WO2019043635A1

WO2019043635A1 - D-amino acid oxidase activity inhibiting compounds

Info

Publication number: WO2019043635A1
Application number: PCT/IB2018/056660
Authority: WO
Inventors: Anssi Haikarainen; Muriel Joubert; Benedek KÁROLYI; Heikki KÄSNÄNEN; Mikko PASSINIEMI; Antti POHJAKALLIO; Gábor SZÁNTÓ; Matti VAISMAA
Original assignee: Richter Gedeon Nyrt.; Orion Corporation
Priority date: 2017-09-01
Filing date: 2018-08-31
Publication date: 2019-03-07

Abstract

Compounds of formula (I), wherein R1 through R3 are as defined in the claims, or pharmaceutically acceptable esters, salts, hydrates or solvates thereof, useful as DAAO inhibitors as well as pharmaceutical compositions containing them and their use as modulators of DAAO activity, D-serine levels, D-serine oxidative products and NMDA receptor activity in the nervous system of a mammalian subject are provided.

Description

The present invention relates to pharmacologically active triazolopyridinone compounds, or pharmaceutically acceptable esters, salts, hydrates or solvates thereof, as well as to pharmaceutical compositions containing them and to their use as modulators of D-amino acid oxidase (DAAO) activity, D-serine levels, D-serine oxidative products and N- methyl-D-aspartate (NMDA) receptor activity in the nervous system of a mammalian subject.

BACKGROUND OF THE INVENTION

NMDA receptors are ion-channel receptors found at most excitatory synapses of the nervous system. They play an important role in processes underlying learning, memory and neuroplasticity. Activation of the ligand-gated NMDA receptor requires the simultaneous binding of an excitatory amino acid giutamate as well as the binding of a co-agonist, which can either be D-serine or glycine. Additionally, at the resting potential, the channel is blocked by Mg²⁺ ions, but sufficient membrane depolarization removes the block allowing Ca² as well as Na⁺ and K⁺ ions to flow through the channel pore (Ozawa, S. et al. Prog, NeurobioL, 54 (199%) 581 ).

Optimal NMDA signaling is pivotal for higher order cognitive functions and imbalance of this system has been proposed to play a role in several cognitive and psychotic symptoms. For example, long term potentiation (LTP), which is believed to be the molecular mechanism in learning, is mediated by NMDA receptors. While direct activation of NMD A receptors by increasing the extracellular concentration of the excitatory amino acid giutamate possesses risk of neuronal excitotoxicity, an indirect enhancement of the endogenous glutaminergic activity via NMDA receptors may offer a safer approach.

DAAO is a flavoenzyme that catalyzes the oxidative deamination of neutral and polar D-amino acids to corresponding imino acids and hydrogen peroxide. DAAO enzyme is located in peroxisomes and is expressed in both the brain and peripheral tissues. One of its endogenous substrates is D-serine, a neurotransmitter involved in MDA receptor activation.

According to the current hypothesis, D-serine is a more relevant co-agonist for the synaptic NMDA receptors than for the extrasynaptic NMDA receptors, which prefer glycine as a co-agonist (Papouin, T. et al. Cell, 150 (2012) 633). Especially the synaptic NMDA receptors are involved in the glutaminergic neurotransmission and are more likely to mediate neuronal excitotoxicity and cell death. Therefore, elevating the D-serine levels in the synaptic cleft via blockade of the breakdown by DAAO enzyme represents an alternative mechanism to enhance NMDA receptor activity and thus brain glutaminergic neurotransmission.

Dysfunction of central nervous system (CNS) glutamatergic signaling, more specifically the hypofunction of the NMDA receptors, has been associated with many psychiatric and neurological disorders. The most studied condition is schizophrenia based on the well-known effects of the NMDA receptor blockers ketamine and phencyclidine, which trigger schizophrenia-like condition in both healthy volunteers and preclinical animal models as well as induce the exacerbation of symptoms in patients with schizophrenia (Lahti, A. C. et al. Newopsychopharmacology, 25 (2001) 455).

Interestingly, decreased levels of D-serine have been observed in schizophrenic patients (Cho, S.-E. et al. Netirosci. Lett, 634 (2016) 42) and in aging rodent brain (Biilard, J.-M. J. Pharm. Biomed. Anal,, 116 (2015) 18). Besides both clinical and preclinical evidence of the involvement of NMDA receptor hypofunction in psychotic and neurocognitive symptoms of schizophrenia, recent scientific literature supports the theory that correcting the ^'NMDA hypofunction with DAAO inhibition is a potential therapy for disorders associated with neurocognitive deficits such as dementias including Alzheimer's disease. Clinical efficacy of increased D-serine has been shown in cognitive impairment and, especially, in cognitive impairment associated with schizophrenia (Kantrowitz, J. T. et al. Lancet Psychiatry, 2 (2015) 403). Benzoate, a weak DAAO enzyme inhibitor, has recently been studied in small scale proof of concept clinical studies. It was found to improve cognition and overall functions in patients with early phase Alzheimer's disease (Lin, C.-H. et al. Biol. Psychiatry, 75 (2014) 678) and a variety of symptom domains and neurocognition in patients with chronic schizophrenia (Lane, H.-Y. et ai. JAMA Psychiatry, 70 (2013) 1267).

It has also been demonstrated that the increased D-serine levels facilitate the survival and function of mature neurons, which may offer disease modifying potential for DAAO enzyme inhibitors in various neurodegenerative conditions (Sultan, S. et al. Neuron, 88 (2015) 957).

Since the role of NMDA receptors in the modulation of brain dopaminergic systems is well established, the augmentation of NMDA receptor function at the level of basal ganglia and limbic system could be beneficial in treating Parkinson's disease and related motor disorders as well as behavioral syndromes associated with this (Heresco-Levy, U. et al. Mov. Disord, 28 (2013) 419),

DAAO enzyme inhibition may also have other than NMDA receptor function enhancing effects. Hydrogen peroxide, a product of DAAO enzyme activity, is a well- known neurotoxin, which may induce neurodegeneration and neuropathic pain through oxidative stress. Reduction of spinal hydrogen peroxide levels by inhibiting DAAO enzyme has been confirmed to exert analgesic effects in preclinical pain models, so dampening the activity of the DAAO enzyme may have therapeutic potential in treating neuropathic pain states (Xie, D. et al. Eur. J. M ^' ed. Chem,, 117 (2016) 19).

Non-limiting examples of disorders that may be treated with compounds inhibiting the DAAO enzyme include cognition-related disorders, neurodegenerative disorders and disorders associated with neuropathic pain. DAAO enzyme inhibitors are useful for treating symptoms or condition associated with MDA receptor hypofunction such as schizophrenia, schizophreniform disorder, schizoaffective disorder and other psychotic disorders (e.g., psychotic disorder, psychosis), dementia and other cognitive disorders, anxiety disorders (e.g., generalized anxiety disorder, panic disorder), mood disorders (e.g., depressive disorders, major depressive disorders, bipolar disorders including bipolar I and II, bipolar mania, bipolar depression, apathy), posttraumatic stress disorder, eating disorders, addiction, sleep disorders, disorders usually first diagnosed in infancy, childhood or adolescence (e.g., attention-deficit disorder, autism spectrum disorders, disruptive behavior disorders), pain (e.g., neuropathic pain, inflammatory pain), neurodegenerative disorders (e.g., Parkinson' s disease, Alzheimer' s disease, Huntington's disease, amyotrophic lateral sclerosi s) and motor defective syndromes including NMDA receptor hypofunction in cerebellum as well as other movement disorders.

Known inhibitors of DAAO include benzoic acid, fused heterocycies (US 2010/0029737, WO 2008/089453/WO 2010/017418, WO 201 1/017634), furopyrroles (WO 2009/020814), 1,2,4-triazines (WO 2014/025993), 3-aminopyrazolines (WO 2007/093829), dihydroxy aromatic heterocycies (WO 2013/073577), hydroxyquinolinones (WO 2010/058314), pyridazinones (WO 2013/027000,

WO 2014/096757), pyridinones (WO 2013/004996), pyrimidinones (WO 2013/004995), pyrrolopyridines (WO 2010/005528), selenophenes and selenazoles (WO 2009/148564), quinazolinones and pyridopyrimidinones (CN 106749045 A), benzo[d]isothiazolones (Terry-Lorenzo, R. T. et al . J. Biomol. Screen., 20 (2015) 1218) and benzisoxazoles (WO 2005/066143, WO 2005/089753).

Several of the DAAO inhibitors known in the art are associated with very poor brain permeability.

Also triazolopyridine derivatives are known,

WO 2006/138695 discloses triazolopyridinone derivatives as cannabinoid receptor 1 (CB-1 ) antagonists. WO 2012/003392 discloses triazolopyridinone derivatives as ion channel modulators for the treatment of cardiovascular diseases. WO 2012/150829 discloses triazolopyridinone derivatives as glycogen synthase kinase-3 (GSK-3) inhibitors. WO 2013/074390 discloses triazolopyridinone derivatives which are useful as therapeutic agents for the treatment of CNS disorders associated with phosphodiesterase 10 (PDE10). WO 2017/0463 8 discloses triazolopyridinone derivatives useful in treating, ameloriating or preventing viral diseases. 6-Bromo-8-fluoro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one has been disclosed in US

2017/0022198. 6~Chloro-7-rnethyi-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 7-

(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 8-fluoro-[l,2,4]triazolo[4,3- a]pyridin-3(2H)-one, 8-c-hloro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 7-chloro- [l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 6-fluoro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 6~(trifluoromethyl)-[l,2,4]triazolo[4,3~a]pyridin-3(2H)~one, 6-chloro-[l,2,4]triazolo[4,3- a]pyridin-3(2H)-one, 7-methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one and 6-methyl- [l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one have been disclosed in Guo, C. et al. Bioorg. Med. Chem., 22 (2014) 3414. 7-Bromo-8-methoxy-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one has been disclosed in WO 201 1/033265. 8-Bromo-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one has been disclosed in WO 2017/046318. 7-Bromo-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one has been disclosed in WO 2015/014283 , 7-Bromo-8-iodo-[l,2,4]triazolo[4,3-a]pyridin-3(2H)- one and 8-bromo-7-chloro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one have been disclosed in WO 2006/138695. 6,8-Dichloro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one has been disclosed in US 2004/0063580, 6-Bromo-[l.,2,4]triazolo[4,3-a]pyridin-3(2H)-one has been disclosed in WO 2016/057522. 8-Methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one has been disclosed in Potts, K. ^'!^'. et al. Tetrahedron, 33 (1977) 1247.

Also the following library compounds have been disclosed:

8-bromo-7-iodo-[ 1 ,2,4]triazolo[4, 3 -a]pyridin-3 (2H)-one

8-chloro-7-iodo-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

7- fjuoro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

6-bromo-8-methyl-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one

8- chloro-6-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

8-bromo-6-methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

6-bromo-7-methyl-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one

6-bromo-8-(trifluoromethyl)-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one

8-(trifluoromet yl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

In the first aspect, the present invention relates to compounds of formula (I),

wherein

Ri and 1¾ are independently H, halogen, Q-ealkyl, haloCi-ealkyl, hydroxyCi-e.alkyl, C_3-5Cycloalkyl,

Cj-ealkoxy or cyano;

Rj is fluoro, chloro, bromo, C^alkyl, difluoromethyl or trif!uoromethyl;

or a pharmaceutically acceptable ester, salt, hydrate or solvate thereof;

with the provisos that

a) when R₃ is chloro, bromo or Ci-ealkyl, i and Ri are not simultaneously H;

b) the compound is not 6-bromo-8-fluoro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 6-chloro- 7-methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 7-(trifluoromethyl)-[l,2,4]triazolo[4,3- a]pyridin-3(2H)-one, 7-bromo-8-methoxy-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 8- fluoro-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 6-fluoro-[l,2,4]triazolo[4,3-a]pyridin- 3(2H)~one, 7-bromo-8-iodo-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 8-bromo-7-chloro- [l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 6,8-dichloro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)- one or 6-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one.

In a further aspect, the present invention provides a compound of formula (II),

wherein

Rj and R₂ are independently H, halogen, C_h lky!, haloC_{1 -6}alkyl, hydroxyCi ^alkyl, C_3-5Cycloalkyl, C_{3 -5}CycloalkylC₁^alkyl, C^alkoxy or cyano;

R₃ is fluoro, chloro, bromo, C_halky!, difluoromethyl, trifluoromethyl or cyano;

or a pharmaceutically acceptable ester, salt, hydrate or solvate thereof;

for use in the treatment or prevention of a disease associated with D-amino acid oxidase.

In a further aspect, the present invention provides the use of a compound of formula (II), as defined above, for the manufacture of a medicament for the treatment or prevention of a disease associated with D-amino acid oxidase.

In a further aspect, the present invention provides a method for the treatment or prevention of a disease associated with D-amino acid oxidase comprising administering to a mammal in need of such treatment or prevention an effective amount of at least one compound of formula (II), as defined above.

In a further aspect, the compounds of formula (I), as defined above, can be administered in combination with other compounds used for the treatment or prevention of a disease associated with D-amino acid oxidase.

In a further aspect, the present invention provides a process for the manufacture of the compounds of formula (I).

The DAAO inhibitors provided by the present invention possess enhanced brain permeability.

The present invention relates to compounds of formul

wherein

Ri and R₂ are independently H, halogen, Ci_₆alkyl, haloC^alkyl, hydroxyC^alkyl, C3.5eyeloa.kyi, C₃ -scy cloalkylC ί

or cyano:

R-3 is fluoro, chloro, bromo, C^alkyl, difluoromethyl or trifluoromethyl;

or a pharmaceutically acceptable ester, salt, hydrate or solvate thereof;

with the provisos that

a) when R₃ is chloro, bromo or d^alkyl, R₃ and R₂ are not simultaneously H;

b) the compound is not 6-bromo-8-fiuoro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 6-chloro- 7-methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 7-(trifiuoromethyl)-[l ,2,4]triazolo[4,3- a]pyridin-3(2H)-one, 7-bromo-8-methoxy-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 8- fluoro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 6-fluoro-[ 1 ,2,4] triazolo[4,3 -a]pyridin- 3(2H)-one, 7-bromo-8-iodo-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 8-bromo-7-chloro- [l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 6,8-dichloro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)- one or 6-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one.

In one embodiment, the present invention relates to compounds of formula (I), wherein Ri and R₂ are independently H, halogen, Ci-eaikyl, haloCi-galkyl,

C_3-5cycloalkyl,

or cyano,

R₃ is fluoro, chloro, bromo, C_halky 1, difluoromethyi or trifluorom ethyl;

with the provisos that

a) when R₃ is fluoro, chloro, bromo, C_halky 1 or trifluoromethyl, i and R₂ are not simultaneously H;

b) the compound is not 8-bromo-7-iodo-[l.,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 8-chloro- 7-iodo-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 6-bromo-8-fluoro-[l,2,4]triazolo[4,3- a]pyridin-3(2H)-one, 6-bromo-8-methyl-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 6-chloro- 7-methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H -one, 8-chloro-6-(trifiuoromethyl)- [ 1 ,2,4]triazolo[4,3-a]pyridin-3 (2H)-one, 8-bromo-6-methyl-[ 1 ,2,4]triazolo[4,3 -ajpyridin- 3(2H)-one, 6-bromo-7-methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 6-bromo-8- (trifluoromethyl)-[l.,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 7-bromo-8-methoxy- [l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 7-bromo-8-iodo-[l,2,4]triazolo[4,3-a]pyridin- 3(2H)-one, 8-bromo-7-chloro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one or 6,8-dichloro- [l,2,4]triazolo[4,3-a]pyridin-3(2H)-one. In one embodiment, the present invention relates to compounds of formula (III),

wherein

] and Ri are independently H, halogen,

hydroxyC

C_3-5Cycloalkyl, C_{3 -5}CycloalkylC_{1 -6}alkyl, C^alkoxy or cyano;

R is fluoro, chloro, bromo,

difluoromethyi or trifluoromethyl.

In one embodiment, the present invention relates to compounds of formula (I), wherein Ri and R₂ are independently H, halogen, methyl, trifluoromethyl, hydroxy methyl, cyclopropyl, methoxy or cyano;

R₃ is fluoro, chloro, bromo, methyl, difluoromethyl or trifluoromethyl.

In one embodiment, the present invention relates to compounds of formula (I), wherein Ri and R₂ are independently H, halogen,

or cyano; R₃ is fluoro, chloro, bromo,

or trifluoromethyl.

In one embodiment, the present invention relates to compounds of formula (I), wherein Rj and R₂ are independently H, halogen, haloCi-ealkyl or hydroxyCi-6aikyi;

j is fluoro, chloro, bromo, C_halky! or trifluoromethyl.

In one embodiment, the present invention relates to compounds of formula (I), wherein Ri and R₂ are independently H, halogen or haloC₄.6alk.yl;

R is chloro, bromo or C_{1 -6}alkyl.

In one embodiment, the present invention relates to compounds of formula (IV),

wherein

Rj is H or halogen;

R₂ is H, halogen,

haloCi-ealkyl, hydroxyCi-ealkyl or cyano;

R₃ is fluoro, chloro, bromo, Ci-₆alkyl, difluoromethyl or trifluoromethyl;

or a compound of formula (V),

wherein

Ri is H;

R₂ is halogen or cyano;

R is chloro or C_halky!. In one embodiment, the present invention relates to compounds of formula (IV

wherein

Ri is H or halogen;

R₂ is H, halogen, C^alkyl, haloC^alkyl or hydroxyCi-ealkyi;

R₃ is fluoro, chloro, bromo, Ci-ealkyl, difluoromethyi or trifluoromethyl.

In one embodiment, the present invention relates to compounds of formula (IV), wherein

Ri is H;

Ri is halogen or Ci-ealkyl,

R₃ is fluoro, chloro, bromo or trifluoromethyl.

In one embodiment, the present invention relates to compounds of formula (I) selected from the group of:

6- Bromo-7-fluoro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one,

7-Bromo-6-(trifluoromethyl)-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one,

7- Chloro-6-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one,

6-Chloro-7-fluoro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one,

6- Bromo-7-chloro-[ 1 ,2,4]triazolo[4,3 -a]pyridin-3 (2H)-one,

7- Bromo-6-chloro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one,

6,7-Dichloro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one,

7-Bromo-6-fluoro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one,

7-Chloro-6-fluoro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one,

6,7-Dibromo-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one,

7 Methyi-d3)-6 trifluoromethylH

7-Methyl-6-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

or a pharmaceutically acceptable ester, salt, hydrate or solvate thereof. The term "halo" or "halogen", as used herein as such or as part of another group, refers to fluoro, chloro, bromo or iodo.

The term "Ci_-6alkyl", as used herein as such or as part of another group, refers to a branched or straight chain saturated hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, i-propyl and t-butyl.

The term "haloCi-ealkyl", as used herein, refers to at least one halogen, as defined above, bonded to the parent molecular moiety through an "Ci-calkyl" group, as defined above. When there are several halogens, the halogens can be identical or different and the halogens can be attached to different carbon atoms or several halogens can be attached to the same carbon atom.

groups include, but are not limited to, difluoromethyl, trifluoromethyi and 2-chioroethyl.

The term "hydroxyCi-ealkyl", as used herein, refers to a hydroxy group bonded to the parent molecular moiety through an "C^alkyl" group, as defined above, including, but not limited to, hydroxymethyi, 2-hydroxyethyl and 3-hydroxypropyl. The term "Cs-scycloaikyl", as used herein as such or as part of another group, refers to cyclopropyl, cyclobutyl or cyciopentyl.

The term

as used herein, refers to a CVscyeloalkyl group, as defined above, bonded to the parent molecular moiety through an

group, as defined above, including, but not limited to, cyclopropylmethyl, cyclobutylmethyl and 2- cyclopropylethyl.

The term

as used herein refers to an C_halky! group, as defined above, bonded to the parent molecular moiety through an oxygen atom including, but not limited to, methoxy, ethoxy, n-propoxy, i-propoxy and t-butoxy.

The term "pharmaceutically acceptable" describes an ingredient that is useful in preparing a pharmaceutical composition, is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes those acceptable for veterinary use as well as human pharmaceutical use.

The term "salt" means nontoxic base addition salts of the compounds of the invention which are generally prepared by reacting the acid with a suitable organic or inorganic base. The term "hydrate" means non-covalent combinations between water and solute.

The term "solvate" means non-covalent combinations between solvent and solute. Solvents include, but are not limited to, ethanol, 2-propanol, acetonitrile and tetrahydrofuran.

In a further aspect, the present invention relates to a compound of formula (II),

wherein

Ri and R₂ are independently H, halogen, Ci-eaikyl, haloCi-galkyl,

Cj-scycloalkyl,

or cyano;

R3 is fluoro, chloro, bromo, C_halky!, difluoromethyl, trifiuorom ethyl or cyano;

or a pharmaceutically acceptable ester, salt, hydrate or solvate thereof;

In a further aspect, the present invention relates to the use of a compound of formula (II), as defined above, for the manufacture of a medicament for the treatment or prevention of a disease associated with D-amino acid oxidase.

In a further aspect, the present invention relates to a method for the treatment or prevention of a disease associated with D-amino acid oxidase comprising administering to a mammal in need of such treatment or prevention an effective amount of at least one compound of formula (II), as defined above.

In one embodiment the disease associated with D-amino acid oxidase is selected from the group of: schizophrenia, schizophreniform disorder, schizoaffective disorder and other psychotic disorders (e.g., psychotic disorder, psychosis), dementia and other cognitive disorders, anxiety disorders (e.g., generalized anxiety disorder, panic disorder), mood disorders (e.g., depressive disorders, major depressive disorders, bipolar disorders including bipolar I and II, bipolar mania, bipolar depression, apathy), posttraumatic stress disorder, eating disorders, addiction, sleep disorders, disorders usually first diagnosed in infancy. childhood or adolescence (e.g., attention-deficit disorder, autism spectrum disorders and disruptive behavior disorders), pain (e.g., neuropathic pain, inflammatory pain), neurodegenerative disorders (e.g., Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis) and motor defective syndromes including ^'NMD A receptor hypofunction in cerebellum as well as other movement disorders.

In one embodiment, the disease associated with D-amino acid oxidase is selected from the group of: schizophrenia, schizophreniform disorder, schizoaffective disorder, cognitive disorders and pain.

The invention, therefore, further relates to combination therapies wherein a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention is administered with another therapeutic agent or agents and/or with serine, for the treatment of one or more of the conditions previously indicated. Such therapeutic agents may be selected from: antidepressants, antipsychotics, anxiolytics, anticonvulsants, mood stabilizers, 5ΗΊΥ_Β ligands, mGluR2 agonists, alpha 7 nicotinic agonists, chemokine receptor CCR1 inhibitors, delta opioid agonists and compounds used in the treatment of Alzheimer's disease, Parkinson's disease, migraine, stroke, neuropathic pain or nociceptive pain.

In a further aspect, the present invention provides a process for the manufacture of the compounds of formula (I) according to the following reaction route:

X = F, C!, Br.

Step a can be carried out using 1-10 equivalents of hydrazine hydrate at elevated rature in solvents, eg, methanol, ethanol, isopropanol or dioxane.

Step b can be carried out using 1-1.5 equivalents of carbonyl-transfer reagent, e.g., phosgene, triphosgene or carbonyl diimidazole in different solvents, e.g., THF, acetonitrile or dioxane.

Step c can be carried out using palladium catalyst, e.g., tris(dibenzylideneacetone)dipalladium(0) or palladium(II) acetate, suitable ligand, e.g., 1, 1 '- bis(diphenylphosphino)ferrocene, base, e.g., cesium carbonate or potassium carbonate, and di-tert-butyl hvdrazodiformate in aprotic solvent e.g., 1 ,2-dichloroethane, chlorobenzene and toluene.

Step d can be carried out using 2-20 equivalents of HC1 in ether-type solvent e.g., ether or dioxane typically in room temperature but sometimes in elevated temperatures. Step e can be carried out using 2-5 equivalents of alkyi-, e.g., methyl hydrazinecarboxylate or semicarbazide at elevated temperature in alcohol, e.g., methanol, ethanoi or isopropyl alcohol.

Step / can be carried out by nitrating the amino group with the use of 1,5-3 equivalents of nitric acid in sulphuric acid.

Step g and h can be carried out together using 1-5 equivalents of chemical reducing agents, e.g., Zn/ammonium chloride in THF/water/MeOH mixture or tin(II) chloride in acidic conditions, followed by the reaction of 1-2 equivalents of triphosgene in the same solvent system, without the isolation of intermediate. Compounds as starting materials for step o, step d/step / and step g are either commercially available, are well-known in the literature or may be prepared using known techniques.

Pharmaceutically acceptable esters of hydroxy groups may be prepared by known methods using pharmaceutically acceptable carboxylic acids that are conventional in the field of pharmaceuticals. Representative examples of pharmaceutically acceptable esters of hydroxy groups include, but are not limited to, esters formed with acetic acid and propionic acid.

Pharmaceutically acceptable salts, such as metal salts and acid addition salts, with organic acids or inorganic acids are well known in the field of pharmaceuticals. Representative examples of pharmaceutically acceptable metal salts include, but are not limited to, lithium, sodium, potassium, calcium, magnesium, aluminum and zinc salts. Representative examples of pharmaceutically acceptable acid addition salts include, but are not limited to, chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, methane sulfonates, formates, tartrates, maieates, citrates, benzoates, salicylates and ascorbates. The present disclosure includes within its scope all the possible isotopicaily labeled forms of the compounds.

The compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, intraarticular, intrathecal, intraperitoneal, direct intraventricular, intracerebroventicular, intramedullary injection, intracisternai injection or infusion, subcutaneous injection or implant), by inhalation spray, eye drops, or nasal, vaginal, rectal, sublingual and topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable excipients appropriate for each route of administration.

Alternatively, one may administer the compound in a local rather than systemic manner, for example, via injection of the compound directly in the renal or cardiac area, often in a depot or sustained release formulation. Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the organ.

The pharmaceutical compositions containing the active ingredient according to the present invention usually contain 0.01 to 500 mg of active ingredient in a single dosage unit, it is, of course possible that the amount of the active ingredient in some compositions exceeds the upper or lower limits defined above.

The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

This dosage level and regimen may be adjusted to provide the optimal therapeutic response. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition and the host undergoing therapy. As a further aspect of the invention there is provided the pharmaceutical manufacture of medicaments containing the compounds of formula (I) or pharmaceutically acceptable esters, salts, hydrates and solvates thereof.

The pharmaceutical compositions of the present invention may be formulated as different pharmaceutical dosage forms, such as but not limited to, solid oral dosage forms like tablets (e.g., buccal, sublingual, effervescents, chewable, orodispersible, freeze dried), capsules, lozenges, pastilles, pills, orodispersible films, granules, powders; liquid oral dosage forms, such as but not limited to, solutions, emulsions, suspensions, syrups, elixires, oral drops; parenteral dosage forms, such as but not limited to, intravenous injections, intramuscular injections, subcutaneous injections; other dosage form , such as but not limited to, eye drops, semi-solid eye preparations, transdermal dosage forms, suppositories, rectal capsules, rectal solutions, emulsions and suspensions, etc.

The pharmaceutical compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, emulsifying, suspending, entrapping, freeze-drying, extrusion, laminating, film-casting, granulating, grinding, encapsulating, dragee-making or tabletting processes.

Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more physiologically acceptable excipients. Any of the well-known techniques and excipients may be used as suitable and as understood in the art.

Suitable excipients for the preparation of the dosage forms may be selected from the following categories, such as but not limited to, tablet and capsule fillers, tablet and capsule binders, release modifying agents, disintegrants, glidants, lubricants, sweetening agents, taste-masking agents, flavoring agents, coating agents, surfactants, antioxidants, buffering agents, complexing agents, emulsifying agents, lyophilization aids, microencapsulating agents, ointment bases, penetration enhancers, solubilizing agents, solvents, suppository bases, suspending agents.

In one embodiment, the invention relates to the use of specific excipients which are able to improve the solubility, dissolution, penetration, absorption or bioavailability of the active ingredient(s), such as but not limited to, hydrophilic polymers, hot melt extrusion excipients, surfactants, buffering agents, complexing agents, emulsifying agents, lyophilization aids, superdisintegrants, microencapsulating agents, penetration enhancers, solubilizing agents, co-solvents, suspending agents. The above described ingredients and different routes of manufacture are merely representative. Other materials as well as processing techniques and the like well known in the art can also be used.

The invention is further explained in the following Examples. It should be understood that the Examples are given by way of illustration only. From the above discussion and the Examples, one skilled in the art can ascertain the essential characteristics of the invention, and without departing from the spirit and scope thereof, can make various changes and modifications to adapt the invention to various uses and conditions. As a result, the invention is not limited by the illustrative examples set forth herein below but rather defined by the claims appended hereto.

In general, the compounds of formula (I) can be prepared according to the general knowledge of one skilled in the art and/or using methods set forth in the following Example sections. Solvents, temperatures, pressures and other reaction conditions can readily be selected by one of ordinary skill in the art. Starting materials are commercially available and/or readily prepared by one skilled in the art.

The present invention will be now illustrated by the following not limiting examples.

In the following examples "room temperature" denotes a temperature in the range from 20 °C to 25 °C.

The abbreviations used in the specific examples have the following meanings:

Cone. Concentrated

DCM Dichloromethane

DMF IN ,N-Dimethylformamide

DMSO Dimethylsuifoxide

EtOH Ethanol EtOAc Ethylacetate

! ^j A Triethylamine

IPA Isopropyl alcohol

MeOH Methanol rt room temperature

THF Tetrahydrofuran S N-iodosuccinimide

NBS N-bromosuccinimide

NCS N-chlorosuccinimide

TFA Trifiuoroacetic acid

DAST (Diethyl amino)sulfur trifluoride dppf 1 , 1 ^'-Bis(dipheny lphosphino)ferrocene

GDI Carbonyldiimidazole

FC Flash Column chromatography

CI 8 Reverse phase chromatography conditions

Preparation example 1 :

General procedure via nitramide

General procedure A

a) Substituted N-(pyridin-2-yl)nitramide

Substituted aminopyridine (1 eq) was mixed with cone. H₂S0₄ at 0 °C. To this mixture was

Dwise a mixture of cone. HN0₃ (1.5 - 3 eq) and cone. I hS() . The reaction mixture was stirred at 0 ^C'C for 1-3 hours after which it was poured into crushed ice. Title compound was collected by filtration and dried in vacuum.

Gen era! procedure B

b) Substituted [l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

The nitramide (1 eq) product from the general procedure A was dissolved in THF/MeOH/H₂0 and NH₄C1 (5-6 eq) was added. The mixture was cooled to 0 °C in an ice bath. Powdered zinc (5-6 eq) was added and the mixture was allowed to react for 0.5 - 1.5 hour. The mixture was filtered through a pad of celite and recooled to 0 °C. Triphosgene (1.3 - 1.6 eq) was added and the reaction mixture was stirred at 0 °C. After typically 1-2 hours but sometimes overnight of reaction time, the mixture was evaporated to dryness and 1 M HC1 solution was added. Crude triazolone was filtered off and dried in vacuum.

Preparation example 2:

General procedure via hydrazide

General procedure C (Hydrazination, general procedure)

To a solution of halogenopyridine (1.0 eq) in indicated solvent at rt was added hydrazine hydrate (1-10 eq.). Reaction mixture was stirred at the indicated temperature for the indicated time. Solvents were concentrated under vacuum. Water or saline solution was then added. Precipitate that formed was filtered off, washed with water and dried under vacuum yielding 2-hydrazinylpyridine. General procedure D (Cyclisation step with CDI)

To a solution of 2-hydrazinylpyridine (1.0 eq) in THF at rt was added at N,N'-carbonyldiimidazole (1.2-1.5 eq). Reaction mixture was stirred at rt for 1 hour- overnight. Solvents were concentrated under vacuum. A 1M aqueous HCi solution was added and the precipitate that formed was filtered off, washed with water and dried under vacuum yielding [l,2,4]triazolo[4,3-a]pyridin-3(2H)-one.

Example 1 : 6-ehforo-8-fli8oro-[l,2,4jtriazolo 4,3-a]pyrklin-3(2H)-osie

The title compound was synthesised according to general procedure D from

5- chloro-3-fluoro-2-hydrazinylpyridine (0. 15 g, 0.93 mmol) and CDI (0.20 mg, 1.21 mmol) in THF (5 ml) with 18 hours reaction time yielding 100 mg of

6- chloro-8-fluoro-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one. 1H NMR (DMSO-d₆) δ: 12.91 (br s, 1H), 7.99 (d, 1H), 7.34-7.44 (m, 1H).

Example 2: 6-Bromo-7-cliIoro- [1 ,2,4]triazolo [4,3-a] pyridin-3(2H)-one

Step : 7Y-(5-bromo-4-chloropyridin-

The title compound was synthesised according to general procedure A from 5-bromo-4-chloropyridin-2-amine (0.50 g, 2.41 mmol) in H₂S0₄ (1 ml) and a mixture of HN0₃ (0.27 mi, 3.92 mmol) and H₂S0₄ (0.27 ml) yielding 0.57 g of N 5-bromo-4-chloropyridin-2-yl)nitramide. ¹H NMR (DMSO-de) δ: 8.74 (s, 1H), 8.03 (d, 1H). Step 2: 6-Bromo-7-chloro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

The title compound was synthesised according to general procedure B from N-(5-bromo-4-chloropyridin-2-yl)nitramide (0.35 g, 1.39 mmol), NH₄C1 (0.37 g, 6.93 mmol), Zi dust (0.45 g, 6.93 mmol) and triphosgene (0.62 g, 2.08 mmol) in THF (12 ml), MeOH (3 ml) and H₂0 (3 ml). The crude product was purified by FC (CI S) yielding 48 mg of 6-bromo-7-cUoro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one. ^! 1 1 NMR (DMSO-d₆) δ: 12.66 (br s, 1H), 8.28 (d, 1 1 1). 7.73 (d, I I f ).

Example 3: 6,7-Dichloro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

Step 1 : 7Y-(4,5-dichloropyridin-2-yl)nitramide

The title compound was synthesised according to general procedure A from 5-bromo-4-chloropyridin-2-amine (0.50 g, 3.07 mmol) in H₂S0₄ (1.5 ml) and a mixture of HN0₃ (0.34 mi, 4.99 mmol) and H₂S0₄ (0.34 ml) yielding 0.60 g of N-(4,5-dichloropyridin-2-yl)nitramide. MS: m/z 208.0 | \ί-Π .

Step 2 : 6, 7-Dichloro-[ 1 ,2,4]triazolo[4, 3 -a]pyridin-3 (2H)-one

The title compound was synthesised according to general procedure B from N-(4,5-dichloropyridin-2-yl)nitramide (0.35 g, 1 .68 mmol), NH₄CI (0.45 g, 8.41 mmol), Zn dust (0.55 g, 8.41 mmol) and triphosgene (0.75 g, 2.52 mmol) in THF (12 ml), MeOH (3 ml) and H₂0 (3 ml). The crude product was purified by FC (C I S) yielding 90 mg of 6,7-dicMoro-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one. 1H NMR (DMSO-de) δ: 12.74 (s, 1H), 8.27 (d, 1H), 7.75 (d, 1 1 1 ).

Example 4: 6-Bromo-7-fluoro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

Step 1 : N-(5-bromo-4-fluoropyridin-2-yl)nitramid

The title compound was synthesised according to general procedure A from 5-bromo-4-fluoropyridin-2-amine (1.00 g, 5.24 mmol) in H₂S0₄ (3 ml) and a mixture of HNO3 (0.58 ml, 8.51 mmol) and H₂S0₄ (0.58 ml) yielding 1 .07 g of N-(5-bromo-4-fluoropyridin-2-yl)nitramide. 1H NMR (DMSO-de) δ: 8.71 (d, 1H), 7.82 (d, 1 1 1 ).

Step 2: 6-Bromo-7-fluoro-[l,2,4]triazolo[4,3-a]pyridin- one

The title compound was synthesised according to general procedure B from N-(5-bromo-4-fluoropyridin-2-yl)nitramide (0.50 g, 2. 12 mmol), NH₄C1 (0.57 g, 10.6 mmol), Zn dust (0.69 g, 10.6 mmol) and triphosgene (0.94 g, 3.18 mmol) in THF (16 ml), MeOH (4 ml) and H₂0 (4 ml). The crude product was purified by FC (C I 8) yielding 26 mg of 6-bromo-7-fluoro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one. 1H NMR (DMSO-d₆) δ: 12 (br s, 1 H), 8.31 (dd, 1 H), 7.35 (dd, 1H).

Example 5: 6-Chloro-7-fluoro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

Step J : 5-Chloro-4-fluoropyridin-2-amine

To a solution of 4-fluoropyridin-2-amine (1.00 g, 8.92 mmol) in MeCN (50 ml) at 0 °C was added NCS (0,60 g, 4,46 mmol). The resulting mixture was stirred for 1 hour at rt, cooled to 0 °C and another portion of NCS (0,60 g, 4.46 mmol) was added. The mixture was stirred for 1 hour at RT, diluted with EtOAc and washed with NaHC0₃ solution. The organic layer was dried with Na₂S0₄, filtered and evaporated to dryness. The crude product was purified by FC (Si()₂) yielding 0.44 g of 5-chloro-4-fluoropyridin-2-amine. 1H NMR (DMSO-d₆) δ: 8.00 (d, 1H), 6,45 (br s, 2H), 6.36 (d, 1H).

Step 2: iV-(5-chloro-4-fluoropyridin-2-yl)nitramide

The title compound was synthesised according to general procedure A from 5-chloro-4-fluoropyridin-2-amine (0.44 g, 3.00 mmol) in H₂S0₄ (1.5 ml) and a mixture of HN0₃ (0.34 mi, 4.88 mmol) and H₂S0₄ (0.34 ml) yielding 0.45 g of N-(5-chloro-4-fluoropyridin-2-yl)nitramide. 1H NMR (DMSO-de) δ: 8.67 (d, 1 H), 7,87 (d, I I I).

Step 3 : 6-Chloro-7-fluoro-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one

The title compound was synthesised according to general procedure B from N-(5-chloro-4-fluoropyridin-2-yl)nitramide (0.45 g, 2,35 mmol), NH₄C1 (0.63 g, 1 1.8 mmol), Zn dust (0.77 g, 1 1.8 mmol) and triphosgene (1.05 g, 3.52 mmol) in THF (16 ml), MeOH (4 ml) and H₂0 (4 ml). The crude product was purified by FC (CI 8) yielding 30 mg of 6-chloro-7-fluoro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one. 1H MR (DMSO-de) δ: 12.60 (br s, IH), 8,32 (d, 1 1 1), 7.41 (d, H i )

Example 6: 7~Bro!iio-6~chIoiO~[l,2,4]triazolo[4,3~a]pyridisi~3(2H)~0!ie

Step 1 : iV-(4-bromo-5-chloropyridin-2-yl)nitramide

The title compound was synthesised according to general procedure A from 4-bromo-5-chloropyridin-2-amine (0.83 g, 4.00 mmol) in H₂S0₄ (2.5 ml) and a mixture of HN0₃ (0,45 ml, 6.50 mmol) and H₂S0₄ (0.45 ml) yielding 1 ,00 g of A^r-(4~bromo-5-chloropyridin-2-yl)nitramide. 1H NMR (DMSO-d₆) δ: 8.64 (s, 1H), 8.17 (s, 1H).

Step 2: 7-Bromo-6-chloro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

The title compound was synthesised according to general procedure B from N-(4-bromo-5-chloropyridin-2-yl)nitramide (0,50 g, 1 ,98 mmol), NH4CI (0.53 g, 9.90 mmol) and Zn dust (0.65 g, 9.90 mmol) and triphosgene (0.88 g, 2.97 mmol) in THF (16 ml), MeOH (4 ml) and H₂0 (4 ml). The crude product was purified by FC (C I 8) yielding 12 mg of 6-chloro-7-fluoro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one. ^! H NMR (DMSO-d₆) δ: 12.67 (br s, 1H), 8,22 (s, 1H), 7,90 (s, 1H).

Example 7: 6-(Difluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one Step 1 : 6-Iodo-2-(4-methoxybenzyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

To a solution of 6-iodo-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one (0.21 g, 0.81 mmol; prepared as in WO 2004/043940) in DMF (3 ml) was added K₂C0₃ (0,23 g, 1 .63 mmol) and 4-methoxybenzyl chloride (0.14 mi, 1.03 mmol). The resulting mixture was stirred at rt for 3 days. H₂0 was added and the precipitated product was filtered off and washed with H₂0 yielding 0.30 g of 6-iodo-2-(4-methoxybenzyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one. 1H NMR (DMSO-de) δ: 8, 1 1 -8, 15 (m, H I ), 7,34 (dd, 1H), 7,21 -7.27 (m, 2H), 7,08 (dd, 1 1 1 ),. 6.86-6.92 (m, 2H), 5.01 (s, 21 1 ), 3.72 (s, 3H).

Step 2 ; 2-(4-Methoxybenzyl)-3 -oxo-2,3-dihydro-[ 1 ,2,4]tri azolo[4,3 -ajpyridi ne-6- carbaldehyde

A mixture of 6-iodo-2-(4-methoxybenzyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one (0.25 g, 0.66 mmol) and THF (4 ml) was cooled to -78 °C. A 2 M solution of /^'-PrMgCl in THF (0.36 ml, 0.72 mmol) was added dropwise and the resulting solution was stirred at -78 °C for 30 min. DMF (0.31 ml, 3.94 mmol) was added and the stirring was continued for 30 min, after which the mixture was allowed to warm to rt. The mixture was stirred at rt for 2 hours and quenched with J M HCl. The precipitated product was filtered off and washed with water yielding 0.15 g of 2-(4-methoxybenzyl)-3-oxo-2,3-dihydro-[l ,2,4]triazolo[4,3- a]p Tidine-6-carbaldehyde. MS: m/z 284,3 | M · i 1 j ^' . Step 3 : 6-(pifluoromethyl)-2-(4-methoxybenzyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

To a solution of 2-(4-methoxybenzyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6- carbaldehyde (0, 13 g, 0.46 mmol) in DCM (3 ml) was added DAST (0.12 ml, 0.92 mmol). The resulting solution was stirred at rt for 18 hours. The mixture was quenched with sat. NaHC0₃ solution and extracted with EtOAc. The combined organic phases were washed with water and brine, dried with Na₂S0₄, filtered and evaporated to dryness yielding 0.14 g of 6-(difluoromethyl)-2-(4-methoxybenzyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one. MS: m/z 306.4 [M+Hf.

Step 4: 6-(Difluoromethyl)-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one

A solution of 6-(difluoromethyl)-2-(4-methoxybenzyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)- one (0.13 g, 0,43 mmol) in TFA (4 ml) was refluxed for 5 hours and then evaporated to dryness. The crude product was purified by FC (CI 8) yielding 18 mg of 6-(difluoromethyl)- [l,2,4]triazolo[4,3-a]pyridin-3(2H)-one. 1H MR (DMSO-d₆) δ: 12.66 (br s, 1H), 8.22-8.25 (m, 1H), 7,26-7,36 (m, 2H), 6.98 (t, H i ).

Example 8: 6-Chloro-7-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

Step 1 : 6-Chloro-7-(trifluoromethyl)-[ 1 ,2,4]triazolo[4,3-a]pyridin-3(2H)-one

The title compound was synthesised according to general procedure D from 5-chloro-2-hydrazinyl-4-(trifluoromethyl)pyridine (0.22 g, 1.03 mmol; prepared as in WO 2011/0255 1) and GDI (0.22 g, 1.33 mmol) in THF (5 ml) with 18 hours reaction time yielding 0.20 g of 6-chloro-7-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one. ^lH vIR (ί)\ί SO- ·!,,) δ: 13.05 (br s, 1H), 8.29 (s, 1H), 7.99 (s, 1H).

Example 9: 6-Bromo-7-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

Step 1 : 5-Bromo-2-hydrazinyl-4-(trifluoromethyl)pyridine

The title compound was synthesised according to general procedure C from 5-bromo-2-chloro-4-(trifluoromethyl)pyridine (0.52 g, 2.00 mmol), hydrazine hydrate (0.87 ml, 18.0 mmol) and IPA (8 ml) at 70 °C with 1 1 hours reaction time. The reaction mixture was evaporated to dryness, EtOAc was added and the solids were filtered off. The filtrate was evaporated to dryness yielding 0.48 g of 5-bromo-2-hydrazinyl-4-

(trifluoromethyl)pyridine. 'H NMR (DMSO~d₆) δ: 8 ,29 (s, 1H), 8.27 (s, I H ), 7. 1 3 (s, 1H), 4.39 (s, 2H). Step 2: 6-Bromo-7-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

The title compound was synthesised according to general procedure D from

5- bromo-2-hydrazinyl-4-(trifluoromethyl)pyridine (0.24 g, 0.95 mmol) and CDI (0.20 g, 1.23 mmol) in THF (5 mi), with 18 hours reaction yielding 0.22 g of

6- bromo-7-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one. ^!H MR (DMSO-d₆) 6: 13 ,02 (br s, 1H), 8.31 (s, 1H), 7.97 (s, 1H).

Example 10: 6,7-Dibromo- l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

Step 1 : N-(4,5-dibromopyridin-2-yl)nitramide

The title compound was synthesised according to general procedure A from 4,5-dibromopyridin-2-amine (0.75 g, 2.97 mmol) in H₂S0₄ (1.5 ml) and a mixture of HNO3 (0.33 ml, 4.83 mmol) and H₂S0₄ (0.35 ml) yielding 0,85 g of N-(4,5-dibromopyridin-2- yDnitramide. 1H NMR (DMSO-de) δ: 8.71 (s, 1H), 8.16 (s, 1H).

Step 2: 6,7-Dibromo-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

The title compound was synthesised according to general procedure B from N-(4,5-dibromopyridin-2-yl)nitramide (0.83 g, 2.80 mmol), NH₄C1 (0.75 g, 14.0 mmol), Zn dust (0.91 g, 14.0 mmol) and triphosgene (1.24 g, 4.19 mmol) in THF (25 ml), MeOH (5 ml) and H₂0 (5 ml). The crude product was purified with FC (Si0₂) yielding 134 nig of 6,7-dibromo-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one. ^JH NMR (DMSO-d₆) δ: 12.66 (br s, i l l ). 8,23 (s, i l l ). 7,87 (s, IH).

Example 11: 6-Bromo-7-(difluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one Step 1 : 5-Bromo-4-(difluoromethyl)-2-hydrazinylpyridine

The title compound was synthesised according to general procedure C from 5-bromo-2-chloro-4-(difluoromethyl)pyridine (0.10 g, 0.41 mmol), hydrazine hydrate (0.10 mi, 2.06 mmol) and LP A (1 mi) at 100 °C with 9 hours reaction time, yielding 0.08 g of 5- bromo-4-(difluoromethyl)-2-hydrazinylpyridine. 1H NMR (DMSO-d₆) δ: 8.14-8.18 (m, 1 H), 8.05 (s, I I I ), 7.00 (t, H), 7.00 (s, H), 4.31 (s, 2H). Step 2; 6-Bromo-7-(difluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

The title compound was synthesised according to general procedure D from 5-bromo-4-(difluoromethyl)-2-hydrazinylpyridine (0.07 g, 0.29 mmol) and CDI (0.06 g, 0.38 mmol) in THF (2 mi) with 1.5 hour reaction time yielding 60 mg of 6-bromo-7-(difluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one. 1H NMR (DMSO-d₆) δ; 12.86 (br s, I H), 8.22-8.24 (m, H), 7.60-7.62 (m, IH), 7,02 (t, I H).

12: 7-Chloro-6-methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

Step I : N-(4-chloro-5-methylpyridin-2-yl)nitramide

The title compound was synthesised according to general procedure A from 4-chloro-5-methylpyridin-2-amine (0.21 g, 1.49 mmol) in H₂S0₄ (0.8 ml) and a mixture of HN0₃ (0.17 ml, 2,44 mmol) and H₂S0₄ (0. 17 ml) yielding 0.25 g of N-(4-chloro-5-methylpyridin-2-yl)nitramide. ^lH NMR (DMSO-d₆) δ: 8.30 (s, IH), 7.87 (s, I H), 2.30 (s, 3H).

Step 2: 7-Chloro-6-methyl-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one

The title compound was synthesised according to general procedure B from N-(4-c-hloro-5-methylpyridin-2-yl)nitramide (0.25 g, 1.33 mmol), NH₄CI (0.36 g, 6.66 mmol), Zn dust (0.44 g, 6.66 mmol) and triphosgene (0.59 g, 2,00 mmol) in THF (8 ml), MeOH (2 ml) and ¾() (2 ml). The crude product was purified with FC (C I 8) yielding 53 mg of 7-chloro-6-methyl-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one. ^!H NMR (DMSO-d₆) δ: 12.51 (br s, IH), 7.85-7.87 (m, IH), 7.49-7.51 (m, IH), 2.17 (d, 3H).

Example 13: 6-Bromo-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-7-carbonitrile Step 1 : N-(5-bromo-4-cyanopyridin-2-yl)nitramide

The title compound was synthesised according to general procedure A from 2-amino-5-bromoisonicotinonitrile (0.46 g, 2.32 mmol) in H₂S0 (1.25 ml) and a mixture of HN0₃ (0.26 ml, 3.79 mmol) and H₂S0₄ (0.25 mi) yielding 0.51 g of N-(5-bromo-4-cyanopyridin-2-yl)nitramide. 1H NMR (DMSO-d₆) δ: 8.92 (s, 1H), 8.26 (s, IH).

Step 2: 6-Bromo-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-7-carbonitrile

The title compound was synthesised according to general procedure B from N-(5-bromo-4-cyanopyridin-2-yl)nitramide (0.50 g, 2.06 mmol), NH₄CI (0.55 g, 10.3 mmol), Z1 dust (0.67 g, 10.3 mmol) and triphosgene (0.92 g, 3.09 mmol) in THF (12 ml), MeOH (3 ml) and H₂0 (3 ml). The crude product was recrystallized from 1-BuOH yielding 164 mg of 6-bromo-3-oxo-2,3-dihydro-[l ,2,4]triazolo[4,3-a]pyridine-7-carbonitrile. 1H NMR (DMSO-de) δ: 13.15 (s, IH), 8.34 d, IH), 8.31 (d, IH).

Example 14: 6,7-Dimethyl-[l,2,4jtriazolo[4,3-a]pyridin-3(2H)-one

Step 1 : 2-Hydrazinyl-4,5-dimethylpyridine

The title compound was synthesised according to general procedure C from 2-chloro-4,5-dimethylpyridine (0.12 g, 0.85 mmol; prepared as in Kaminski, T. et al. Eur. J. Org. Chem. (2003) 3855), hydrazine hydrate (0.41 ml, 8.47 mmol) and EtOH (0.4 ml) at 160 °C with 42 hours reaction time yielding 0.075 g of 2-hydrazinyl-4,5-dimethylpyridine. MS: m/z 138.1 [ M ! f | .

Step 2: 6,7-Dimethyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

The title compound was synthesised according to general procedure D from 2-hydrazinyl-4,5-dimethylpyridine (0.07 g, 0.53 mmol) and CDI (0.11 g, 0.69 mmol) in THF (2 ml ) with 1.5 hour reaction time. The crude product was purified with FC (CI 8) yielding 25 mg of 6,7-dimethyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one. 1H NMR (DMSO- d₆) δ; 12.21 (br s, I H), 7.58-7.62 (m, IH), 6.97-7.01 (m, 1H), 2, 19 (d, 3H), 2, 10 (d, 3H),

Example 15: 6-Chloro-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-7-carbonitrile Step 1 : N-(5-chloro-4-cyanopyridin-2-yl)nitramide

The title compound was synthesised according to general procedure A from 2-amino-5-chloroisonicotinonitrile (0.90 g, 5.86 mmol) in H₂S0₄ (3 ml) and a mixture of HN0₃ (0.66 ml, 9.55 mmol) and H₂S0₄ (0.66 ml) yielding 1 .02 g of N-(5-chloro-4-cyanopyridin-2-yl)nitramide. 1H NMR (DMSO-d₆) δ: 8.85 (d, IH), 8.30 (d, IH). Step 2: 6-Chloro-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-7-carbonitrile

The title compound was synthesised according to general procedure B from N-(5-chloro-4-cyanopyridin-2-yl)nitramide (0,50 g, 2.52 mmol), NH₄C1 (0.67 g, 12.6 mmol) and Zn dust (0.82 g, 12.6 mmol) and triphosgene (1.12 g, 3.78 mmol) in THF (12 ml), MeOl I (3 ml) and H₂0 (3 ml). The crude product was purified with FC (CI 8) yielding 53 mg of 6-chloro-3-oxo-2,3-dihydro-[l ,2,4]triazolo[4,3-a]pyridine-7-carbonitrile. Ή MR (DMSO-de) δ: 13. 17 (br s, 1 H), 8.36 (d, IH), 8,33 (d, 1H).

Example 16: 6-ChIoro-8-Oi!oro-7-methyl-| 1,2,4 ]triazolo[4,3-a]pyridin-3(2H)-one Step 1 : N-(5-chloro-3-fluoro-4-methylpyridin-2-yl)nitramide

The title compound was synthesised according to general procedure A from 5-chloro-3-fluoro-4-methylpyridin-2-amine (0.59 g, 3.64 mmol; prepared as in US 201 1/030 193) in H₂S0₄ (3 ml) and a mixture of HN0₃ (0.41 ml, 6.01 mmol) and H₂S0₄ (0.41 ml) yielding 0.62 g of A-(5-chloro-3-fiuoro-4-methylpyridin-2-yl)nitramide. ^! H NMR

(DMSO-de) δ: 8,49 (s, III), 2,39 (d, 3H). Step 2: 6-Chloro-8-fluoro-7-methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

The title compound was synthesised according to general procedure B from A^r 5-chloro-3-fluoro-4-methylpyridin--2-yl)mtraniide (0.60 g, 2.92 mmol), H₄C1 (0.78 g, 14.6 mmol) and Zn dust (0.95 g, 14.6 mmol) and triphosgene (1.30 g, 4.38 mmol) in THF (24 ml), MeOH (6 ml) and H₂0 (6 ml). The crude product was purified with FC (C I 8) yielding 131 mg of 6~chloro-8-fluoro-7~methyl~[l,2,4]triazolo[4,3-a]pyridin-3(2Fi)-one. H MR (DMSO-d₆) δ: 12.78 (br s, 1H), 8.00-8.03 (m, 1 1 1). 2.19-2.21 (m, 3H). Example 17: 6-Bromo-7-chloro-8-fluoro-[l,2,4]triazolo[4,3-ajpyridin-3(2H)-

Step 1 : 4-Chloro-3-fluoropyridin-2-amine

A mixture of 4-chloro-2,3-difluoropyridine (0.50 g, 3.34 mmol), IP A (3 ml), 4 M HC1 in dioxane (84 μΐ, 0.33 mmol) and 25% H₄OH solution (2.08 ml, 13.4 mmol) in a sealed tube was heated at 80 °C for 18 hours. The solvent was evaporated and to the residue was added H₂0 and NaHC0₃ solution. The precipitated solid was filtered off and washed with water yielding 0.22 g of 4-cMoro-3-fluoropyridin-2-amine. Ή N.MR (DMSO-de) δ: 7.70 (d, IH), 6.66-6.70 (m, IH), 6.54 (s, 2H).

Step 2: 5-Bromo-4-chloro-3-fluoropyridin-2-amine

To a solution of 4-chloro-3-fluoropyridin-2-amine (0.11 g, 0.75 mmol) in MeCN (3 mi) was added NBS (0.13 g, 0,75 mmol). The resulting mixture was stirred at rt for 1 hour. EtOAc was added and the solution was washed with sat. NaHC03 solution, H₂0 and brine. The organic phase was dried with Na₂S0₄, filtered and evaporated to dryness yielding 0, 15 g of 5-bromo-4-chloro-3-fluoropyridin-2-amine. MS: m/z 226.9 [M+Hjf.

Step 3 : iV-(5-bromo-4-chloro-3-fluoropyridin-2-yl)nitramide

The title compound was synthesised according to general procedure A from

5-bromo-4-chloro-3-fluoropyridin-2-amine (0. 15 g, 0.67 mmol) in H₂S0₄ (0,5 ml) and a mixture of HN0₃ (91 μΐ, 1.33 mmol) and H₂S0 (90 μΐ) yielding 0.11 g of N-(5-bromo-4-chloro-3-fluoropyridin-2-yl)nitramide. MS: m/z 271 .9 [M+H]^"1".

Step 4: 6-Bromo-7-chloro-8-f!uoro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

The title compound was synthesised according to general procedure B from N-(5-bromo-4-chloro-3-fluoropyridin-2-yl)nitramide (0.10 g, 0.37 mmol), NH₄CI (0, 10 g, 1.85 mmol), Zn dust (0.12 g, 1.85 mmol) and triphosgene (0.17 g, 0.56 mmol) in THF (5 ml), MeOH (1 ml) and H₂0 (1 ml). After completion of the reaction, the mixture was extracted with EtOAc, Organic layer was extracted with 1 M aqueous NaOH solution. The basic water layer was then acidified with 1M HC1 solution and extracted with EtOAc. This latter organic layer was dried (Na₂S0₄) and solvents were evaporated. Purification of the evaporation residue by preparative RP HPLC afforded 10 nig of 6-bromo-7-chloro-8-fluoro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one. Ή NMR (MeOH-c ) δ: 8.10 (d, 1H). MS: m/z 267.9 [M+H]⁺.

Example 18: 7-Fluoro-6-methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one Step 1 : N-(5-bromo-4-fluoropyridin-2-yl)acetamide

To a solution of 5-bromo-4-fluoropyridin-2-amine (2.00 g, 10.5 mmol) in pyridine (10 ml) was added acetyl chloride (1.12 ml , 1 5.7 mmol) dropwise. The resulting mixture was stirred at rt for 18 hours. The solvent was evaporated and to the evaporation residue was added EtOAc. The solution was washed with Na₂C0₃ solution, H₂0 and brine, dried with Na₂S0₄, filtered and evaporated to dryness yielding 1.87 g of A⁷-(5-bromo-4~fluoropyridin-2- yl)acetamide. 1H NMR (DMSO-d₆) δ: 10.93 (s, 1 H), 8,56 (d, 1 H), 8,04 (d, 1 H), 2. 1 (s, 3H).

Step 2: A^r--(4--fluoro-5--methylpyridin--2-yl)acetamide

To a degassed solution of A^r~(5-bromo-4~fluoropyridin-2-yl)acetamide (1.85 g, 7.94 mmol) in 1 ,4-dioxane (30 ml) and H₂0 (3 ml) was added K <( ^'( ) : (3.29 g, 23.8 mmol), 2,4,6- trimethyl-l,3,5,2,4,6-trioxatriborinane (1.67 ml, 1 1.9 mmol) and Pd(dppf)Cl₂ (0.29 g, 0.40 mmol). The resulting mixture was refluxed for 4 hours,allowed to cool and filtered through a pad of Celite eluting with MTBE. The filtrate was evaporated to dryness and the residue was purified by FC (Si0₂) yielding 1.05 g of still impure N-(4-fluoro-5-methylpyridin-2- yl)acetamide. MS: m/z 169.1 [M+Hf. Step 3 : 4-Fluoro-5-methylpyridin-2-amine

To a solution of N-(4-fluoro-5-methylpyridin-2-yl)acetamide (0.50 g, 2.97 mmol) in THF (5 ml) was added cone, HQ (1 ml). The resulting mixture was stirred at 60 °C for 7 hours and at rt for 1 8 hours and evaporated to dryness. The residue was dissolved in H₂0 and pH was adjusted to 9 with 1 M NaOH solution. The aqueous mixture was extracted with EtOAc, the combined organic phases were washed with brine, dried with Na₂S0₄, filtered and evaporated yielding 0.37 g of impure 4-fluoro-5-methylpyridin-2-amine which was used in the next step without further purification , MS: m/z 127,3 [ M i l ] ^' .

Step 4: N-(4-fluoro-5-methylpyridin-2-yl)nitramide

The title compound was synthesised according to general procedure A from impure 4- fluoro-5-methylpyridin-2-amine (0.37 g, < 2.90 mmol) in H₂S0₄ (2 ml) and a mixture of HN0₃ (0.36 mi, 5.28 mmol) and H₂S0₄ (0.36 mi) yielding 0.37 g of A^r-(4-fluoro-5- methylpyridin-2-yl)nitramide. MS: m/z 172.0 i \! i ! | .

Step 5 : 7-Fluoro-6-methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

The title compound was svnthesised according to general procedure B from JV-(4-fluoro-5- methylpyridin-2-yl)nitramide (0.37 g, 2.19 mmol), NH₄C1 (0.59 g, 10.9 mmol), Zn dust (0.71 g, 10.9 mmol) and triphosgene (0.97 g, 0.56 mmol) in THF (15 ml), MeOH (3 ml) and H₂0 (3 ml). The crude product was purified by FC (CI 8) yielding 5 mg of 7-fluoro-6- methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one. 1H NMR (MeOH-d₄) δ: 7.71-7.75 (m, 1H), 6.87 (d, 1H), 2, 16-2.19 (m, 3H),

Example 19: 7-Bromo-6-methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one Step 1 : 4-Bromo-2-chloro-5-methylpyridine 1 -oxide

To a solution of 4-bromo-2-chloro-5-methylpyridine (0.15 g, 0.73 mmol) in DCM (5 ml) was added 77% mCPBA (0.33 g, 1.45 mmol). The resulting mixture was stirred at rt for 3 days. EtOAc was added followed by 1 : 1 mixture of Na₂S0₃ and Na₂C0 solutions. The resulting mixture was stirred vigorously for 0.5 hour and the organic phase was separated. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with aq. ^'Na₂C0₃ solution and brine, dried with Na₂S0₄, filtered and evaporated yielding 0.13 g of 4-bromo-2-chloro-5-methylpyridine 1 -oxide. 1H NMR (CDCi₃) δ: 8.20-8.23 (m, 1 1 1), 7.66 (s, 1Ϊ-Ι), 2.31-2.34 (m, 3H).

Step 2: 4-Bromo-2-hydrazinyl-5-methylpyridine 1 -oxide

To a solution of 4-bromo-2-chloro-5-methylpyridine 1. -oxide (0.13 g, 0.58 mmol) in EtOH (0.5 mi) was added hydrazine hydrate (0.50 ml, 10.2 mmol). The resulting mixture was stirred at rt for 18 hours and at 40 °C for 5 hours. The cooled mixture was filtered and the solid was washed with ice cold EtOH yielding 73 mg of 4-bromo-2-hydrazinyl-5- niethylpyridine 1 -oxide. Ί Ι MR ( M SO-d,.) δ; 8,07-8, 10 (m, I I I ). 7.84 (s, I H), 7,23 (s, 1H), 4.47 (d, 2H), 2.13 (d, 3H). Step 3 : 4-Bromo-2-hydrazinyl-5-methylpyridine

4-bromo-2-hydrazinyl-5-methylpyridine 1-oxide (70 mg, 0.32 mmol) was dissolved in 12% solution of TiC in HC1. The resulting mixture was stirred at rt for 0.5 hour. pH was adjusted to 10 with 1 M NaOH solution and the mixture was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na₂S0₄), filtered and evaporated yielding 34 mg of impure 4-bromo-2-hydrazinyl-5-methylpyridine. MS: m/z 204.0 [M-HHjf. Step 4: 7-Bromo-6-methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

The title compound was synthesised according to general procedure D from impure 4- bromo-2-hydrazinyl-5-methylpyridine (34 mg, < 0.17 mmol) and CD I (36 mg, 0.22 mmol) in THF (1 ml) with 18 hours reaction time. The crude product was purified using FC (CI 8) yielding 13 mg of 7-bromo-6-methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one. Ή NMR

(DMSO-de) 6: 12.50 (br s, IH), 7.83 (s, IH), 7.68 (s, H i), 2.18 (d, 3H). Example 20: 6-(Difluoromethyl)-7-methyl-[l,2,4Jtriazolo[4,3-a]pyridin-3(2H)-one

Step ; iV-(5-formyl-4-methylpyridin-2-yl)pivalamide

To a solution ofN-(5-bromo-4-methylpyridin-2-yl)pivalamide (1.05 g, 3.87 mmol; prepared as in WO 2013/028474) in THF (15 ml) at -78 °C was added 2.5 M BuLi (3.87 ml, 9.68 mmol) dropwise. The resulting mixture was stirred at -78 °C for 1 hour. DMF (1.74 ml, 23.2 mmol) was added dropwise and the mixture was stirred at -78 °C for 15 minutes. Stirring was continued at rt for 2 hours and the reaction was quenched with H₂0. The mixture was extracted with EtOAc and the combined organic phases were washed with H₂0 and brine, dried with Na₂S0₄, filtered and evaporated. The crude product was purified by FC (Si02) yielding 0.28 g of N-(5-formyl-4-methylpyridin-2-yl)pivalamide. 1H MR (DMSO-de) δ: 10.23 (s, 1H), 10.13 (s, 1 H), 8.73 (s, 1H), 8.06-8.08 (m, 1 H), 2,60 (d, 3H), 1.25 (s, 9H).

Step 2: N-(5-(difluoromethyl)-4-methylpyridin-2-yl)pivalamide

To a solution ofN-(5-formyl-4-methylpyridin-2-yl)pivalamide (0.28 g, 1.27 mmol) in DCM (10 ml) at 0 °C was added DAST (0.50 ml, 3.81 mmol) dropwise. Stirring was continued at 0 °C for 15 minutes and at rt for 2 days. NaHC0₃ solution was added and stirring was continued for 15 min. Organic phase was separated and the aqueous phase was extracted with DCM. The combined organic phases were washed with aq. NaHC0 solution, H₂0 and brine, dried with ^'Na₂S0₄, filtered and evaporated yielding 0.28 g of N-(5-(difluoromethyl)- 4-methylpyridin-2-yl)pivaiamide. 1H NMR (DMSO-de) δ: 10.00 (s, IH), 8.40 (s, IH), 8.04 (s, IH), 7.16 (t, IH), 2,41 (d, 3H), 1 .24 (s, 9H).

Step 3 : 5-(Difluoromethyl)-4-methylpyridin-2-amine

To a solution of iV-(5-(difluoromethyl)-4-methylpyridin-2-yl)pivalamide (0.28 g, 1.16 mmol) in MeOH (3 nil) was added cone. HCl (0.5 ml). The resulting solution was heated in a sealed tube at 100 °C for 55 hours. MeOH was evaporated off and pH was adjusted to 10 with 1 M NaOH solution. The mixture was extracted with EtOAc. Combined organic phases were washed with H₂0 and brine, dried with Na₂S0 , filtered and evaporated yielding 0.12 g of impure 5-(difluoromethyl)-4-methylpyridin-2-amine. MS: m/z 159.3

( \ i n r .

Step 4: N-(5-(difluoromethyl)-4-methylpyridin-2-yl)nitraniide

The title compound was synthesised according to general procedure A from impure 5-(difluoromethyl)-4-methylpyridin-2-amine (0.12 g, < 0.76 mmol) in H₂S0₄ (0.75 nil) and a mixture o ! 1XO: (94 μΐ, 1.37 mmol) and 1 1 SO ; (0.10 ml) yielding 82 mg of impure N-(4- fluoro-5-methylpyridin-2-yl)nitramide. MS: m/z 204.0 [M+H ^~. Step 5: 6-(Difluoromethyl)-7-methyl-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one

The title compound was synthesised according to general procedure B from impure N-(4-fluoro-5-methylpyridin-2-yl)nitramide (80 mg, < 0.39 mmol), NH₄CI (0. 1 1 g, 1.97 mmol), Zn dust (0.13 g, 1.97 mmol) and triphosgene (0.18 g, 0.59 mmol) in THF (3 ml), MeOH (0.75 ml) and H₂0 (0.75 ml). The crude product was purified by FC (C 18) yielding 5 n g of 6-(difluoromethyl)-7-methyl-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one. ³ H NMR (DMSO-de) δ: 12.49 (br s, 1H), 8.10-8.14 (m, 1H), 7.12 (s, 1H), 7.02 (t, 1H), 2.3 1 (s, 3H). Example 21: 6,7-I)idiIoro~8-f1uoro-[l,2,4]triazolo[4,3-a]pyridisi~3(2H)-08ie

Step 1 : 4,5-Dichloro-3-fluoropyridin-2-amine

To a solution of 4-chloro-3-fluoropyridin-2-amine (0.16 g, 1 .09 mmol; Example 17, Step 1 ) in MeCN was added NCS (0.15 g, 1.09 mmol). The resulting mixture was stirred at rt for 2 h, at 55 °C for 1.5 hour, at 70 °C for 1.5 hours and finally at rt for 18 hours. EtOAc was added and the mixture was washed twice with sat. NaHC0 solution, H₂0 and brine, dried with ^'Na₂S04, filtered and evaporated yielding 0.14 g of 4,5-dichloro-3-fluoropyridin-2- amine. MS: m/z 182.9 ( M l l j .

Step 2: N-(4,5-dichloro-3-fluoropyridin-2-yl)nitramide

The title compound was synthesised according to general procedure A from 4,5-dichloro-3- fluoropyridin-2-amine (0. 14 g, 0.80 mmol) in H₂S0₄ (1 ml) and a mixture of HN0₃ (0.1 ml, 1.43 mmol) and H₂S0₄ (0.15 ml) yielding 0.1 1 g of N-(4,5-dicMoro-3-fluoropyridin-2- yljnitramide. MS: m/z 227.9

Step 3 : 6,7-Dichloro-8-fluoro-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one

The title compound was synthesised according to general procedure B from A^r-(4,5~dichloro-3~fluoropyridin-2-yl)mtraniide (0.1 1 g, 0.49 mmol), NH₄C1 (0.13 g, 2.43 mmol), Zn dust (0.16 g, 2.43 mmol) and triphosgene (0.22 g, 0.73 mmol) in THF (4 ml), MeOH (1 ml) and H₂0 (1 ml). The crude product was purified by FC (CI 8) yielding 4 mg of 6,7-dichk)ro-8-fluoro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one. ¹H NMR (MeOH~d₄) δ: 8.03 (d, IH). Example 22: 6-(Difluoromethyl)-7-fluoro-[.l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

Step 1 : tert-Butyl (4-fluoro-5-iodopyridin-2-yl)carbamate

To a solution of 4-fluoro-5-iodopyridin-2-amine (2.00 g, 8.40 mmol) in t-BuOH (12 ml) was added di-tert-butyl dicarbonate (2.02 g, 9.24 mmol). The resulting mixture was stirred at 40 °C for 7 hours and at rt for 18 hours. Di-tert-butyl dicarbonate (2.02 g, 9.24 mmol) was added and stirring at 55 °C was continued for 8 hours. The solvent was evaporated off and the residue was recrystallized from IPA yielding 1.55 g of tert-butyl (4-fluoro-5- iodopyridin-2-yl)carbamate. Ή NMR (DMSO-d₆) δ: 10.29 (s, H), 8.53 (d, IH), 7.69 (d, IH), 1.47 (s, 9H).

Step 2: tert-Butyl (4-fluoro-5-formylpyridin-2-yl)carbamate

To a solution of fers-butyl (4-fluoro-5-iodopyridin-2-yl)carbamate (1.48 g, 4.38 mmol) in THF (15 ml) at 0 °C was added 1.3 M solution οΠ-PrMgCl- LiCl in THF (7.74 ml, 10.0 mmol) dropwise. Ater 15 minutes stirring at 0 °C DMF (3.12 ml, 41.7 mmol) was added. Stirring was continued at 0 °C for 10 minutes and at rt for 2 hours. The reaction mixture was quenched with NH₄C1 solution and extracted with EtOAc. The combined organic phases were washed with H?0 and brine, dried with a₂S0₄, filtered and evaporated to dryness. EtOAc (15 ml) was added to the residue and the mixture was stored overnight at - 18 °C. The precipitated solid was filtered off yielding 0.30 g of iert-buiyl (4~fiuoro-5- formylpyridin-2-yl)carbamate. ¹H NMR (DMSO-d₆) δ: 10.74 (s, 1 H), 10.04 (s, 1 H), 8.72 (d, IB), 7.72 (d, 1H), 1.49 (s, 9H).

Step 3 : fert-Butyl (5-(difluoromethyl)-4-fluoropyridin-2-yl)carbamate

To a solution of fert-butyl (4-fluoro-5-formylpyridin-2-yl)carbamate (0.26 g, 1.08 mmol) in DCM (10 ml) at 0 °C was added DAST (0.43 ml, 3.25 mmol) dropwise. Stirring was continued at 0 °C for 15 minutes and at rt for 18 h. The reacton mixture was cooled to 0 °C and quenched with NaHC0₃ solution. After 15 minutes stirring the mixture was extracted with DCM. The combined organic phases were washed with NaHC0₃ solution, H₂0 and brine, dried with Na₂S0₄, filtered and evaporated yielding 0.26 g of tert-butyl (5- (difluoromethyl)-4-fluoropyridin-2-yl)cart)amate. 1H NMR (DMSO-de) δ: 10.50 (s, 1H), 8.48 (d, 1 H), 7.73 (d, 1H), 7, 17 (t, I N ), 1.48 (s, 9H), Step 4: 5-(Difluoromethyl)-4-fluoropyridin-2-amine

To a solution of feri-butyl (5-(difluoromethyl)-4-fluoropyridin-2-yl)carbamate (0.25 g, 0.95 mmol) in DCM (2 ml) was added TFA (2 ml). The resulting mixture was stirred at it for 1.5 hours and evaporated to dryness. To the residue was added NaHC(¾ solution and the aqueous mixture was extracted with EtOAc. The combined organic phases were washed with brine, dried with Na₂S0₄, filtered and evaporated to dryness yielding 0.15 g of 5-(difluoromethyl)-4-fluoropyridin-2-amine. 1H NMR (DMSO-de) δ: 8.05-8. 12 (m, 1H), 6.96 (t, I H), 6.78 (s, 2H), 6.25 (d, IH).

Step 5 : N-(5-(difluoromethyl)-4-fluoropyridin-2-yl)nitramide

The title compound was synthesised according to general procedure A from 5-(difluoromethyl)-4-fluoropyridin-2-amine (0, 15 g, 0.93 mmol) in H₂S0₄ (1.5 ml) and a mixture of HN0₃ (0. 1 1 ml, 1.67 mmol) and H₂S0₄ (0.15 ml) yielding 0.15 g of N-(5- (difluoromethyl)-4-fluoropyridin-2-yl)nitramide. ^lH NMR (DMSO-d₆) δ: 8.57.8,62 (m, IH), 7.78 (d, 1H), 7.22 (t, IH).

Step 6: 6-(Difluoromethyl)-7-fluoro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

The title compound was synthesised according to general procedure B from N-(5-(difluoromethyl)-4-fluoropyridin-2-yl)nitramide (0.14 g, 0.68 mmol), NH₄C1 (0. 18 g, 3.38 mmol ), Zn dust (0.22 g, 3.38 mmol) and triphosgene (0.30 g, 1.01 mmol) in THF (5 ml), MeOH (1.2 ml) and H₂0 (1.2 ml). The crude product was extracted from acidic aqueous phase with EtOAc (no precipitate). The combined organic extracts were washed with brine, dried with ¾8θ₄, filtered and evaporated. The obtained crude product was purified by FC (CI 8) yielding 40 nig of 6-(difluoromethyl)-7-fluoro-[l,2,4]triazolo[4,3- a]pyridin-3(2H)-one. 'H NMR (600 MHz, DMSO-de) δ: 12,64 (s, 1H), 8.33-8.40 (m, 1 H), 7.32 (d, 1H), 7.05 (t, 1H).

Example 23: 6,7-Difluoro-[l,2,4]triazolo[4,3-ajpyridin-3(2M)-one

Step 1 : iV-(4,5-difluoropyridin-2-yl)nitramide

The title compound was synthesised according to general procedure A from 4,5-difluoropyridin-2-amine (0.23 g, 1 .77 mmol) in H₂S0₄ (1.5 ml) and a mixture of HN0₃ (0.20 ml, 2.92 mmol) and H₂S0₄ (0.22 ml). After pouring to ice the aqueous mixture was extracted with EtOAc and the combined organic extracts were washed with H₂0 and brine, dried with Na₂S0₄, filtered and evaporated yielding 0.30 g of N-(4,5-difluoropyridin-2-yl)nitramide. ^!H NMR (DMSO-de) δ: 8.26-8.34 (m, 1H), 7.58- 7.68 (m, i l l ).

Step 2: 6,7-Difluoro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

The title compound was synthesised according to general procedure B from N-(4,5-difluoropyridin-2-yl)nitramide (0.29 g, 1.66 mmol), NH₄CI (0.44 g, 8.28 mmol), Zn dust (0.54 g, 8.28 mmol) and triphosgene (0.74 g, 2.48 mmol) in THF (8 ml), MeOH (2 ml) and H₂0 (2 ml). The precipitated product was filtered off yielding 85 mg of 6,7-difluoro- [l,2,4]triazolo[4,3-a]pyridin-3(2H)-one. ^]H NMR (DMSO-de) δ: 12.78 (br s, 1H), 7.80-7.86 (m, I I I ). 6.76-6.85 (m, 1H). Example 24: 7-Bromo-6-fluoro-[l,2,4]triazolo[4,3-a] pyridin-3(2H)-one

To a solution of 4-bromo-2,5-difluoropyridine (0.10 g, 0.52 mmol) in IPA (1 mi) was added 4 M HCl in 1 ,4-dioxane (13 μί, 0.05 mmol) and hydrazine hydrate (75 μ], 1 .55 mmol). The resulting mixture was stirred at 80 °C for 9 hours, followed by 18 hours at rt. H₂0 was added and the mixture was extracted with EtOAc, The combine organic phases were washed with brine, dried with Na₂S0₄ and filtered. The solution was concentrated to about 7 ml and THF (6 ml) was added. The mixture was cooled to 0 °C and triphosgene (0.15 g, 0.52 mmol) was added. The resulting mixture was stirred at 0 °C for 1 hour. The solvents were evaporated off and 1 M HCl was added. The precipitated solid was filtered off and washed with H₂0 yielding 25 mg of 7-bromo-6-fluoro-[l,2,4]triazoio[4,3-a]pyridin-3(2H)- one. 1H NMR (600 MHz, DMSO-d₆) δ: 12.73 (br s, 1 H), 8.22 (d, lH), 7,89 (d, I I I ).

Example 25: 7-(Methyl-<i3)-6-(trifluoromethyl)-[l,2,4]triazolo[4,3-alpyridin-3(2H)-one

Step 1 : (2-Chloro-5-(trifluoromethyl)pyridin-4-yl)methan-i/₂-ol

To a solution of methyl 2-chloro-5-(trifluoromethyl)i sonicotinate (2.97 g, 12.4 mmol) in THF (40 mi) and MeOH-i ₄ (7 ml) at 0 °C was added NaBD₄ (1.04 g, 24.8 mmol). The resulting mixture was stirred at rt for 15 min and NaBD₄ (0.26 g, 6.20 mmol) was added. After 1 hour, H₂0 and H₄C1 solution were added and the resulting mixture was extracted with EtOAc. The combined organic phases were washed with H₂0 and brine, dried with Na₂S0₄, filtered and evaporated to dryness. The crude product was purified by FC (Si0₂) yielding 2.13 g of (2-chloro-5-(trifluoromethyl)pyridin-4-yl)methan-i/₂-ol. Ή NMR (CDCI₃) δ: 8.58-8.61 (m, 1 H), 7.83-7.84 (m, 1H), 2, 15-2, 17 (m, ! ! ! }

Step 2: 4-(Bromomethyl-i¾)-2-chloro-5-(trifluoromethyl)pyridine

To a solution of (2-chloro-5-(trifluoromethyl)pyridin-4-yl)methan-i¾-ol (1.18 g, 5.52 mmoi) in DCM (15 ml) at 0 °C was added PPh₃ (1.61 g, 6.14 mmol) and the resulting mixture was stirred for 10 minutes. NBS (1.09 g, 6.14 mmol) was added in portions. The resulting mixture was stirred at 0 °C for 1.5 hour and evaporated to dryness. The title compound was isolated with FC (Si0₂) yielding 1.59 g of 4-(bromomethyl-c¾)-2-chloro-5- (trifluoromethyl)pyridine. Ή NMR (CTX^'i :) δ: 8.64-8.67 (m, i l l ). 7,59-7,61 (m, H I ). Step 3 : 2-Chloro-4-(methyl-i¾)-5-(trifluoromethyl)pyridine

To a mixture of LiAlD4 (0.15 g, 3.62 mmol) in THF (10 ml) at 0 °C was added dropwise a solution of 4-(bromomethyl-£/₂)-2-chloro-5-(trifluoromethyl)pyridine (1.00 g, 3.62 mmol) in THF (10 ml). The resulting mixture was stirred at rt for 1 hour and cooled to 0 °C. NaHS0₄ solution (1M) was added until the pH of the solution was 5. The resulting mixture was extraxted with DCM. The combined organic phases were washed with H₂0 and brine, dried with Na₂S0₄, filtered and evaporated to dryness yielding 0.62 g of 2-chloro-4-(methyl-t¾)- 5-(trifluoromethyl)pyridine. 1H NMR (CDCI₃) δ: 8.57-8.59 (m, 1H), 7.28-7.30 (m, 1 1 1 )

Step 4: 2-Hydrazinyl-4-(methyl-£¾)-5-(trifluoromethyl)pyridine

The title compound was synthesised according to general procedure C from 2-chloro-4-(methyl-i¾)-5-(trifluoromethyl)pyridine (0.62 g, 3.12 mmol) and hydrazine hydrate (1.51 ml, 31.2 mmol) in IPA (6 ml) in a sealed tube at 1 10 °C with lh reaction time yielding 0.53 g of 2-hydrazinyl-4-(methyl-i¾)-5-(trifluoromethyl)pyridine. Ή NMR (DMSO-d₆) 6: 8.16 (s, I I I). 8.15 (s, IH), 6.66 (s, IH), 4.30 (br s, 2H). Step 5: 7-(Methyi-t¾)-6-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

The title compound was synthesised according to general procedure D from 2-hydrazinyl-4- (methyl-t¾)-5-(trifluoromethyl)pyridine (0.53 g, 2.73 mmol) and CDI (0.53 g, 3.28 mmol) in THF (15 ml) with 1 hour reaction time. The crude product was purified by FC (CI 8) yielding 0.32 g of 7-(methyl-i¾)-6-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)- one. 1H NMR (DMSO-d₆) δ: 12.61 (br s, IH), 8, 12-8, 15 (m, H I ), 7.24 (s, IH), Example 26: 7-(Difluoromethyl)-6-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin- 3(2H)-one

Step 1 : 2-Chloro-4-(difluoromethyl)-5-(trifluoromethyl)pyridine

To a solution of 2-chloro-5-(trifluoromethyl)isonicotinaldehyde (0.10 g, 0.48 mmol) in DCM (4 nil) at 0 °C was added DAST (0.13 ml, 0.95 mmol) dropwise. The resulting mixture was stirred at 0 °C for 0.5 hour and at rt 18 hours. The reaction mixture was cooled in ice bath and quenched with sat. NaHCOj solution. The aqueous phase was extracted twice with DCM. The combined organic phases were washed with H₂0 and brine, dried with Na₂S0₄, filtered and evaporated to dryness yielding 0.12 g of crude 2-chloro-4- (difluoromethyl)-5 trifluorornethyi)pyridine. ^: ! 1 NMR (DMSO-d6) δ: 9.05-8,99 (m, 1 1 1 }.. 8.07-8.02 (m, 1 1 1 ), 7.35 (t, IH).

Step 2: 4-(Difluoromethyl)-2-hydrazinyl-5-(trifluoromethyl)pyridine

The title compound was synthesised according to general procedure C from 2-chloro-4-(difluoromethyl)-5-(trifluoromethyl)pyridine (0.11 g, 0.48 mmol), hydrazine hydrate (0, 18 ml, 3,80 mmol) and IPA (1 ml) at 100 °C with 1 hour reaction time. The reaction mixture was evaporated to dryness, EtOAc was added and the solution was washed with H₂0 and brine, dried with Na₂S0₄, filtered and evaporated to dryness yielding 0.10 g of 4-(difluoromethyl)-2-hydrazinyl-5-(trifluoromethyl)pyridine. 1H NMR (DMSO-d6) δ: 8.73 (br s, IH), 8.36 (br s, 1H), 7.13 (t, IH), 7.06 (br s, 1H), 4.53 (br s, 2H).

Step 3 : 7-(Oifluoromethyl)-6-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

The title compound was synthesised according to general procedure D from 4- (difluoromethyl)-2-hydrazinyl-5-(trifluoromethyl)pyridine (0.10 g, 0.44 mmol) and GDI (86 mg, 0.53 mmol) in THF (3 ml), with 18 hours reaction yielding 70 mg of 7- (difluoromethyi)-6 trifluoromethyi) 1,2,4]triazolo[4,3-a]pyridin~3(2H)-one. ^!H NMR (400MHz, DMSO-d6) δ: 13.01 (br s, 1H), 8.35-8.28 (m, 1 H), 7.78-7.72 (m, 1H), 7.09 (t, 1H). Example 27: 6-bromo-8--chIoro-"[l,2,4]triazoIo 4,3-a]pyrklin-3(2H)-osie

Step 1 : 5-bromo-3-chloro-2-hydrazinylpyridine

NH₂

. NH

C!

To a solution of 5-bromo-2,3-dichloropyridine (500 mg, 2,20 mmol) in EtOH (5 mL) was added hydrazine hydrate (0.33 mL, 6.61 mmol) and the reaction mixture was stirred at 80 °C for 24 hours. After completion of the reaction, it was concentrated under reduced pressure at 25 °C. The resulting caide mass was triturated with EtOH (1 mL) at 0 °C. The solid precipitate was filtered, washed with Et₂0 (2 mL) and dried under reduced pressure to get 480 mg of 5-bromo-3-chloro-2-hydrazinylpyridine. 1H-NMR (400 MHz, DMSO-£¾) 5: 8.14 (s, 1 1 1 ).. 7.92 (s, !H), 7,86 (s, IH), 4,24 (brs, 2H). LCMS: [ M i l l = 222.1.

Step 2: 6-bromo-8-chloro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

The title compound was synthesised according to general procedure D from 5-bromo-3- chloro-2-hydrazinylpyridine (101 mg, 0.45 mmol), CDI (88 mg, 0.54 mmol) in THF (3 ml) yielding 71 mg of 6-bromo-8-chloro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one.

MS: m/z 250 ( M l l j . 1H NMR (DMSO-de) δ: 12.87 (br s, 1 i I ). 8.13 (d, I I I), 7.65 (d, 1H)

Example 28: 6-flsioro~7-methyI-[l₅2,4]iriazoIo[4₅3-a]pyrid½-3(2H)-osie

Ste 1 : 5-fluoro-2-hydrazinyl-4-methylpyridine

To a solution of 2-chloro-5-fluoro-4-methylpyridine (200 mg, 1.4 mmol) in «-butanol (2 mi) at rt was added hydrazine hydrate (0.7 mi, 13.7 mmol). Reaction mixture was stirred at 150 °C for 7 hours, then at 160 °C for 22 hours. Solvents were evaporated under vacuum. Water was added to the mixture. Precipitate formed was filtered off, washed with water and dried under vacuum yielding 66 mg of 5-fluoro-2-hydrazinyl-4-methylpyridine and 2-chloro-5-hydrazinyl-4-methylpyridine as a 8/2 mixture.

MS: m/z 142 | M 1 11 ^' .

Step 2: 6-fluoro-7-methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

The title compound was synthesised according to general procedure D from the mixture of 5-fluoro-2-hydrazinyl-4-methylpyridine and 2-chloro-5-hydrazinyl-4-methylpyridine (66 mg, 0.46 mmol) and CDI (91 mg, 0.56 mmol) in THF (3 ml) yielding 30 mg of 6-fluoro-7- methyl-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one.

MS: m/z 168 | M · S ! | Ί ί NMR (DMSO-d₆) δ: 12,46 (br s, 1H), 7,96 (d, 1H), 7, 17 (m, I I I ), 2.17-2.26 (m, 3H) Example 29: 6,7-bis(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

Step 1 : 2-hydrazinyl-4,5-bi s(trifluoromethyl)pyridine

To a solution of 2-chloro-4,5-bis(trif!uoromethyl)pyridine (212 mg, 0.85 mmol) in 2-propanol (2 ml) at rt was added hydrazine hydrate (425 mg, 8.5 mmol). Reaction mixture was stirred at 150 °C for 2 hours. Solvents were evaporated under vacuum. Water was added and the mixture was stirred at rt overnight. Precipitate that formed was filtered off, washed with water and dried under vacuum yielding 46 mg of 2-hy draziny 1-4,5 - bis(trifluoromethyl)pyridine.

MS: m/z 246 [ Μ Ι Π ^' . Ή NM R (DMSO-de) δ: 8.99 (br s, IH), 8.47 (s, IH), 7.19 (br s, 1H), 4.60 (br s, 2H) fluoromethyl)-[l.,2,4]triazolo[4,3-a]pyridin-3(2H)-one

The title compound was synthesised according to general procedure D from 2-hydrazinyl- 4,5-bis(trifluoromethyl)pyridine (46 mg, 0.19 mmol) and CDI (37 mg, 0.22 mmol) in THF (3 ml), with stirring at rt for 4 days. Then CDI (15 mg, 0.10 mmol) was added and the mixture was stirred at 40 °C for 2 more hours. General work-up yielded 18 mg of 6,7-bis(trifluoromethyl)-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one.

MS: m/z 272 [M+Hf . Ή NMR (DMSO-d₆) 5: 13. 16 (br s, IH), 8.37 (s, IH), 8.09 (s, IH)

Example 30: 7-methyl-6-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

Step : 2-hydrazinyl-4-methyl-5-(trifluoromethyl)pyridine

To a solution of 2-chloro-4-methyl-5-(trifluoromethyl)pyridine (200 n g, 1 .02 mmol) in

2-propanol (3 nil) at rt was added hydrazine hydrate (0.5 ml, 10.2 mmol). Reaction mixture was heated up to 100 °C for 2 hours, then heated up to 120 °C in a microwave reactor and stirred for 0.5 hour. Solvents were evaporated under vacuum. Water was added and the precipitate formed was filtered off, washed with water and dried under vacuum yielding 150 mg of 2-hydrazinyl-4-methyl-5-(trifluoromethyl)pyridine.

MS: m/z 192 [M+tlf . 1H NMR. (DMSO-de) δ: 8.16 (s, 1H), 8.15 (d, 1H), 6,66 (s, \ \ \ ), 4.30 (s, 2H), 2.28-2.31 (m, 3H)

Step 2; 7-methyl-6-(trifluoromethyl)-[ 1 ,2,4]triazolo[4,3-a]pyridin-3(2H)-one

The title compound was synthesised according to general procedure D from 2-hydrazinyl-4- methyl-5-(trifluoromethyl)pyridine (148 mg, 0.77 mmol), GDI (151 mg, 0.93 mmol) in THF (3 ml). Resulting cmde compound was dissolved in I M aqueous NaOH solution and washed 3-times with EtOAc. Aqueous layer was acidifed with cone. HC1. Precipitate formed was filtered off washed with water and dried under vacuum yielding 67 mg of 7- methyl-6-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one.

MS: m/z 218 [M+Hf . 1H NMR (DMSO-de) δ: 12.60 (br s, 1H), 8.13 (s, 1H), 7,24 (s, 1H), 2.31 (s, 3H) Example 31: 6-bromo-7-cyclopropyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

Step 1 : 5-bromo-2-chloro-4-cyclopropylpyridine

To a degassed solution of 5-bromo-2-chloro-4-iodopyridine (1 g, 3.14 mmol) in dioxane/water (15 mL, 8:2) was added cyclopropaneboronic acid (0.54 g, 6.28 mmol), K₂C0₃ (0.85 g, 6.28 mmol) and [1 , -Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.45 g, 0.062 mmol) and the reaction mixture was stirred at 80 °C for 12 hours. After completion of the reaction, it was diluted with EtOAc (50 mL) and filtered through celite. The organic layer was washed with water (25 mL), dried (anhydrous a₂S0₄), filtered and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (silica gel) to get 550 mg of 2,5-dichloro-4-cyclopropylpyridine.

1H-NMR (400 MHz, DMSO-t¾) 6: 8.50 (s, 1H), 7.1 1 (s, 1 H), 2.13-2.17 (m, 1 H), 1 .12 1.17 (m, 2H), 0,96-0,97 (rn, 211). LCMS: 232.9 Step 2: tert-butyI-2-(5-bromo-4-cyclopropyIpyridin-2-yl)hydrazine-l-carboxyIate

To a solution of 5-bromo-2-chloro-4-cyclopropylpyridine (0.25 mg, 1.07 mmol) in EtOH ( 10 mL) was added hydrazine hydrate (0.26 mL, 5.37 mmol) and the reaction mixture was stirred at 130 °C for 2 hours in a microwave reactor (Biotage). The reaction mixture was concentrated under reduced pressure. The resulting crude mass was dissolved in THF (5 mL, Et₃N (0.45 mL, 3.23 mmol) and di-tert-butyl dicarbonate (2.3 mL, 10.7 mmol) were added and the reaction mixture was stirred at rt for 5 hours. After completion of the reaction, the reaction mixture was diluted with EtOAc (50 mL), washed with water (25 mL), dried (Na₂S0₄), filtered and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (silica gel) to get 130 mg of tert-butyl 2-(5-bromo-4-cyclopropylpyridin-2-yl)hydrazine- 1 -carboxylate. 1H-NMR (400 MHz, DM^' O- ,⁾ δ: 8.79 (s, 1H), 8.24 (s, ! ! ! ). 8.07 (s, 1H), 6.03 (s, IH), 2.03-2.07 (m, IH), 1 .43 (s, 9H), 1.06-1.1 1 (m, 2H), 0.63-0.64 (m, 2H). LCMS: | M 2f ! |

329.9. Step 3 : 5-bromo-4-cyclopropyl-2-hydrazinylpyridine hydrochloride

To a solution of tert-butyl 2-(5-bromo-4-cyclopropylpyridin-2-yl)hydrazine- l -carboxylate (130 mg, 0.039 mmol) in dioxane (2 mL) was added 4M HCl in dioxane (5 mL) at 0 °C and the reaction mixture was stirred at it for 4 hours. After completion of the reaction, it was concentrated under reduced pressure to give 85 mg of 5-bromo-4-cyclopropyl-2- hydrazinylpyridine hydrochloride. 1H-NMR (400 MHz, DMSO-t¾) δ: 10.03 (s, 3H), 9.10 (s, I I I ). 8.31 (s, IH), 6.43 (s, IH), 2.10-2.14 (m, IH), 1 .1 1-1 .16 (m, 2H), 0.76-0.78 (m, 2H). LCMS: [M+H]- 228.2.

Step 4: 6-bromo-7-cyclopropyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

The title compound was synthesised according to general procedure D from 5-bromo-4-cyclopropyl-2-hydrazinylpyridine hydrochloride 69 mg, 0.26 mmol) and GDI (51 mg, 0.31 mmol) in THF (3 ml), with addition of ¾ (26 mg, 0.26 mmol) yielding 38 mg of 6-bromo-7-cyclopropyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one.

MS: mJz 256 [ M 1 1 ] . 1H NMR (DMSO-d₆) δ: 12.45 (s, IH), 8.07 (d, I H), 6.91 (m, IH), 1.92-1.99 (m, I H), 0.97-1 .02 (m, 2H), 0.74-0.84 (m, 2H)

Exam pie 32 : 6-chloro-7-c clopropy 1- [1 ,2,4] iriazol© [4,3-a] py ridin-3(2H)-one step 1 : 2,5-dichloro-4-cyclopropylpyridine

To a degassed solution of 4-bromo-2,5-dichloropyridine (1.5 g, 6.63 mmol) in toluene/water (10 mL, 8:2) was added cyclopropaneboronic acid (0.85 g, 9.95 mmol), potassium phosphate tribasic (2.81 g, 13.27 mmol), tricyclohexyl phosphine (2.23 g, 7.96 mmol) and palladium acetate (0.29 g, 1.32 mmol ) and the reaction mixture was stirred at 140 °C for 3 hours in a microwave initiator (Biotage). After completion of the reaction, it was diluted with EtOAc (50 mL) and filtered through celite. The organic layer was washed with water (25 mL), dried (anhydrous Na₂S0₄), filtered and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (silica gel) to get 700 mg of 2,5-dichloro-4-cyclopropylpyridine. 1H-NMR (400 MHz, DMSO~£¾) δ: 8.40 (s, 1 H), 7.14 (s, ! ! ! ).. 2.09-2.12 (m, I I I ), 1 . 16 (t, 2H), 0,97 (t 21 1 ) LCMS: j M ! f | 187.9.

Step 2: tert-butyl 2-(5-chloro-4-cyclopropylpyridin-2-yl)hydrazine- 1 -carboxylate

To a solution of 2,5-dichloro-4-cyclopropylpyridine (700 mg, 3.70 mmol) in EtOH (10 mL) at it was added hydrazine hydrate (2.2 mL, 4.28 mmol) and the reaction mixture stirred at 140 °C for I hour in a microwave reactor (Biotage). After completion of the reaction, the reaction mixture was concentrated under reduced pressure at 20 °C. The resulting crude mass was dissolved in THF (10 mL), Et₃N (1.87 mL, 18.51 mmol) and di-tert-butyl dicarbonate (4.0 mL, 18.51 mmol) were added at 0 °C and the reaction mixture was stirred at it for 16 hours. After completion of the reaction, the reaction mixture was diluted with DCM (25 mL) and washed with water (10 ml) dried (Na₂S0₄), filtered and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (silica gel) to get 350 mg of tert-butyl 2-(5-chloro-4-cyclopropylpyridin-2- yl)hydrazine-l-carboxylate. 1H- MR (400 MHz, OMSO~d₆) δ: 8.78 (s, IH), 8.20 (s, IH), 7.98 (s, I H), 6.02 (s, I H), 2.08-2, 12 (m, I H), 1.40 (s, 9H), 1 .07-1 .1 1 (m, 2H), 0,63-0,65 (m, 2H). LCMS: [ \1 l l j 284.0. Step 3 : 5-chloro-4-cyclopropyl-2-hydrazinylpyridine hydrochloride

To a solution of tert-butyl 2-(5-chloro-4-cyclopropylpyridin-2-yl)hydrazine-l-carboxylate (210 mg, 0.0074 mmol) in Et₂0 (2 mL) was added 4M HCl in Et₂0 (5 mL) at 0 °C and the reaction mixture was stirred at rt for 4 hours. After completion of the reaction, it was concentrated under reduced pressure to get 160 mg of 5-chloro-4~cyclopropyl-2~ hydrazinylpyridine hydrochloride. ' H-NMR (400 MHz, DMSO-afc) δ; 10.09 (s, 3H), 9.14 (s, IH), 8,20 (s, IH), 6.45 (s, IH), 2.13-2.17 (m, IH), 1.1 1-1.16 (m, 2H), 0.73-0.77 (m, 21 1 ) LCMS: I X i ί ί | 284.2.

Step 4: 6-chloro-7-cyclopropyl-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one

The title compound was synthesised according to general procedure D from 5-bromo-4- cyclopropyl-2-hydrazinylpyridine hydrochloride (70 mg, 0,32 mmol) and CDI (62 mg, 0.38 mmol) in THF (3 ml), with addition of NEtj (32 mg, 0.32 mmol) yielding 27 mg of 6- chloro-7-cyclopropyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one.

MS: m/z 210 I M I ! j . 1H NMR (DMSO-de) δ: 12,46 (s, IH), 8.00 (d, IH), 6.92 (m, IH), 1.96-2.01 (m, IH), 0.99-1.02 (m, 2H), 0,80-0,82 (m, 2H)

Example 33 : 7~(difliior omethyl)- [1 ,2,4] triazolo [4,3-a] p ridin-3(2H)-one Step 1 : 4-(difluoromethyl)-2-fluoropyridine

To a solution of 2-fluoroisonicotinaldehyde (1 .7 g, 13.6 mmol) in DCM (20 ml) was added DAST (4.4 niL, 34.2 mmol) at 0 °C and the reaction mixture was stirred at rt for 12 hours. After completion of the reaction, the reaction mixture was diluted with DCM (50 mL), washed with water (10 mL), dried (anhydrous Na₂S0₄), filtered and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (silica gel ) to get 0.8 g of 4-(difluoromethyl)-2-fluoropyridine. Ί i-XM . (400 MHz, OMSO-d₆) δ: 8.45 (d, IH), 7.57 (d, IH), 7.44 (s, IH), 7. 15 (t, IH).

Step 2: tert-butyl 2-(4-(difluoromethyl)pyridin-2-yl)hydrazine-l-carboxylate

H

To a solution of 4-(difluoromethyl)-2-fluoropyridine (800 mg, 5.440 mmol) in EtOH (10 ml) was added hydrazine hydrate (1.3 mL, 27.2 mmol) at rt and the reaction mixture stirred at 80 °C for 12 hours. After completion of the reaction, it was concentrated under reduced pressure. The resulting crude mass was dissolved in THF (10 mi), Et₃N (2.2 mL, 16.3 mmol) and di-tert-butyl di carbonate (9.4 mL, 43.5 mmol) were added at 0 °C and the reaction mixture was stirred at rt for 16 hours. After completion of the reaction, the reaction mixture was diluted with EtOAc (30 mL), washed with water (25 mL), dried (anhydrous Na₂S0₄), filtered and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (silica gel) to get 550 mg of tert-butyl 2-(4- (difluoromethyl)pyridin-2-yl)hydrazine-l -carboxylate. Ί i-XM R. (400 MHz, DMSO-<¾) δ: 8.89 (s, IH), 8.5 1 (s, 1H), 8.18 (d, 1H), 6.98 (t, IH), 6.80 (d, i l l ). 6.62 (s, 1H), 1.41 (s, 9H) ί CMS: I J i f ] 260.0. Step 3 : tert-butyl 2-(4-(dif!uoromethyl)pyridin-2-yl)hydrazine-l-carboxylate hydrochloride

To a solution of tert-butyl 2-(4-(difluoromethyl)pyridin-2-yl)hydrazine-l-carboxylate (500 mg, 0.039 mmol) in dioxane (5 ml) was added 4M HCI in dioxane (5 ml) at 0 °C and the reaction mixture was stirred at rt for 4 hours. After completion of the reaction, it was concentrated under reduced pressure to get 450 mg of tert-butyl 2-(4- (difluoromethyl)pyridin-2-yl)hydrazine-l-carboxylate hydrochloride. Ή-NMR (400 MHz, DMSO-i¾) δ: 9.82 (s, 3H), 8.33 (d, IH), 6.94-7.22 (m, 3H). LCMS: [M+H]=160.2

Step 4: 7-(difluoromethyl)-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one

The title compound was synthesised according to general procedure D from 4-(difluoromethyl)-2-hydrazinylpyridine hydrochloride OS-037 (100 mg, 0.51 mmol) and GDI (99 mg, 0.61 mmol) in THF (3 ml), with addition of I¾N (52 mg, 0.51 mmol) yielding 53 mg of 7-(difluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one.

MS: m/z 186 [M+H]⁺, ^! I I NMR (DMSO-d₆) δ: 12,74 (br s, I I I ), 7,94 (d, 1 1 1 ), 7.51 (s, 1 1 1 }.. 6.97 (t, IH), 6.63 (d, IH)

Example 34: 7-chIoro-6-fleoro- l,2,4]trkzofo 4,3-ajpyridisi-3(2H)--08ie

Step 1 : 4-chloro-5-fluoro-2-hydrazineylpyridine

To a solution of 4-chloro-2,5-difluoropyridine (200 nig, 1.33 mmol) and 4M HCl in dioxane (0.33 ml, 1.33 mmol) in 2-propanol (3 ml) was added hydrazine hydrate (134 mg, 2.68 mmol). Reaction mixture was stirred at rt for 1 month. Solvents were evaporated under vacuum. Aqueous NaHC0₃ solution was added to the mixture. Precipitate formed was filtered oft^" washed with water and dried under vacuum yielding 51 mg of 4-chloro-5- fluoro-2-hydrazinylpyridine and 2,5-difluoro-4-hydrazinylpyridine as a 1/1 mixture.

MS: m/z 162 I M I f ] . 1H NMR (DMSO-d₆) δ: 8. 19 (br s, IH), 8.09 (d, 1 1 1 ).. 7.70 (d, 1 1 1 }.. 7.66 (d, H), 6.88 (d, IH), 6.55 (d, IH), 4.39 (d, 2H), 4.21 (br s, 2H )

Step 2: 7-chloro-6-fluoro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

To a solution containing the mixture of 4-chloro-5-fluoro-2-hydrazinylpyridine and 2,5-difluoro-4-hydrazinylpyridine (50 mg, 0.31 mmol) in THF (3 ml) at 0°C was added triphosgene (92 mg, 0.31 mmol). Reaction mixture was stirred at 0°C for 1 hour. Solvents were evaporated under vacuum. A solution of IM aqueous HCl was then added and the mixture was extracted 3 times with EtOAc. Organic layers were concentrated under vacuum. Evaporation residue was dissolved in IM NaOH solution and extracted twice with EtOAc. Aqueous phase was acidified with cone, HCl and extracted twice with EtOAc. Organic layers were dried and concentrated under vacuum. Evaporation residue was stirred in Et₂0, filtered off and dried under vacuum yielding 1 1 mg of pure 7-chloro-6-fluoro- [l,2,4]triazolo[4,3-a]pyridii -3(2H)-one. MS: m/z 188 [M+Hf. ¹H NMR ( DM SO-d,.) δ: 12.71 (br s, IH), 8.27 (dd, IH), 7.75 (dd, IH)

Example 35: 6-flsioro-7-(irifleoroii5ethyl)-[1 ,2,4]triazolo[4,3-a]pyr5di8i~3(2H)-oiie Step 1 : di-tert-butyl l-(5-fluoro-4-(trifluoromethyl)pyridin-2-yl)hydrazine-l,2'

dicarboxylate

A solution of di-tert-butyl hydrazine- 1,2-dicarboxylate (1 6 nig, 0.50 mmol), dppf (28 mg, 0.05 mmol) and C^'s_.>C() : (180 mg, 0.55 mmol) in toluene (3 ml) was degassed under inert atmosphere for 1 5 minutes at RT. 2-Chloro-5-fluoro-4-(trifluoromethyl)pyridine (100 mg, 0.50 mmol) and Pd₂(dba)₃ (46 mg, 0.05 mmol) were added, mixture was degassed again for 10 minutes, heated up to 100°C and stirred for 4 hours. Reaction mixture was diluted in EtOAc, washed with water and brine and concentrated under vacuum. Crude product was purified by reverse phase flash column chromatography (CH₃CN/MeOH/water) yielding 61 mg of di-tert-butyl 1 -(5-fluoro-4-(trifluoromethyl)pyridin-2-yl)hydrazine- 1 ,2-dicarboxyf ate. MS: in z 6 [M+Hf.

Step 2: 5-Fluoro-2-hydrazinyl-4-(trifluoromethyl)pyridine hydrochloride

To a solution of di-tert-butyl l-(5-fluoro-4-(trifluoromethyl)pyridin-2-yl)hydrazine- 1 ,2- dicarboxylate (222 mg, 0.56 mmol) in Et₂0 (1 5 ml) at rt was added 1M HQ in Et₂0 (1 1.2 mi, 1 1.2 mmol added in 2 batches). Reaction mixture was stirred at rt for 2 x 24 hours. Solvents were evaporated to dryness. Residue was taken back in minimum of Et₂0, precipite formed was filtered off and dried under vacuum yielding 89 mg of tert-butyl l -(5- fluoro-4-(trifluoromethyl)pyridin-2-yl)hydrazinecarboxylate hydrochloride. Compound was dissolved in 4M HQ in dioxane (2.2 ml added in 3 batches). Reaction mixture was stirred at rt for 2 x 24 hours and finaly stirred at 50 °C for 8 hours. Solvents were evaporated under vacuum. 5-Fluoro-2-hydrazinyl-4-(trifluoromethyl)pyridine hydrochloride obtained (42 mg) was used directly in the next step. MS: m/z 196 | \ ! H j .

Step 3 : 6-fluoro-7-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

The title compound was synthesised according to general procedure D from 5-Fluoro-2- hydrazinyl-4-(trifluoromethyl)pyridine hydrochloride (42 mg, 0.21 mmol) and CDI (42 mg, 0.26 mmol) in THF (2 mi). Resulting crude compound was dissolved in 1M aqueous NaOH solution and washed twice with EtOAc. Aqueous layer was acidifed with cone. HC1 and extracted with EtOAc. Organic layer was dried, concentrated under vaccum yielding 6.1 mg of pure 6-fluoro-7-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one.

MS: m/z 222 [M+FTf . ^! H NMR (DMSO-de) δ: 13.07 (br s, 1 1 1 ). 8.37 (d, 1 1 1 ), 8.02 (d, 1H) Example 36: 7-Iodo-6-methyl-[l,2,4jtriazolo[4,3-a]pyridin-3(2H)-one

Step 1 : 2-Hydrazinyl-4-iodo-5-methylpyridine

,

A mixture of 2-fluoro-4-iodo-5-methylpyridine (0.237 g, 1.0 mmol), 2-propanol (0.4 mL) and hydrazine hydrate (0. 125 mL, 2,0 mmol) was heated at 80 °C for 4 hours. More hydrazine hydrate (0.05 mL, 0.8 mmol) was added and heating was continued for another seven hours. The mixture was concentrated and dried under vacuum to provide the title compound (0.17 g). 1H NMR (DMSO-de) δ: 7.82 (s, 1H), 7.32 (s, 1H), 7.25 (s, 1H), 4.10 (br s, 2H), 2.16 (s, 3H).

Step 2: 7~Iodo-6-methyI-[l,2,4]triazolo[4,3~a]pyridin-3(2H)-one

A flask was charged with 2-hydrazinyl-4-iodo-5-methylpyridine (0.17 g, 0.68 mmoi), THF (5 niL) and N,N'-carbonyldiimidazole (0.166 g, 1.02 mmol). The mixture was stirred for one hour. 1 M HQ solution (5 mL) was added and organic solvent was evaporated under vacuum. Title compound was filtered out and dried under vacuum (0,056 g), ' ] [ NMR (DMSO-d₆) δ: 12.44 (br s, i l l ). 7.91 (s, 1H), 7.76-7.79 (m, 1H), 2.19 (d, 3H). LC-MS m/z 276,0 (M ] [ ) . Example 37: 7-Chloro-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carbonitrile

Step 1 : N-(4-Chloro-5-cyanopyridin-2-yl)nitramide

Title compound was synthesised according to General procedure A from 6-amino-4- chloronicotinonitrile (0.80 g, 5.2 mmol) in H₂S0₄ (4.5 mL) and a mixture of HN0₃ (0.44 mL, 10.5 mmol) and H₂S0₄ (0.7 mL) yielding 0.36 g of jV-(4-chloro-5-cyanopyridin-2- yDnitramide. LC-MS m/z 199.0 (M+H)⁺.

Step 2: 7-Chloro-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carbonitrile

Title compound was synthesised according to General procedure B from N-(4-chloro-5-cyanopyridin-2-yl)nitramide (0,36 g, 1.8 mmol), NH₄CI (0,485 g, 9.1 mmol), Zn dust (0.593 g, 9.1 mmol) and triphosgene (0.807 g, 2.7 mmol) in THF (8 mL), MeOH (1.5 mL) and H₂0 (2 mL). Crude material was purified by column chromatography (CI 8 on silica, H₂0/MeCN) yielding 0.013 g of 7-chloro-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3- a]pyridine-6-carbonitrile. 1H NMR (DMSO-de) δ: 12,82 (br s, I I I ), 8.93 (d, 1H), 7.73 (d, 1H). LC-MS m/z 195.0 (M+H)⁺.

Example 38: 7~M thyI~3~oxo-2 -dihydro-[l,2,4]triazoIo[4 ~a]pyridiiK^>-6~carboH8triS Step 1 : iV-(5-cyano-4-methylpyridin-2-yl)nitramide

Title compound was synthesised according to General procedure A from 6-amino-4-methylnicotinomtrile (1 .40 g, 10.5 mmol) in H₂S0₄ (9 mL) and a mixture of HNO3 (0.88 mL, 21.0 mmol) and H₂S0₄ (1.5 mL) yielding 0.9 g of N-(5-cyano-4- methylpyridin-2-yl)nitramide. LC-MS m/z 179.0 (M+Hf . Step 2: 7-Methyl-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carbonitrile

Title compound was synthesised according to General procedure B from N-(5-cyano-4-methylpyridin-2-yl)nitramide (0.97 g, 5.4 mmol), H₄C1 (1.46 g, 27.2 mmol), Zn dust (1.78 g, 27.2 mmol) and triphosgene (2.42 g, 8.2 mmol) in THF (40 mL), MeOH (10 mL) and H₂0 (10 mL). Crude precipitate was dissolved in 0.5 M NaOH solution and extracted with EtOAc. The aqueous layer was acidified with cone. HCL Title compound was filtered out, washed with water and dried under vacuum (0, 177 g). ¹H NMR (DMSO- d₆) δ: 12.60 (br s, 1H), 8.70 (d, 1H), 7.18-7.20 (m, 1H), 2.31 (d, 3H). LC-MS m/z 175.1 (M+H)⁺.

Example 39: 6-Methyl-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-7-carbonitrUe

Step 1 : 4-Cyano-3-methylpyridine 1 -oxide

To a stirred solution of 3-methylpyridine-4-carbonitrile (2.0 g, 16.9 mmol) in dry C! ί >(Ί > (100 mL) was added m-CPBA (14.56 g, 84.4 mmol) at 0 °C. The reaction mixture was stirred at rt for 16 hours. After completion of the reaction, the reaction mixture was poured onto ice and 10% NaHC0₃ solution. Aqueous layer was extracted with 10% methanol in CH₂C1₂, combined organic layers were dried over anh. Na₂S0₄ and concentrated under vacuum The resulting material was purified by column chromatography (silica gel) to give 1.6 g of title compound. 1H-NMR (DMSO-dfc) 6: 8.42 (s, I I I ), 8.24 (d, i l l ). 7.86 (d, H I), 2.39 (s, 3H).

Step 2: 2-Chloro-5-methylisonicotinonitrile

Cooled POCI3 (16 mL) was added dropwise to 4-cyano-3-methylpyridine 1 -oxide (1.6 g, 12 mmol) at 0 °C and the resulting reaction mass was heated at 70 °C for 16 hours. After completion of reaction, the reaction mixture was poured into ice water, neutralised with 10% NaHCO solution and extracted with EtOAc. The organic layer was dried over anhydrous Na₂S0₄ and concentrated under reduced pressure_. The resulting crude material was purified by column chromatography (silica gel) to give a mixture of title compound and 2-chloro-3-methylisonicotinonitrile (1.15 g). GC-MS m/z 1 52.0 ( X! I I ) .

Step 3 : 2-((4-methoxybenzyl) amino)-5-methylisonicotinonitrile

To a stirred solution of 2-chloro-5-methylisonicotinonitrile and 2-chloro-3- methylisonicotinonitrile (1.15 g, 7.6 mmol) in toluene (10 mL) was added sodium tert- butoxide (2. 18 g, 22.7 mmol) and -methoxy benzyl amine 2.07 g, 15.1 mmol) at rt. After 10 minutes, ΒΓΝΑΡ (0.939 g, 1.5 mmol) and palladium acetate (0.168 g, 0.76 mmol) were added and the reaction mixture was stirred at 50 °C for 4 hours. After completion of the reaction the mixture was diluted with EtOAc, washed with water, dried over anhydrous Na₂S0 and concentrated under reduced pressure_. The resulting crude material was purified by column chromatography (silica gel) to give 0.55 g of title compound. 1H-NMR (DMSO- d₆) 6. 8.07 (s, H i ).. 7.30 (s, I I I ), 7.25 (d, IH), 7,23 (d, l l f _.K 6.88 (d, 1 1 1 ), 6.86 (d, H i ). 6,81 (t, IH), 4.38 (d, 2H), 3.72 (s, 3H), 2.22 (s, 3H).

Step 4: 2-amino-5-methylisonicotinonitrile

A solution of 2-chloro-5-methylisonicotinonitrile (550 nig, 2.17 mmol) in TFA (8 mL) was heated at 50 °C for 8 hours. After completion of the reaction, the mixture was poured onto ice water and neutralised with 10% NaHC0₃ solution. The mixture was extracted with ethyl acetate, dried over anh. Na₂S0₄ and concentrated under reduced pressure. The resulting material was purified by column chromatography (silica gel) to give 0.19 g of title compound. 1H- MR (DMSO-i¾) δ: 8.02 (s, IH), 6.71 (s, 111), 6.26 (s, 2H), 2.23 (s, 3H),

Step 5 : N-(4-cyano-5-methylpyridin-2-yl)nitramide

Title compound was synthesised according to General procedure A from 2-amino-5- methylisonicotinonitrile (0.19 g, 1.4 mmol) in H₂S0₄ (1.5 mL) and a mixture of HN0 (0.20 mL, 2.9 mmol) and H₂S0₄ (0.3 mL) yielding 0.22 g of N-(4-cyano-5-methylpyridin-2- yljnitramide. I (^"-MS m/z 179.1 (M+H)^÷.

Step 6: 6-Methyl-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-7-carbonitrile

Title compound was synthesised according to General procedure B from N-(4-cyano-5-methylpyridin-2-yl)nitramide (0.22 g, 1.2 mmol), NH₄CI (0.33 g, 6.2 mmol), Zn dust (0.40 g, 6.2 mmol) and triphosgene (0.55 g, 1.9 mmol) in THF (6 mL), MeOH (1.5 mL) and H₂0 (1.5 mL). Crude precipitate was dissolved in 0.5 M NaOH solution and the solution was extracted with EtOAc, The aqueous layer was acidified with cone. HQ. Title compound was filtered out, washed with water and dried under vacuum (0.020 g). Ή NMR (DMSO-de) δ: 12.97 (s, IH), 8.13 (d, IH), 7.87-7.94 (m, IH), 2.23-2.24 (m, 3H). LC-MS m/z 175.1 (M+H)⁺.

Example 40: 6-Iodo-7-methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

Step 1 : 2-Hydrazinyl-5-iodo-4-methylpyridine

Hydrazine monohydrate (190 mg, 3.80 mmol) was added to a solution of 2-fluoro-5-iodo-4- methylpyridine (300 mg, 1.27 mmol) in dioxane (3 mL). The reaction mixture was stirred at 80 °C for 6 hours, then at 90 °C for 7.5 hours. After completion of the reaction, water was added. The precipitate formed was filtered off, washed with water and dried under vacuum at 40°C yielding 183 mg of 2-hydrazinyl-5-iodo-4-methylpyridine. 1H NMR (400 MHz, DMSO-de) o: 8. 1 5 (s, 1 H), 7.51 (s, 1 H), 6.74 (s, 1 H), 4.14 (br s, 2H), 2,22 (s, 3H).

Step 2: 6-Iodo-7-methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

Ν,Ν'-Carbonyldiimidazole (155 mg, 0.96 mmol) was added to a solution of 2-hydrazinyl-5- iodo-4-methylpyridine (183 mg, 0.74 mmol) in THF (4 mL) at rt. The reaction mixture was stirred at rt for 1 hour. After completion of the reaction, water was added. The precipitate formed was filtered off, washed with water and dried under vacuum at 40 °C yielding 6~ iodo-7-methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one. More product was precipitated from the mother solution after evaporation of THF. Total yield 139 mg. 1H NMR (400 MHz, DMSO-de) δ: 12,38 (br s, III), 8.1 1 (s, III), 7.21 (s, IH), 2.28 (s, 3H). Example 41: 7-C Ioro-6-(triflnoro!Bethyl)-| l,2,4|triazolo

Step 1 : 4-Chloro-2-hydrazinyl-5-(trifluoromethyl)pyridine

Hydrazine monohydrate (75 mg, 1.50 mmol) was added to a solution of 4-chloro-2-fluoro- 5-(trifluoromethyl)pyridine (100 mg, 0.50 mmol) in dioxane (1.2 mL). The reaction mixture was stirred at rt for 2.5 hours. After completion of the reaction, water was added to the mixture and dioxane was evaporated. The precipitate formed was filtered off, washed with water and dried under vacuum at 40 °C yielding 73 mg of 4-chloro-2-hydrazinyl-5- (trifiuoromethyl)pyridine. 1H NMR (400 MHz, DMSO-d₆) δ: 8.64 (s, IH), 8.28 (s, IH), 6.91 (br s, IH), 4,48 (s, 2H).

Step 2: 7-Chloro-6-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

N,iV-Carbonyldiimidazole (72 mg, 0.45 mmol) was added to a solution of 4-chloro-2- hydrazinyl-5-(trifluoromethyl)pyridine (70 mg, 0.33 mmol) in THF (2.5 mL) at rt. The reaction mixture was stirred at rt for 2 hours. After completion of the reaction, aq. 1 M HCi solution was added. The precipitate formed was filtered off, washed with water and dried under vacuum at 40°C. The crude material was dissolved in 1 mL of 1 M NaOH solution. The water solution was washed twice with EtOAc and then acidified (pH 2-3) with 6 M HCI solution. The precipitate formed was filtered off, washed with water and dried under vacuum at 40 °C yielding 20 mg of 7-chloro-6-(trifluoromethyl)-[l ,2,4]triazolo[4,3- a]pyridin-3(2H)-one. 1H NMR (600 MHz, DMSQ~d₆) δ: 12.84 (s, H), 8.3 1 (s, IH), 7,76 (s, 1 1 1 ). Example 42: 7-Bromo-6-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

Step 1 : N-[4-Bromo-5-(trifluoromethyl)pyridin-2-yl]nitramide

N-[4-Bromo-5-(trifluoromethyl)pyridin-2-yl]nitramide was prepared according to General procedure A with 4-bromo-5-(trifluoromethyl)pyridin-2-amine (600 mg, 1.49 mmol) in cone. H₂SO₄ (2 mL) and a mixture of 65% HNO₃ (0.29 mL, 4.23 mmol) and cone. H₂SO₄ (0.26 mL), Yield 542 mg. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.75 (s, 1 H), 8.24 (s, 1H).

Step 2; 7-Bromo-6-(trifluoromethyl)-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one

7-Bromo-6-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one was prepared according to General procedure B using V-[4-bromo-5-(trifluoromethyl)pyridin-2- yljnitramide (236 mg, 0.83 mmol), NH₄CI (265 mg, 4.95 mmol), Zn dust (324 mg, 4.95 mmol) and triphosgene (367 mg, 1.24 mmol) in THF (9 mL), MeOH (1.7 mL) and H₂0 (1.7 mL). After completion of the reaction, 1 M HCl solution was added and organic solvents were evaporated. The precipitated product was filtered off, washed with water and dried in vacuum at 40 °C yielding 60 mg of the title compound, 1H NMR (400 MHz, DMSO-d₆) δ: 12.81 (br s, i l l ). 8.24 (s, i l l ). 7.92 (s, i l l ). Example 43: 7-Fluoro-6-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

Step : 4-Fluoro-5-iodopyridin-2-amine

To a solution of 4-fluoropyridin-2-amine (2.5 g, 22.3 mmol) in acetonitrile (25 niL) was added TFA (0.85 mL, 11.16 mmol), S (5.5 g, 24.55 mmol) at 0 °C and the reaction mixture was stirred at rt for 4 hours. After completion of the reaction, the reaction mixture was diluted with EtOAc (75 mL). The organic layer was washed with water (20 mL), dried (anhydrous Na<SO . ). filtered and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (silica gel) to get 2.2 g of 4-fluoro-5- iodopyridin-2-amine. 1H NMR (400 MHz, DMSO-de) δ: 8,21-8.24 (d, 1 H), 7.10 (s, 2H), 6.31-6.34 (d, 1H). UPLC: [M+H] = 239.1.

Step 2: DiBoc-protected 4-fluoro-5-iodopyridin-2-amine

To a solution of 4-fluoro-5-iodopyridin-2-amine (2.0 g, 8.40 mmol) in THF (20 mL) was added Et₃N (3.4 mL, 25.20 mmol), di-tert-butyl di carbonate (4.5 mL, 21.00 mmol) and the reaction mixture was stirred at 70 °C for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting crude material was purified by column chromatography (silica gel) to get 1 .6 g of diBoc-protected 4-fluoro-5- iodopyridin-2-amine. 1H NMR (400 MHz, DMSO-d₆) δ: 8.80 (d, 1H), 7.58 (d, 1H), 1.39 (s, 1 81 1 ) UPLC: [M+H] = 439,0.

Step 3 : DiBoc-protected 4-fluoro-5-(trifluoromethyl)pyridin-2-amine

To a solution of diBoc-protected 4-fluoro-5-iodopyridin-2-amine (1 .5 g, 3.42 mrnol) in DMF (10 niL) was added Cul (0.98 g, 5.13 mmol), methyl 2,2-difluoro-2- (fluorosulfonyl)acetate (0.98 g, 5.13 mmol) and the reaction mixture was stirred at 100°C for 6 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The evaporation residue was dissolved in EtOAc (100 mL) and washed with water (25 mL), dried (anhydrous Na₂S0₄), filtered and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (silica gel) to get 800 mg of diBoc-protected 4-fluoro-5-(trifluoromethyl)pyridin-2-amine. 1H NMR (400 MHz, DMSO-de) δ: 8.89 (d, l H), 7.88 (d, I I I ). 1.43 (s, 18H). LCMS: [M+H, diBoc- deprotected mass] ^:= 108.9.

Step 4: 4-Fluoro-5-(trifluoromethyl)pyridin-2-amine

To a solution of diBoc-protected 4-fluoro-5-(trifluoromethyl)pyridin-2-amine (300 mg, 0.0789 mmol) in DCM (3 mL) was added TFA (0,9 g, 7.89 mmol) at 0 °C and the reaction mixture was stirred at rt for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude mass was dissolved in EtOAc (10 mL), washed with NaHC0₃ (10%) and water, dried (anhydrous Na₂S0₄), filtered and concentrated under reduced pressure. The resulting crude material was triturated with n- hexane (5 mL) to get 85 mg of 4-fluoro-5-(trifluoromethyl)pyridin-2-amine. ^!H NMR (400 MHz, DMSO-de) δ: 8,23 (d, 1 1 1 ), 7.08 (s, .?.! ] ), 6.34 (d, U l ) LCMS: [M+H] - 181.1.

Step 5 : N-[4-Fluoro-5-(trifluoromethyl)pyridin-2-yl]nitramide

N-[4-Fluoro-5-(trifluoromethyl)pyridin-2-yl]nitramide was prepared according to General procedure A using 4-fluoro-5-(trifluoromethyl)pyridin-2-amine (100 nig, 0.56 mmol) in 5 cone. H₂S0₄ (0.38 mL) and a mixture of 65% HN0₃ (0.066 mL, 0.96 mmol) and cone.

H₂S0₄ (0.059 mL). Yield 96 mg. Ή NMR (600 MHz, DMSO-d₆) δ: 8.83 (d, 1H), 7.93 (d, 1H).

Step 6: 7-Fluoro-6-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

Q

7-Fluoro-6-(trifluoromethyl)-[ 1 ,2,4]triazolo[4,3-a]pyridin-3(2H)-one was prepared according to Example 42 Step 2 using N-[4-fluoro-5-(trifluoromethyl)pyridin-2-5 yljnitramide (95 mg, 0.42 mmol), H₄C1 (135 mg, 2.53 mmol), Zn dust (166 mg, 2.53 mmol) and tri phosgene (188 mg, 0.63 mmol) in THF (3.7 mL), MeOH (0.75 mL) and H₂0 (0.75 mL). Yield 30 mg. 1H NMR (600 MHz, DMSO-de) δ: 12.74 (s, 1H), 8.40 (d, 1H), 7.45 id. l i l). 0 Example 44: 6-bromo-7-methoxy-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

Step 1 : 5-bromo-2-chloro-4-methoxypyridine

5

A solution of sodium methylate in methanol (0.95 ml, 0.90 mmol, 21%) was added dropwise to a flask containing 5-bromo-2,4,-dichloro-pyridine (0.75 g, 3.31 mmol) at 0 °C. The reaction mixture was stirred at rt for 4 hours after which it was poured into ice-cold water and extracted with EtOAc. Organic phases were combined, washed with brine, dried (Na₂S0₄), filtered and evaporated to dryness yielding 0.68 g of 5-bromo-2-chloro-4- methoxypyridine, Ί ί NMR (DMSO-d₆) δ: 8.43 (s, 1H), 7.32 (s, 1H), 3.99 (s, 3H).

Step 2 : 6-bromo-7-methoxy-[ 1 ,2,4]triazolo[4,3 -a]pyridin-3 (2H)-one

A solution of hydrogen chloride in 1,4-dioxane (4M, 0.020ml) was added to the solution of 5-bromo-2-chloro-4-methoxypyridine (0.18 g, 0.81 mmol) and methyl hydrazinecarboxyiate (0.30 g, 3.34 mmol) in ethanol (5 mi). The reaction mixture was heated in microwave reactor at 160 °C for 9 hours. The mixture was cooled and evaporated to dryness. Purification of the evaporation residue by preparative reverse phase HPLC afforded 4.8 mg of 6-bromo-7-methoxy-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one. ¹H NMR (DMSO-de) δ: 12.24 (br s, 1H), 8.08 (s, 1H), 6.63 (s, 1H), 3.87 (s, 3H).

Example 45: 7-(hydroxymethyl)-6-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-

3{2H)-osie

Step 1 : (2-Chloro-5-(trifluoromethyl)pyridin-4-yl)methanol

To a solution of methyl 2-chloro-5-(trifluoromethyl)isonicotinate (2.00 g, 8.35 mmol) in Ti ll (6 ml) and MeOH (28 ml) at 0 °C was added NaBH₄ (0.62 g, 16.7 mmol). The resulting mixture was stirred at rt for 1 hour. H₂0 was added and the organic solvents were evaporated off. The resulting mixture was extracted with EtOAc. The combined organic phases were washed with H₂0 and brine, dried with Na₂S0₄, filtered and evaporated to dryness yielding 1.74 g of (2-chloro-5-(trifluoromethyl)pyridin-4-yl)methanol.

(CDCI₃) δ: 8.61 -8.56 (m, 1H), 7,86-7,82 (m, 1 H), 4.94 (s, 2H), 2.24 (br s, 1 H),

Step 2: (2-Hydrazinyl-5-(trifluoromethyl)pyridin-4-yl)methanol

The title compound was synthesised according to general procedure C from (2-chloro-5-(trifluoromethyl)pyridin-4-yl)methanol (1 ,00 g, 4.73 rnmol) and hydrazine hydrate (2.29 ml, 47.3 mmol) in EPA (10 ml) in a sealed tube at 110 °C with 3 hours reaction time yielding 0.75 g of (2-hydrazinyl-5-(trifluoromethyl)pyridin-4-yl)methanol. 1H NMR (DMSO-d6) δ: 8.26 (br s, 1H), 8.15 (s, 1 H), 7.05 (br s, 1H), 5.53 (t, 1H), 4,56-4.50 (m, 2H) 4.33 (br s, 2H). Step 3 : 7-(hydroxymethyl)-6-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one

The title compound was synthesised according to general procedure D from (2-hydrazinyl- 5-(trifluoromethyl)pyridin-4-yl)methanol (0,73 g, 3.52 mmol) and GDI (0.69 g, 4.23 mmol) in THF ( 15 ml) yielding, after aqueous workup, 0.55 g of 7-(hydroxymethyl)-6- (trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one. 1H NMR (DMSO-d6) 6: 12.65 (br s, 1H), 8, 18-8, 13 (m, 1 H), 7.34-7.27 (m, lH), 5.74 (t, 1H), 4,50 (d, 2H).

8-F 7-H 6-Cl :. i S li ^'.^" -.Ci

8-H 7-Q 6-Br •·>ς 8-H 7-CD3 6-CF3

8-H 7-Cl 6-Cl 26 8-H 7-CHF₂ 6-CF3

8-H 7-F 6-Br 27 8-Cl 7-H 6-Br

8-H 7-F 6-Cl 28 8-H 7-CH3 6-F

8-H 7-Br 6-Cl 29 8-H 7-CF3 6-CF3

8-H 7-H 6-CHF2 30 8-H 7-CH3 6-CF3

8-H 6-Cl 7-CF3 31 8-H 7-cyclopropyl 6-Br

8-H 6-Br 7-CF3 32 8-H 7-cyclopropyl 6-Cl

8-H 7-Br 6-Br 33 8-H 6-H 7-CHF2

8-H 7- CHF₂ 6-Br 34 8-H 7-Cl 6-F

8-H 7-Cl 6-CH3 35 8-H 7-CF3 6-F

8-H 7-CN 6-Br 36 8-H 7-1 6-CH3

8-H 7-CH₃ 6-CH3 37 8-H 6-CN 7-Cl

8-H 7-CN 6-Cl 38 8-H 6-CN 7-CH3

8-F 7-CH3 6-Cl 39 8-H 7-CN 6-CH3

8-F 7-Cl 6-Br 40 8-H 6-1 7-CH3

8-H 7-F 6-CH3 41 8-H 7-Cl 6-CF3

8-H 7-Br 6-CH3 42 8-H 7-Br 6-CF3

8-H 7-CH3 6-CHF2 43 8-H 7-F 6-CF3

8-F 7-Cl 6-Cl 44 8-H 7-OCH3 6-Br

8-H 7-F 6-CHF2 45 8-H 7-CH2OH 6-CF3

8-H 7-F 6-F

Prepara tion of pharmaceutical compositions

The following formulation examples illustrate representative pharmaceutical compositions of this invention. The present invention, however, is not limited to the following pharmaceutical compositions.

A) Solid oral dosage forms

L, Tablets

Active ingredient(s) 0.01 - 90%

Filler 1 99.9%

Binder 0 20%

Disintegrate 0 20%

Lubricant 0 10%

Other specific excipient(s) 0

II., Orodispersible films

Active ingredient(s) 1 - 90%

Film forming agent 99.9%

Plasticizer 0 40%

Other specific excipient(s) 0 - 50%

B) Liquid oral dosage forms

HI, Oral suspensions

Active ingredient(s) 0,01 - 50%

Liquid vehicle 10 - 99.9%

Wetting agent 0

Thickener 0 50°

Buffering agent quantum satis

Osmotic agent 0 - 50%

Preservatives quantum satis

Active ingredient(s) 0.01 - 50%

Solvent 10 - 99.9%

Sugar component 1 - 20%

Flavouring agents 0 - 10%

C) Parenteral dosage fo ms V., Intravenous injections

Active ingredient(s) 0,01 -- 50%

Solvent 10 - 99.9%

Co-solvent 0 - 99,9%

Osmotic agent 0 - 50%

Buffering agent quantum satis

D) Other dosage forms

VI, Suppositories

Active ingredient(s) 0,01 - 50%

Suppository base 1 - 99.9%

Surface-active agents 0 - 20%

Lubricants 0 - 20%

Preservatives quantum satis

VII., Eye drops

Active ingredient(s) 0,01 - 50%

Water 0 - 99.9%

Solvent 0 - 99,9%

Osmotic agent 0 - 20%

Viscosity enhancer 0 - 20%

Buffering agent quantum satis

Preservatives quantum satis

As already mentioned hereinbefore, the compounds of formula (I) show valuable pharmacological properties, namely they exhibit DAAO inhibiting activity and possess enhanced brain permeability. Said properties are demonstrated with the pharmacological tests presented below.

BIOLOGICAL ACTIVITY

Assessment of DAAO enzyme iehibitiosi, in vitro

The DAAO inhibiting activity of compounds was determined by using D-kynurenine as substrate for DAAO. DAAO transforms D-kynurenine into D-kynurenic acid and production of the latter can be detected by fluorescence spectroscopy. The changes in fluorescence were monitored in a Novostar (BMG) fluorescence plate reader (excitation/emission wavelength: 344/405 nm).

Recombinant human DAAO enzyme was supplied by Novoprotein (Summit, NJ, USA), D-kynurenine was supplied by Sigma- Aldrich. On the day of the assay compounds were serially diluted in DMSO. First, 2 μΐ of diluted compounds were added to the wells of a white 96 well plate (Tomtec), then 3 μΐ of assay buffer (40 mM Tris, pH=8.3) was added. In the following step 85 μΐ of a mixture of DAAO, FAD and BSA in assay buffer was added to the wells. The final concentrations were the followings: DAAO 150 ng/100 μΐ, FAD 20 μΜ and BSA 0.08 mg/ml. Then the plate was incubated in 37 °C for 15 minutes to reach equilibrium. After this 10 μΐ of 10 mM D-kynurenine in assay buffer was added to the wells. The plate was incubated at 37 °C for 15 minutes again. Finally, the change in fluorescence was determined for 15 minutes at 37 °C in a Novostar plate reader. The slope of change in fluorescence was determined by the software of Novostar reader and was used for evaluation of DAAO activity. Concentration-response relationships for compounds were determined from 5-7 concentration points prepared by threefold serial dilutions establishing IC₅₀ values, concentration of compounds required to display 50% inhibition of DAAO activity in the presence of 1 mM D-kynurenine, Data are presented in Table 1

Table 1. IC₅₀ values (in nM) for inhibiting the human DAAO enzyme by the test

compounds.

Determination of drag penetration in Caco-2 assay

Penetration of test compounds through Caco-2 monolayers (Hellinger, E. et al. Eur. J. I' harm. Set, 41 (2010) 96) was investigated at a nominal concentration of 1 μΜ in both inward apical (A) to basolateral (B) and outward (B to A) directions, and apparent permeability (Papp) and permeability directional ratio (PDR= P_APPB _t0 A Pa pA to B) were calculated.

Caco-2 cells were seeded at a density of ~ 500,000 cells/1.12 cm² on basement membrane matrix covered Transwell^R polycarbonate filters (0.45 μη pore size; 1.12 cm² surface area; Costar). The cultures were grown at 37 °C in an atmosphere of 5% C0₂ and 95% relative humidity and used for permeability assays on days between 19-21.

The test compound dosing solution was added to the donor side of individual Transwells and transport buffer without test compound was added to the receiver side. The 12-well plate was placed in a shaking water bath (120-140 rpm) with saturating humidity at 37°C. The plates were incubated up to 40 minutes. The concentration of the test compound present in the donor and receiver side was analysed using HPLC-UV.

Permeability screening was performed under iso-pH condition (pH 7.4_a-7.4B).

The apparent permeability (P_app) of the compounds across the cell monolayers is calculated using the following equation:

Where P_app = apparent permeability in cm/sec, Vr is the volume of medium in the receiver chamber, A to B Vr = 1.5 mL, B to A Vr = 0.5 mL; Co is the initial concentration of the test drug in the donor chamber, A = 1.12 cm² is the surface area of cell monolayer, dC/dt is the linear slope of the drug concentration in the receiver chamber with time.

Flux through the monolayer was linear with time (dC/dt is constant).

The permeability directional ratio (PDR) for B to A (basolateral to apical) and A to B (apical to basolateral) transport is defined by the following equation: Where P_app B to A and P_apP A to B represent the apparent permeability of test compound from the basal to apical, and apical to basal side of the cellular monolayer, respectively. Data are presented in Table 2.

Characterization of the pharmacokinetic profile is¾ rat plasma and brain samples

Pharmacokinetics of compounds was studied in adult Crl:WI(Han) rats (250-300 g) purchased from Charles River Laboratories. The test items were suspended in 5% TweenSO in water and dosed orally by gavage at 10 mg/kg (dose volume 2.5 ml/kg). Blood samples of 0.5-1 mi (to yield at least 150 μ! of plasma) were collected at time points 1, 2 and 4 hours by cardiac puncture under carbon dioxide anesthesia into pre-cooled K₂EDTA polypropylene tubes and kept cooled until the separation of plasma by centrifugation. Brain tissue samples were collected after the collection of blood and flushed with ice cold saline. The tissue samples were thereafter frozen on dry ice and stored at -80 °C.

Liquid chromatography-tandem mass spectrometric (UHPLC -MS/MS) methods were used for the determination of the compounds in rat plasma and brain tissue. The tissue samples were weighed, homogenized with cold phosphate buffer pH 7.2 ( :4, w/w), and the homogenates were stored at -70 °C prior to analysis. The stock solutions of compounds were prepared in acetonitrile and diluted with distilled water: acetonitrile mixture (50:50) to obtain the series of concentrations as working standards. The calibration standards were prepared by spiking the working standards into blank plasma or tissue homogenates (1 :9 v/v). Low, medium and high quality control samples were prepared in the same fashion. The calibration standards and the quality controls were stored at -70 °C prior to analysis. Thawed plasma and tissue homogenate samples, calibration standards, quality controls and analyte-free blank samples were extracted by pipetting 50 μΐ of sample and 2.5 ml of mixture of ethylacetate:hexane (50:50, v/v) in glass vials, followed by vortexing for 3 minutes and centrifugation for 7 minutes (4400 rpm, 10 °C). After evaporation and reconstitution of the organic extract with mobile phase, the samples were analysed using reversed-phase chromatography followed by mass spectrometry with electrospray ionization and selected ion monitoring.

The results of the characterization of the pharmacokinetic profile in rat plasma and brain samples are shown in Table 2. The results show that the compounds of formula (I) possess enhanced brain permeability. Table 2. In vitro penetration properties and rat pharmacokinetic data after single oral dosing with 10 mg/kg of the compound.

aPenetration of test compounds through Caco-2 cell monolayers

b Permeability Directional Ratio (PDR=Papp_out/Pappm)

Claims

1. A compound of formula (I),

wherein

Rj and R₂ are independently H, halogen, C_h lky!, haloC^alkyl,

hydroxyCi-ealkyl, C3-₅cycloalkyl,

or cyano; R₃ is fluoro, chloro, bromo,

difluoromethyl or trifluoromethyl;

or a pharmaceutically acceptable ester, salt, hydrate or solvate thereof;

with the provisos that

a) when R₃ is chloro, bromo or

] and R₂ are not simultaneously I f : b) the compound is not 6-bromo-8-fluoro-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)- one, 6-chloro-7-methyl-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 7- (trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 7-bromo-8-methoxy- [l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 8-fluoro-[l,2,4]triazolo[4,3-a]pyridin- 3(2H)-one, 6-fluoro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 7-bromo-8-iodo- [l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 8-bromo-7-chloro-[l ,2,4]triazolo[4,3- a]pyridin-3(2H)-one, 6,8-dichloro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one or 6- (trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one.

A compound according to claim 1, wherein

Ri and R₂ are independently H, halogen, Ci-ealkyl, haloCi-ealkyl,

hydroxyCi-salkyl, C_3-5cycloalkyl, C₃ CycioalkyiC_! -₆alkyl, C_1-6alkoxy or cyano; R is fluoro, chloro, bromo, C^alkyl, difluoromethyl or trifluoromethyl;

with the provisos that

a) when R is fluoro, chloro, bromo, C_halky 1 or trifluoromethyl, Ri and ₂ are not simultaneously H;

b) the compound is not 8-bromo-7-iodo-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 8-chloro-7-iodo-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 6-bromo-8-fluoro- [l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 6-bromo-8-methyl-[l,2,4]triazolo[4,3- a]pyridin-3(2H)-one, 6-chloro-7-methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 8-chloro-6-(trifluoromethyl)-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 8-bromo-6- methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 6-bromo-7-methyl- [l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 6-bromo-8-(trifluoromethyl)- [l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 7-bromo-8-methoxy-[l,2,4]triazolo[4,3- a]pyridin-3 (2H)-one, 7-bromo-8-iodo-[ J ,2,4]triazol o[4,3 -ajjpyridin-3 (2H)-one, 8- bromo-7-chloro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one or 6,8-dichloro- [l,

2,4]triazolo[4,3-a]pyridin-3(2H)-one.

3. A compound according any one of claims 1 or 2, wherein the compound is a compound of formula (III),

wherein

Ri and R₂ are independently H, halogen, Ci-ealkyl,

hydroxyCi-6alkyl, CVscycloalkyl, Cs-scycioalkyiCi-ealkyl, d^alkoxy or cyano; j is fluoro, chloro, bromo, (Ί _fla lkyi . difluoromethyl or trifluoromethyl.

4. A compound according any one of claims 1 or 2, wherein

Ri and R2 are independently H, halogen, methyl, trifluoromethyl,

hydroxymethyl, cyclopropyi, methoxy or cyano;

Rj is fluoro, chloro, bromo, methyl, difluoromethyl or trifluoromethyl.

5. A compound according to any one of claims 1 or 2, wherein

Rj and R₂ are independently H, halogen, haloCi-ealkyl, hydroxyCi-ealkyl or cyano;

R₃ is fluoro, chloro, bromo, C^alkyl or trifluoromethyl.

6. A compound according to claim 5, wherein

Ri and R₂ are independently H, halogen,

or hydroxyCi-eaikyi; Rj is fluoro, chloro, bromo, C^alkyl or trifluoromethyl.

7. A compound according to claim 6, wherein

Ri and R₂ are independently H, halogen or haloCi-ealkyl,

R₃ is chloro, bromo or Cj-ealkyl.

8. A compound according to any one of claims 1 or 2, wherein the compound is a compound of formula (IV),

wherein

Ri is H or halogen;

R₂ is H, halogen, d-ealkyl, halod-ealkyl, hydroxyd-ealkyl or cyano,

R₃ is fluoro, chloro, bromo, d-ealkyl, difluoromethyi or trifluoromethyl; or a compound of formula (V),

wherein

Ri is H;

R₂ is halogen or cyano;

Rj is chloro or C^alkyl.

9. A compound according to claim 8, wherein the compound is a compound of formula (IV),

wherein Ri is H or halogen;

R.2 is H, halogen, Ci_₆alkyl, haloCi-ealkyl or hydroxyCi-ealkyl;

R₃ is fluoro, chloro, bromo, C_1-6alkyl, difluoromethyl or trifluorom ethyl.

10. A compound according to claim 9, wherein

Ri is H;

R₂ is halogen or Ci-eaikyl;

R3 is fluoro, chloro, bromo or trifluorom ethyl.

1 1. A compound according to claim 1, selected from the group of:

6- Bromo-7-fluoro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

7- Bromo-6-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

7-Chloro-6-(trifluoromethyl)-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

6-Chloro-7-fluoro-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

6- Bromo-7-chloro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

7- Bromo-6-chloro-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

6,7-Dichloro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

7-Bromo-6-fluoro-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

7-Chloro-6-fluoro-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

6,7-Dibromo-[ l,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

7-(^Iethyl-d3)-6-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one; 7-Methyl-6-(trifluoromethyl)-[l ,2,4]triazolo[4,3-a]p>Tidin-3(2H)-one;

or a pharmaceutical ly acceptable ester, salt, hydrate or solvate thereof.

12, A compound of formula (II),

wherein

Ri and R₂ are independently H, halogen, C_halky!, haloCi-ealkyl,

hydroxyCi-salkyl, C _-5Cycloalkyl,

-ealkyL C_{1 -6}alkoxy or cyano; R₃ is fluoro, chloro, bromo, C^alkyl, difluoromethyl, trifluoromethyl or cyano; or a pharmaceutically acceptable ester, salt, hydrate or solvate thereof;

13. A compound according to claim 12, wherein the disease is schizophrenia, schizophreniform disorder, schizoaffective disorder or another psychotic disorders, a cognitive disorder, an anxiety disorder, a mood disorder, posttraumatic stress disorder, an eating disorder, addiction, a sleep disorder, a disorder usually first diagnosed in infancy, childhood or adolescence, pain, a neurodegenerative disorder, a motor defective syndrome or another movement disorder.

14. A compound according to claim 13, wherein the disease is schizophrenia, schizophreniform disorder, schizoaffective disorder, a cognitive disorder or pain.

15. Use of a compound of formula (II),

wherein

Ri and R₂ are independently H, halogen, Ci-ealkyl,

hydroxyCi-₆alkyl, CVscycloaikyl, Cs-scycioalkylCi-ealkyl, d^alkoxy or cyano; R₃ is fluoro, chloro, bromo, C_1-6alkyl, difluoromethyl, trifluorom ethyl or cyano; or a pharmaceutically acceptable ester, salt, hydrate or solvate thereof;

for the manufacture of a medicament for the treatment or prevention of a disease associated with D-amino acid oxidase.

16. Use according to claim 15, wherein the disease is schizophrenia, schizophreniform disorder, schizoaffective disorder or another psychotic disorder, a cognitive disorder, an anxiety disorder, a mood disorder, posttraumatic stress disorder, an eating disorder, addiction, a sleep disorder, a disorder usually first diagnosed in infancy, childhood or adolescence, pain, a neurodegenerative disorder, a motor defective syndrome or another movement disorder,

17. Use according to claim 16, wherein the disease is schizophrenia, schizophreniform disorder, schizoaffective disorder, a cognitive disorder or pain.

18. A method for the treatment or prevention of a disease associated with D-amino acid oxidase comprising administering to a mammal in need of such treatment or prevention an effective amount of at least one compound of formula (II),

wherein

Ri and ft? are independently H, halogen, Ci-ealkyl, haloCi-ealkyl,

C_3-5Cycloalkyl, CVealkoxy or cyano; R₃ is fluoro, chloro, bromo, C_1-6alkyl, difluoromethyl, trifluorom ethyl or cyano; or a pharmaceutically acceptable ester, salt, hydrate or solvate thereof.

19. A method according to claim 18, wherein the disease is schizophrenia, schizophreniform disorder, schizoaffective disorder or another psychotic disorder, a cognitive disorder, an anxiety disorder, a mood disorder, posttraumatic stress disorder, an eating disorder, addiction, a sleep disorder, a disorder usually first diagnosed in infancy, childhood or adolescence, pain, a neurodegenerative disorder, a motor defective syndrome or another movement disorder.

20. A method according to claim 19, wherein the disease is schizophrenia, schizophreniform disorder, schizoaffective disorder, a cognitive disorder or pain.

21. A pharmaceutical composition comprising as active ingredient at least one compound according to any one of claims 1 to 1 1 and at least one pharmaceutically acceptable excipient.

22. A pharmaceutical composition according to claim 21, wherein the composition further comprises one or more other active ingredients.

23. A pharmaceutical composition according to claim 22, wherein the other active ingredient(s) are selected from antidepressants, antipsychotics, anxiolytics, anticonvulsants, mood stabilizers, 5HTi_B ligands, mGluR2 agonists, alpha 7 nicotinic agonists, chemokine receptor CCRl inhibitors, delta opioid agonists and compounds used in the treatment of Alzheimer's disease, Parkinson's disease, migraine, stroke, neuropathic pain or nociceptive pain.

24. Process for preparing the compounds of formula (I) according to claim 1

characterized by

Route A step 1) reacting a 2-haiopyridine of formula (VI) R, H

(VI)

- wherein X is F, CI, Br, I, and Ri, R₂ and R3 are described above for compound of formula (I) with hydrazine hydrate, then step 2) the so obtained 2-hydrazinopyridine (VII) is reacted

(VII) with carbonyl diimidazole to obtain derivative of formula (I) Route B step 1) reacting a 2-aminopyridine of formula (VIII)

(V!i!)

- wherein R_ls R₂ and R3 are described above for compound of formula (I) with nitric acid in the presence of sulphuric acid, then step 2) the so obtained N-nitro-pyridine-2-amine (IX) is reacted

(IX)

- wherein Rj, R₂ and R₃ are described above for compound of formula (I) with zinc/ammonium chloride, then step 3) the so obtained 2-hydrazinopyridine (VII) is reacted

(VII)

- wherein Rj, R₂ and R₃ are described above for compound of formula (I) with triphosgene to obtain derivative of formula (I).

Route C

step 1) reacting a 2-halopyridine of formula (VI) R₃ H

R,

(VI) - wherein X is CI, Br, I, and Ri, R₂ and R₃ are described above for compound of formula (I) with methyl hydrazinocarboxylate to obtain derivative of formula (1).

step 1) reacting a 2-halopyridine of formula (VI)

(V!)

- wherein X is CI, Br, I, and Ri, R₂ and R₃ are described above for compound of formula (I) with tris(dibenzylideneacetone)dipalladium(0) in the presence of l , l '-bis(diphenylphosphino)ferrocene and cesium carbonate then step 2) the so obtained di-tert-butyl l-(pyridin-2-yl)hydrazine-l,2-dicarboxylate (X) is reacted

(X) wherein i, R₂ and R₃ are described above for compound of formula (I) with HCl/dioxane to obtain 2-hydrazinopyridine of formula(VII). This compound is reacted further as described in Route A above, starting from Route A / step 2.