl-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
2-Methyl-pyrimidine-4-carboxylic acid [2-(3,5-difluoro-phenyl)-4,4-difluoro-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
2-Methyl-pyrimidine-4-carboxylic acid [2-(3,5-difluoro-phenyl)-4-fluoro-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
2-Methyl-pyrimidine-4-carboxylic acid [2-(3,5-difluoro-phenyl)-4-fluoro-4-methyl-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
2-Methyl-pyrimidine-4-carboxylic acid [2-(3,5-difluoro-phenyl)-4-hydroxy-4-methyl-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
2-Methyl-pyrimidine-4-carboxylic acid [2-(3,5-difluoro-phenyl)-4-hydroxy-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
2-Methyl-pyrimidine-4-carboxylic acid [4,4-difluoro-2-(4-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
2-Methyl-pyrimidine-4-carboxylic acid [4-fluoro-2-(4-fluoro-phenyl)-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
2-Methyl-pyrimidine-4-carboxylic acid [4-fluoro-2-(4-fluoro-phenyl)-4-methyl-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide;
2-Methyl-pyrimidine-4-carboxylic acid [2-(4-fluoro-phenyl)-4-hydroxy-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide; and
2-Methyl-pyrimidine-4-carboxylic acid [2-(4-fluoro-phenyl)-4-hydroxy-4-methyl-1-oxo-2-aza-spiro[4.5]dec-7-yl]-amide; or a pharmaceutically acceptable salt thereof.

### Claim 33 (depends on 20)

The method of claim 20, wherein the mammal is a human.

### Claim 34 (depends on 20)

The method of claim 20, wherein the central nervous system disease or disorder is a cognitive, neurodegenerative, psychiatric or neurological disease or disorder.

### Claim 35 (depends on 34)

The method of claim 34, wherein the cognitive or neurodegenerative disease or disorder is selected from a group consisting of a mood disorder, an anxiety, a schizophrenia, Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's chorea, amyotrophic lateral sclerosis, Creutzfeld-Jakob disease, a trauma-induced neurodegeneration, AIDS-induced encephalopathy, a non-AIDS-induced encephalopathy, Fragile X syndrome, an autism spectrum disorder, and a combination thereof.

### Claim 36 (depends on 20)

The method of treating gastroesophageal reflux comprising administering a therapeutically effective amount of the compound of claim 20 or a pharmaceutically acceptable salt thereof.

### Claim 37 (depends on 20)

The method of treating alcohol dependence comprising administering a therapeutically effective amount of the compound of claim 20 or a pharmaceutically acceptable salt thereof.