# US 8,785,653 B2 · (3-aryl-1H-1,2,4-triazol-5-yl)-linked heterocycle derivatives

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- Number: US 8,785,653 B2
- Document ID: US8785653B2
- Status: Granted
- Kind: B2
- Application number: 13/922,371
- Filed: 2013-06-20
- Published: 2013-10-24
- Granted: 2014-07-22
- Earliest claimed: 2009-12-17
- Assignees: H. Lundbeck A/S
- Applicants: H. Lundbeck A/S
- Inventors: Ask Puschl; Jacob Nielsen; Jan Kehler; John Paul Kilburn; Mauro Marigo; Morton Langgard
- Web page: https://patentgrep.com/patent/US8785653B2

## CPC

- C07D 487/04: Ortho-condensed systems
- 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 25/28: 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 25/32: Alcohol-abuse
- A61P 25/36: Opioid-abuse
- C07D 471/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

This invention is directed to compounds of formula I having the structure which are PDE10A enzyme inhibitors. The invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. The present invention also provides processes for the preparation of the compounds of formula I. The present invention further provides a method of treating a subject suffering from a neurodegenerative disorder comprising administering to the subject a therapeutically effective amount of a compound of formula I. The present invention also provides a method of treating a subject suffering from a drug addiction comprising administering to the subject a therapeutically effective amount of a compound of formula I. The present invention further provides a method of treating a subject suffering from a psychiatric disorder comprising administering to the subject a therapeutically effective amount of a compound of formula I.

## Claims

### Claim 1

A method of treating a subject suffering from a psychiatric disorder comprising administration of a therapeutically effective amount of the compound of formula I
wherein HET-1 is a heteroaromatic group of formula II containing from 2 to 4 nitrogen atoms:
wherein Y is N or CH,
Z is N or C,
and wherein HET-1 may optionally be substituted with up to three R7, R8 and R9 substituents individually selected from hydrogen, C1-C6 alkyl; halogen; cyano, halo(C1-C6)alkyl; aryl, alkoxy and C1-C6 hydroxyalkyl, and wherein * denotes the attachment point,
Q is phenyl, optionally substituted with one, two or three R2, R3, R4, R5 and R6 substituents, wherein R2, R3, R4, R5 and R6 are each selected independently from hydrogen, C1-C6 alkoxy and halogen; or a monocyclic 5-membered or 6-membered heteroaromatic group containing 1 or 2 heteroatoms,
-L- is a linker selected from —S—CH2—, —CH2—S—, —CH2—CH2—, —CH═CH—,and —C≡C—,
R1is selected from H, C1-C6 alkyl; C1-C6 alkyl(C3-C8)cycloalkyl; C1-C6 hydroxyalkyl, CH2CN, CH2C(O)NH2, C1-C6 arylalkyl, and C1-C6 alkyl-heterocycloalkyl,
and wherein the psychiatric disorder is selected from the group consisting of schizophrenia, schizophreniform disorder and schizoaffective disorder.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 2)

The method of claim 2 wherein the schizophrenia is paranoid schizophrenia, disorganized schizophrenia, catatonic schizophrenia, undifferentiated schizophrenia, or residual type schizophrenia.

### Claim 4 (depends on 2)

The method of claim 2 wherein the schizophrenia is treatment resistant.

### Claim 5 (depends on 1)

The method of claim 1 wherein the psychiatric disorder is schizoaffective disorder.

### Claim 6 (depends on 5)

The method of claim 5 wherein the schizoaffective disorder is of the delusional type or the depressive type.

### Claim 7 (depends on 1)

The method of claim 1 further comprising administration of at least one neuroleptic agent.

### Claim 8 (depends on 7)

The method of claim 7 wherein the neuroleptic agent is selected from the group consisting of sertindole, olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant.

### Claim 9 (depends on 1)

The method of claim 1 wherein the psychiatric disorder is schizophreniform disorder.

### Claim 10 (depends on 1)

The method of claim 1 wherein the compound is selected from the group consisting of:
8-Methoxy-5-methyl-2-(5-phenyl-2H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]triazolo[1,5-a]pyridine;
5-Methyl-2-(5-phenyl-2H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]triazolo [1,5-a]pyridine;
5-Methyl-2-(1-methyl-5-phenyl-1H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]triazolo[1,5-a]pyridine;
8-Methoxy-5-methyl-2-[2-(2-methyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1 ,2 ,4 ]triazolo[1,5-a]pyridine;
8-Methoxy-5-methyl-2-[2-(2-methyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo [1,5-a]pyridine;
8-Methyl-2-[2-(2-methyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine;
5,7-Dimethyl-2-[2-(2-methyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyrimidine;
5,8-Dimethyl-2-[2-(2-methyl-5-phenyl-2H-[1,2,4]triazol-3 -yl)-ethyl]-[1,2,4]triazolo [1,5-a]pyrazine;
8-Methoxy-5-methyl-2-[2-(5-phenyl-2-propyl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolol[1,5-a]pyridine;
5-Methyl-2-[2-(2-methyl-5-phenyl-1,2,4]triazol-3-yl)-ethyl]1,2,4]triazolo[1,5-a]pyridine;
8-Methoxy-2-[2- (2-methyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine;
{5-2-(8-Methoxy-5-methyl-[1,2,4 ]triazolo[1,5-a]pyridin-2-yl)-ethyl]-3-phenyl-[1,2,4]triazol- 1-yl}-acetic acid ethyl ester;
2-{5-[2-(8-Methoxy-5 -methyl-[1,2,4]triazolo [1,5-a]pyridin-2-yl)-ethyl]-3-phenyl-[1,2,4 ]triazol-1-yl}-ethanol;
5,8-Dimethyl-2-[2-(2-methyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine;
5,8-Dimethyl-2-[2-(2-methyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5-c]pyrimidine;
8-Ethyl-5-methyl-2-[2-(2-methyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethyl[-]1,2,4]triazolo[1,5-a]pyridine;
8-Ethyl-5-methyl-2-[2-(5-phenyl-2-propyl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine;
8-Ethyl-2-[2-(2-isopropyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]-5-methyl-]1,2,4 ]triazolo[1,5-a]pyridine;
3-{5-[2-(8-Methoxy-5-methyl-[1,2,4]triazolo [1,5-a]pyridin-2-yl)-ethyl]-3-phenyl-[1,2,4]triazol-1-yl}-propionitrile;
3-{5-[2-(8-Ethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl]-3 -phenyl-[1,2,4]triazol-1-yl}-propionitrile;
2-[2-(2-Isopropyl-5-phenyl-2H-[1,2,4]triazol-3 -yl)-ethyl]-8-methoxy-5-methyl-[1,2,4 ]triazolo[1,5-a]pyridine;
3-{5-[2-(5,8-Dimethyl-[1,2,4 ]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-3-phenyl-[1,2,4]triazol-1-yl}-propionitrile;
3-{2-[2-(8-Ethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl]-4-phenyl-imidazol-1-yl}-propylamine;
3-{5-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-3-phenyl-[1,2,4]triazol-1-yl}-propylamine;
2-{2- [2-(2-Methoxy-ethyl)-5-phenyl-2H- [1,2,4 ]triazol-3-yl]-ethyl}-5,8-dimethyl-[1,2,4 ]triazolo[1,5-a]pyrazine; and
8-Methoxy-2-{2-[2-(2-methoxy-ethyl)-5-phenyl-2H-[1,2,4]triazol-3-yl]-ethyl}-5-methyl-[1,2,4]triazolo[1,5-a]pyridine
and pharmaceutically acceptable salts thereof.