2-aminopyridine derivatives as adenosine a2b receptor antagonists and melatonin mt3 receptor ligands

专利摘要:
Derivatives of 2-aminopyridine as receptor antagonists a2 b adenosine and mt3 receptor ligands of melatonin. The present invention relates to novel pyridine derivatives of formula (I) {image-01} As antagonists of the adenosine a receptor2 b and melatonin receptor ligands mt3, to the process for their preparation, to pharmaceutical compositions comprising said compounds and to the use of said compound for the manufacture of a medicament for the treatment of pathological conditions or diseases that can be improved by antagonizing the a2 b adenosine receptor and by the inhibition of the mt receptor3 of the melatonin, such as respiratory diseases, metabolic disorders, neurological diseases and cancer. (Machine-translation by Google Translate, not legally binding)
公开号:ES2580702A1
申请号:ES201530233
申请日:2015-02-25
公开日:2016-08-25
发明作者:Julio César CASTRO PALOMINO LARIA；Juan Alberto CAMACHO GÓMEZ；Adela MENDOZA LIZALDEZ
申请人:Palobiofarma SL；
IPC主号:

专利说明:

2-Aminopyridine derivatives as adenosine A2b receptor antagonists and MT3 melatonin receptor ligands Field of the Invention
The present invention relates to conveniently substituted novel pyridine derivatives, such as adenosine A2b receptor antagonists and MT3 melatonin receptor ligands.
Other objects of the present invention are to provide a process for preparing such compounds; pharmaceutical compositions comprising an effective amount of these compounds; the use of these compounds for the manufacture of a medicament for the treatment of pathological conditions or diseases that can be improved by the antagonism of the adenosine A2b receptor and by the inhibition of the MT3 receptor of melatonin, such as respiratory diseases, metabolic disorders, diseases Neurological and cancer. Background of the invention
Adenosine regulates its function through four subtypes of receptors that are: A1, A2a, A2b and A3. These receptors are grouped according to the effects on the enzyme adenylate cyclase. The A1 and A3 receptors inhibit cAMP production through coupling to protein G. The A2a and A2b receptors increase cAMP levels by stimulating the enzyme adenylate cyclase, also by coupling to protein G.
Related to the affinity of all subtypes of natural adenosine receptors, it is known that the A2b receptor is the one with the lowest affinity, the A3 receptor has an intermediate affinity and the A1 and A2a receptors have the highest affinity. In this sense, it is believed that the A2b receptor is inactive under physiological conditions, and is activated in situations of increased extracellular levels of adenosine.
Several scientific publications have shown the potential of adenosine A2b receptor antagonists for the treatment of respiratory diseases and inflammation. (Feoktistov I, et al, Adenosine A2B receptors as therapeutic targets. Drug Dev Res 45: 198–206, 1998; Rosi S et al, The influence of brain inflammation upon neuronal adenosine A2B receptors. J Neurochem 86: 220-227, 2003 : Mustafa SJ, et al, Effect of a specific and selective A2B adenosine receptor antagonist on adenosine agonist AMP and allergen-induced airway responsiveness and cellular influex in a mouse model of asthma.J Pharmacol Exp Ther 320: 1246-1251, 2007; Sun CX, et al, Role of A2B adenosine receptor


signaling in adenosine-dependent pulmonary inflammation and injury. J Clin Invest 116: 2173-2182, 2006).
Specifically, there are several studies that suggest the therapeutic benefit of adenosine A2b receptor antagonists, including the treatment of asthma (Landells LJ, et al, The role of adenosine receptors in the action of theophylline on human peripheral blood mononuclear cells from healthy and asthmatic subjects. Br J Pharmacol 129: 11401144, 2000), type II diabetes (Volpini R, et al, Medicinal chemistry and pharmacology of A2B adenosine receptors. Curr Top Med Chem 3: 427-443, 2003) and Alzheimer's disease (Rosi S, et al, The influence of brain inflammation upon neuronal adenosine A2B receptors. J Neurochem 86: 220-227, 2003).
Potential of A2b adenosine receptor modulators in the treatment of respiratory diseases
Adenosine can affect both mast cell degranulation and inflammation mediator production. Recently, new evidence suggests that A2b adenosine receptors mediate the production and release of proinflammatory mediators such as IL-8, IL-4 and IL-3 from mast cells; Therefore, it is considered that adenosine A2b receptor antagonists could be promising therapeutic agents in the treatment of asthma, chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH) and pulmonary fibrosis.
a) Asthma
Asthma is a lung disease characterized by hypersensitivity of the respiratory tract and inflammation. The physiological effects of adenosine in asthma through the stimulation of its receptors located on the cell surface and the subsequent signaling pathway, are a function of the local concentration of adenosine. (Handbook of Experimental Pharmacology, Adenosine receptors in Health and Disease, Vol. 193, page 239-362). Adenosine acts on its different receptors and induces the release of inflammatory mediators that are important in the pathogenesis of airway remodeling in asthmatics.
Studies have been published that demonstrate the effect of adenosine A2b receptor antagonists on mice deficient in the enzyme adenosine deaminase- (ADA). These studies show that mice treated with adenosine A2b receptor antagonists have less lung inflammation, less fibrosis and greater enlargement of the alveolar airspace, than untreated mice, suggesting that A2b receptor signaling


Adenosine is a critical pathway for lung inflammation and lesions in vivo. (Chun-Xiao Sun et al, Role of A2B adenosine receptor signalling in adenosine-dependent pulmonary inflammation and injury, J. Clin. Invest. 116: 2173-2182 (2006). Doi: 10.1172 / JCI27303; Caruso M et al, Adenosine signalling pathways as potential therapeutic targets in respiratory disease, Expert Opin. Ther. Targets (2013) 17 (7): 761-772 and its references).
A recent study has shown that in the asthma model in guinea pigs, animals pretreated with an adenosine A2b receptor antagonist improved changes in the trachea response, total blood lymphocytes and pathological changes in the lung. These results showed a preventive effect of the A2b antagonist of adenosine receptors in ovalbumin-induced asthma. (Pejman et al,
The effect of adenosine A2A and A2B antagonists on tracheal responsiveness, serum levels of cytokines and lung inflammation in guinea pig model of asthma, Advanced Pharmaceutical Bulletin, 2014, 4 (2), 131-138 and their references).
Another recent study indicates that adenosine A2b receptors in humans could indirectly mediate bronchoconstriction in response to adenosine and would play a leading role in airway inflammation and adenosine-induced hyperactivity. Antagonists of this receptor would probably limit the proinflammatory effects of adenosine. (Cicala, C et al, Adenosine signaling in airways: Toward a promising antiasthmatic approach. Eur J Pharmacol (2013), http://dx.doi.org/10.1016/j.ejphar.2013.06.033i).
b) Chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by airflow obstruction, not being completely reversible.
There are studies that show that levels of adenosine A2b receptors are elevated in surgical lung biopsies of patients with severe COPD. In addition, it has been determined that the mediators that are regulated by said receptor were elevated in samples taken from them, and activation of adenosine A2b receptors on cells isolated from the airways of COPD patients studied has been demonstrated. directly induce the production of said mediators; It is therefore suggested that patients suffering from COPD may benefit from adenosine-based therapies, such as treatment with drug antagonists.


A2b adenosine receptors. (Zhou Y, et al, Alterations in Adenosine Metabolism and Signaling in Patients with Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis. 2010, PLoS ONE 5 (2): e9224. Doi: 10.1371 / journal.pone.0009224; Varani K et al , Alteration of adenosine receptors in patients with chronic obstructive pulmonary disease, Am J Respir Crit Care Med. 2006 Feb 15: 173 (4): 398-406).
c) Pulmonary hypertension
Pulmonary hypertension (PH) was initially classified as primary (idiopathic) or secondary, depending on the presence or absence of identifiable causes as risk factors. The current classification was adopted in 2008 and includes five groups. See, for example, Simonneau et al, Updated clinical classification of pulmonary hypertension, 2009, J Am Coll Car dio, 54 (l): S43-54.
A variety of factors contribute to the pathogenesis of PH, including the proliferation of lung cells, which contribute to vascular remodeling. For example, pulmonary vascular remodeling is mainly caused by the proliferation of arterial endothelial cells and smooth muscle cells of patients with PH. (Steiner, et al., Interleukin-6 overexpression induces pulmonary hypertension, 2009, Circ. Res., Available at http://circres.ahajournals.org).
Several studies have shown the proliferation of lung cells, cytokines, growth factors and chemokines in the serum and / or in the lungs of patients. These altered expressions indicate a possible inflammatory mechanism or mediation in the pathogenesis of the disease. For example, it has been shown that endothelin-1 growth factor (ET-1) and interleukin 6 inflammatory cytokine (IL-6) is elevated in the serum and lungs of patients with PH. (A. Giaid, et al, Expression of endothelin-1 in the lungs of patients with pulmonary hypertension, 1993, N. Engl. J. Med, 329 (26): 1967-8 and Steiner, et al., Interleukin-6 overexpression induces pulmonary hypertension, 2009, Circ. Res., available at http://circres.ahajournals.org).
Other authors relate the role of adenosine A2b receptors in pulmonary hypertension, identifying a new disease progression mechanism and supporting the development of new antagonists of these receptors, for the treatment of this disease, associated for example with interstitial diseases of lungs. (Karmouty-Quintana, H et al, The A2b adenosine receptor modulates pulmonary


hypertension associated with interstitial lung disease. 2012, FASEB J. June; 26 (6): 2546-2557).
Other studies suggest the use of these antagonists in animal models with the HP phenotype, since such antagonists are able to stop damage to the lungs of the animals. (Karmouty-Quintana H, et al., ADORA2B and Hyaluronan modulate Pulmonary Hypertension associated with Chronic Obstructive Pulmonary Disease, July 2013).
d) Idiopathic Pulmonary Fibrosis
Idiopathic Pulmonary Fibrosis (IPF) is characterized by an insidious onset of dyspnea or cough. However, a subgroup of patients has a short duration of symptoms, with rapid progression towards the terminal stage of the disease.
A recent study showed that mice with partial deficiency in the enzyme adenosine deaminase showed a positive regulation of adenosine A2b receptors, developing spontaneous and progressive pulmonary fibrosis and died due to respiratory distress. (Chunn JL et al, Partially adenosine deaminase-deficient mice develop pulmonary fibrosis in association with adenosine elevations, Am J Physiol Lung Cell Mol Physiol. 2006 Mar; 290 (3): L579-87). The previous results suggest a possible regulatory role of adenosine and its receptors in IPF. (Selman M et al, Accelerated Variant of Idiopathic Pulmonary Fibrosis: Clinical Behavior and Gene Expression Pattern, 2007, PLoS ONE 2 (5): e482. Doi: 10.1371 / journal.pone.0000482 and its references).
Other studies have shown that adenosine A2b receptors may play a role in the pathogenesis of interstitial fibrosis, among other chronic lung diseases, probably due to the ability of adenosine A2b receptors to stimulate IL-6 production, and that These receptors can stimulate fibrosis indirectly in the lung. (Cronstein, BN, 2011, Adenosine receptors and fibrosis: a translational review, F1000 Biology Reports 2011, 3:21). On the other hand, the protective effect of adenosine A2b receptor antagonists on pulmonary fibrogenesis has been demonstrated, verifying said effect in the bleomycin-induced pulmonary fibrosis model, which suggests that said adenosine receptors may be a therapeutic option in The treatment of pulmonary fibrosis. (Edwin SL et al, Adenosine in fibrosis, Mod Rheumatol. 2010 April; 20 (2): 114-122). Potential for adenosine A2b receptor antagonists in Oncology
Adenosine receptors are found increased in various tumor cells. Activation of receptors by specific ligands, agonists or antagonists, modulate the


tumor growth through a series of signaling pathways. Specifically, the A2b adenosine receptor is not stimulated by virtue of the physiological levels of adenosine, therefore, it can play an important role in conditions associated with a high level or massive adenosine release, such as ischemia or the development of tumors, where the appearance of hypoxia is frequently observed. Several mechanisms have now been described by which adenosine A2b receptors may be involved in the development and progression of tumors. (Fishman P et al, Adenosine Receptors and Cancer, Handb Exp Pharmacol. 2009; (193): 399–441).
For example, in the case of breast cancer, it has been described that adenosine A2b receptor antagonists have a toxic effect on breast tumor cells that overexpress the 1-Fos antigen (Fra-1), a antigen that has proven to be key in the development of metastases in breast cancer. (Desmet C J et al, Identification of a pharmacologically tractable Fra-1 / ADORA2B axis promoting breast cancer metastasis, PNAS, March 26, 2013, vol. 110, no. 13, page 5139-5144).
In addition, there are studies that suggest that selective adenosine A2b receptor antagonists may be useful as potential new therapeutic products in inhibiting the growth of prostate cancer cells. (Wei Q et al, A2B adenosine receptor blockade inhibits growth of prostate cancer cells, Purinergic Signaling (2013), 9: 271-280).
Related to melanoma, new evidence suggests that the adenosine A2b receptor is involved in tumor progression in some murine tumor models. For example, it has been shown that the pharmacological block of the adenosine A2b receptor reverses immune suppression in the tumor microenvironment and leads to a significant delay in the growth of melanomas, noting that adenosine A2b receptor antagonists could be useful as adjuvants in the Melanoma treatment (Iannone, R et al, Therapeutic Potential of PSB1115 in Melanoma, Neoplasia, 2013, Vol. 15, No. 12). Potential of adenosine A2b receptor antagonists in metabolic disorders
In the case of metabolic disorders, for example in obesity, studies show the role of the adenosine A2b receptor in the mediation of metabolic homeostasis, correlating the results with obese patients, and identifying the adenosine A2b receptor as a regulator important in the high cholesterol diet, characteristic of type II induced diabetes, thus pointing to its therapeutic potential. (Johnston-Cox H, et al, The


A2b Adenosine Receptor Modulates Glucose Homeostasis and Obesity. 2012. PLoS ONE 7 (7): e40584. doi: 10.1371 / journal.pone.0040584).
Other studies indicate that adenosine and adenosine receptors are involved in glucose homeostasis. Today it has been established that such receptors are reasonable targets for anti-diabetic therapy. In particular, adenosine A2b receptor antagonists have shown an antidiabetic potential primarily due to increased plasma insulin levels in conditions when adenosine levels were elevated in vivo, and increased insulin release in vitro. (Rusing, D et al, The impact of adenosine and A2b receptors on glucose homeostasis, J Pharm Pharmacol. 2006 Dec; 58 (12): 1639-45). Potential for adenosine A2b receptor antagonists in the central nervous system
Recently it has been pointed out that the adenosine A2b receptor modulates different physiological and pathological processes in the brain, basically basing its therapeutic role on the low affinity that said receptor has for adenosine, since this is activated when adenosine concentrations reach concentrations of the micromolar order, so especially in the progression of neurodegenerative diseases can play an important role. (Popoli, P, Pepponi, R, Potential Therapeutic Relevance of Adenosine A2B and A2A Receptors in the Central Nervous System, CNS & Neurological Disorders -Drug Targets, 2012, Volume 11, Number 6, September 2012, pp. 664-674 (11 )). Potential of MT3 melatonin receptor ligands in the treatment of various pathologies
The MT3 melatonin receptor was discovered in 1988 by Duncan et al (Duncan MJ, et al,
2- [125I] iodomelatonin binding sites in hamster brain membranes: pharmacological characteristics and regional distribution. Endocrinology 1988, 122: 1825-1833). Said receptor has a low affinity for melatonin compared to the other two known MT1 and MT2 receptors.
Currently, the role of melatonin in many pathophysiological processes is well known, as well as in the control of the circadian rhythm; However, melatonin has a short half-life, being rapidly metabolized. Therefore, it becomes necessary to have


more stable melatonin analogues and with superior therapeutic effects or those of the hormone itself.
Today it is well known that ligands of the melatoninergic system possess important pharmacological properties in relation to the central nervous system as anxiolytics and antipsychotics (Lewis, AJ et al, Neuropharmacology of pineal secretions, Drug Metabol Drug Interact. 1990; 8 (3- 4): 247-312), for the treatment of Parkinson's disease (Erlich, SS et al, The pineal gland: anatomy, physiology, and clinical significance, J Neurosurg, 1985, 63, 321-341) and for the treatment of Alzheimer's disease (Skene, DJ et al, Daily variation in the concentration of melatonin and 5-methoxytryptophol in the human pineal gland: effect of age and Alzheimer's disease, Brain Research, 1990, Sep 24, 528 (1): 170 -4).
These compounds have also demonstrated activity in relation to certain types of cancer (Melatonin-Clinical Perspectives, Oxford University Press, 1988, pp. 164-165), diabetes (Clinical Endocrinology, 1986, 24, pp. 359-364), and in the treatment of obesity (International Journal of Eating Disorders, 1996, 20 (4), pp. 443-446).
As said before, melatonin is involved in both synchronization of the biorhythm and neuroprotection due to oxidative stress. Several studies currently link the MT3 melatonin receptor with the enzyme quinone reductase 2 (QR2) (Boutin JA et al, Studies of the melatonin binding site location onto quinone reductase 2 by directed mutagenesis, Arch Biochem Biophys. 2008 Sep 1; 477 (1 ): 12-9 and its references), (Nosjean, O et al, Identification of the melatonin-binding site MT3 as the quinone reductase 2, J Biol Chem. 2000 Oct 6; 275 (40): 31311-7).
Said quinone reductase 2 enzyme (QR2) is a flavoprotein that catalyzes the reduction of its substrates and enhances the production of harmful quinones and oxygen-reactive molecules. Several published studies show that this enzyme is altered in patients suffering from neurological disorders, such as Parkinson's disease (Fu, Y et al, Quinone Reductase 2 Is a Catechol Quinone Reductase, Biol Chem. 2008 August 29; 283 (35): 23829-23835) and Alzheimer's disease, evidencing in the latter case that patients suffering from said disease have significantly higher levels of QR2 than the control subjects, suggesting the role of this enzyme in the progression of the disease, due to an increase in the levels of toxic quinones, with the consequent loss of cognitive functions. (Hashimoto, T et al, Increased


hippocampal quinone reductase 2 in Alzheimer's disease, Neurosci Lett. 2011 Sep 8; 502 (1): 10-2).
In a recent study, overexpression of quinone reductase 2 (QR2) has been demonstrated in animal models of learning deficit and induced amnesia. The QR2 enzyme is a cytosolic flavoprotein that catalyzes the reduction of its substrates and increases the production of harmful quinones and reactive oxygen species (ROS), which is associated with learning and memory deficiencies, associated with age, as well. as with the progression of Alzheimer's disease. Adult mice that lack the QR2 enzyme (QR2 knock-out) demonstrated that they have improved learning abilities in various tasks, which suggests an important role for the QR2 enzyme in cognitive behaviors, representing the enzyme inhibitors a new therapeutic strategy towards the treatment of learning deficits, especially observed in aged brains. (Benoit CE et al, Loss of quinone reductase 2 function selectively facilitates learning behaviors, The Journal of Neuroscience, 2010, September 22, 30 (38): 12690-12700 and its references).
Other authors have published the effect of resveratrol, a polyphenolic compound present in grapes, red wine, peanuts, among others, on the QR2 enzyme, in the treatment of bleomycin-induced pulmonary fibrosis, demonstrating that the total antioxidant capacity of Tissue was reduced by the effect of bleomycin compared to the control group and increased by the effect of resveratrol, thus providing evidence that resveratrol has a promising potential in the treatment of bleomycin-induced pulmonary fibrosis in rats. (Akgedik, R et al, Effect of Resveratrol on Treatment of Bleomycin-Induced Pulmonary Fibrosis in Rats, Inflammation, October 2012, Vol. 35, No. 5).
Additionally, it has been shown that resveratrol has a high affinity for said quinone reductase 2 enzyme (QR2), indicating that the inhibition of the QR2 enzyme by resveratrol can protect cells against various pathological processes associated with cancer. (John SE et al, Design, synthesis, biological and structural evaluation of functionalized resveratrol analogues as inhibitors of quinone reductase 2, Bioorg Med Chem, 2013, Oct 1; 21 (19): 6022-37).
Other studies have suggested that the enzyme quinone reductase 2 could play an important role in the regulation of the catecholamine oxidation process, which may be involved in the etiology of Parkinson's disease. (Fu, Y et al,


Quinone Reductase 2 Is a Catechol Quinone Reductase, Biol Chem. 2008 August 29; 283 (35): 23829-23835).
In relation to patent literature, there are documents that disclose new compounds as adenosine A2b receptor antagonists. For example, patent application WO 2006/044610 discloses a method for the treatment and prevention of airway remodeling and / or pulmonary inflammation by administration of adenosine A2b receptor antagonists, to mammals that are genetically or environmentally predisposed to said disease Said patent application discloses a compound that inhibits pulmonary inflammation and reduces the number of inflammatory cells, as well as proinflammatory cytokines and chemokines in bronchoalveolar lavage fluid. Thus, these results provide strong support for the hypothesis that adenosine A2b receptor antagonists could be promising therapeutic agents in the treatment not only of asthma and COPD, but also of pulmonary fibrosis.
Another document, patent application WO 2005/070926 discloses a double antagonist of the A2b / A3 receptors, of the amino-thiazole type, useful for the treatment of a condition mediated by the activation of the adenosine A2b receptor.
Other authors suggest the application of adenosine A2b receptor antagonists for the treatment of neurological disorders, such as Alzheimer's disease, hypervascularization, and type I hypersensitivity disorders (WO 2004/106337, WO 2006/138376).
Moreover, patent application WO 2005/012282 discloses compounds useful in the treatment of disorders of the melatoninergic system, such as stress, cardiovascular diseases, Parkinson's disease, Alzheimer's disease, obesity, diabetes, among others. The compounds described in this case exhibit a high affinity for melatonin receptors and an important selectivity for MT3 type binding sites. Different types of compounds with similar activities are described in patent documents EP1466604, FR2823153 and FR2821843
Compounds that possess both melatonin MT3 receptor inhibition activity, and adenosine A2b receptor antagonist activity are highly desirable since such bifunctional compounds would improve known diseases of being susceptible to improvement by treatment with an A2b receptor antagonist of adenosine and it is also known that they are susceptible to improvement by inhibition of the MT3 receptor of melatonin, through two independent modes of action, while


that have single molecule pharmacokinetics. This could result in an increase in efficacy with a similar therapeutic index (i.e., the amount of therapeutic agent that causes therapeutic effect to the amount that causes toxicity) to individual agents or a similar efficacy with a higher therapeutic index.
5 Examples of known diseases of being susceptible to improvement by treatment with an adenosine A2b receptor antagonist and also known to be susceptible to improvement by inhibition of the MT3 melatonin receptor are respiratory diseases such as pulmonary fibrosis, neurological disorders such as Alzheimer's disease, metabolic disorders such as type II diabetes and cancer.
In addition, the compounds of the present invention are potent adenosine A2b receptor antagonists and potent MT3 melatonin receptor ligands. Object of the invention
In one of its aspects (aspect 1), the present invention relates to pyridine derivatives of formula (I): R2R1
R3 fifteenNNH2
(I)
in which:
-R1 represents a hydrogen atom or a halogen atom;-R2 represents a six-membered heteroaryl ring optionally substituted by
One or more substituents selected from the group consisting of halogen atom, C1-C4 haloalkyl, linear or branched C1-C6 alkyl, C3-C12 cycloalkyl, linear or branched C1-C6 alkoxy and C3-C12 cycloalkoxy; -R3 represents a six-membered heteroaryl ring optionally substituted by one or more substituents selected from the group consisting of halogen atom,
C1-C4 haloalkyl, linear or branched C1-C6 alkyl, C3-C12 cycloalkyl, linear or branched C1-C6 alkoxy and C3-C12 cycloalkoxy.
N-oxides of said compounds and pharmaceutically acceptable salts thereof, with the proviso that compound (I) is not one of the group consisting of:
-5- (pyridin-4-yl) -6- (pyridin-4-yl) pyridin-2-amine


-5- (pyridin-3-yl) -6- (pyridin-3-yl) pyridin-2-amine -5- (pyrazin-2-yl) -6- (pyridin-4-yl) pyridin-2-amine -5- (4-methylpyridin-2-yl) -6- (pyridin-4-yl) pyridin-2-amine
Other aspects of the present invention are:
Aspect 2) procedures for the preparation of the compounds of aspect 1,
Aspect 3) pharmaceutical compositions comprising an effective amount of a compound of aspect 1,
Aspect 4) pharmaceutical compositions according to aspect 3, further comprising a therapeutically effective amount of Pirferidone, Nintendanib, the AM152 antagonist of lysophosphatidic acid receptor 1 (LPA1), dopamine agonists such as L-Dopa, ropinirole or pramiprexole, Monoxigenase B (MAO-B) enzyme inhibitors such as Seleginine or Rasagiline, and acetylcholinesterase enzyme inhibitors such as Galantamine, Rivastigmine, Donepezil or Tacrine.
Aspect 5) the use of compounds of aspect 1 in the manufacture of a medicament for the treatment of diseases that can be improved by antagonism of the adenosine A2b receptor and / or by the inhibition of the MT3 receptor of melatonin,
Aspect 6) methods for the treatment of diseases that can be improved by antagonism of the adenosine A2b receptor and / or by the inhibition of the MT3 receptor of melatonin, by the administration of the compounds of aspect 1 or the pharmaceutical compositions of aspects 2 or 3 to a subject in need of such treatment, and
Aspect 7) combination products of the compounds of aspect 1 with a therapeutic agent selected from Pirferidone, Nintendanib, the AM152 antagonist of lysophosphatidic acid receptor 1 (LPA1), dopamine agonists such as L-Dopa, ropinirole or pramiprexole, inhibitors of the enzyme Monoxygenase B (MAO-B) such as Seleginine or Rasagiline, and acetylcholinesterase enzyme inhibitors such as Galantamine, Rivastigmine, Donepezil or Tacrine.
As stated above, the pyridine derivatives of the invention are useful in the treatment or prevention of diseases known to be susceptible to improvement by treatment with adenosine A2b receptor antagonists and / or by inhibition of the MT3 receptor of melatonin. . Such diseases are, for example, acute or chronic respiratory diseases, such as asthma, chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis disease, metabolic disorders, such as


Obesity, diabetes and atherosclerosis, cancer and neurological diseases, such as senile dementia, Alzheimer's disease and Parkinson's disease.
Accordingly, derivatives of the present invention and pharmaceutically acceptable salts or N-oxides thereof, and pharmaceutical compositions comprising such compounds and / or salts thereof, can be used in a method of treating disease conditions or diseases. of the human body, which comprises administering to an individual in need of said treatment, an effective amount of the pyridine derivatives of the invention or a pharmaceutically acceptable salt thereof.
As used herein, the term halogen atom comprises chlorine, fluorine, bromine atoms.
or iodine; typically a fluorine, chlorine or bromine atom. Halo when used as a prefix has the same meaning.
As used herein, the term "haloalkyl" is used to designate a C1-C4 alkyl group substituted by one or more halogen atoms, preferably one, two or three halogen atoms. Preferably, the halogen atoms are selected from the group consisting of fluorine or chlorine atoms. In a preferred embodiment, the haloalkyl groups are C1-C4 alkyl substituted by one, two or three fluorine or chlorine atoms.
As used herein, the term "C1-C6 alkyl" is used to designate linear or branched hydrocarbon radicals (CnH2n + 1) with 1 to 6 carbon atoms. Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, tertbutyl, n-pentyl, 1-methyl-butyl, 2-methyl-butyl, isopentyl, 1-ethylpropyl, 1, 1 -dimethylpropyl, 1,2-dimethylpropyl, n-hexyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl radicals 2 -methylpentyl and 3-methylpentyl. Preferably C1-C6 alkyl is a C1-C4 alkyl.
As used herein, the term "cycloalkyl" encompasses cyclic hydrocarbon groups having 3 to 12 carbon atoms. Said cycloalkyl groups may have a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, by way of example, individual ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantyl, bicyclo [2.2.1] heptane, 1,3,3- trimethylbicyclo [2.2.1] hept-2-yl, (2,3,3-trimethylbicyclo [2.2.1] hept-2-yl).


Also included in the definition of the term cycloalkyl are carbocyclic groups as defined in the previous paragraph that are condensed with an aryl group, for example indane and the like.
As used herein, the term "C1-C6 alkoxy" is used to designate radicals containing a linear or branched C1-C6 alkyl group attached to an oxygen atom (C2H2n + 1-O-). Preferred alkoxy radicals include methoxy, ethoxy, n-propoxy, ipropoxy, n-butoxy, sec-butoxy, t-butoxy, trifluoromethoxy, difluoromethoxy, hydroxymethoxy, 2-hydroxyethoxy or 2-hydroxypropoxy.
As used herein, the term "cycloalkoxy" is used to designate radicals containing a C3-C12 cycloalkyl groups attached to an oxygen atom.
As used herein, the term "six-membered heteroaryl ring" is used to designate a six-membered heteroaromatic ring containing carbon, hydrogen and one or more nitrogen atoms. Such radicals may be optionally substituted by one or more substituents selected from the group consisting of halogen atom, C1-C4 haloalkyl, linear or branched C1-C6 alkyl, C3-C12 cycloalkyl, linear or branched C1-C6 alkoxy and C3- cycloalkoxy C12 Preferred radicals are pyridyl and optionally substituted pyrimidinyl. When a heteroaryl radical carries 2 or more substituents, the substituents may be the same or different.
As used herein, some of the atoms, radicals, chains or cycles present in the general structures of the invention are "optionally substituted." This means that these atoms, radicals, chains or cycles may or may not be substituted or substituted in any position by one or more substituents, for example 1, 2, 3 or 4 substituents, whereby the hydrogen atoms attached to the atoms, unsubstituted radicals, chains or cycles are replaced by chemically acceptable atoms, radicals, chains or cycles. When two or more substituents are present, the substituents may be the same or different.
As used herein, the term "pharmaceutically acceptable salt" is used to designate salts with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, sulfuric, phosphoric, diphosphoric acid, hydrobromic, iohydric and nitric acid and acids.


organic, for example citric, fumaric, maleic, malic, mandelic, ascorbic, oxalic, succinic, tartaric, benzoic, acetic, methanesulfonic, ethanesulfonic, benzenesulfonic or p-toluenesulfonic acid. Pharmaceutically acceptable bases include alkali metal hydroxides and organic bases (for example, sodium or potassium) and alkaline earth metal (for example, calcium or magnesium), for example alkyl amines, arylalkyl amines and heterocyclic amines.
Other preferred salts according to the invention are quaternary ammonium compounds, in which an equivalent of an anion (Xn), in which -n indicates the negative charge of the anion and can be -1, -2 or -3, typically -1, is associated with the positive charge of the atom of N. Xn can be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulfate, nitrate, phosphate, or an anion of an organic acid such as , for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulfonate and p-toluenesulfonate. X-n is preferably an anion selected from chloride, bromide, iodide, sulfate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably X-n is chloride, bromide, trifluoroacetate or methanesulfonate.
According to an embodiment of the present invention, in the compounds of formula (I), R 1 represents a hydrogen atom or a halogen atom. In a preferred embodiment, R1 represents a halogen atom. In an even more preferred embodiment R1 represents a chlorine or bromine atom.
In accordance with another preferred embodiment of the present invention in the R2
compounds of formula (I), represents a six-membered heteroaryl ring optionally substituted by one or more substituents selected from the group consisting of halogen atom, C1-C4 haloalkyl, linear or branched C1-C6 alkyl, C3-C12 cycloalkyl, alkoxy C1-C6 linear or branched and C3-C12 cycloalkoxy.
In a more preferred embodiment, R2 represents a six-membered heteroaryl ring having one or two nitrogen atoms, optionally substituted by one or more substituents selected from the group consisting of halogen atom, C1-C4 haloalkyl, C1-C6 alkyl linear or branched, C3-C12 cycloalkyl, linear or branched C1-C6 alkoxy and C3-C12 cycloalkoxy.


In another preferred embodiment, R2 represents a pyridyl group optionally substituted by one
or more substituents selected from the group consisting of halogen atom, C1-C4 haloalkyl, linear or branched C1-C6 alkyl, C3-C12 cycloalkyl, linear or branched C1-C6 alkoxy and C3-C12 cycloalkoxy.
In a more preferred embodiment, R2 represents a 4-pyridyl group optionally substituted by a halogen atom. In an even more preferred embodiment, R2 represents a fluoro-pyridyl group optionally further substituted by one or more substituents selected from the group consisting of halogen atom, C1-C4 haloalkyl, linear or branched C1-C6 alkyl, C3-C12 cycloalkyl, linear or branched C1-C6 alkoxy and C3-C12 cycloalkoxy.
In accordance with another embodiment of the present invention in the compounds of the formula (I) R3 represents a six-membered heteroaryl ring optionally substituted by one or more substituents selected from the group consisting of halogen, C1-C4 haloalkyl, C1-C6 alkyl linear or branched, C3-C12 cycloalkyl, linear or branched C1-C6 alkoxy and C3-C12 cycloalkoxy groups.
In a more preferred embodiment R3 represents a six-membered heteroaryl ring having one or two nitrogen atoms, optionally substituted by one or more substituents selected from the group consisting of halogen atom, C1-C4 haloalkyl, linear C1-C6 alkyl or branched, C3-C12 cycloalkyl, linear or branched C1-C6 alkoxy and C3-C12 cycloalkoxy.
In a preferred embodiment, R3 represents a group selected from pyridyl and pyrimidinyl optionally substituted by one or more substituents selected from the group consisting of halogen atom, C1-C4 haloalkyl, linear or branched C1-C6 alkyl, C3-C12 cycloalkyl, linear or branched C1-C6 alkoxy and C3-C12 cycloalkoxy.
In a more preferred embodiment, R3 represents a 3-pyridyl group or a 4-pyridyl group optionally substituted by one or more substituents selected from the group consisting of halogen atom, C1-C4 haloalkyl, linear or branched C1-C6 alkyl, cycloalkyl C3-C12, linear or branched C1-C6 alkoxy and C3-C12 cycloalkoxy.
In a more preferred embodiment, R3 represents a 3-pyridyl group or a 4-pyridyl group optionally substituted by one or more substituents selected from the group consisting of halogen atom, C1-C4 haloalkyl, linear or branched C1-C6 alkyl and alkoxy C1-C6 linear or branched.In a more preferred embodiment of the present invention in the compounds of formula (I), R1 represents a chlorine or bromine atom, R2 represents a


4-pyridyl group optionally substituted by one or two fluorine atoms and R3 represents a 3-pyridyl or 4-pyridyl group optionally substituted by one or more substituents selected from the group consisting of halogen atom, C1-C4 haloalkyl, C1- alkyl C6 linear or branched and C1-C6 alkoxy linear or branched.
Particular individual compounds of the present invention include: 5- (pyridin-4-yl) -6- (pyrimidin-5-yl) pyridin-2-amine, 5- (3-fluoropyridin-4-yl) -6- (pyrimidin -5-yl) pyridin-2-amine, 6- (pyridin-3-yl) -5- (pyridin-4-yl) pyridin-2-amine, 5- (3-fluoropyridin-4-yl) -6- (pyridin-3-yl) pyridin-2-amine, 6- (pyridin-3-yl) -5- (pyrimidin-5-yl) pyridin-2-amine, 6- (5-fluoropyridin-3-yl) - 5- (3-fluoropyridin-4-yl) pyridin-2-amine, 5- (3-fluoropyridin-4-yl) -6- (5-methoxypyridin-3-yl) pyridin-2-amine, 6- [5 - (trifluoromethyl) pyridin-3-yl] -5- (3-fluoropyridin-4-yl) pyridin-2-amine, 6- (5-chloropyridin-3-yl) -5- (3-fluoropyridin-4-yl ) pyridin-2-amine, 5- (3-fluoropyridin-4-yl) -6- (6-methoxypyridin-3-yl) pyridin-2-amine, 5- (3-fluoropyridin-4-yl) -6- (pyridin-4-yl) pyridin-2-amine, 5,6-bis (3-fluoropyridin-4-yl) pyridin-2-amine, 5- (3-chloropyridin-4-yl) -6- (pyridin- 3-yl) pyridin-2-amine, 5- (3-chloropyridin-4-yl) -6- (pyridin-4-yl) pyridin-2-amine, 3-chloro-5- (pyridin-4-yl) -6- (pyrimidin-5-yl) pyridin-2-amine, 3-bromo-5- (pyridin-4-yl) -6- (pyrimidin- 5-yl) pyridin-2-amine, 3-chloro-5- (3-fluoropyridin-4-yl) -6- (pyrimidin-5-yl) pyridin-2-amine, 3-bromo-5- (3- fluoropyridin-4-yl) -6- (pyrimidin-5-yl) pyridin-2-amine, 3-chloro-6- (pyridin-3-yl) -5- (pyridin-4-yl) pyridin-2-amine , 3-Bromo-6- (pyridin-3-yl) -5- (pyridin-4-yl) pyridin-2-amine, 3-chloro-5- (3-fluoropyridin-4-yl) -6- (pyridin -3-yl) pyridin-2-amine,


3-Bromo-5- (3-fluoropyridin-4-yl) -6- (pyridin-3-yl) pyridin-2-amine,3-chloro-6- (pyridin-3-yl) -5- (pyrimidin-5-yl) pyridin-2-amine,3-Bromo-6- (pyridin-3-yl) -5- (pyrimidin-5-yl) pyridin-2-amine,3-chloro-6- (5-fluoropyridin-3-yl) -5- (3-fluoropyridin-4-yl) pyri-din-2-amine,
5 3-Bromo-6- (5-fluoropyridin-3-yl) -5- (3-fluoropyridin-4-yl) pyridin-2-amine, 3-chloro-5- (3-fluoropyridin-4-yl) - 6- (5-methoxypyridin-3-yl) pyridin-2-amine, 3-bromo-5- (3-fluoropyridin-4-yl) -6- (5-methoxypyridin-3-yl) pyridin-2-amine, 3-Chloro-6- [5- (trifluoromethyl) pyridin-3-yl] -5- (3-fluoropyridin-4-yl) pyridin-2-amine, 3-bromo-6- [5- (trifluoromethyl) pyridine- 3-yl] -5- (3-fluoropyridin-4-yl) pyridin-2-amine,
10 3-Chloro-6- (5-chloropyridin-3-yl) -5- (3-fluoropyridin-4-yl) pyridin-2-amine, 3-chloro-5- (3-fluoropyridin-4-yl) - 6- (pyridin-4-yl) pyridin-2-amine, 3-bromo-5- (3-fluoropyridin-4-yl) -6- (pyridin-4-yl) pyridin-2-amine, 3-chloro- 5- (3-fluoropyridin-4-yl) -6- (6-methoxypyridin-3-yl) pyridin-2-amine, 3-bromo-5- (3-fluoropyridin-4-yl) -6- (6- methoxypyridin-3-yl) pyridin-2-amine,
15-Chloro-5,6-bis (3-fluoropyridin-4-yl) pyridin-2-amine, 3-chloro-5- (3-chloropyridin-4-yl) -6- (pyridin-3-yl) pyridin-2-amine, 3-chloro-5- (3-chloropyridin-4-yl) -6- (pyridin-4-yl) pyridin-2-amine. The compounds of this invention can be prepared by using the
procedures described below. To facilitate the description of the procedures,
20 specific examples have been used, which in no way restricts the scope of the present invention. The synthesis of the compound of general formula (I) is summarized in Scheme 1.
Scheme 1
to) b)IC)R2d)R2R1
Br NNH2R3NNH2R3NNH2R3NNH2R3NNH2
(II) (III)(IV)(Ia)(Ib)


The compounds of formula (Ia) in the above scheme are compounds according to the present invention in which the substituent R1 is a hydrogen atom and the compounds of formula (Ib) in said scheme are compounds according to the present invention in which the substituent R1 is a halogen atom. Otherwise, groups R2 and R3 are groups as defined for the compounds of the present invention, that is, optionally substituted six-membered heteroaryl rings.
Reagents and conditions:
Stage (a): boronic acid derivative or boronate of R3, Pd (dppf) Cl2 • CH2Cl2, Cs2CO3, dioxane / H2O, 24h, 100 ° C.
Stage (b) NIS, AcOH, Ambient temperature.
Stage (c) boronic acid or bordered derivative of R2, Pd (dppf) Cl2 • CH2Cl2, Cs2CO3, dioxane / H2O, 24h, 100 ° C.
Stage (d) NBS or NCS, DMF, Ambient temperature.
The derivatives of general formula (I) are prepared in several steps starting from the commercially available 6-bromopyridin-2-amine derivatives of formula (II), according to Scheme 1. The starting reagent (II) is reacted by a Suzuki type coupling with boronic acid or bordered derivative of R3 using a palladium catalyst such as [1,1'-bis (diphenylphosphino) ferrocene] dichloropaladium (II), dichloromethane complex (Pd (dppf) Cl2 • CH2Cl2) in dioxane in the presence of an aqueous solution of a base such as cesium carbonate and at temperatures between 25 ° C and 110 ° C to provide compounds of formula (III). Iodination of the derivatives of formula (III) using Nyodosuccinimide in polar solvents such as glacial acetic acid and temperatures ranging from 0 ° C to 50 ° C provides the compounds of formula (IV). These products are reacted by an additional Suzuki type coupling similar to the first step with a corresponding boronic acid or bordered derivative of R2 under the standard procedures for the palladium catalyzed reaction described above to give compounds of formula (Ia), which are also the object of the present invention when R1 represents a hydrogen atom. After halogenation of the derivative (Ia) using a halogenating agent (such as N-chloro, -N-bromosuccinimide, N-iodosuccinimide or 1-fluoro-4-methyl1,4-diazoniabicyclo [2.2.2] octanobis (tetrafluoroborate), N-fluoro-N′-methyl-triethylene diamine bis (tetrafluoroborate) in polar aprotic solvents such as DMF and temperatures ranging from 0 ° C to 50 ° C provides compounds of formula (Ib), which are the object of the present invention.


To synthesize the compounds of formula (I) when the substituents R2 and R3 are the same, the sequence of reactions shown in Scheme 2 can be used.
Scheme 2
R2R2R1 e) I f) d) IN NH2 IN NH2 R3N NH2 R3N NH2
(V) (VI) (Ic) (Id)
The compounds of formula (Ic) in the above scheme are compounds according to the present invention in which the substituent R1 is a hydrogen atom and the compounds of formula (Id) in said scheme are compounds according to the present invention in which the R1 substituent is a halogen atom. In addition, the R2 and R3 groups are groups as defined for the compounds of the present invention, that is to say six-heteroaryl rings.
10 members optionally substituted but with the condition that both groups are identical.
Reagents and conditions:
Stage (e): NIS, DMF, Ambient temperature.
Stage (f): boronic acid or bordered derivative of R2 (R2 which is equal to R3), Pd (dppf) Cl2 • CH2Cl2, Cs2CO3, dioxane / H2O, 24h, 100 ° C.
Stage (d): NCS or NBS, DMF, Ambient temperature.
The compounds of formula (VI) are obtained by iodination of the derivative (V) using N-iodosuccinimide in DMF at temperatures ranging from 0 ° C to 50 ° C. These diiodinated derivatives of formula (VI) are reacted by a coupling of type Suzuki with the corresponding boronic acids or derivatives under standard procedures in a palladium catalyzed reaction to provide the compounds of formula (Ic), which are also the object of the present invention when R 1 represents a hydrogen atom. The introduction of a halogen atom is carried out analogously to the halogenation reaction described above in reaction (d) in the
Scheme 1 to give the compounds of formula (Id), which are the object of the present invention.
Pharmacological activity
Radioligand competition binding assay of the A2b subtype adenosine receptor


The adenosine A2b subtype receptor binding assay was carried out using a recombinant human source (HEK-293 cells) and [3H] DPCPX as radioligand, according to the assay described by Fredholm et al. (International Union of Pharmacology XXV nomenclature and classification of adenosine receptors, Pharmacol Rev. 2001
December 5; 53 (4): 527-52).
MT3 melatonin site binding study
MT3 site binding experiments were carried out on hamster brain membranes using [125I] 2-iodomelatonin as radioligand according to the protocol described by Pickering, DS et al. (Pickering, DS et al, 1990, Pharmacological characterization of
10 melatonin binding sites in the Syrian hamster hypothalamus, Eur J Pharmacol 1990 3 Jan; 175 (1): 71-7). Results
Table 1 shows the activity of the A2a and A2b adenosine receptors (Ki values) and the IC50 values of the melatonin MT3 receptor of some compounds herein.
15 invention.
Table 1
Compounds ExampleshA2b, Ki (nM)hA2a, Ki (nM)IC50 MT3 (nM)
3-chloro-6- (pyridin-3-yl) -5 (pyridin-4-yl) pyridin-2amine 1934.5500130
3-Bromo-6- (pyridin-3-yl) -5 (pyridin-4-yl) pyridin-2amine twenty46.1300140
3-Chloro-5- (3-fluoropyridin4-yl) -6- (pyridin-3-yl) pyridin2-amine twenty-one23.9480098
As can be seen from the results described in Table 1, the compounds of the present invention are potent antagonists of the adenosine A2b receptor and the melatonin 20 MT3 receptor, and show selectivity against the adenosine A2a receptor.
Derivatives of the invention are useful in the treatment or prevention of diseases known to be susceptible to improvement by treatment with an antagonist of a


Adenosine receptor, in particular, are susceptible to improvement by treatment with adenosine A2b receptor antagonist and by inhibition of the MT3 melatonin receptor. Such diseases are, for example, respiratory diseases, metabolic disorders, neurological diseases and cancer.
Accordingly, derivatives of the invention and pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising such compounds and / or salts thereof, can be used in a method of treating disorders of the human body, which comprises administering to a subject requiring such treatment an effective amount of the 2-amino pyridine derivative of formula (I) of the invention or a pharmaceutically acceptable salt thereof.
The present invention also provides pharmaceutical compositions comprising, as active ingredient, at least one 2-amino pyridine derivative of formula (I) or a pharmaceutically acceptable salt thereof in association with, other therapeutic agents, a pharmaceutically acceptable excipient such as a vehicle or diluent. The active ingredient may comprise 0.001% to 99% by weight, preferably from 0.01% to 90% by weight of the composition depending on the nature of the formulation and whether an additional dilution should be made before application. Preferably, the compositions are prepared in a form suitable for oral, topical, nasal, rectal, percutaneous or injectable administration.
Pharmaceutically acceptable excipients, which are mixed with the active compound or salts of such a compound, to form the compositions of this invention, are well known per se and the actual excipients used depend, among other things, on the desired method of administration of the compositions. .
The compositions of this invention are preferably adapted for injectable and oral administration. In this case, the compositions for oral administration may take the form of tablets, sustained-release tablets, sublingual tablets, capsules, inhalation aerosols, inhalation solutions, dry powder inhalation, or liquid preparations, such as mixtures, elixirs, syrups or suspensions, which contain all the compound of the invention; Such preparations can be prepared by methods well known in the art.
Diluents that can be used in the preparation of the compositions include liquid and solid diluents that are compatible with the active ingredient, together with coloring or flavoring agents, if desired. The tablets or capsules may conveniently contain between 2 and 500 mg of active ingredient or the equivalent amount of a salt thereof.


The liquid composition adapted for oral use may be in the form of solutions or suspensions. The solutions may be aqueous solutions of a soluble salt or other derivative of the active compound in association with, for example, sucrose to form syrup. The suspensions may comprise an insoluble active compound of the invention or a pharmaceutically acceptable salt thereof in association with water, together with a suspending agent or flavoring agent.
Compositions for parenteral injection may be prepared from soluble salts, which may or may not be lyophilized and may be dissolved in pyrogen-free aqueous media or other fluid suitable for parenteral injection.
Effective doses are usually in the range of 2-2000 mg of active ingredient per day. The daily dose can be administered in one or more treatments, preferably 1 to 4 treatments, per day.
The present invention will be further illustrated by the following examples. They are given below by way of illustration and in no way limit the scope of the invention. The synthesis of the compounds of the invention is illustrated by the following examples that include the preparation of the intermediate compounds, which do not limit the scope of the invention in any way. Abbreviations:
Throughout the present application the following abbreviations are used for which their definitions are given below: AcOH: DMF acetic acid: DPCPX dimethylformamide: 8-Cyclopentyl-1,3-dipropylxanthine dppf: 1,1'-bis (diphenylphosphino ) ferrocene HEK-293: Human embryonic kidney cells 293 NBS: N-bromine succinimide NCS: N-chloro succinimide NIS: N-iodine succinimide
Examples


General. Reagents, solvents and starting products were purchased from commercial sources. The term "concentration" refers to evaporation under vacuum using a Büchi rotary evaporator. When indicated, the reaction products were purified by flash chromatography on silica gel (40-63 microns) with the indicated solvent system.
5 Spectroscopic data was measured on a Varian Mercury 400 spectrometer. Melting points were measured on a Büchi 535 instrument. The HPLC-MS was performed on a Gilson instrument equipped with a Gilson 321 piston pump, a Gilson 864 vacuum degasser , a Gilson 189 injection module, a Gilson 1/1000 splitter, a Gilson 307 pump, a Gilson 170 detector, and a Thermoquest Fennigan aQa detector. 10 Intermediate 1: 6-bromo-5-iodopyridin-2-amine
N-iodosuccinimide (0.256 g, 1.16 mmol) was added to a solution of 6-bromopyridine-2amine (0.2 g, 1.16 mmol) in dichloromethane (10 ml). The mixture was stirred at room temperature 2 hours. The solvent was evaporated under reduced pressure. A black solid is obtained, which when washed several times with water becomes beige. The compound obtained (0.325 g,
15 77%) was used without further purification in the next step. 1H-NMR (400 MHz, DMSO-d6): δ = 6.25 (d, 1H), 6.58 (s, 2H), 7.68 (d, 1H).
HPLC-MS: Rt 3,223 m / z 300.8 (MH +).
Intermediate 2: 5,6-diiodopyridin-2-amine
Intermediate 2 was synthesized using the procedure described for Intermediate 1 starting 20 of 6-iodopyridin-2-amine.
1H-NMR (400 MHz, DMSO-d6): δ = 6.26 (d, 1H), 6.49 (s, 1H), 7.54 (d, 1H).
HPLC-MS: Rt 3,373 m / z 346.8 (MH +).
Intermediate 3: 6- (pyrimidin-5-yl) pyridin-2-amine
A mixture of 6-bromopyridin-2-amine (0.5 g, 2.89 mmol) and boronic (pyrimidin-5-yl) pinacolester (0.80 g, 3.9 mmol), [1,1 '- bis (diphenylphosphino) ferrocene] dichloropaladium (II), complex with dichloromethane (0.047 g, 0.057 mmol) and 2M aqueous cesium carbonate solution (3 ml) in 1,4-dioxane (15 ml) was heated to 110 ° C and allowed to stir 20 hours. The


The mixture was cooled, filtered over celite to remove the palladium residues and then partitioned between ethyl acetate and 1M aqueous sodium hydroxide solution. The organic phase was further divided with sodium bicarbonate and brine. The final organic phase was dried (MgSO4) and evaporated under reduced pressure. The residue precipitates as a black solid using pentane (0.671 g, 65%), and was used without further purification in the next step.
1H-NMR (400 MHz, DMSO-d6): δ = 6.20 (s, 2H), 6.51 (d, 1H), 7.20 (d, 1H), 7.52 (t, 1H), 9.18 (s, 1 H), 9.31 (s, 2 H).
HPLC-MS: Rt 1,718 m / z 173.1 (MH +).
The following intermediates 4 to 11 were synthesized from 6-bromopyridin-2-amine using the procedure described for Intermediate 3, and the corresponding boronic acid or boroned derivative:
Intermediate 4: 6- (pyridin-3-yl) pyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 6.09 (s, 2H), 6.47 (d, 1H), 7.12 (d, 1H), 7.45 (t, 1H), 7.49 (t, 1H), 8.29 (d, 1H), 8.56 (d, 1H), 9.15 (s, 1H).
HPLC-MS: Rt 2,229 m / z 172.1 (MH +).
Intermediate 5: 6- (5-fluoropyridin-3-yl) pyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 6.17 (s, 2H), 6.50 (d, 1H), 7.22 (d, 1H), 7.51 (t, 1H), 8.19 (dd, 1H), 8.57 (d, 1H), 9.06 (s, 1H).
HPLC-MS: Rt 2,420 m / z 190.1 (MH +).
Intermediate 6: 6- (5-methoxypyridin-3-yl) pyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 3.89 (s, 3H), 6.11 (s, 2H), 6.47 (d, 1H), 7.15 (d, 1H), 7.48 (t, 1H), 7.84 (dd, 1H), 8.28 (d, 1H), 8.75 (d, 1H).
HPLC-MS: Rt 2.406 m / z 202.1 (MH +).
Intermediate 7: 6- [5- (trifluoromethyl) pyridin-3-yl] pyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 6.25 (s, 2H), 6.53 (d, 1H), 7.32 (d, 1H), 7.53 (t, 1H), 8.67 (s, 1 H), 8.96 (d, 1 H), 9.46 (d, 1 H).
HPLC-MS: Rt 3,213 m / z 240.1 (MH +).
Intermediate 8: 6- (pyridin-4-yl) pyridin-2-amine


1H-NMR (400 MHz, DMSO-d6): δ = 6.15 (s, 2H), 6.53 (d, 1H), 7.20 (d, 1H), 7.51 (t, 1H), 7.92 (d, 2H), 8.62 (d, 2H).
HPLC-MS: Rt 2,146 m / z 172.1 (MH +).
Intermediate 9: 6- (5-chloropyridin-3-yl) pyridin-2-amine
5 1H-NMR (400 MHz, DMSO-d6): δ = 6.17 (s, 2H), 6.50 (d, 1H), 7.21 (d, 1H), 7.50 (t, 1H) , 8.42 (t, 1H), 8.61 (d, 1H), 9.12 (d, 1H).
HPLC-MS: Rt 2,830 m / z 206.0 (MH +).
Intermediate 10: 6- (6-methoxypyridin-3-yl) pyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 3.89 (s, 3H), 6.01 (s, 2H), 6.41 (d, 1H), 6.88 (d, 1H), 7.03 10 (d, 1H), 7.45 (t, 1H), 8.25 (dd, 1H), 8.74 (s, 1H).
HPLC-MS: Rt 2,779 m / z 202.1 (MH +).
Intermediate 11: 6- (3-fluoropyridin-4-yl) pyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 6.20 (s, 2H), 6.56 (d, 1H), 7.05 (dd, 1H), 7.53 (t, 1H), 7.91 (dd, 1H), 8.51 (d, 1H), 8.63 (d, 1H).
HPLC-MS: Rt 2,380 m / z 190.1 (MH +).
Intermediate 12: 5-iodo-6- (pyrimidin-5-yl) pyridin-2-amine
N-iodosuccinimide (0.796 g, 3.54 mmol) was added to a solution of 6- (pyrimidin-5-yl) pyridin
20 2-amine (0.67 g, 3.9 mmol) in glacial acetic acid (2 ml). The mixture was stirred at room temperature 4 hours. The acid was evaporated under reduced pressure and the residue was basified with saturated aqueous sodium bicarbonate solution. The aqueous phase was removed and a brown solid was obtained by washing with water which was purified by column (97: 3 dichloromethane: methanol). The purified compound was a beige solid (0.531 g,
25 47.5%).


1H-NMR (400 MHz, DMSO-d6): δ = 6.36 (d, 1H), 6.43 (s, 2H), 7.86 (d, 1H), 8.94 (s, 2H), 9.21 (s, 1 H).
HPLC-MS: Rt 2,441 m / z 299.0 (MH +).
The following intermediates 13 to 20 were synthesized using the procedure described for Intermediate 12, but starting from the corresponding 6-substituted pyridin-2-amine.
Intermediate 13: 5-iodo-6- (pyridin-3-yl) pyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 6.30 (d, 1H), 6.32 (s, 2H), 7.45 (t, 1H), 7.83 (d, 1H), 7.87 (d, 1H), 8.57 (d, 1H), 8.66 (s, 1H).
HPLC-MS: Rt 2,817 m / z 297.9 (MH +).
Intermediate 14: 6- (5-fluoropyridin-3-yl) -5-iodopyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 6.33 (d, 1H), 6.38 (s, 2H), 7.82 (dd, 1H), 7.84 (d, 1H), 8.55 (s, 1 H), 8.60 (d, 1 H).
HPLC-MS: Rt 3,086 m / z 315.9 (MH +).
Intermediate 15: 5-iodo-6- (5-methoxypyridin-3-yl) pyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 3.86 (s, 3H), 6.31 (d, 1H), 6.33 (s, 2H), 7.42 (dd, 1H), 7.83 (d, 1H), 8.25 (d, 1H), 8.29 (d, 1H).
HPLC-MS: Rt 2,990 m / z 327.9 (MH +).
Intermediate 16: 6- [5- (trifluoromethyl) pyridin-3-yl] -5-iodopyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 6.35 (d, 1H), 6.43 (s, 2H), 7.86 (d, 1H), 8.28 (s, 1H), 9.00 (dd, 1H), 9.02 (d, 1H).
HPLC-MS: Rt 3,795 m / z 365.9 (MH +).
Intermediate 17: 5-iodo-6- (pyridin-4-yl) pyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 6.33 (d, 1H), 6.38 (s, 2H), 7.48 (d, 2H), 7.84 (d, 1H), 8.65 (d, 2H).
HPLC-MS: Rt 2,744 m / z 298.0 (MH +).
Intermediate 18: 6- (5-chloropyridin-3-yl) -5-iodopyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 6.33 (d, 1H), 6.37 (s, 2H), 7.84 (d, 1H), 8.01 (t, 1H), 8.65 (t, 2H).


HPLC-MS: Rt 3,426 m / z 331.9 (MH +).
Intermediate 19: 6- (6-methoxypyridin-3-yl) -5-iodopyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 3.90 (s, 3H), 6.28 (d, 3H), 6.86 (d, 1H), 7.81 (dd, 2H), 8.30 (d, 1 H).
5 HPLC-MS: Rt 3.401 m / z 328.0 (MH +).
Intermediate 20: 6- (3-fluoropyridin-4-yl) -5-iodopyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 6.37 (d, 1H), 6.40 (s, 2H), 7.40 (dd, 1H), 7.82 (d, 1H), 8.52 (dd, 1H), 8.67 (d, 1H).
HPLC-MS: Rt 2.937 m / z 315.9 (MH +). Examples Example 1: 5- (pyridin-4-yl) -6- (pyrimidin-5-yl) pyridin-2-amine
NEITHER
N
N NH2 N
N NH2
N
N
A mixture of 5-iodo-6- (pyrimidin-5-yl) pyridin-2-amine (0.53 g, 1.77 mmol) and (pyridin-4-yl) pinacolester boronic acid (0.91 g, 4 , 42 mmol), [1,1'-bis (diphenylphosphino) 15 ferrocene] dichloropaladium (II), dichloromethane complex (0.087 g, 0.107 mmol) and 2M aqueous cesium carbonate solution (3.6 ml) in 1 , 4-dioxane (14.3 ml) was heated to 110 ° C and stirred for 20 hours. The mixture was cooled and then partitioned between ethyl acetate and 1M aqueous sodium hydroxide solution. The organic phase was partitioned with sodium bicarbonate and brine. The final organic phase was dried (MgSO4) and evaporated. The residue precipitates
20 as a light pink fine solid, washed with diethyl ether and dried (0.286 g, 54.8%).
1H-NMR (400 MHz, DMSO-d6): δ = 6.52 (s, 2H), 6.64 (d, 1H), 7.13 (d, 2H), 7.58 (d, 1H), 8.44 (d, 2H), 8.61 (s, 2H), 9.09 (s, 1H).
HPLC-MS: Rt 1,886 m / z 250.1 (MH +). Example 2: 5- (3-fluoropyridin-4-yl) -6- (pyrimidin-5-yl) pyridin-2-amine


The product was synthesized from 6- (pyrimidin-5-yl) pyridin-2-amine and 3-fluoropyridin-4boronic acid following the procedure described for example 1.
1H-NMR (400 MHz, DMSO-d6): δ = 6.61 (s, 2H), 6.65 (d, 1H), 7.38 (dd, 1H), 7.57 (d, 1H), 8.39 (d, 1H), 8.43 (d, 1H), 8.62 (s, 2H), 9.10 (s, 1H).
5 HPLC-MS: Rt 2,082 m / z 268.0 (MH +). Example 3: 6- (pyridin-3-yl) -5- (pyridin-4-yl) pyridin-2-amine
The product was synthesized from 6- (pyridin-3-yl) pyridin-2-amine and pyridin-4-boronic acid following the procedure described for example 1.
1H-NMR (400 MHz, DMSO-d6): δ = 6.42 (s, 2H), 6.59 (d, 1H), 7.06 (d, 2H), 7.30 (dd, 1H), 10 7.55 (d, 1H), 7.63 (d, 1H), 8.37 (d, 1H), 8.39 (d, 2H), 8.46 (d, 1H).
HPLC-MS: Rt 2,804 m / z 249.1 (MH +).
Example 4: 5- (3-fluoropyridin-4-yl) -6- (pyridin-3-yl) pyridin-2-amine
The product was synthesized from 6- (pyridin-3-yl) pyridin-2-amine and 3-fluoropyridin-4boronic acid following the procedure described for example 1.
15 1H-NMR (400 MHz, DMSO-d6): δ = 6.50 (s, 2H), 6.60 (d, 1H), 7.30 (m, 2H), 7.52 (d, 1H) , 7.61 (d, 1H), 8.35 (d, 1H), 8.37 (m, 2H), 8.45 (d, 1H).
HPLC-MS: Rt 2,357 m / z 267.1 (MH +).
Example 5: 6- (pyridin-3-yl) -5- (pyrimidin-5-yl) pyridin-2-amine
The product was synthesized from 6- (pyridin-3-yl) pyridin-2-amine and the boronic pyrimidin-520 acid following the procedure described for example 1.
1H-NMR (400 MHz, DMSO-d6): δ = 6.45 (s, 2H), 6.62 (d, 1H), 7.31 (dd, 1H), 7.61 (d, 1H), 7.64 (dd, 1H), 8.40 (d, 1H), 8.47 (dd, 1H), 8.50 (s, 2H), 8.99 (s, 1H).
HPLC-MS: Rt 1,753 m / z 250.1 (MH +).
Example 6: 6- (5-fluoropyridin-3-yl) -5- (3-fluoropyridin-4-yl) pyridin-2-amine
The product was synthesized from 6- (5-fluoropyridin-3-yl) pyridin-2-amine and 3fluoropyridin-4-boronic acid following the procedure described for example 1.
1H-NMR (400 MHz, DMSO-d6): δ = 6.57 (s, 2H), 6.64 (d, 1H), 7.36 (dd, 1H), 7.56 (d, 1H), 7.59 (dd, 1H), 8.19 (t, 1H), 8.39 (d, 1H), 8.42 (d, 1H), 8.50 (d, 1H).


HPLC-MS: Rt 2,534 m / z 285.0 (MH +).
Example 7: 5- (3-fluoropyridin-4-yl) -6- (5-methoxypyridin-3-yl) pyridin-2-amine
The product was synthesized from 6- (5-methoxypyridin-3-yl) pyridin-2-amine and 3fluoropyridin-4-boronic acid following the procedure described for example 1.
5 1H-NMR (400 MHz, DMSO-d6): δ = 3.69 (s, 3H), 6.52 (s, 2H), 6.60 (d, 1H), 7.20 (dd, 1H) , 7.32 (dd, 1H), 7.52 (d, 1H), 7.94 (d, 1H), 8.18 (d, 1H), 8.36 (d, 1H), 8.41 ( d, 1H).
HPLC-MS: Rt 2,499 m / z 297.1 (MH +).
Example 8: 6- [5- (trifluoromethyl) pyridin-3-yl] -5- (3-fluoropyridin-4-yl) pyridin-2-amine
The product was synthesized from 6- (5- (trifluoromethyl) pyridin-3-yl) pyridin-2-amine and 310 fluoropyridin-4-boronic acid following the procedure described for example 1.
1H-NMR (400 MHz, DMSO-d6): δ = 6.64 (s, 2H), 6.66 (d, 1H), 7.39 (dd, 1H), 7.58 (d, 1H), 8.01 (t, 1H), 8.40 (d, 1H), 8.42 (d, 1H), 8.63 (d, 1H), 8.89 (d, 1H).
HPLC-MS: Rt 3,134 m / z 335.0 (MH +).
Example 9: 6- (5-chloropyridin-3-yl) -5- (3-fluoropyridin-4-yl) pyridin-2-amine
The product was synthesized from 6- (5-chloropyridin-3-yl) pyridin-2-amine and 3fluoropyridin-4-boronic acid following the procedure described for example 1.
1H-NMR (400 MHz, DMSO-d6): δ = 6.57 (s, 2H), 6.63 (d, 1H), 7.36 (dd, 1H), 7.55 (d, 1H), 7.80 (t, 1H), 8.24 (t, 1H), 8.39 (dd, 1H), 8.43 (d, 1H), 8.54 (d, 1H).
HPLC-MS: Rt 2,860 m / z 301.0 (MH +). Example 10: 5- (3-fluoropyridin-4-yl) -6- (6-methoxypyridin-3-yl) pyridin-2-amine
The product was synthesized from 6- (6-methoxypyridin-3-yl) pyridin-2-amine and 3fluoropyridin-4-boronic acid following the procedure described for example 1.
1H-NMR (400 MHz, DMSO-d6): δ = 3.81 (s, 3H), 6.48 (s, 2H), 6.58 (d, 1H), 6.74 (d, 1H), 7.40 (s, 1H), 7.50 (d, 1H), 7.59 (d, 1H), 7.95 (s, 1H), 8.41 (d, 2H).
HPLC-MS: Rt 2,741 m / z 297.1 (MH +).
Example 11: 5- (3-fluoropyridin-4-yl) -6- (pyridin-4-yl) pyridin-2-amine
The product was synthesized from 6- (pyridin-4-yl) pyridin-2-amine and 3-fluoropyridin-4boronic acid following the procedure described for example 1.


1H-NMR (400 MHz, DMSO-d6): δ = 6.54 (s, 2H), 6.63 (d, 1H), 7.19 (d, 2H), 7.32 (dd, 1H), 7.53 (d, 1H), 8.37 (dd, 1H), 8.40 (d, 1H), 8.46 (d, 2H).
Example 12: 5,6-bis (3-fluoropyridin-4-yl) pyridin-2-amine
The product was synthesized from 6- (3-fluoropyridin-4-yl) pyridin-2-amine and fluoropyridin-4-boronic acid following the procedure described for example 1.
1H-NMR (400 MHz, DMSO-d6): δ = 6.59 (s, 2H), 6.67 (d, 1H), 7.19 (dd, 1H), 7.41 (dd, 1H), 7.58 (d, 1H), 8.30 (dd, 1H), 8.41 (dd, 1H), 8.43 (d, 2H).
HPLC-MS: Rt 2.408 m / z 285.0 (MH +).
Example 13: 5- (3-Chloropyridin-4-yl) -6- (pyridin-3-yl) pyridin-2-amine
The product was synthesized from 6- (pyridin-3-yl) pyridin-2-amine and 3-chloropyridin-4boronic acid following the procedure described for example 1.
1H-NMR (400 MHz, DMSO-d6): δ = 6.46 (s, 2H), 6.59 (d, 1H), 7.26 (dd, 1H), 7.32 (d, 1H), 7.43 (d, 1H), 7.57 (m, 1H), 8.35 (d, 1H), 8.42 (dd, 2H), 8.54 (s, 1H).
HPLC-MS: Rt 2,560 m / z 283.0 (MH +). Example 14: 5- (3-Chloropyridin-4-yl) -6- (pyridin-4-yl) pyridin-2-amine
The product was synthesized from 6- (pyridin-4-yl) pyridin-2-amine and 3-chloropyridin-4boronic acid following the procedure described for example 1.
1H-NMR (400 MHz, DMSO-d6): δ = 6.48 (s, 2H), 6.61 (d, 1H), 7.15 (dd, 2H), 7.29 (d, 1H), 7.43 (d, 1H), 8.43 (d, 2H), 8.57 (s, 1H).
20 HPLC-MS: Rt 2,563 m / z 283.0 (MH +).
Example 15: 3-Chloro-5- (pyridin-4-yl) -6- (pyrimidin-5-yl) pyridin-2-amine
N
N X
N
N NH2 N
N NH2
N
N
N-Chlorosuccinimide (0.0613 g, 0.46 mmol) was added to a solution of 6- (pyridin-4-yl) -5 (pyrimidin-5-yl) pyridin-2-amine (0.135 g, 0.46 mmol) in N, N-dimethylformamide (0.8 ml). The mixture was stirred at room temperature 4 hours, then treated with a solution.


of saturated aqueous sodium chloride (10 ml), filtered and washed with water. The solid was dried in vacuo to give 0.1 g of the compound with 65.3%.
1H-NMR (400 MHz, DMSO-d6): δ = 6.88 (s, 2H), 7.18 (d, 2H), 7.84 (s, 1H), 8.47 (d, 2H), 8.62 (s, 2H), 9.10 (s, 1H).
HPLC-MS: Rt 2,416 m / z 284.0 (MH +).
The compounds of examples 16 to 38 were synthesized using the procedure described for example 15 from the corresponding 2-aminopyridine-5,6-disubstituted derivative and the corresponding N-halosuccinimide.
Example 16: 3-Bromo-5- (pyridin-4-yl) -6- (pyrimidin-5-yl) pyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 6.82 (s, 2H), 7.19 (d, 2H), 7.96 (s, 1H), 8.47 (d, 2H), 8.62 (s, 2H), 9.11 (s, 1H).
HPLC-MS: Rt 2,536 m / z 328.0 (MH +).
Example 17: 3-Chloro-5- (3-fluoropyridin-4-yl) -6- (pyrimidin-5-yl) pyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 6.98 (s, 2H), 7.44 (dd, 1H), 7.87 (s, 1H), 8.42 (d, 1H), 8.46 (d, 1H), 8.64 (s, 2H), 9.12 (s, 1H).
HPLC-MS: Rt 2,676 m / z 302.0 (MH +).
Example 18: 3-Bromo-5- (3-fluoropyridin-4-yl) -6- (pyrimidin-5-yl) pyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 6.92 (s, 2H), 7.44 (dd, 1H), 7.99 (s, 1H), 8.42 (d, 1H), 8.45 (d, 1H), 8.64 (s, 2H), 9.12 (s, 1H).
HPLC-MS: Rt 2,717 m / z 348.0 (MH +).
Example 19: 3-Chloro-6- (pyridin-3-yl) -5- (pyridin-4-yl) pyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 6.78 (s, 2H), 7.12 (d, 2H), 7.32 (dd, 1H), 7.63 (d, 1H), 7.78 (s, 1H), 8.38 (s, 1H), 8.42 (d, 2H), 8.48 (d, 1H).
HPLC-MS: Rt 2,714 m / z 283.0 (MH +).
Example 20: 3-Bromo-6- (pyridin-3-yl) -5- (pyridin-4-yl) pyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 6.72 (s, 2H), 7.12 (d, 2H), 7.32 (dd, 1H), 7.63 (d, 1H), 7.91 (s, 1H), 8.39 (s, 1H), 8.43 (d, 2H), 8.48 (d, 1H).
HPLC-MS: Rt 2,810 m / z 329.0 (MH +).


Example 21: 3-Chloro-5- (3-fluoropyridin-4-yl) -6- (pyridin-3-yl) pyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 6.89 (s, 2H), 7.31 (dd, 1H), 7.40 (t, 1H), 7.61 (d, 1H), 7.80 (s, 1H), 8.38 (d, 1H), 8.40 (s, 1H), 8.42 (d, 1H), 8.48 (d, 1H).
HPLC-MS: Rt 2,904 m / z 301.0 (MH +). 5 Example 22: 3-Bromo-5- (3-fluoropyridin-4-yl) -6- (pyridin-3-yl) pyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 6.81 (s, 2H), 7.31 (dd, 1H), 7.40 (t, 1H), 7.61 (d, 1H), 7.92 (s, 1H), 8.38 (d, 1H), 8.41 (d, 1H), 8.42 (d, 1H), 8.48 (d, 1H).
HPLC-MS: Rt 3,055 m / z 345.0 (MH +).
Example 23: 3-Chloro-6- (pyridin-3-yl) -5- (pyrimidin-5-yl) pyridin-2-amine
10 1H-NMR (400 MHz, DMSO-d6): δ = 6.82 (s, 2H), 7.33 (dd, 1H), 7.64 (d, 1H), 7.92 (s, 1H) , 8.42 (d, 1H), 8.49 (d, 1H), 8.55 (s, 2H), 9.02 (s, 1H).
HPLC-MS: Rt 2,283 m / z 284.0 (MH +).
Example 24: 3-Bromo-6- (pyridin-3-yl) -5- (pyrimidin-5-yl) pyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 6.74 (s, 2H), 7.32 (dd, 1H), 7.64 (d, 1H), 8.04 (s, 1H), 8.42 (d, 1H), 8.49 (d, 1H), 8.55 (s, 2H), 9.02 (s, 1H).
HPLC-MS: Rt 2,381 m / z 330.0 (MH +).
Example 25: 3-Chloro-6- (5-fluoropyridin-3-yl) -5- (3-fluoropyridin-4-yl) pyri-din-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 6.93 (s, 2H), 7.41 (dd, 1H), 7.59 (d, 1H), 7.83 (s, 1H), 8.20 (s, 1H), 8.41 (d, 1H), 8.45 (s, 1H), 8.52 (d, 1H).
HPLC-MS: Rt 3,121 m / z 319.0 (MH +).
Example 26: 3-Bromo-6- (5-fluoropyridin-3-yl) -5- (3-fluoropyridin-4-yl) pyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 6.87 (s, 2H), 7.42 (dd, 1H), 7.60 (d, 1H), 7.96 (s, 1H), 8.21 (s, 1H), 8.41 (d, 1H), 8.44 (s, 1H), 8.52 (d, 1H).
HPLC-MS: Rt 3,199 m / z 365.0 (MH +). Example 27: 3-Chloro-5- (3-fluoropyridin-4-yl) -6- (5-methoxypyridin-3-yl) pyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 3.69 (s, 3H), 6.89 (s, 2H), 7.21 (dd, 1H), 7.40 (dd, 1H), 7.81 (s, 1H), 7.96 (s, 1H), 8.21 (d, 1H), 8.40 (d, 1H), 8.44 (s, 1H).
HPLC-MS: Rt 3,037 m / z 331.0 (MH +).


Example 28: 3-Bromo-5- (3-fluoropyridin-4-yl) -6- (5-methoxypyridin-3-yl) pyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 3.69 (s, 3H), 6.82 (s, 2H), 7.23 (dd, 1H), 7.41 (dd, 1H), 7.94 (s, 1H), 7.97 (s, 1H), 8.22 (d, 1H), 8.40 (d, 1H), 8.44 (s, 1H).
HPLC-MS: Rt 3,130 m / z 377.0 (MH +).
Example 29: 3-Chloro-6- [5- (trifluoromethyl) pyridin-3-yl] -5- (3-fluoropyridin-4-yl) pyridin-2amine
1H-NMR (400 MHz, DMSO-d6): δ = 7.01 (s, 2H), 7.46 (dd, 1H), 7.87 (s, 1H), 8.02 (s, 1H), 8.42 (d, 1H), 8.45 (s, 1H), 8.64 (s, 1H), 8.92 (d, 1H).
HPLC-MS: Rt 3,678 m / z 369.0 (MH +).
Example 30: 3-Bromo-6- [5- (trifluoromethyl) pyridin-3-yl] -5- (3-fluoropyridin-4-yl) pyridin-2amine
1H-NMR (400 MHz, DMSO-d6): δ = 6, 93 (s, 2H), 7.46 (dd, 1H), 8.00 (s, 1H), 8.03 (s, 1H) , 8.42 (d, 1H), 8.45 (s, 1H), 8.64 (d, 1H), 8.92 (d, 1H).
HPLC-MS: Rt 3,769 m / z 413.0 (MH +). Example 31: 3-Chloro-6- (5-chloropyridin-3-yl) -5- (3-fluoropyridin-4-yl) pyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 6.94 (s, 2H), 7.42 (dd, 1H), 7.81 (t, 1H), 7.84 (s, 1H), 8.25 (d, 1H), 8.42 (d, 1H), 8.46 (d, 1H), 8.56 (d, 1H).
Example 32: 3-Chloro-5- (3-fluoropyridin-4-yl) -6- (pyridin-4-yl) pyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 6.89 (s, 2H), 7.20 (d, 2H), 7.39 (dd, 1H), 7.81 (s, 1H), 20 8.39 (d, 1H), 8.43 (s, 1H), 8.48 (d, 2H).
HPLC-MS: Rt 2,866 m / z 301.0 (MH +).
Example 33: 3-Bromo-5- (3-fluoropyridin-4-yl) -6- (pyridin-4-yl) pyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 6.85 (s, 2H), 7.20 (d, 2H), 7.40 (t, 1H), 7.94 (s, 1H), 8.40 (d, 1H), 8.43 (s, 1H), 8.48 (d, 2H).
HPLC-MS: Rt 2,963 m / z 347.0 (MH +).
Example 34: 3-Chloro-5- (3-fluoropyridin-4-yl) -6- (6-methoxypyridin-3-yl) pyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 3.81 (s, 3H), 6.75 (d, 1H), 6.80 (s, 2H), 7.40 (dd, 1H), 7.59 (dd, 1H), 7.75 (s, 1H), 7.96 (d, 1H), 8.40 (d, 1H), 8.45 (s, 1H).


HPLC-MS: Rt 3,329 m / z 331.0 (MH +).
Example 35: 3-Bromo-5- (3-fluoropyridin-4-yl) -6- (6-methoxypyridin-3-yl) pyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 3.82 (s, 3H), 6.74 (d, 3H), 7.41 (s, 1H), 7.59 (d, 1H), 7.88 (s, 1H), 7.97 (d, 1H), 8.40 (d, 1H), 8.45 (s, 1H).
5 HPLC-MS: Rt 3,431 m / z 377.0 (MH +).
Example 36: 3-Chloro-5,6-bis (3-fluoropyridin-4-yl) pyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 6.86 (s, 2H), 7.20 (dd, 1H), 7.42 (dd, 1H), 7.82 (s, 1H), 8.40 (dd, 1H), 8.44 (dd, 1H), 8.45 (d, 2H).
Example 37: 3-Chloro-5- (3-chloropyridin-4-yl) -6- (pyridin-3-yl) pyridin-2-amine
10 1H-NMR (400 MHz, DMSO-d6): δ = 6.90 (s, 2H), 7.35 (dd, 1H), 7.48 (d, 1H), 7.64 (m, 1H) , 7.78 (s, 1H), 7.57 (m, 1H), 8.44 (d, 1H), 8.52 (m, 2H), 8.63 (s, 1H).
HPLC-MS: Rt 3,120 m / z 317.0 (MH +).
Example 38: 3-Chloro-5- (3-chloropyridin-4-yl) -6- (pyridin-4-yl) pyridin-2-amine
1H-NMR (400 MHz, DMSO-d6): δ = 6.86 (s, 2H), 7.16 (d, 2H), 7.38 (d, 1H), 7.72 (s, 1H), 8.46 15 (t, 3H), 8.59 (s, 1H).
HPLC-MS: Rt 3,118 m / z 317.0 (MH +).

权利要求:
Claims (1)
[1]
1-A compound of formula (I):
 R2R1
R3
 5NNH2
(I)
in which:
- R1 represents a hydrogen atom or a halogen atom;
10 -R2 represents a six-membered heteroaryl ring optionally substituted by one or more substituents selected from the group consisting of halogen atom, C1-C4 haloalkyl, linear or branched C1-C6 alkyl, C3-C12 cycloalkyl, linear C1-C6 alkoxy or branched and C3-C12 cycloalkoxy; -R3 represents a six-membered heteroaryl ring optionally substituted by
One or more substituents selected from the group consisting of halogen atom, C1-C4 haloalkyl, linear or branched C1-C6 alkyl, C3-C12 cycloalkyl, linear or branched C1-C6 alkoxy and C3-C12 cycloalkoxy,
N-oxides of said compounds and pharmaceutically acceptable salts thereof, with the proviso that the compound (I) is not one of the group consisting of:
-5- (pyridin-4-yl) -6- (pyridin-4-yl) pyridin-2-amine-5- (pyridin-3-yl) -6- (pyridin-3-yl) pyridin-2-amine-5- (pyrazin-2-yl) -6- (pyridin-4-yl) pyridin-2-amine-5- (4-methylpyridin-2-yl) -6- (pyridin-4-yl) pyridin-2-amine
A compound according to claim 1 wherein R3 represents a six-membered heteroaryl ring having one or two nitrogen atoms optionally substituted by one or more substituents selected from the group consisting of halogen atom, C1- haloalkyl C4, linear or branched C1-C6 alkyl, C3-C12 cycloalkyl, linear or branched C1-C6 alkoxy and C3-C12 cycloalkoxy.

3-A compound according to claim 2 wherein R3 represents a group selected from pyridyl or pyrimidinyl optionally substituted by one or more substituents selected from the group consisting of halogen atom, C1-C4 haloalkyl, linear C1-C6 alkyl or branched, C3-C12 cycloalkyl, linear or branched C1-C6 alkoxy and C3-C12 cycloalkoxy. 4-A compound according to claim 3 wherein R3 is selected from a 3-pyridyl group or a 4-pyridyl group optionally substituted by one or more substituents selected from the group consisting of halogen atom, C1-C4 haloalkyl , linear or branched C1-C6 alkyl, C3-C12 cycloalkyl, linear or branched C1-C6 alkoxy and C3-C12 cycloalkoxy. 5-A compound according to any one of claims 1 to 4 wherein R2 represents a pyridyl group optionally substituted by one or more substituents selected from the group consisting of halogen atom, C1-C4 haloalkyl, linear C1-C6 alkyl or branched, C3-C12 cycloalkyl, linear or branched C1-C6 alkoxy and C3-C12 cycloalkoxy groups. 6-A compound according to claim 5 wherein R2 represents a 4-pyridyl group optionally substituted by a halogen atom. 7-A compound according to any of claims 1-6 wherein R1 represents a chlorine atom or a bromine atom. 8-A compound according to claim 1 wherein R1 represents a chlorine atom or a bromine atom, R2 represents a 4-pyridyl group optionally substituted by one or two fluorine atoms and R3 represents a group selected from between a 3-pyridyl or 4-pyridyl group optionally substituted by one or more substituents selected from the group consisting of halogen atom, C1-C4 haloalkyl, linear or branched C1-C6 alkyl, C3-C12 cycloalkyl, linear or branched C1-C6 alkoxy and C3-C12 cycloalkoxy. 9-A compound according to claim 1, which is one of:
5- (pyridin-4-yl) -6- (pyrimidin-5-yl) pyridin-2-amine, 5- (3-fluoropyridin-4-yl) -6- (pyrimidin-5-yl) pyridin-2- amine, 6- (pyridin-3-yl) -5- (pyridin-4-yl) pyridin-2-amine, 5- (3-fluoropyridin-4-yl) -6- (pyridin-3-yl) pyridin- 2-amine, 6- (pyridin-3-yl) -5- (pyrimidin-5-yl) pyridin-2-amine, 6- (5-fluoropyridin-3-yl) -5- (3-fluoropyridin-4- il) pyridin-2-amine, 5- (3-fluoropyridin-4-yl) -6- (5-methoxypyridin-3-yl) pyridin-2-amine, 6- [5- (trifluoromethyl) pyridin-3-yl ] -5- (3-fluoropyridin-4-yl) pyridin-2-amine, 6- (5-chloropyridin-3-yl) -5- (3-fluoropyridin-4-yl) pyridin-2-amine, 5- (3-fluoropyridin-4-yl) -6- (6-methoxypyridin-3-yl) pyridin-2-amine,

5- (3-fluoropyridin-4-yl) -6- (pyridin-4-yl) pyridin-2-amine, 5,6-bis (3-fluoropyridin-4-yl) pyridin-2-amine, 5- ( 3-Chloropyridin-4-yl) -6- (pyridin-3-yl) pyridin-2-amine, 5- (3-chloropyridin-4-yl) -6- (pyridin-4-yl) pyridin-2-amine , 3-Chloro-5- (pyridin-4-yl) -6- (pyrimidin-5-yl) pyridin-2-amine, 3-bromo-5- (pyridin-4-yl) -6- (pyrimidin-5 -yl) pyridin-2-amine, 3-chloro-5- (3-fluoropyridin-4-yl) -6- (pyrimidin-5-yl) pyridin-2-amine, 3-bromo-5- (3-fluoropyridin -4-yl) -6- (pyrimidin-5-yl) pyridin-2-amine, 3-chloro-6- (pyridin-3-yl) -5- (pyridin-4-yl) pyridin-2-amine, 3-Bromo-6- (pyridin-3-yl) -5- (pyridin-4-yl) pyridin-2-amine, 3-chloro-5- (3-fluoropyridin-4-yl) -6- (pyridin- 3-yl) pyridin-2-amine, 3-bromo-5- (3-fluoropyridin-4-yl) -6- (pyridin-3-yl) pyridin-2-amine, 3-chloro-6- (pyridin- 3-yl) -5- (pyrimidin-5-yl) pyridin-2-amine, 3-bromo-6- (pyridin-3-yl) -5- (pyrimidin-5-yl) pyridin-2-amine, 3 -chloro-6- (5-fluoropyridin-3-yl) -5- (3-fluoropyridin-4-yl) pyri-din-2-amine, 3-bromo-6- (5-fluoropyridin-3-yl) - 5- (3-fluoropyridin-4-yl) pyridin-2-amine, 3-chloro-5 - (3-fluoropyridin-4-yl) -6- (5-methoxypyridin-3-yl) pyridin-2-amine, 3-bromo-5- (3-fluoropyridin-4-yl) -6- (5-methoxypyridine -3-yl) pyridin-2-amine, 3-chloro-6- [5- (trifluoromethyl) pyridin-3-yl] -5- (3-fluoropyridin-4-yl) pyridin-2-amine, 3-bromine -6- [5- (trifluoromethyl) pyridin-3-yl] -5- (3-fluoropyridin-4-yl) pyridin-2-amine, 3-chloro-6- (5-chloropyridin-3-yl) -5 - (3-fluoropyridin-4-yl) pyridin-2-amine, 3-chloro-5- (3-fluoropyridin-4-yl) -6- (pyridin-4-yl) pyridin-2-amine, 3-bromine -5- (3-fluoropyridin-4-yl) -6- (pyridin-4-yl) pyridin-2-amine, 3-chloro-5- (3-fluoropyridin-4-yl) -6- (6-methoxypyridine -3-yl) pyridin-2-amine, 3-bromo-5- (3-fluoropyridin-4-yl) -6- (6-methoxypyridin-3-yl) pyridin-2-amine, 3-chloro-5, 6-bis (3-fluoropyridin-4-yl) pyridin-2-amine, 3-chloro-5- (3-chloropyridin-4-yl) -6- (pyridin-3-yl) pyridin-2-amine, 3 -chloro-5- (3-chloropyridin-4-yl) -6- (pyridin-4-yl) pyridin-2-amine.
10-Use of a compound according to any of claims 1 to 9 for the manufacture of a medicament for the treatment of a disease or pathological condition in which the disease or pathological condition is selected from the group consisting of respiratory diseases, disorders Metabolic, neurological diseases and cancer.

11-Use according to claim 10 characterized in that the treatment is of a disease or pathological condition selected from the group consisting of asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, obesity, diabetes, atherosclerosis, senile dementia, Alzheimer's disease, Parkinson and
5 cancer 12-A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 9 and a pharmaceutically acceptable diluent or carrier. 13-A pharmaceutical composition according to claim 12 further comprising
10 a therapeutically effective amount of a therapeutic agent selected from Pirferidone, Nintendanib, the AM152 antagonist of LPA1, dopamine agonists selected from L-Dopa, ropinirole or pramiprexole, inhibitors of the enzyme Monoxygenase B (MAO-B) selected from Seleginine or Rasagiline, and acetylcholinesterase enzyme inhibitors selected from Galantamine, Rivastigmine, Donepezil
15 or Tacrina. 14-A combination product comprising a compound according to any one of claims 1 to 9 and at least one therapeutic agent selected from Pirferidone, Nintendanib, the AM152 antagonist of LPA1, dopamine agonists selected from L-Dopa, ropinirole or pramiprexole, enzyme inhibitors
Monoxygenase B (MAO-B) selected from among Seleginine or Rasagiline, and acetylcholinesterase enzyme inhibitors selected from Galantamine, Rivastigmine, Donepezil
or Tacrina.

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公开号 | 公开日

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CA2977905A1|2016-09-01|

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CN107406425B|2020-06-26|

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AU2016223683A1|2017-10-05|

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DK3262034T3|2020-01-20|

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JP2018506557A|2018-03-08|

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HUE047751T2|2020-05-28|

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RS59862B1|2020-03-31|

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PT3262034T|2020-02-10|

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CN107406425A|2017-11-28|

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ES2769999T3|2020-06-30|

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KR20170140178A|2017-12-20|

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WO2016135048A1|2016-09-01|

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ZA201706358B|2018-12-19|

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EA032032B1|2019-03-29|

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MX2017010949A|2017-12-15|

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SI3262034T1|2020-03-31|

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EP3262034A1|2018-01-03|

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LT3262034T|2020-01-10|

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US10253017B2|2019-04-09|

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EP3262034B1|2019-12-04|

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BR112017017704A2|2018-04-10|

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KR102231924B1|2021-03-25|

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ES2580702B1|2017-06-08|

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PL3262034T3|2020-07-13|

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AU2016223683B8|2019-10-24|

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AU2016223683B2|2019-06-20|

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US20180037569A1|2018-02-08|

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CA2977905C|2021-01-19|

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JP6585729B2|2019-10-02|

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AU2016223683A8|2019-10-24|

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ES201530233A|ES2580702B1|2015-02-25|2015-02-25|2-Aminopyridine derivatives as adenosine A2b receptor antagonists and MT3 melatonin receptor ligands|ES201530233A| ES2580702B1|2015-02-25|2015-02-25|2-Aminopyridine derivatives as adenosine A2b receptor antagonists and MT3 melatonin receptor ligands|

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BR112017017704-8A| BR112017017704A2|2015-02-25|2016-02-19|2-aminopyridine derivatives as a2b adenosine receptor antagonists and mt3 melatonin receptor ligands|

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SI201630630T| SI3262034T1|2015-02-25|2016-02-19|Derivatives of 2-aminopyridine as adenosine a2b receptor antagonists and ligands of the melatonin mt3 receptors|

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PT167051879T| PT3262034T|2015-02-25|2016-02-19|Derivatives of 2-aminopyridine as adenosine a2b receptor antagonists and ligands of the melatonin mt3 receptors|

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PCT/EP2016/053509| WO2016135048A1|2015-02-25|2016-02-19|Derivatives of 2-aminopyridine as adenosine a2b receptor antagonists and ligands of the melatonin mt3 receptors|

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EP16705187.9A| EP3262034B1|2015-02-25|2016-02-19|Derivatives of 2-aminopyridine as adenosine a2b receptor antagonists and ligands of the melatonin mt3 receptors|

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RS20200048A| RS59862B1|2015-02-25|2016-02-19|Derivatives of 2-aminopyridine as adenosine a2b receptor antagonists and ligands of the melatonin mt3 receptors|

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JP2017544925A| JP6585729B2|2015-02-25|2016-02-19|2-Aminopyridine derivatives as adenosine A2B receptor antagonists and ligands of melatonin MT3 receptor|

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AU2016223683A| AU2016223683B8|2015-02-25|2016-02-19|Derivatives of 2-aminopyridine as adenosine a2b receptor antagonists and ligands of the melatonin mt3 receptors|

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US15/552,039| US10253017B2|2015-02-25|2016-02-19|Derivatives of 2-aminopyridine as adenosine A2B receptor antagonists and ligands of the melatonin MT3 receptors|

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MX2017010949A| MX2017010949A|2015-02-25|2016-02-19|Derivatives of 2-aminopyridine as adenosine a2b receptor antagonists and ligands of the melatonin mt3 receptors.|

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ES16705187T| ES2769999T3|2015-02-25|2016-02-19|2-Aminopyridine derivatives as adenosine A2b receptor antagonists and melatonin MT3 receptor ligands|

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LTEP16705187.9T| LT3262034T|2015-02-25|2016-02-19|Derivatives of 2-aminopyridine as adenosine a2b receptor antagonists and ligands of the melatonin mt3 receptors|

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PL16705187T| PL3262034T3|2015-02-25|2016-02-19|Derivatives of 2-aminopyridine as adenosine a2b receptor antagonists and ligands of the melatonin mt3 receptors|

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CA2977905A| CA2977905C|2015-02-25|2016-02-19|Derivatives of 2-aminopyridine as adenosine a2b receptor antagonists and ligands of the melatonin mt3 receptors|

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DK16705187.9T| DK3262034T3|2015-02-25|2016-02-19|Derivatives of 2-aminopyridine as adenosine A2B receptor antagonists and ligands of the melatonin MT3 receptors|

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HUE16705187A| HUE047751T2|2015-02-25|2016-02-19|Derivatives of 2-aminopyridine as adenosine a2b receptor antagonists and ligands of the melatonin mt3 receptors|

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