# US 10,479,790 B2 · COMT inhibiting methods and compositions

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,479,790 B2
- Document ID: US10479790B2
- Status: Granted
- Kind: B2
- Application number: 16/018,496
- Filed: 2018-06-26
- Published: 2018-10-25
- Granted: 2019-11-19
- Earliest claimed: 2015-01-30
- Assignees: Lieber Institute for Brain Development
- Applicants: Lieber Institute for Brain Development
- Inventors: James Barrow; Glen Ernst; Yifang Huang; Ingrid Price Buchler; Daniel Weinberger
- Web page: https://patentgrep.com/patent/US10479790B2

## CPC

- C07D 471/10: Spiro-condensed systems
- A61K 31/198: Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00)
- A61K 31/47: Quinolines; Isoquinolines
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/4725: containing further heterocyclic rings
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- 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 25/24: 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
- A61P 25/30: for treating abuse or dependence
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 215/36: Sulfur atoms (C07D215/24 takes precedence)
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 471/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present inventions include a method of inhibiting COMT enzyme in a subject as well as compounds of formula I, or a pharmaceutically acceptable salt thereof, that are useful in the treatment of various disorders mediated by COMT, including Parkinson's disease and/or schizophrenia.

## Claims

### Claim 1

A method of treating a neurological or psychiatric disorder for which inhibiting COMT provides a therapeutic effect, or treating symptoms associated with the neurological or psychiatric disorder, comprising administering to a subject in need thereof an effective amount of a COMT-inhibiting compound in accordance with formula I, or a pharmaceutically acceptable salt thereof,
wherein:
X is selected from hydrogen, halogen, C≡N, CF3, and C1-C4 alkyl;
Z is selected from SO2R1 and SO2NR2R3;
R1 is selected from C1-C10 alkyl, C3-C10 cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl and heteroarylalkyl, any of which may be substituted with one or more groups selected from halogen, C≡N, CF3, OH, C1-C4 alkyl or C2-C4 alkenyl, alkoxy, nitro, amino, C1-C4 alkylamino, oxo, C3-C10 cycloalkyl, acyl, aryl, aralkyl, heterocyclyl, heteroaryl, CON(R)2, SO2R, and SO2N(R)2, where each R is independently C1-C4 alkyl or (R)2 forms a carbocyclic ring;
R2 and R3 are independently selected from hydrogen and any of the groups as defined for R1, with the proviso that at least one of R2 and R3 is different from hydrogen; or R2 and R3 may together form a 3-10 membered monocyclic, bicyclic or spirocyclic nitrogen-containing ring system that contains 0-3 additional heteroatoms selected from oxygen (O), nitrogen (N), and sulfur (S), and which may be further substituted with one or more groups selected from halogen, C≡N, CF3, OH, C1-C4 alkyl or C2-C4 alkenyl, C3-C6 cycloalkyl, alkoxy, nitro, amino, C1-C4 alkoxycarbonyl, acyl, C1-C4 alkylamino, oxo, SO2CH3, aryl, aralkyl, heterocyclyl, heteroaryl and heteroarylalkyl;
with the proviso that when X is hydrogen and Z is SO2R1, R1 is not C4 alkyl, C8 alkyl, tetrahydropyran or propylcyclopropane;
or when X is H and Z is SO2NR2R3, R2 and R3 do not together form a 1-piperidinyl ring substituted with a α-methyl group;
or when X is C1 and Z is SO2R1, R1 is not C3 alkyl, C4 alkyl or C5-C6 cycloalkyl;
or when X is C1 and Z is SO2NR2R3, R2 and R3 do not together form an unsubstituted, 1-pyrrolidinyl ring.

### Claim 2 (depends on 1)

The method of claim 1, wherein the disorder is Parkinson's disease.

### Claim 3 (depends on 1)

The method of claim 1, wherein the disorder is selected from major depression, a depressive phase of bipolar disorder and age-associated cognitive symptoms.

### Claim 4 (depends on 1)

The method of claim 1, wherein the disorder is schizophrenia.

### Claim 5 (depends on 1)

The method of claim 1, wherein X is either of hydrogen, halogen or methyl.

### Claim 6 (depends on 1)

The method of claim 1, wherein Z is SO2NR2R3 with R2 and R3 may together form a 3-10 membered monocyclic, bicyclic or spirocyclic nitrogen-containing ring system that contains 0-3 additional heteroatoms selected from oxygen (O), nitrogen (N), and sulfur (S), and which may be further substituted with one or more groups selected from halogen, C1-C4 alkyl or C2-C4 alkenyl, C3-C6 cycloalkyl, C1-C4 alkoxy, arylalkoxy, nitro, amino, C1-C4 alkoxycarbonyl, acyl, C1-C4 alkylamino, oxo, SO2CH3, aryl, aralkyl, heterocyclyl, and heteroaryl.

### Claim 7 (depends on 1)

The method of claim 1, wherein Z is SO2R1 and R1 is selected from C1-C10 alkyl, C3-C10 cycloalkyl, phenyl, naphthyl, aralkyl, C-attached piperidinyl, C-attached 1H-benzimidazolyl, C-attached tetrahydro-2H-pyranyl and pyridinyl, any of which may be substituted with one or more groups selected from halogen, CF3, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted 1H-indazolyl, substituted or unsubstituted aralkyl, and acyl.

### Claim 8 (depends on 1)

The method of claim 1, wherein the compound is selected from the group consisting of:
5-tosylquinolin-8-ol;
5-(4-fluorophenyl)sulfonylquinolin-8-ol;
5-(3,4-dimethylphenyl)sulfonylquinolin-8-ol;
5-(3,5-dimethylphenyl)sulfonylquinolin-8-ol;
5-(4-tert-butylphenyl)sulfonylquinolin-8-ol;
5-(3-phenylphenyl)sulfonylquinolin-8-ol;
5-(m-tolylsulfonyl)quinolin-8-ol;
5-(3,5-dichlorophenyl)sulfonylquinolin-8-ol;
5-(4-chlorophenyl)sulfonylquinolin-8-ol;
5-(2,4-dimethylphenyl)sulfonylquinolin-8-ol;
5-[4-(trifluoromethyl)phenyl]sulfonylquinolin-8-ol;
5-(2-naphthylsulfonyl)quinolin-8-ol;
5-[3-(trifluoromethyl)phenyl]sulfonylquinolin-8-ol;
5-(3-chlorophenyl)sulfonylquinolin-8-ol;
5-(3,4-dichlorophenyl)sulfonylquinolin-8-ol;
5-(2-pyridylsulfonyl)quinolin-8-ol;
5-(4-pyridylsulfonyl)quinolin-8-ol;
5-(4-methoxyphenyl)sulfonylquinolin-8-ol;
5-(3-pyridylsulfonyl)quinolin-8-ol;
5-(4-fluoro-2-methyl-phenyl)sulfonylquinolin-8-ol;
5-[2-(trifluoromethyl)phenyl]sulfonylquinolin-8-ol;
5-(benzenesulfonyl)quinolin-8-ol;
5-[3-(4-pyridyl)phenyl] sulfonylquinolin-8-ol;
5-[3-(3-chloro-4-fluoro-phenyl)phenyl]sulfonylquinolin-8-ol;
5-[3-(5-quinolyl)phenyl] sulfonylquinolin-8-ol;
5-[3-(1H-indazol-4-yl)phenyl] sulfonylquinolin-8-ol;
5-[(3-methyl-4-pyridyl)sulfonyl]quinolin-8-ol;
5-[1-[(2-chlorophenyl)methyl]benzimidazol-4-yl]sulfonylquinolin-8-ol;
5-[2-(p-tolyl)ethylsulfonyl]quinolin-8-ol;
5-cyclohexylsulfonylquinolin-8-ol;
5-cyclopentylsulfonylquinolin-8-ol;
5-(p-tolylmethylsulfonyl)quinolin-8-ol;
5-ethylsulfonylquinolin-8-ol;
5-(4-piperidyl sulfonyl)quinolin-8-ol;
5-[[1-[(4-fluorophenyl)methyl]-4-piperidyl]sulfonyl]quinolin-8-ol;
5-[[1-[(2,3-dichlorophenyl)methyl]-4-piperidyl] sulfonyl]quinolin-8-ol;
5-[[1-(2,3-dimethylphenyl)-4-piperidyl] sulfonyl] quinolin-8-ol;
5-(3,4-dihydro-1H-isoquinolin-2-ylsulfonyl)quinolin-8-ol;
5-(4-phenylpiperazin-1-yl)sulfonylquinolin-8-ol;
8-hydroxy-N-[(3-methoxyphenyl)methyl]-N-methyl-quinoline-5-sulfonamide;
5-(4-benzylpiperazin-1-yl)sulfonylquinolin-8-ol;
8-hydroxy-N-(4-methylbenzyl)quinoline-5-sulfonamide;
N-benzyl-8-hydroxy-N-methylquinoline-5-sulfonamide;
8-hydroxy-N-(4-methylphenyl)-N-methylquinoline-5-sulfonamide;
5-isoindolin-2-ylsulfonylquinolin-8-ol;
8-hydroxy-N-methyl-N-phenethyl-quinoline-5-sulfonamide;
N-[(4-fluorophenyl)methyl]-8-hydroxy-N-methyl-quinoline-5-sulfonamide;
8-hydroxy-N-methyl-N-[(1R)-1-phenylethyl]quinoline-5-sulfonamide;
8-hydroxy-N-methyl-N-[(1 S)-1-phenylethyl] quinoline-5-sulfonamide;
N-[(2-fluorophenyl)methyl]-8-hydroxy-N-methyl-quinoline-5-sulfonamide;
N-[(3-chlorophenyl)methyl]-8-hydroxy-N-methyl-quinoline-5-sulfonamide;
8-hydroxy-N-methyl-N-(3-pyridylmethyl)quinoline-5-sulfonamide;
8-hydroxy-N-methyl-N-(2-naphthylmethyl)quinoline-5-sulfonamide;
N-benzyl-N-ethyl-8-hydroxy-quinoline-5-sulfonamide;
N-benzyl-N-(2-dimethylaminoethyl)-8-hydroxy-quinoline-5-sulfonamide;
5-(2-phenylpyrrolidin-1-yl)sulfonylquinolin-8-ol;
5-pyrrolidin-1-ylsulfonylquinolin-8-ol;
5-(4-methylpiperazin-1-yl)sulfonylquinolin-8-ol;
5-[(2-phenyl-1-piperidyl)sulfonyl]quinolin-8-ol;
5-(3-(4-fluorophenyl)pyrrolidin-1-yl)sulfonylquinolin-8-ol;
5-(piperidin-1-yl)sulfonylquinolin-8-ol;
5-(4-morpholin-1-yl)sulfonylquinolin-8-ol;
N-[(4-(trifluoromethyl)phenyl)methyl]-8-hydroxy-N-methyl-quinoline-5-sulfonamide;
N-ethyl-8-hydroxy-N-(4-pyridylmethyl)quinoline-5-sulfonamide;
5-(6,8-dihydro-5H-1,7-naphthyridin-7-ylsulfonyl)quinolin-8-ol;
N,N-diethyl-8-hydroxy-quinoline-5-sulfonamide;
5-[4-(5-chloro-2-pyridyl)piperazin-1-yl] sulfonylquinolin-8-ol;
5-[(3R,4R)-3,4-difluoropyrrolidin-1-yl]sulfonylquinolin-8-ol;
5-[2-(o-tolyl)pyrrolidin-1-yl] sulfonylquinolin-8-ol;
5-[2-(3-pyridyl)pyrrolidin-1-yl] sulfonylquinolin-8-ol;
5-[(4-phenyl-1-piperidyl)sulfonyl]quinolin-8-ol;
5-[2-(4-fluorophenyl)pyrrolidin-1-yl] sulfonylquinolin-8-ol;
5-(2-benzylpyrrolidin-1-yl)sulfonylquinolin-8-ol;
5-(2-cyclohexylpyrrolidin-1-yl)sulfonylquinolin-8-ol;
5-[2-(4-methoxyphenyl)pyrrolidin-1-yl]sulfonylquinolin-8-ol;
5-(2-isopropylpyrrolidin-1-yl)sulfonylquinolin-8-ol;
5-[2-(4-pyridyl)pyrrolidin-1-yl] sulfonylquinolin-8-ol;
5-[2-(2-pyridyl)pyrrolidin-1-yl] sulfonylquinolin-8-ol;
5-[2-[2-(trifluoromethyl)phenyl]pyrrolidin-1-yl]sulfonylquinolin-8-ol;
5-(2-isobutylpyrrolidin-1-yl)sulfonylquinolin-8-ol;
5-[(4-hydroxy-4-phenyl-1-piperidyl)sulfonyl] quinolin-8-ol;
5-[(4-benzyl-1-piperidyl)sulfonyl]quinolin-8-ol;
[1-[(8-hydroxy-5-quinolyl)sulfonyl]-4-piperidyl]-phenyl-methanone;
1-[1-[(8-hydroxy-5-quinolyl)sulfonyl]-4-phenyl-4-piperidyl]ethanone;
8-[(8-hydroxy-5-quinolyl)sulfonyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one;
methyl 4-[(8-hydroxy-5-quinolyl)sulfonyl]piperazine-1-carboxylate;
5-[4-(3-methoxypropyl)piperazin-1-yl]sulfonylquinolin-8-ol;
2-[4-[(8-hydroxy-5-quinolyl)sulfonyl]piperazin-1-yl]benzonitrile;
5-(3-azabicyclo[3.2.2]nonan-3-ylsulfonyl)quinolin-8-ol;
5-[4-(2-phenylphenyl)piperazin-1-yl] sulfonylquinolin-8-ol;
5-[4-(2,5-dimethylphenyl)piperazin-1-yl] sulfonylquinolin-8-ol;
5-[4-[4-(trifluoromethyl)phenyl]piperazin-1-yl]sulfonylquinolin-8-ol;
5-[4-[bis(4-fluorophenyl)methyl]piperazin-1-yl]sulfonylquinolin-8-ol;
5-[4-(4-fluorophenyl)piperazin-1-yl] sulfonylquinolin-8-ol;
5-[4-(2,3-dichlorophenyl)piperazin-1-yl] sulfonylquinolin-8-ol;
5-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl] sulfonylquinolin-8-ol;
5-[3-[4-(trifluoromethoxy)phenoxy]azetidin-1-yl] sulfonylquinolin-8-ol;
5-[4-(2,3-dimethylphenyl)piperazin-1-yl] sulfonylquinolin-8-ol;
5-[4-[(4-fluorophenyl)methyl]piperazin-1-yl] sulfonylquinolin-8-ol;
5-[(3-phenyl-1-piperidyl)sulfonyl]quinolin-8-ol;
tert-butyl 4-[(8-hydroxy-5-quinolyl)sulfonyl]piperazine-1-carboxylate;
5-piperazin-1-ylsulfonylquinolin-8-ol;
tert-butyl 4-[(8-hydroxy-5-quinolyl)sulfonyl]-3-methyl-piperazine-1-carboxylate;
5-(2-methylpiperazin-1-yl)sulfonylquinolin-8-ol;
7-iodo-5-(p-tolylsulfonyl)quinolin-8-ol;
7-bromo-5-(p-tolylsulfonyl)quinolin-8-ol;
7-chloro-5-(p-tolylsulfonyl)quinolin-8-ol;
7-fluoro-5-(p-tolylsulfonyl)quinolin-8-ol;
7-methyl-5-pyrrolidin-1-ylsulfonyl-quinolin-8-ol;
7-chloro-5-[4-[(4-fluorophenyl)methyl]piperazin-1-yl] sulfonyl-quinolin-8-ol;
7-fluoro-5-[4-[(4-fluorophenyl)methyl]piperazin-1-yl] sulfonyl-quinolin-8-ol;
5-[4-[(4-fluorophenyl)methyl]piperazin-1-yl]sulfonyl-7-methyl-quinolin-8-ol;
8-hydroxy-N,7-dimethyl-N-[(1R)-1-phenylethyl] quinoline-5-sulfonamide;
5-[(3R,4R)-3,4-difluoropyrrolidin-1-yl]sulfonyl-7-methyl-quinolin-8-ol;
7-chloro-8-hydroxy-N-methyl-N-[(1R)-1-phenylethyl]quinoline-5-sulfonamide;
7-chloro-5-[(2 S)-2-methylpyrrolidin-1-yl] sulfonyl-quinolin-8-ol;
7-chloro-5-[(2R)-2-methylpyrrolidin-1-yl] sulfonyl-quinolin-8-ol;
7-bromo-8-hydroxy-N-methyl-N-[(1R)-1-phenylethyl]quinoline-5-sulfonamide;
7-bromo-5-[4-[(4-fluorophenyl)methyl]piperazin-1-yl]sulfonyl-quinolin-8-ol;
7-fluoro-5-pyrrolidin-1-ylsulfonyl-quinolin-8-ol;
7-fluoro-8-hydroxy-N-methyl-N-[(1R)-1-phenylethyl] quinoline-5-sulfonamide;
5-(p-tolylsulfonyl)-7-(trifluoromethyl)quinolin-8-ol;
5-cyclopentylsulfonyl-7-(trifluoromethyl)quinolin-8-ol;
5-[[1-(4-fluorophenyl)-4-piperidyl]sulfonyl]quinolin-8-ol; and
5-[(2-methylpyrrolidin-1-yl)sulfonyl] quinolin-8-ol.

### Claim 9

A method of treating a neurological or psychiatric disorder for which inhibiting COMT provides a therapeutic effect, or treating symptoms associated with the neurological or psychiatric disorder, comprising administering to a subject in need thereof an effective amount of a COMT-inhibiting compound in accordance with formula I, or a pharmaceutically acceptable salt thereof:
wherein:
X is halogen or CF3;
Z is SO2NR2R3; and
R2 and R3 together form a 3-10 membered monocyclic nitrogen-containing ring system that may be optionally substituted with one or more groups selected from halogen, C≡N, CF3, OH, C1-C4 alkyl or C2-C4 alkenyl, C3-C6 cycloalkyl, alkoxy, nitro, amino, C1-C4 alkoxycarbonyl, acyl, C1-C4 alkylamino, oxo, SO2CH3, aryl, aralkyl, heterocyclyl, heteroaryl and heteroarylalkyl.

### Claim 10 (depends on 9)

The method according to claim 9, wherein: R2 and R3 together form a pyrrolidine ring system that may be optionally substituted with one or more groups selected from halogen, C≡N, CF3, OH, and C1-C4 alkyl.

### Claim 11 (depends on 9)

The method according to claim 9, wherein:
R2 and R3 are independently selected from any of the groups as defined for R1; or R2 and R3 may together form a 3-10 membered monocyclic, bicyclic or spirocyclic nitrogen-containing ring system that contains 0-3 additional heteroatoms selected from oxygen (O), nitrogen (N), and sulfur (S), and which may be further substituted with one or more groups selected from halogen, C≡N, CF3, OH, C1-C4 alkyl or C2-C4 alkenyl, C3-C6 cycloalkyl, alkoxy, nitro, amino, C1-C4 alkoxycarbonyl, acyl, C1-C4 alkylamino, oxo, SO2CH3, aryl, aralkyl, heterocyclyl, heteroaryl and heteroarylalkyl.

### Claim 12 (depends on 9)

The method according to claim 9, wherein the halogen is fluorine.

### Claim 13 (depends on 12)

The method according to claim 12, wherein the compound is selected from the group consisting of:
7-fluoro-5-(p-tolylsulfonyl)quinolin-8-ol;
7-fluoro-5-[4-[(4-fluorophenyl)methyl]piperazin-1-yl] sulfonyl-quinolin-8-ol;
7-fluoro-5-pyrrolidin-1-ylsulfonyl-quinolin-8-ol; and
7-fluoro-8-hydroxy-N-methyl-N-[(1R)-1-phenylethyl] quinoline-5-sulfonamide.

### Claim 14 (depends on 1)

The method according to claim 1, wherein R2 and R3 together form a 3-10 membered monocyclic, bicyclic or spirocyclic nitrogen-containing ring system that contains 0-1 additional heteroatoms selected from oxygen (O), nitrogen (N), and sulfur (S), and which may be further substituted with one or more groups selected from halogen, C≡N, CF3, OH, C1-C4 alkyl or C2-C4 alkenyl, C3-C6 cycloalkyl, alkoxy, nitro, amino, C1-C4 alkoxycarbonyl, acyl, C1-C4 alkylamino, oxo, SO2CH3, aryl, aralkyl, heterocyclyl, heteroaryl and heteroarylalkyl.

### Claim 15 (depends on 1)

The method according to claim 1, wherein the disorder is selected from attention deficit disorder, attention deficit/hyperactivity disorder, substance dependency, and impulse control disorders.

### Claim 16 (depends on 1)

The method according to claim 1, wherein the compound of formula I is administered in combination with L-DOPA and the disorder is Parkinson's disease.

### Claim 17

A method of reducing the risk of a neurological or psychiatric disorder for which inhibiting COMT provides a therapeutic effect comprising administering to a subject in need thereof an effective amount of a COMT-inhibiting compound in accordance with formula I, or a pharmaceutically acceptable salt thereof,
wherein:
X is selected from hydrogen, halogen, C≡N, CF3, and C1-C4 alkyl;
Z is selected from SO2R1 and SO2NR2R3;
R1 is selected from C1-C10 alkyl, C3-C10 cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl and heteroarylalkyl, any of which may be substituted with one or more groups selected from halogen, C≡N, CF3, OH, C1-C4 alkyl or C2-C4 alkenyl, alkoxy, nitro, amino, C1-C4 alkylamino, oxo, C3-C10 cycloalkyl, acyl, aryl, aralkyl, heterocyclyl, heteroaryl, CON(R)2, SO2R, and SO2N(R)2, where each R is independently C1-C4 alkyl or (R)2 forms a carbocyclic ring;
R2 and R3 are independently selected from hydrogen and any of the groups as defined for R1, with the proviso that at least one of R2 and R3 is different from hydrogen; or R2 and R3 may together form a 3-10 membered monocyclic, bicyclic or spirocyclic nitrogen-containing ring system that contains 0-3 additional heteroatoms selected from oxygen (O), nitrogen (N), and sulfur (S), and which may be further substituted with one or more groups selected from halogen, C≡N, CF3, OH, C1-C4 alkyl or C2-C4 alkenyl, C3-C6 cycloalkyl, alkoxy, nitro, amino, C1-C4 alkoxycarbonyl, acyl, C1-C4 alkylamino, oxo, SO2CH3, aryl, aralkyl, heterocyclyl, heteroaryl and heteroarylalkyl;
with the proviso that when X is hydrogen and Z is SO2R1, R1 is not C4 alkyl, C8 alkyl, tetrahydropyran or propylcyclopropane;
or when X is H and Z is SO2NR2R3, R2 and R3 do not together form a 1-piperidinyl ring substituted with a α-methyl group;
or when X is C1 and Z is SO2R1, R1 is not C3 alkyl, C4 alkyl or C5-C6 cycloalkyl;
or when X is C1 and Z is SO2NR2R3, R2 and R3 do not together form an unsubstituted, 1-pyrrolidinyl ring.

### Claim 18 (depends on 17)

The method of claim 17, wherein the neurological or psychiatric disorder is schizophrenia, depression, or a depressive phase of bipolar disorder.

### Claim 19

A method of reducing the risk of a neurological or psychiatric disorder for which inhibiting COMT provides a therapeutic effect, the method comprising administering to a subject in need thereof an effective amount of a COMT-inhibiting compound in accordance with formula I, or a pharmaceutically acceptable salt thereof:
wherein:
X is halogen or CF3;
Z is SO2NR2R3; and
R2 and R3 together form a 3-10 membered monocyclic nitrogen-containing ring system that may be optionally substituted with one or more groups selected from halogen, C≡N, CF3, OH, C1-C4 alkyl or C2-C4 alkenyl, C3-C6 cycloalkyl, alkoxy, nitro, amino, C1-C4 alkoxycarbonyl, acyl, C1-C4 alkylamino, oxo, SO2CH3, aryl, aralkyl, heterocyclyl, heteroaryl and heteroarylalkyl.

### Claim 20 (depends on 19)

The method of claim 19, wherein the neurological or psychiatric disorder is schizophrenia, depression, or a depressive phase of bipolar disorder.