# US 2014/0155393 A1 · 1,2,4-TRIAZOLO[4,3-a]PYRIDINE DERIVATIVES AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS

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- Number: US 2014/0155393 A1
- Document ID: US20140155393A1
- Status: Published application
- Kind: A1
- Application number: 13/883,818
- Filed: 2011-11-08
- Published: 2014-06-05
- Earliest claimed: 2010-11-08
- Assignees: Janssen Pharmaceuticals, Inc.
- Inventors: José Maria Cid-Núñez; Andrés Avelino Trabanco-Suárez; Juan Antonio Vega Ramiro; Daniel Oehlrich; Gary John Tresadern; Gregor James Macdonald
- Web page: https://patentgrep.com/patent/US20140155393A1

## CPC

- A61K 31/498: Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
- A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0095: {Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches (A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006)}
- A61K 9/06: Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)}
- A61K 9/2009: {Inorganic compounds}
- A61K 9/2018: {Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates}
- A61K 9/2059: {Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin}
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- 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 31/542: ortho- or peri-condensed with heterocyclic ring systems
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/06: Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61K 47/38: Cellulose; Derivatives thereof
- A61P 1/14: Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/06: Antimigraine agents
- A61P 25/08: Antiepileptics; Anticonvulsants
- 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 25/24: 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 25/32: Alcohol-abuse
- A61P 25/34: Tobacco-abuse
- A61P 25/36: Opioid-abuse
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 471/02: in which the condensed system contains two hetero rings
- C07D 471/04: Ortho-condensed systems
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to novel triazolo[4,3-a]pyridine derivatives of Formula (I) wherein all radicals are as defined in the claims. The compounds according to the invention are positive allosteric modulators of the metabotropic glutamate receptor subtype 2 (“mGluR2”), which are useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes to prepare such compounds and compositions, and to the use of such compounds for the prevention or treatment of neurological and psychiatric disorders and diseases in which mGluR2 is involved.

## Claims

### Claim 1

A compound of formula (I)
or a stereochemically isomeric form thereof,
wherein
R1 is selected from the group consisting of C1-6alkyl, (C3-8cycloalkyl)C1-3alkyl, (C1-3alkyloxy)C1-3alkyl, and C1-3alkyl substituted with 1, 2 or 3 fluoro substituents;
R2 is selected from the group consisting of Cl, CF3, —CN and cyclopropyl;
R3 is selected from the group consisting of hydrogen, methyl and CF3;
R4 is selected from the group consisting of hydrogen and methyl;
or R3 and R4 together with the carbon to which they are bound form a cyclopropyl ring or a carbonyl group;
L is selected from the group consisting of (L-a), (L-b), (L-c), (L-d), (L-e), (L-f), (L-g) and (L-h):
wherein
R5a, R5b, R5c and R5d are each independently selected from the group consisting of phenyl; phenyl substituted with 1 or 2 substituents each independently selected from the group consisting of C1-3alkyloxy and halo; pyridinyl; pyridinyl substituted with 1 or 2 substituents each independently selected from the group consisting of C1-3alkyl, C1-3alkyloxy and halo; pyrimidinyl; and pyrimidinyl substituted with 1 or 2 substituents each independently selected from the group consisting of C1-3alkyl, C1-3alkyloxy and halo;
R6e is selected from the group consisting of hydrogen and C1-3alkyl;
R5f, R5g, and R5h are each independently selected from phenyl and phenyl substituted with 1 or 2 fluoro substituents;
R6a, R6b and R6c are each independently selected from the group consisting of hydrogen; fluoro; C1-3alkyl; C1-3alkyl substituted with 1, 2 or 3 fluoro substituents; C1-3alkyloxy; C1-3alkyloxy substituted with 1, 2 or 3 fluoro substituents; and C3-6cycloalkyl;
R6h is C1-3alkyl;
R7a, R8a, R7b, R8b, R7c, R8c, R7d, and R8d are each independently selected from the group consisting of hydrogen, halo and methyl; or each R7a and R8a, R7b and R8b, R7c and R8c, and R7d and R8d together with the carbon to which they are attached form a cyclopropyl or a carbonyl group;
R9b is selected from the group consisting of hydrogen, C1-3alkyl and C3-6cycloalkyl;
wherein
each halo is selected from the group consisting of fluoro, chloro, bromo and iodo;
or a pharmaceutically acceptable salt or a solvate thereof.

### Claim 2 (depends on 1)

The compound according to claim 1, or a stereoisomeric form thereof, wherein R1 is (C3-8cycloalkyl)C1-3alkyl.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein R2 is CF3.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein R3 and R4 are hydrogen.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein L is selected from (L-a), wherein R5a is phenyl; R6a is selected from the group consisting of hydrogen and methyl; and R7a and R8a are hydrogen;
(L-b), wherein R5b is phenyl optionally substituted with one or two fluoro substituents; R6b is selected from the group consisting of hydrogen and methyl; R7b and R8b are hydrogen; and R9b is selected from the group consisting of hydrogen and methyl;
(L-c), wherein R5c is phenyl optionally substituted with 1 or 2 fluoro substituents; R6c is selected from the group consisting of hydrogen and methyl; and R7c and R8c are hydrogen;
(L-g), wherein R5g is selected from phenyl, optionally substituted with 1 or 2 fluoro substituents;
(L-h), wherein R5h is phenyl and R6h is methyl; and
L is (L-f), wherein R5f is selected from phenyl, optionally substituted with 1 or 2 fluoro substituents.

### Claim 6 (depends on 5)

The compound according claim 5,
wherein L is selected from (L-a), wherein R5a is phenyl; R6a is selected from the group consisting of hydrogen and methyl; and R7a and R8a are hydrogen;
(L-b), wherein R5b is phenyl optionally substituted with a fluoro substituent; R6b is selected from the group consisting of hydrogen and methyl; R7b and R8b are hydrogen; and R9b is selected from the group consisting of hydrogen and methyl;
(L-c), wherein R5c is phenyl; R6c is selected from the group consisting of hydrogen and methyl; and R7c and R8c are hydrogen;
(L-g), wherein R5g is selected from phenyl, optionally substituted with 1 or 2 fluoro substituents;
(L-h), wherein R5h is phenyl and R6h is methyl;
L is (L-f), wherein R5f is selected from phenyl, optionally substituted with 1 or 2 fluoro substituents.

### Claim 7 (depends on 1)

The compound according to claim 1, selected from the group consisting of
3-(cyclopropylmethyl)-7-[(3-phenyl-1-piperidinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,
3-(cyclopropylmethyl)-7-[[(2R)-2-phenyl-4-morpholinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,
3-(cyclopropylmethyl)-7-[(3-methyl-3-phenyl-1-piperazinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine (*R),
3-(cyclopropylmethyl)-7-[(3-methyl-3-phenyl-1-piperazinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine (*R) hydrochloride,
3-(cyclopropylmethyl)-7-[(3-methyl-3-phenyl-1-piperazinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine (*R) hydrochloride hydrate,
3-(cyclopropylmethyl)-7-[(3-methyl-3-phenyl-1-piperazinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine (*S),
3-(cyclopropylmethyl)-7-[(3-methyl-3-phenyl-1-piperazinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine (*S) hydrochloride,
3-(cyclopropylmethyl)-7-[(3-methyl-3-phenyl-1-piperazinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine (*S) hydrochloride hydrate,
3-(cyclopropylmethyl)-7-[[(2S)-2-phenyl-4-morpholinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,
3-(Cyclopropylmethyl)-7-[(3-phenyl-1-piperazinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,
3-(Cyclopropylmethyl)-7-[(3-phenyl-1-piperazinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine (*R),
3-(cyclopropylmethyl)-7-[(3-phenyl-1-piperazinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine (*S),
3-(cyclopropylmethyl)-7-[[3-(2-fluorophenyl)-1-piperazinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine (*R),
3-(cyclopropylmethyl)-7-[[3-(2-fluorophenyl)-1-piperazinyl]methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine (*S),
3-(Cyclopropylmethyl)-7-[(4-methyl-3-phenyl-1-piperazinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,
3-(Cyclopropylmethyl)-7-[(4-methyl-3-phenyl-1-piperazinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine (*R),
3-(cyclopropylmethyl)-7-[(4-methyl-3-phenyl-1-piperazinyl)methyl]-8(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine (*S),
3-(cyclopropylmethyl)-7-[(2-methyl-2-phenyl-4-morpholinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine (*R),
3-(cyclopropylmethyl)-7-[(2-methyl-2-phenyl-4-morpholinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine (*R) hydrochloride,
3-(cyclopropylmethyl)-7-[(2-methyl-2-phenyl-4-morpholinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine (*R) hydrochloride hydrate,
3-(cyclopropylmethyl)-7-[(2-methyl-2-phenyl-4-morpholinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine (*S),
3-(cyclopropylmethyl)-7-[(2-methyl-2-phenyl-4-morpholinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine (*S) hydrochloride,
3-(cyclopropylmethyl)-7-[(2-methyl-2-phenyl-4-morpholinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine (*S) hydrochloride hydrate,
3-(Cyclopropylmethyl)-7-[(3-methyl-3-phenyl-1-piperidinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine,
3-(Cyclopropylmethyl)-7-[(3-methyl-3-phenyl-1-piperidinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine hydrochloride,
3-methyl-7-[(3-methyl-3-phenyl-1-piperidinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine (*S),
3-methyl-7-[(3-methyl-3-phenyl-1-piperidinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine (*R),
2-[[3-(cyclopropylmethyl)-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-7-yl]methyl]-5-(2,4-difluorophenyl)-2,5-diazabicyclo[4.1.0]heptane (cis),
3-(cyclopropylmethyl)-7-[(3-methyl-3-phenyl-1-pyrrolidinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine (*R), and
3-(cyclopropylmethyl)-7-[(3-methyl-3-phenyl-1-pyrrolidinyl)methyl]-8-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridine (*S);
3-(cyclopropylmethyl)-7-{[(2*R)-2-(2,4-difluorophenyl)morpholin-4-yl]methyl}-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine,
3-(cyclopropylmethyl)-7-{[(2*S)-2-(2,4-difluorophenyl)morpholin-4-yl]methyl}-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine,
3-(cyclopropylmethyl)-7-{[3-(2,4-difluorophenyl)piperazin-1-yl]methyl}-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine,
3-(cyclopropylmethyl)-7-{[(3*R)-3-(2,4-difluorophenyl)piperazin-1-yl]methyl}-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine and
3-(cyclopropylmethyl)-7-{[(3*S)-3-(2,4-difluorophenyl)piperazin-1-yl]methyl}-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine.
or a stereoisomeric form, a pharmaceutically acceptable salt or a solvate thereof.

### Claim 8 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier or excipient.

### Claim 9

(canceled)

### Claim 10 (depends on 1)

A method for the treatment of a patient with a central nervous system disorder selected from the group of anxiety disorders, psychotic disorders, personality disorders, substance-related disorders, eating disorders, mood disorders, migraine, epilepsy or convulsive disorders, childhood disorders, cognitive disorders, neurodegeneration, neurotoxicity and ischemia comprising administering a therapeutically effective amount of a compound of claim 1 to said patient.

### Claim 11 (depends on 10)

The method according to claim 10, wherein
the psychotic disorders are selected from the group of schizophrenia, delusional disorder, schizoaffective disorder, schizophreniform disorder and substance-induced psychotic disorder;
the anxiety disorders are selected from the group of agoraphobia, generalized anxiety disorder (GAD), mixed anxiety and depression, obsessive-compulsive disorder (OCD), panic disorder, posttraumatic stress disorder (PTSD), social phobia and other phobias;
the personality disorders are selected from the group of obsessive-compulsive personality disorder and schizoid, schizotypal disorder;
the substance abuse or substance-related disorders are selected from the group of alcohol abuse, alcohol dependence, alcohol withdrawal, alcohol withdrawal delirium, alcohol-induced psychotic disorder, amphetamine dependence, amphetamine withdrawal, cocaine dependence, cocaine withdrawal, nicotine dependence, nicotine withdrawal, opioid dependence and opioid withdrawal;
the eating disorders are selected from the group of anorexia nervosa and bulimia nervosa;
the mood disorders are selected from the group of bipolar disorders (I & II), cyclothymic disorder, depression, dysthymic disorder, major depressive disorder, treatment resistant depression, bipolar depression, and substance-induced mood disorder;
the epilepsy or convulsive disorders are selected from the group of generalized nonconvulsive epilepsy, generalized convulsive epilepsy, petit mal status epilepticus, grand mal status epilepticus, partial epilepsy with or without impairment of consciousness, infantile spasms, epilepsy partialis continua, and other forms of epilepsy;
the cognitive disorder is selected from the group of delirium, substance-induced persisting delirium, dementia, dementia due to HIV disease, dementia due to Huntington's disease, dementia due to Parkinson's disease, dementia of the Alzheimer's type, behavioral and psychological symptoms of dementia, substance-induced persisting dementia and mild cognitive impairment.

### Claim 12 (depends on 10)

The method according to claim 10 wherein the treatment is for a central nervous system disorder selected from the group of schizophrenia, behavioral and psychological symptoms of dementia, major depressive disorder, treatment resistant depression, bipolar depression, anxiety, depression, generalised anxiety disorder, post-traumatic stress disorder, bipolar mania, epilepsy, attention-deficit/hyperactivity disorder, substance abuse and mixed anxiety and depression.

### Claim 13 (depends on 1)

A method for the treatment of a patient with a central nervous system disorder selected from the group of anxiety disorders, psychotic disorders, personality disorders, substance-related disorders, eating disorders, mood disorders, migraine, epilepsy or convulsive disorders, childhood disorders, cognitive disorders, neurodegeneration, neurotoxicity and ischemia comprising administering a therapeutically effective amount of a compound of claim 1 in combination with an or thosteric agonist of mGluR2 to said patient.

### Claim 14 (depends on 1, 8)

A process for preparing a pharmaceutical composition as defined in claim 8, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound as defined in claim 1.

### Claim 15 (depends on 1)

A product comprising
(a) a compound as defined in claim 1; and
(b) an mGluR2 orthosteric agonist.