Amino quinazoline derivatives as p2x3 inhibitors

Abstract

The present disclosure relates to compounds of formula I, which in select embodiments inhibit P2X purinoceptor 3: [Image disponible dans le document PDF, Image available in the PDF document] mula (1). More specifically, the present disclosure relates to amino quinazoline derivative compounds, methods of preparing such compounds, pharmaceutical compositions containing them and use thereof. The compounds of the present may be useful in the treatment of many disorders associated with P2X<com:Sub>3< / com:Sub> receptors mechanisms, such as respiratory diseases including cough, asthma, idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD).

Description

AMINO QUINAZOLINE DERIVATIVES AS P2X3 INHIBITORS FIELD The present disclosure relates to compounds inhibiting P2X purinoceptor 3 (hereinafter P2X<com:Sub>3< / com:Sub> inhibitors); particularly the disclosure relates to compounds that are amino quinazoline derivatives, methods of preparing such compounds, pharmaceutical compositions containing them and therapeutic use thereof. The compounds of the disclosure may be useful in the treatment of many disorders associated with P2X<com:Sub>3< / com:Sub> receptors mechanisms, such as respiratory diseases including cough, asthma, idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). BACKGROUND P2X receptors are cell surface ion channels activated by extracellular Adenosine 5- TriPhosphate (ATP). P2X receptor family are trimeric assemblies composed of seven distinct subunit subtypes (P2X1-7) that assemble as homomeric and heteromeric channels. All subunits share a common topology containing intracellular termini, two transmembrane helices forming the ion channels and a large extracellular domain containing the ATP binding site. Homomeric P2X<com:Sub>1< / com:Sub>, P2X<com:Sub>2< / com:Sub>, P2X<com:Sub>3< / com:Sub>, P2X<com:Sub>4< / com:Sub>, P2X<com:Sub>5< / com:Sub>, and P2X<com:Sub>7< / com:Sub> channels and heteromeric <com:Math><semantics>P2X2 / 3<annotation encoding="application / x-tex">P2X_{2 / 3}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>P2X1 / 5<annotation encoding="application / x-tex">P2X_{1 / 5}< / annotation>< / semantics>< / com:Math> channels have been fully characterized following heterologous expression. P2X receptors are abundantly distributed, and functional responses are seen in neurons, glia, epithelia, endothelia, bone, muscle, and hemopoietic tissues. On smooth muscles, P2X receptors respond to ATP released from sympathetic motor nerves (e.g., in ejaculation). On sensory nerves, they are involved in the initiation of afferent signals in several viscera (e.g., bladder, intestine) and play a key role in sensing tissue-damaging and inflammatory stimuli. Paracrine roles for ATP signaling through P2X receptors are likely in neurohypophysis, ducted glands, airway epithelia, kidney, bone and hemopoietic tissues. (RA. North: Molecular Physiology of P2X Receptors; Physiol Rev, Vol 82, Oct 2002). All P2X receptors are non-selective cation channels permeable to Na+ and Ca+ ions and are activated by ATP; however, the pharmacology of the receptor subtypes varies with respect to sensitivity to ATP and to small molecules antagonists. (K Kaczmarek-Hajek et al: Molecular and functional properties of P2X receptors – recent progress and persisting challenges; Purinergic Signalling 8:375-417, 2012) In humans, the P2X<com:Sub>3< / com:Sub> receptor has been reported in heart and spinal cord at the mRNA level and in DRG, intestine (myenteric plexus neurons), urinary bladder (urothelium and suburothelium), and dental pulp at the protein level (Garcia-Guzman M et al: Molecular characterization and pharmacological properties of the human P2X<com:Sub>3< / com:Sub> purinoceptor: Brain Res Mol Brain Res. 1997;47(1–2):59–66). The neurophysiological role of P2X<com:Sub>3< / com:Sub> receptors in sensory nerve function in the airways is similar to that mediating somatic nociception (Undem BJ and Nassenstein C: Airway nerves and dyspnea associated with inflammatory airway disease, Respir Physiol Nerobiol 167: 36-44, 2009). This similarity has driven hypotheses concerning the involvement of P2X<com:Sub>3< / com:Sub> receptors in the symptoms of airway dysfunction including cough and bronchial hyper-reactivity (Ford AP: In pursuit of P2X<com:Sub>3< / com:Sub> antagonists: novel therapeutics for chronic pain and and afferent sensitization, Purinergic signal 8 (suppl 1):3-26, 2012; North RA, Jarvis MF P2X Receptors as Drug Targets; Mol Pharmacol, 83:759-769, 2013). P2X<com:Sub>3< / com:Sub> subunits are also co-localized in many neurons, particularly within DRG, nodose ganglia, nucleus tractus solitarius, and taste buds (Cheung KK, Burnstock G: Localization of P2X<com:Sub>3< / com:Sub> receptors and coexpression with P2X2 receptors during rat embryonic neurogenesis. J Comp Neurol 443(4):368–382 2002) P2X<com:Sub>3< / com:Sub> antagonists have been proposed for the treatment of diabetic neuropathic pain (Guo J et al: Contributions of purinergic P2X<com:Sub>3< / com:Sub> receptors within the midbrain periaqueductal gray to diabetes-induced neuropathic pain, J Physiol Sci Jan;65(1):99-104 2015). P2X<com:Sub>3< / com:Sub> and P2X<com:Sub>2 / 3< / com:Sub> channels play an important role in the development of articular hyperalgesia of arthritic joints (Teixeira JM et al: P2X<com:Sub>3< / com:Sub> and P2X<com:Sub>2 / 3< / com:Sub> Receptors Play a Crucial Role in Articular Hyperalgesia Development Through Inflammatory Mechanisms in the Knee Joint Experimental Synovitis, Mol Neurobiol Oct;54(8):6174-6186, 2017). P2X<com:Sub>3< / com:Sub> are also a potential target for the rapeutic treatment of bladder pain. They were also proposed to be analgesic targets to treat ureteral colicky pain and to facilitate ureteral stone passage (Canda AE et al: Physiology and pharmacology of the human ureter: basis for current and future treatments, Urol Int. 78(4):289-98, 2007). P2X<com:Sub>3< / com:Sub> over-expression is involved in poor recurrence-free survival in hepatocellular carcinoma patients and identifies the P2X<com:Sub>3< / com:Sub> as a potential therapeutic target (Maynard JP) et al: P2X<com:Sub>3< / com:Sub> purinergic receptor overexpression is associated with poor recurrence-free survival in hepatocellular carcinoma patients Oncotarget Dec 1;6(38):41162-79, 2015). It has been suggested that P2X<com:Sub>3< / com:Sub> antagonists may improve recovery of erectile function (Li CL et al: Effects of intracavernous injection of P2X<com:Sub>3< / com:Sub> and NK1 receptor antagonists on erectile dysfunction induced by spinal cord transection in rats, Andrologia. Feb;47(1):25-9, 2015). ATP enhances citric acid-evoked and histamine-evoked cough in preclinical models, effects that can be attenuated by P2X<com:Sub>3< / com:Sub> selective antagonists (Kamei J and Takahashi Y: Involvement of ionotropic purinergic receptors in the histamine-induced enhancement of the cough reflex sensitivity in guinea pigs, Oct 10;547(1-3):160-4, 2006). In humans, local delivery of ATP initiates cough and bronchospasm (Basoglu OK et al: Effects of aerosolized adenosine 5'-triphosphate vs adenosine 5'-monophosphate on dyspnea and airway caliber in healthy nonsmokers and patients with asthma, Chest. Oct; 128(4): 1905-9, 2005). The therapeutic promise of P2X<com:Sub>3< / com:Sub> antagonists for the treatment of chronic cough was first recognized by Ford and Undem (Ford AP, Undem BJ: The therapeutic promise of ATP antagonism at P2X<com:Sub>3< / com:Sub> receptors in respiratory and urological disorders, Front Cell Neurosci, Dec 19;7:267, 2013). P2X<com:Sub>3< / com:Sub> are expressed by airway afferent nerves and mediate hypersensitivity of the cough reflex, which is dramatically reduced by the oral P2X<com:Sub>3< / com:Sub> antagonist, AF-219 (Abdulqawi et al: P2X<com:Sub>3< / com:Sub> receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study, Lancet 385, 1198-205, 2015). ATP is a key neurotransmitter in the taste system, acting largely via <com:Math><semantics>P2X2 / 3<annotation encoding="application / x-tex">P2X_{2 / 3}< / annotation>< / semantics>< / com:Math> heteromultimer receptors. Consequently, disruption of taste function may be an unintentional consequence of therapeutic trials of pain, chronic cough and other conditions using purinergic P2X<com:Sub>3< / com:Sub> antagonists (Vandenbeuch A et al: Role of the ectonucleotidase NTPDase2 in taste bud function, Proc Natl Acad Sci U S A, Sep 3;110(36):14789-94, 2013. Bo X et al: Localization of ATP-gated P2X2 and P2X<com:Sub>3< / com:Sub> receptor immunoreactive nerves in rat taste buds, Neuroreport, 10(5):1107-11, 1999). Various compounds have been described in the literature as P2X<com:Sub>3< / com:Sub> and / or P2X<com:Sub>2 / 3< / com:Sub> Inhibitors. WO2017058645 (Afferent Pharmaceuticals INC) discloses the use of diaminopyrimidine P2X<com:Sub>3< / com:Sub> / P2X<com:Sub>2 / 3< / com:Sub> antagonists for the treatment of disorders including cough, chronic cough and urge to cough, including cough associated with a respiratory disease or disorder, administering an efficacious amount of the compound disclosed. However, amino quinazoline derivatives are not disclosed. WO2017011729 (Patara Pharma LLC), discloses the use of cromolyn or a pharmaceutically acceptable salt thereof and P2X<com:Sub>3< / com:Sub> and / or a P2X<com:Sub>2 / 3< / com:Sub> receptor antagonist as antitussive agent, for the treatment of lung diseases and conditions. WO2016091776, (Evotec AG), discloses 1,3-thiazol-2-yl substituted benzamide compounds that inhibit P2X<com:Sub>3< / com:Sub> receptor and to pharmaceutical compositions containing such compounds, and the use of compounds for the treatment of several disorders, including the respiratory diseases. WO2016088838 (Shionogi), discloses purine derivatives compounds having a novel P2X<com:Sub>3< / com:Sub> and / or P2X<com:Sub>2 / 3< / com:Sub> receptor antagonizing effect. WO2016084922, (Shionogi), discloses triazine derivatives compounds having a novel P2X<com:Sub>3< / com:Sub> and / or P2X<com:Sub>2 / 3< / com:Sub> receptor antagonizing effect WO2008123963 (Renovis) relates to fused heterocyclic compounds of the class tetrahydropyrido[4,3-d]pyrimidines and pharmaceutical compositions comprising such compounds. Also provided are methods for preventing and / or treating several disorders, such as neurodegenerative disorders, pain, asthma, autoimmune disorders administering the disclosed comoounds. WO2008130481 (Renovis) discloses 2-cyanophenyl fused heterocyclic compounds of the class tetrahydropyrido[4,3-d]pyrimidines and pharmaceutical compositions comprising such compounds. WO2010033168 (Renovis) discloses a series of benzamides substituted with phenyl or pyridyl which are stated to be useful for treatment of diseases associated with P2X purinergic receptors, and more particularly to P2X<com:Sub>3< / com:Sub> receptor and / or P2X<com:Sub>2 / 3< / com:Sub> receptor antagonists. However, amino quinazoline derivatives are not disclosed. WO2009110985 (Renovis) relates to phenyl- and pyridyl-substituted benzamide compounds and pharmaceutical compositions comprising such compounds, but not thiazole-substituted benzamides, rendering said compounds different from the compounds of the present disclosure. WO2008000645 (Roche) discloses tetrazole substituted arylamides compounds antagonists of P2X<com:Sub>3< / com:Sub> and / or P2X<com:Sub>2 / 3< / com:Sub> receptors, useful for the treatment of genitourinary, pain, gastrointestinal and respiratory diseases, conditions and disorders. Despite the above cited prior art, there is still the need of novel amino quinazoline compounds for treatment of diseases associated with P2X<com:Sub>3< / com:Sub> receptors in many therapeutic areas such as in particular the respiratory diseases, preferably having a selective action on the <com:Math><semantics>P2X3<annotation encoding="application / x-tex">P2X_3< / annotation>< / semantics>< / com:Math> receptor. Of note, the state of the art does not describe or suggest amino quinazoline derivatives compounds of general formula (I) of the present disclosure which represent a solution to the aforementioned need. SUMMARY Certain exemplary embodiments provide a compound of formula (I) [Image disponible dans le document PDF, Image available in the PDF document] (I) wherein Z is (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)heterocycloalkyl, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N-, heteroaryl, or aryl, wherein any of such heteroaryl, heterocycloalkyl and aryl may be optionally substituted by one or more groups each independently (C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub>)alkyl-, halo, CN, <com:Math><semantics>(RARB)NC(O)<annotation encoding="application / x-tex">(R^AR^B)NC(O)< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>haloalkyl-, <com:Math><semantics>RAO<annotation encoding="application / x-tex">R^AO< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>(RARB)N(C1−C6)<annotation encoding="application / x-tex">(R^AR^B)N(C_1-C_6)< / annotation>< / semantics>< / com:Math>alkylene-, <com:Math><semantics>(C3−C6)<annotation encoding="application / x-tex">(C_3-C_6)< / annotation>< / semantics>< / com:Math> C<com:Sub>7< / com:Sub>)cycloalkyl-, R<com:Sup>C< / com:Sup>SO<com:Sub>2< / com:Sub>-, or (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N-; <com:Math><semantics>𝑹1<annotation encoding="application / x-tex">\mathbf{R}_1< / annotation>< / semantics>< / com:Math> is H or (C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkyl; <com:Math><semantics>𝑹2<annotation encoding="application / x-tex">\mathbf{R}_2< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>alkyl-, heteroaryl<com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math>alkyl-, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>heterocycloalkyl-<com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math>alkyl-, is <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>heterocycloalkyl-<com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math>alkyl-, is <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>heterocycloalkyl-<com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math>alkyl-, is <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math> C<com:Sub>6< / com:Sub>)alkyl-, heteroaryl-<com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>hydroxyalkyl-, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>heterocycloalkyl, <com:Math><semantics>(C3−<annotation encoding="application / x-tex">(C_3-< / annotation>< / semantics>< / com:Math> C<com:Sub>8< / com:Sub>)cycloalkyl-(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl-, aryl-(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkyl-, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkylene-, <com:Math><semantics>(RARB)N(O)C(C1−C4)<annotation encoding="application / x-tex">(R^AR^B)N(O)C(C_1-C_4)< / annotation>< / semantics>< / com:Math>alkylene- or <com:Math><semantics>RAO(C1−C4)<annotation encoding="application / x-tex">R^AO(C_1-C_4)< / annotation>< / semantics>< / com:Math>alkylene- wherein any of such alkyl, alkylene, aryl, heteroaryl and heterocycloalkyl may be optionally substituted by one or more of <com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>RAO(C1−C4)<annotation encoding="application / x-tex">R^AO(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkylene-, <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> C<com:Sub>6< / com:Sub>)haloalkyl, halo, oxo, R<com:Sup>A< / com:Sup>O-, (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)heterocycloalkyl-(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl-, heteroaryl, <com:Math><semantics>(RARB)N−<annotation encoding="application / x-tex">(R^AR^B)N-< / annotation>< / semantics>< / com:Math> -NHC(O)<com:Math><semantics>RC<annotation encoding="application / x-tex">R^{C}< / annotation>< / semantics>< / com:Math>, -C(O)N(<com:Math><semantics>RARB<annotation encoding="application / x-tex">R^{A}R^{B}< / annotation>< / semantics>< / com:Math>), -SO<com:Sub>2< / com:Sub>N(<com:Math><semantics>RARB<annotation encoding="application / x-tex">R^{A}R^{B}< / annotation>< / semantics>< / com:Math>), -O(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkylene- N(R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>), aryl optionally substituted by halo, -OR<com:Sup>C< / com:Sup>, aryl-(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkyl-, or -C(O)R<com:Sup>A< / com:Sup>; <com:Math><semantics>ℝA<annotation encoding="application / x-tex">\mathbb{R}^{A}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>ℝB<annotation encoding="application / x-tex">\mathbb{R}^{B}< / annotation>< / semantics>< / com:Math> are at each occurrence independently H, (C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkyl-, (C<com:Sub>3< / com:Sub>- <com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)cycloalkyl-, or <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> haloalkyl, or R<com:Sup>A< / com:Sup> and R<com:Sup>B< / com:Sup> may form together with the nitrogen atom to which they are attached a 5 or 6 membered saturated heterocyclic monocyclic ring system optionally containing a further heteroatom which is nitrogen or oxygen, which may be optionally substituted by one or more groups each independently <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math>alkyl and oxo; <com:Math><semantics>𝑹𝑪<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{C}}< / annotation>< / semantics>< / com:Math> is at each occurrence H, (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N-, or aryl-(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkyl-; Y is -OR<com:Sup>D< / com:Sup>, R<com:Sup>C< / com:Sup>SO<com:Sub>2< / com:Sub>, halo, -NHSO<com:Sub>2< / com:Sub>R<com:Sup>C< / com:Sup>, heteroaryl, or (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)heterocycloalkyl, wherein any of such heteroaryl and heterocycloalkyl may be optionally substituted by one or more groups each independently <com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math> alkyl, or <com:Math><semantics>−C(O)N(RARB)<annotation encoding="application / x-tex">-C(O)N(R^AR^B)< / annotation>< / semantics>< / com:Math>; R<com:Sup>D< / com:Sup> is H, (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl, (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)heterocycloalkyl-(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl-, R<com:Sup>C< / com:Sup>OC(O)(C<com:Sub>1< / com:Sub>- C<com:Sub>4< / com:Sub>)alkylene-, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkylene-, (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)heterocycloalkyl, <com:Math><semantics>(C3−<annotation encoding="application / x-tex">(C_3-< / annotation>< / semantics>< / com:Math> C<com:Sub>8< / com:Sub>)cycloalkyl-(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl-, R<com:Sup>C< / com:Sup>O(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkylene-, or (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N(O)C(C<com:Sub>1< / com:Sub>- C<com:Sub>4< / com:Sub>)alkylene-, wherein any of such heterocycloalkyl may be optionally substituted by one or more groups reach independently (C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub>)alkyl-; J is H, (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N-, (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)haloalkyl, -OR<com:Sup>C< / com:Sup> or halo. Other exemplary embodiments provide a compound, wherein the compound is: 6-(5-methylpyridin-2-yl)-N-((6-methylpyridin-3-yl)methyl)quinazolin-4- amine, N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)-6-(5-methylpyridin-2- yl)quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] (trifluoromethyl)quinazolin-4-amine, N-((6-methylpyridazin-3-yl)methyl)-6-(5-methylpyridin-2-yl)quinazolin-4- amine, [Image disponible dans le document PDF, Image available in the PDF document] yl)quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] yl)ethyl)quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] yl)ethyl)quinazoline-2,4-diamine, [Image disponible dans le document PDF, Image available in the PDF document] morpholinoquinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] yl)amino)propanamide, N-cyclopropyl-2-((2-(cyclopropylamino)-6-(4-fluorophenyl)quinazolin-4- yl)amino)propanamide, [Image disponible dans le document PDF, Image available in the PDF document] yl)methyl)quinazolin-4-amine, N-((6-methylpyridin-3-yl)methyl)-6-(5-methylthiophen-2-yl)quinazolin-4- amine, N-((6-methylpyridin-3-yl)methyl)-6-(p-tolyl)quinazolin-4-amine, N-((6-methylpyridazin-3-yl)methyl)-6-(2-methylpyrimidin-5-yl)quinazolin- 4-amine, (R)-6-(4-fluorophenyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5- yl)ethyl)quinazolin-4-amine, 6-(4-fluorophenyl)-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)quinazolin-4- amine, 2-(4-(((6-methylpyridin-3-yl)methyl)amino)quinazolin-6-yl)benzonitrile, 2-(4-(((6-methylpyridin-3-yl)methyl)amino)quinazolin-6-yl)benzamide, 6-(4-fluorophenyl)-N-((6-methylpyridin-3-yl)methyl)quinazolin-4-amine formate, 6-(4-fluorophenyl)-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine, N-((3,5-difluoropyridin-2-yl)methyl)-6-(4-fluorophenyl)quinazolin-4-amine hydrochloride, 6-(4-fluorophenyl)-N-methyl-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl) quinazolin-4-amine, <com:Math><semantics>(R)−6−(3,3)<annotation encoding="application / x-tex">(R)-6-(3,3)< / annotation>< / semantics>< / com:Math> difluoropyrrolidin-1-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5- yl)ethyl)quinazolin-4-amine, (R)-6-morpholino-N-(1-(2-(trifluoromethyl)pyrimidin-5- yl)ethyl)quinazolin-4-amine, (R)-1-methyl-4-(4-((1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)amino) quinazolin-6-yl)piperazin-2-one, N-((6-methylpyridazin-3-yl)methyl)-6-morpholinoquinazolin-4-amine, Single enantiomer 1 of 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol- 5-yl)ethyl]quinazolin-4-amine, Single enantiomer 2 of 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol- 5-yl)ethyl]quinazolin-4-amine, Single enantiomer 1 of N2-cyclopropyl-6-(4-fluorophenyl)-N4-[1-(3-methyl- 1,2,4-oxadiazol-5-yl)ethyl]quinazoline-2,4-diamine, Single enantiomer 2 of N2-cyclopropyl-6-(4-fluorophenyl)-N4-[1-(3-methyl- 1,2,4-oxadiazol-5-yl)ethyl]quinazoline-2,4-diamine, Single enantiomer 1 of 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol- 5-yl)ethyl]-2-morpholino-quinazolin-4-amine, Single enantiomer 2 of 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol- 5-yl)ethyl]-2-morpholino-quinazolin-4-amine, Single enantiomer 1 of 6-(4-fluorophenyl)-N2,N2-dimethyl-N4-[1-(3- methyl-1,2,4-oxadiazol-5-yl)ethyl]quinazoline-2,4-diamine, or Single enantiomer 2 of 6-(4-fluorophenyl)-N2,N2-dimethyl-N4-[1-(3-methyl- 1,2,4-oxadiazol-5-yl)ethyl]quinazoline-2,4-diamine. Yet other exemplary embodiments provide a compound of formula Ib [Image disponible dans le document PDF, Image available in the PDF document] (Ib) wherein R<com:Sub>3< / com:Sub> is OH or halo, R<com:Sub>4< / com:Sub> is H or OH, R<com:Sub>5< / com:Sub> is -OMe, <com:Math><semantics>𝑹6<annotation encoding="application / x-tex">\mathbf{R}_6< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>Z<annotation encoding="application / x-tex">Z< / annotation>< / semantics>< / com:Math>, Z is (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)heterocycloalkyl, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N-, heteroaryl, or aryl, wherein any of such heteroaryl, heterocycloalkyl and aryl may be optionally substituted by one or more groups each independently (C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub>)alkyl-, halo, CN, <com:Math><semantics>(RARB)NC(O)<annotation encoding="application / x-tex">(R^AR^B)NC(O)< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>haloalkyl-, <com:Math><semantics>RAO<annotation encoding="application / x-tex">R^AO< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>(RARB)N(C1−C6)<annotation encoding="application / x-tex">(R^AR^B)N(C_1-C_6)< / annotation>< / semantics>< / com:Math>alkylene-, <com:Math><semantics>(C3−C6)<annotation encoding="application / x-tex">(C_3-C_6)< / annotation>< / semantics>< / com:Math> C<com:Sub>7< / com:Sub>)cycloalkyl-, R<com:Sup>C< / com:Sup>SO<com:Sub>2< / com:Sub>-, or (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N-. The present disclosure refers to compounds of formula (I) [Image disponible dans le document PDF, Image available in the PDF document] (I) wherein Z is selected from the group consisting of (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)heterocycloalkyl, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N-, heteroaryl, aryl, wherein any of such alkyl, heteroaryl, heterocycloalky and aryl may be optionally substituted by one or more groups selected from (C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub>)alkyl-, halo, CN, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)NC(O)-, (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)haloalkyl-, R<com:Sup>A< / com:Sup>O-, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkylene-, (C<com:Sub>3< / com:Sub>-C<com:Sub>7< / com:Sub>)cycloalkyl-, <com:Math><semantics>RCSO2<annotation encoding="application / x-tex">R^{C}SO_{2}< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>(RARB)N<annotation encoding="application / x-tex">(R^{A}R^{B})N< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>𝑹1<annotation encoding="application / x-tex">\mathbf{R}_1< / annotation>< / semantics>< / com:Math> is H or (C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkyl; <com:Math><semantics>𝑹2<annotation encoding="application / x-tex">\mathbf{R}_2< / annotation>< / semantics>< / com:Math> is selected from the group consisting of <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl-, heteroaryl<com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkyl-, (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)heterocycloalkyl-(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl-, heteroaryl-<com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>hydroxyalkyl-, <com:Math><semantics>(C3−<annotation encoding="application / x-tex">(C_3-< / annotation>< / semantics>< / com:Math> C<com:Sub>8< / com:Sub>)heterocycloalkyl, (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)cycloalkyl-(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl-, aryl-(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkyl-, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N(C<com:Sub>1< / com:Sub>- C<com:Sub>6< / com:Sub>)alkylene-, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N(O)C(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkylene-, R<com:Sup>A< / com:Sup>O(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkylene- wherein any of such alkyl, alkylene, aryl, heteroaryl and heterocycloalkyl may be optionally substituted by one or more groups selected from <com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math>alkyl, <com:Math><semantics>RAO(C1−C4)<annotation encoding="application / x-tex">R^AO(C_1-C_4)< / annotation>< / semantics>< / com:Math>alkylene-, <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>haloalkyl, halo, oxo, <com:Math><semantics>RAO<annotation encoding="application / x-tex">R^AO< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>heterocycloalkyl-<com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>alkyl-, heteroaryl, <com:Math><semantics>(RARB)N<annotation encoding="application / x-tex">(R^AR^B)N< / annotation>< / semantics>< / com:Math>-, -NHC(O)<com:Math><semantics>RC<annotation encoding="application / x-tex">R^{C}< / annotation>< / semantics>< / com:Math>, -C(O)N(<com:Math><semantics>RARB<annotation encoding="application / x-tex">R^{A}R^{B}< / annotation>< / semantics>< / com:Math>), -SO<com:Sub>2< / com:Sub>N(<com:Math><semantics>RARB<annotation encoding="application / x-tex">R^{A}R^{B}< / annotation>< / semantics>< / com:Math>), -O(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkylene-N(<com:Math><semantics>RARB<annotation encoding="application / x-tex">R^{A}R^{B}< / annotation>< / semantics>< / com:Math>), aryl optionally substituted by halo, -OR<com:Sup>C< / com:Sup>, aryl-(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkyl-, -C(O)R<com:Sup>A< / com:Sup>; R<com:Sup>A< / com:Sup> and R<com:Sup>B< / com:Sup> are at each occurrence independently H or selected from the group consisting of <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkyl-, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> haloalkyl, or R<com:Sup>A< / com:Sup> and R<com:Sup>B< / com:Sup> may form together with the nitrogen atom to which they are attached a 5 or 6 membered saturated heterocyclic monocyclic ring system optionally containing a further heteroatom which is nitrogen or oxygen, which may be optionally substituted by one or more groups selected (<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math>)alkyl and oxo; <Formule mathématique disponible dans le document PDF, Math available in the PDF document>${\bf R}^{\bf C}$ is at each occurrence H or selected from the group consisting of (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl, <com:Math><semantics>(RARB)N<annotation encoding="application / x-tex">(R^AR^B)N< / annotation>< / semantics>< / com:Math>-, aryl-<com:Math><semantics>(C1<annotation encoding="application / x-tex">(C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4)<annotation encoding="application / x-tex">C_4)< / annotation>< / semantics>< / com:Math>alkyl-; Y is selected from the group consisting of H, -OR<com:Sup>D< / com:Sup>, R<com:Sup>C< / com:Sup>SO<com:Sub>2< / com:Sub>, halo, -NHSO<com:Sub>2< / com:Sub>R<com:Sup>C< / com:Sup>, heteroaryl, (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)heterocycloalkyl, wherein any of such heteroaryl and heterocycloalkyl may be optionally substituted by one or more groups selected from (C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub>)alkyl and - <com:Math><semantics>C(O)N(RARB);<annotation encoding="application / x-tex">C(O)N(R^AR^B);< / annotation>< / semantics>< / com:Math> <com:Math><semantics>𝑹𝑫<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{D}}< / annotation>< / semantics>< / com:Math> is selected from the group consisting of H, (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl, (C<com:Sub>3< / com:Sub>- <com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)heterocycloalkyl-(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math>)alkyl-, <com:Math><semantics>RCOC(O)(C1<annotation encoding="application / x-tex">R^COC(O)(C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math>)alkylene-, <com:Math><semantics>(RARB)N(C1<annotation encoding="application / x-tex">(R^AR^B)N(C_1< / annotation>< / semantics>< / com:Math>- <com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math>)alkylene-, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>heterocycloalkyl, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>cycloalkyl-<com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>alkyl-, <com:Math><semantics>RCO(C1−C6)<annotation encoding="application / x-tex">R^CO(C_1-C_6)< / annotation>< / semantics>< / com:Math> C4)alkylene-, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N(O)C(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkylene-, wherein any of such heterocycloalkyl may be optionally substituted by one or more groups selected from (C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub>)alkyl; J is H or selected from the group consisting of <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>(RARB)N<annotation encoding="application / x-tex">(R^AR^B)N< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> haloalkyl, -OR<com:Sup>C< / com:Sup> and halo. In a second aspect, the disclosure refers to a pharmaceutical composition comprising a compound of formula (I) or pharmaceutically acceptable salt thereof, either alone or in combination with another one or more active ingredient, in admixture with one or more pharmaceutically acceptable carrier or excipient. In a third aspect, the disclosure provides a compound of formula (I) for the use as a medicament. In a further aspect, the disclosure provides the use of a compound of formula (I) for use in treatment of any disease wherein the P2X3 receptors are involved. In a further aspect, the disclosure refers to a compound of formula (I) for use in the prevention and / or treatment of respiratory diseases including cough, sub-acute or chronic cough, treatment-resistant cough, idiopathic chronic cough, post-viral cough, iatrogenic cough, asthma, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and cough associated with respiratory diseases such as COPD, asthma and bronchospasm. In a further aspect, the disclosure refers to a compound of formula Ib [Image disponible dans le document PDF, Image available in the PDF document] (Ib) wherein 15 R<com:Sub>3< / com:Sub> is OH or halo, R<com:Sub>4< / com:Sub> is H or OH, R<com:Sub>5< / com:Sub> is halo or -OMe, <com:Math><semantics>𝑹6<annotation encoding="application / x-tex">\mathbf{R}_6< / annotation>< / semantics>< / com:Math> is halo or <com:Math><semantics>𝒁<annotation encoding="application / x-tex">\mathbf{Z}< / annotation>< / semantics>< / com:Math>, Z is as defined above. In a further aspect, the disclosure refers to the use of compound of formula (Ib) as intermediate in the preparation of compounds of formula (I). DETAILED DESCRIPTION The invention relates to a compound of formula (I) [Image disponible dans le document PDF, Image available in the PDF document] (I) wherein Z is selected from the group consisting of (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)heterocycloalkyl, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N-, heteroaryl, aryl, wherein any of such alkyl, heteroaryl, heterocycloalky and aryl may be optionally substituted by one or more groups selected from (C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub>)alkyl-, halo, CN, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)NC(O)-, (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)haloalkyl-, R<com:Sup>A< / com:Sup>O-, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkylene-, (C<com:Sub>3< / com:Sub>-C<com:Sub>7< / com:Sub>)cycloalkyl-, <com:Math><semantics>RCSO2<annotation encoding="application / x-tex">R^{C}SO_2< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>(RARB)N<annotation encoding="application / x-tex">(R^AR^B)N< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>𝑹1<annotation encoding="application / x-tex">\mathbf{R}_1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math>alkyl; <com:Math><semantics>𝑹𝟐<annotation encoding="application / x-tex">\mathbf{R_2}< / annotation>< / semantics>< / com:Math> is selected from the group consisting of <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl-, heteroaryl<com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkyl-, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>heterocycloalkyl-<com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>alkyl-, heteroaryl-<com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>hydroxyalkyl-, <com:Math><semantics>(C3−<annotation encoding="application / x-tex">(C_3-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)heterocycloalkyl, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>cycloalkyl-<com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>alkyl-, aryl-<com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math>alkyl-, <com:Math><semantics>(RARB)N(C1−C4)<annotation encoding="application / x-tex">(R^AR^B)N(C_1-C_4)< / annotation>< / semantics>< / com:Math> C<com:Sub>6< / com:Sub>)alkylene-, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N(O)C(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkylene-, R<com:Sup>A< / com:Sup>O(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkylene- wherein any of such alkyl, alkylene, aryl, heteroaryl and heterocycloalkyl may be optionally substituted by one or more groups selected from <com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math>alkyl, <com:Math><semantics>RAO(C1−C4)<annotation encoding="application / x-tex">R^AO(C_1-C_4)< / annotation>< / semantics>< / com:Math>alkylene-, <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>haloalkyl, halo, oxo, R<com:Sup>A< / com:Sup>O-, (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)heterocycloalkyl-(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl-, heteroaryl, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N-, -NHC(O)R<com:Sup>C< / com:Sup>, -C(O)N(R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>), -SO<com:Sub>2< / com:Sub>N(R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>), -O(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkylene-N(R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>), aryl optionally substituted by halo, -OR<com:Sup>C< / com:Sup>, aryl-(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkyl-, -C(O)R<com:Sup>A< / com:Sup>; R<com:Sup>A< / com:Sup> and R<com:Sup>B< / com:Sup> are at each occurrence independently H or selected from the group consisting of <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkyl-, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> haloalkyl, or R<com:Sup>A< / com:Sup> and R<com:Sup>B< / com:Sup> may form together with the nitrogen atom to which they are attached a 5 or 6 membered saturated heterocyclic monocyclic ring system optionally containing a further heteroatom which is nitrogen or oxygen, which may be optionally substituted by one or more groups selected <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkyl and oxo; <com:Math><semantics>𝑹𝑪<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{C}}< / annotation>< / semantics>< / com:Math> is at each occurrence H or selected from the group consisting of (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl, <com:Math><semantics>(RARB)N<annotation encoding="application / x-tex">(R^{A}R^{B})N< / annotation>< / semantics>< / com:Math>-, aryl-<com:Math><semantics>(C1<annotation encoding="application / x-tex">(C_{1}< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4)<annotation encoding="application / x-tex">C_{4})< / annotation>< / semantics>< / com:Math>alkyl-; Y is selected from the group consisting of H, -ORD, RCSO2, halo, -NHSO2RC, heteroaryl, (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)heterocycloalkyl, wherein any of such heteroaryl and heterocycloalkyl may be optionally substituted by one or more groups selected from (C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub>)alkyl and - <com:Math><semantics>C(O)N(RARB);<annotation encoding="application / x-tex">C(O)N(R^AR^B);< / annotation>< / semantics>< / com:Math> <com:Math><semantics>𝑹𝑫<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{D}}< / annotation>< / semantics>< / com:Math> is selected from the group consisting of H, (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl, (C<com:Sub>3< / com:Sub>- <com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)heterocycloalkyl-(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math>)alkyl-, <com:Math><semantics>RCOC(O)(C1<annotation encoding="application / x-tex">R^COC(O)(C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math>)alkylene-, <com:Math><semantics>(RARB)N(C1<annotation encoding="application / x-tex">(R^AR^B)N(C_1< / annotation>< / semantics>< / com:Math>- <com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math>)alkylene-, (<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)heterocycloalkyl, (<com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math>)cycloalkyl-(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math>)alkyl-, <com:Math><semantics>RCO(C1<annotation encoding="application / x-tex">R^CO(C_1< / annotation>< / semantics>< / com:Math>- C4)alkylene-, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N(O)C(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkylene-, wherein any of such heterocycloalkyl may be optionally substituted by one or more groups selected from (C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub>)alkyl; J is H or selected from the group consisting of (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N-, (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>) haloalkyl, -OR<com:Sup>C< / com:Sup> and halo. DEFINITIONS The term "pharmaceutically acceptable salts", as used herein, refers to derivatives of compounds of formula (I) wherein the parent compound is suitably modified by converting any of the free acid or basic group, if present, into the corresponding addition salt with any base or acid conventionally intended as being pharmaceutically acceptable. Suitable examples of said salts may thus include mineral or organic acid addition salts of basic residues such as amino groups, as well as mineral or organic basic addition salts of acid residues such as carboxylic groups. Cations of inorganic bases which can be suitably used to prepare salts comprise ions of alkali or alkaline earth metals such as potassium, sodium, calcium or magnesium. Those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt comprise, for example, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, succinic acid and citric acid. The term "halogen" or "halogen atoms" as used herein includes fluorine, chlorine, bromine, and iodine atom, preferably chlorine or fluorine. The term "<com:Math><semantics>(Cx−Cy)<annotation encoding="application / x-tex">(C_x-C_y)< / annotation>< / semantics>< / com:Math> alkyl" wherein x and y are integers, refers to a straight or branched chain alkyl radical having from x to y carbon atoms. Thus, when x is 1 and y is 6, for example, the term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl. As used herein, the term "<com:Math><semantics>(Cx−Cy)<annotation encoding="application / x-tex">(C_x-C_y)< / annotation>< / semantics>< / com:Math>alkylene" wherein x and y are integers, refers to a C<com:Sub>x< / com:Sub>-C<com:Sub>y< / com:Sub>alkyl radical having in total two unsatisfied valencies, such as a divalent methylene radical. The expressions "(C<com:Sub>x< / com:Sub>-C<com:Sub>y< / com:Sub>) haloalkyl" wherein x and y are integers, refer to the above defined "C<com:Sub>x< / com:Sub>-C<com:Sub>y< / com:Sub>alkyl" groups wherein one or more hydrogen atoms are replaced by one or more halogen atoms, which can be the same or different. Examples of said "(C<com:Sub>x< / com:Sub>-C<com:Sub>y< / com:Sub>) haloalkyl" groups may thus include halogenated, poly-halogenated and fully halogenated alkyl groups wherein all of the hydrogen atoms are replaced by halogen atoms, e.g. trifluoromethyl or difluoro methyl, trifluoroethyl groups. By way of analogy, the terms "<com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> hydroxyalkyl" or "<com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> aminoalkyl" refer to the above defined "(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>) alkyl" groups wherein one or more hydrogen atoms are replaced by one or more hydroxy (OH) or amino group respectively. Examples include respectively hydroxymethyl, aminomethyl, dimethylaminopropyl and the like. In the present description, unless otherwise provided, the aminoalkyl encompasses alkyl groups (i.e. "(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>) alkyl" groups) substituted by one or more amino group (- NR<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>). Thus, an example of aminoalkyl is a mono-aminoalkyl group such as R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>N- <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl. With reference to the substituent R<com:Sup>A< / com:Sup> and R<com:Sup>B< / com:Sup> as defined above and below, when R<com:Sup>A< / com:Sup> and R<com:Sup>B< / com:Sup> are taken together with the nitrogen atom they are linked to form 5 to 6 membered heterocyclic radical, at least one further ring carbon atom in the said heterocyclic radical is optionally replaced by at least one heteroatom (e.g. N, S or O) and / or may bear -oxo (=O) substituent groups. It is understood that the said heterocyclic radical might be further optionally substituted on any available position in the ring, namely on a carbon atom, or on any heteroatom available for substitution. Substitution on a carbon atom includes spiro disubstitution as well as substitution on two adjacent carbon atoms, in both cases thus form an additional 5 to 6 membered heterocyclic ring. Examples of said heterocycle radicals are 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-methylpiperazinyl, piperazin- 4yl-2-one, 4-morpholinyl, morpholinyl-3-one, 1-(piperazin-1-yl)ethenone. The term "(C<com:Sub>x< / com:Sub>-C<com:Sub>y< / com:Sub>) cycloalkyl" wherein x and y are integers, refers to saturated cyclic hydrocarbon groups containing the indicated number of ring carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. The term "aryl" refers to mono cyclic carbon ring systems which have 6 ring atoms wherein the ring is aromatic. Examples of suitable aryl monocyclic ring systems include, for instance, phenyl. The term "heteroaryl" refers to a mono- or bi-cyclic aromatic radical containing one or more heteroatoms selected from S, N and O, and includes radicals having two such monocyclic rings, or one such monocyclic ring and one monocyclic aryl ring, which are fused through a common bond. Examples of suitable 5,6-membered heteroaryl are: are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, tetrazolyl and triazinyl. The term "heterocyclyl" or "heterocyclic" relate to a saturated mono-, bi- or tri- cyclic non-aromatic radical containing one or more heteroatoms selected from S, N and O. In the case of bicyclic heterocyclic systems, included within the scope of the term are fused, spiro and bridged bicyclic systems. The term "<com:Math><semantics>(Cx−Cy)<annotation encoding="application / x-tex">(C_x-C_y)< / annotation>< / semantics>< / com:Math> heterocycloalkyl" wherein x and y are integers, refers to saturated or partially unsaturated monocyclic (<com:Math><semantics>Cx<annotation encoding="application / x-tex">C_x< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>Cy<annotation encoding="application / x-tex">C_y< / annotation>< / semantics>< / com:Math>) cycloalkyl groups in which at least one ring carbon atom is replaced by at least one heteroatom (e.g. N, S or O) or may bear an -oxo (=O) substituent group. Said heterocycloalkyl (i.e. heterocyclic radical or group) may be further optionally substituted on the available positions in the ring, namely on a carbon atom, or on an heteroatom available for substitution. Substitution on a carbon atom includes spiro disubstitution as well as substitution on two adjacent carbon atoms, in both cases thus form additional condensed 5 to 6 membered heterocyclic ring. Examples of (C<com:Sub>x< / com:Sub>-C<com:Sub>y< / com:Sub>) heterocycloalkyl are represented by: pyrrolidinyl, imidazolidinyl, thiazolidinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, dihydro- or tetrahydro-pyridinyl, tetrahydrothiophenyl, azetidinyl, oxetanyl, tetrahydropyranyl, pyranyl, 2H- or 4H- pyranyl, dihydro- or tetrahydrofuranyl, dihydroisoxazolyl, pyrrolidin-2-one-yl, dihydropyrrolyl radicals and the like. Specific examples of said heterocycle radicals are tetrahydrothiophene 1,1-dioxide, 3,3-difluoropyrrolidinyl, 1-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 1-piperidinyl, 1- piperazinyl, 4-morpholinyl. The expressions "Aryloxyl" and "Aryl (<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math>) alkoxyl" likewise "heteroAryloxyl" and "Heteroaryl (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>) alkoxyl" refer to Aryl or Heteroaryl groups attached through an oxygen bridge and chained Aryl-alkoxyl or HeteroAryl-alkoxyl groups. Examples of such groups are phenyloxy, benzyloxy and pyridinyloxy respectively. The term "aryl (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>) alkyl" refers to an aryl ring linked to a straight-chained or branched alkyl groups wherein the number of carbon atoms is from 1 to 6, e.g. phenylmethyl (i.e. benzyl), phenylethyl or phenylpropyl. The term <com:Math><semantics>(Cz−Ck)<annotation encoding="application / x-tex">(C_z-C_k)< / annotation>< / semantics>< / com:Math>heterocycloalkyl-<com:Math><semantics>(Cx−Cy)<annotation encoding="application / x-tex">(C_x-C_y)< / annotation>< / semantics>< / com:Math>alkyl wherein z and k are integers, refers to an heterocyclic ring linked to a straight-chained or branched alkyl groups having from x to y carbon atoms. Likewise, the term "heteroaryl <com:Math><semantics>(Cx−Cy)<annotation encoding="application / x-tex">(C_x-C_y)< / annotation>< / semantics>< / com:Math>alkyl" or "aryl <com:Math><semantics>(Cx−Cy)<annotation encoding="application / x-tex">(C_x-C_y)< / annotation>< / semantics>< / com:Math>alkyl" refers to an heteroaryl or aryl ring linked to a straight-chained or branched alkyl groups having from x to y carbon atoms. The expression "ring system" refers to mono- or bicyclic or polycyclic ring systems which may be saturated, partially unsaturated or unsaturated, such as aryl, <com:Math><semantics>(C3−C10)<annotation encoding="application / x-tex">(C_3-C_{10})< / annotation>< / semantics>< / com:Math> cycloalkyl, (C<com:Sub>3< / com:Sub>-C<com:Sub>6< / com:Sub>) heterocycloalkyl or heteroaryl. The terms "group", "radical" or "fragment" or "substituent" are synonymous and are intended to indicate functional groups or fragments of molecules attachable to a bond or other fragments or molecules. Thus, as an example, a "heterocyclic radical" herein refers to a mono- or bi-cyclic saturated or partially saturated heterocyclic moiety (group, radical), preferably a 4 to 11 membered monocyclic radical, at least one further ring carbon atom in the said heterocyclic radical is optionally replaced by at least one further heteroatom independently selected from N, S or O and / or may bear an -oxo (=O) substituent group, said heterocyclic radical is further optionally including spiro disubstitution as well as substitution on two adjacent or vicinal atoms forming an additional 5 to 6 membered cyclic or heterocyclic, saturated, partially saturated or aromatic ring. Examples of said heterocycle radicals are 1-pyrrolidinyl, 1-piperidinyl, 1- piperazinyl, 4-morpholinyl and the like. A dash ("-") that is not between two letters or symbols is meant to represent the point of attachment for a substituent. When graphically represented the point of attachment in a cyclic functional group is indicated with a dot ("•") localized in one of the available ring atom where the functional group is attachable to a bond or other fragment of molecules. An oxo moiety is represented by (O) as an alternative to the other common representation, e.g. (=0). Thus, in terms of general formula, the carbonyl group is herein represented as -C(O)-, in general, the bracketed group is a lateral group, not included into the chain, and brackets are used, when deemed useful, to help disambiguating linear chemical formulas; e.g. the sulfonyl group -SO<com:Sub>2< / com:Sub>- might be also represented as <com:Math><semantics>−S(O)2<annotation encoding="application / x-tex">-S(O)_2< / annotation>< / semantics>< / com:Math>- to disambiguate e.g. with respect to the sulfinic group <com:Math><semantics>−S(O)O<annotation encoding="application / x-tex">-S(O)O< / annotation>< / semantics>< / com:Math>-. Whenever basic amino or quaternary ammonium groups are present in the compounds of formula I, physiologically acceptable anions may be present, selected among chloride, bromide, iodide, trifluoroacetate, formate, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p-toluenesulfonate, pamoate and naphthalene disulfonate. Likewise, in the presence of acidic groups such as COOH groups, corresponding physiological cation salts may be present as well, for instance including alkaline or alkaline earth metal ions. It will be apparent that compounds of formula (I) when contain one or more stereogenic center, may exist as optical stereoisomers. Where the compounds according to the invention have at least one stereogenic center, they may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more stereogenic centers, they may additionally exist as diastereoisomers. All such single enantiomers, diastereoisomers and mixtures thereof in any proportion are encompassed within the scope of the present invention. The absolute configuration (R) or (S) for carbon bearing a stereogenic center is assigned on the basis of Cahn-Ingold-Prelog nomenclature rules based on groups' priorities. The invention further concerns the corresponding deuterated derivatives of compounds of formula (I). All preferred groups or embodiments described above and herebelow for compounds of formula I may be combined among each other and apply as well mutatis mutandis. In a preferred embodiment, the invention is directed to compounds of formula (I) as defined above [Image disponible dans le document PDF, Image available in the PDF document] (I) wherein Z is selected from the group consisting of heteroaryl, aryl, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N-, (C<com:Sub>3< / com:Sub>- C<com:Sub>8< / com:Sub>)heterocycloalkyl, wherein any of such heteroaryl, aryl and heterocycloalkyl may be optionally substituted by one or more groups selected from (C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub>)alkyl, halo, CN, <com:Math><semantics>(RARB)NC(O)<annotation encoding="application / x-tex">(R^AR^B)NC(O)< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>𝑹1<annotation encoding="application / x-tex">\mathbf{R}_1< / annotation>< / semantics>< / com:Math> is H or (C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkyl; R<com:Sub>2< / com:Sub> is selected from the group consisting of heteroaryl(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkyl-, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N(O)C(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkylene-, wherein any of such heteroaryl may be optionally substituted by one or more groups selected from (C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub>)alkyl, halo, (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>) haloalkyl; <com:Math><semantics>ℝA<annotation encoding="application / x-tex">\mathbb{R}^{A}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>ℝB<annotation encoding="application / x-tex">\mathbb{R}^{B}< / annotation>< / semantics>< / com:Math> are at each occurrence independently H, (C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkyl- and (C<com:Sub>3< / com:Sub>- C<com:Sub>8< / com:Sub>)cycloalkyl-, or R<com:Sup>A< / com:Sup> and R<com:Sup>B< / com:Sup> may form together with the nitrogen atom to which they are attached a 5 or 6 membered saturated heterocyclic monocyclic ring system optionally containing a further heteroatom which is oxygen or nitrogen, which may be optionally substituted by one or more groups selected from oxo, (C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkyl; Y is H; J is H or selected from the group consisting of (C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkyl, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N-, halo, (C<com:Sub>1< / com:Sub>- C<com:Sub>6< / com:Sub>)haloalkyl. In another preferred embodiment, the invention refers to compounds of formula (I) wherein Z is selected from the group consisting of heteroaryl and aryl, wherein any of such heteroaryl and aryl may be optionally substituted by one or more groups selected from <com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math>alkyl and halo; <com:Math><semantics>𝑹1<annotation encoding="application / x-tex">\mathbf{R}_1< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>𝑹𝟐<annotation encoding="application / x-tex">\mathbf{R_2}< / annotation>< / semantics>< / com:Math> is selected from the group consisting of <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>heterocycloalkyl-<com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>alkyl-, preferably (piperidinyl)methyl; heteroaryl(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math>)alkyl-, preferably (pyridinyl)methyl, (pyridinyl)ethyl, (pyridazinyl)methyl, (pyridazinyl)ethyl (pyrimidinyl)methyl, (pyrimidinyl)ethyl, (oxadiazolyl)ethyl, (thiadiazolyl)ethyl <com:Math><semantics>([1,2,4]<annotation encoding="application / x-tex">([1,2,4]< / annotation>< / semantics>< / com:Math>triazolo<com:Math><semantics>[4,3−<annotation encoding="application / x-tex">[4,3-< / annotation>< / semantics>< / com:Math> a pyrimidin-3-yl) methyl, and Wherein any of such alkyl, heteroaryl and heterocycloalkyl may be optionally substituted by one or more groups selected from <com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> haloalkyl and -OH; Y is selected from the group consisting of H and -OR<com:Sup>D< / com:Sup>, R<com:Sup>D< / com:Sup> is at each occurrence selected from the group consisting of (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl, preferably methyl, (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)heterocycloalkyl-(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl-, preferably (oxetanyl)methyl, (morpholinyl)methyl, [Image disponible dans le document PDF, Image available in the PDF document] (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)heterocycloalkyl, preferably tetrahydropyranyl, pyrrolidinyl, and <com:Math><semantics>RCO(C1−C4)<annotation encoding="application / x-tex">R^{C}O(C_1-C_4)< / annotation>< / semantics>< / com:Math>alkylene-, preferably methoxyethyl; J is at each occurrence selected from the group consisting of H and -OR<com:Sup>C< / com:Sup>, preferably is H or -OH; <com:Math><semantics>𝑹𝑪<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{C}}< / annotation>< / semantics>< / com:Math> is at each occurrence selected from the group consisting of H and (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl. According to a preferred embodiment, the invention refers to at least one of the compounds listed in the Table 1 below and pharmaceutical acceptable salts thereof. Table 1: List of preferred compounds having Formula (I) [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] In a further preferred embodiment, the invention refers to compound of formula (I) wherein Z is selected from the group consisting of heteroaryl, preferably pyrimidinyl, thiazolyl, pyridinyl, thiophenyl, aryl, preferably phenyl, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N-, wherein R<com:Sup>A< / com:Sup> and R<com:Sup>B< / com:Sup> form together with the nitrogen atom to which they are attached a 5 or 6 membered saturated heterocyclic monocyclic ring system containing a further heteroatom which is oxygen or nitrogen, said heterocyclic radical being optionally in its turn further substituted with one or more oxo, methyl and fluorine; any of such heteroaryl and aryl is further optionally substituted by one or more groups selected from methyl, fluorine, R<com:Sup>C< / com:Sup>SO<com:Sub>2< / com:Sub>- wherein R<com:Sup>C< / com:Sup> is selected form the group consisting of fluorine, -OH and (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N- wherein R<com:Sup>A< / com:Sup> and R<com:Sup>B< / com:Sup> are H, CN, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)NC(O)- wherein R<com:Sup>A< / com:Sup> and R<com:Sup>B< / com:Sup> are H, <com:Math><semantics>𝑹1<annotation encoding="application / x-tex">\mathbf{R}_1< / annotation>< / semantics>< / com:Math> is H or methyl; R<com:Sub>2< / com:Sub> is selected from the group consisting of heteroaryl(C1-C4)alkyl-, preferably (pyridinyl)methyl, (pyridazyl)methyl, (pyrimidinyl)ethyl, (oxadiazolyl)ethyl (RARB)N(O)C(C1-C4)alkylene-, preferably RARB are H, cyclopropyl; any of said heteroaryl may be optionally substituted by one or more groups selected from methyl, fluorine, and trifluoromethyl. Y is H; J is H or selected from the group consisting of halo, preferably chlorine, (C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkyl, preferably methyl, (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)haloalkyl preferably trifluoromethyl, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N- wherein R<com:Sup>A< / com:Sup> and R<com:Sup>B< / com:Sup> are at each occurrence independently H, cyclopropyl and methyl or, in alternative, R<com:Sup>A< / com:Sup> and R<com:Sup>B< / com:Sup> form together with the nitrogen atom to which they are attached a 6 membered saturated heterocyclic monocyclic ring system containing a further heteroatom which is oxygen. According to a preferred embodiment, the invention refers to at least one of the compounds listed in the Table 2 below and pharmaceutical acceptable salts thereof. Table 2: List of preferred compounds having Formula (I) [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] In a further preferred embodiment, the invention is addressed to compound of formula (I) wherein Z is H or selected from the group consisting of heteroaryl and aryl, wherein any of such heteroaryl and aryl may be optionally substituted by one or more groups selected from <com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math>alkyl and halo; R1 is H; R2 is selected from the group consisting of heteroaryl(C1-C4)alkyl-, wherein any of such heteroaryl may be optionally substituted by one or more groups selected from <com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math>alkyl and <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> haloalkyl; Y is H; J is H or halo. According to a preferred embodiment, the invention refers to at least one compound of Table 3, selected from: Table 3: List of preferred compounds having Formula (I) [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] In a preferred embodiment, the invention refers to a compound of formula (I) [Image disponible dans le document PDF, Image available in the PDF document] (I) wherein Z is selected from the group consisting of heteroaryl and aryl, wherein any of such heteroaryl and aryl may be optionally substituted by one or more groups selected from (C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub>)alkyl, halo, CN, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)NC(O)-, (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)haloalkyl, R<com:Sup>A< / com:Sup>O-, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkylene-, (C<com:Sub>3< / com:Sub>-C<com:Sub>7< / com:Sub>)cycloalkyl-, R<com:Sup>C< / com:Sup>SO<com:Sub>2< / com:Sub>-, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N-; <com:Math><semantics>𝑹1<annotation encoding="application / x-tex">\mathbf{R}_1< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math>alkyl, <com:Math><semantics>𝑹2<annotation encoding="application / x-tex">\mathbf{R}_2< / annotation>< / semantics>< / com:Math> is selected from the group consisting of <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl, heteroaryl<com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkyl-, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>heterocycloalkyl-<com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>alkyl, heteroaryl-<com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>hydroxyalkyl, <com:Math><semantics>aryl−(C1−<annotation encoding="application / x-tex">aryl-(C_1-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math>)alkyl-, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>heterocycloalkyl, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>cycloalkyl-<com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>alkyl-, <com:Math><semantics>(RARB)N(C1−C6)<annotation encoding="application / x-tex">(R^AR^B)N(C_1-C_6)< / annotation>< / semantics>< / com:Math> C<com:Sub>6< / com:Sub>)alkylene-; R<com:Sup>A< / com:Sup>O(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkylene, wherein any of such alkyl, alkylene, aryl, heteroaryl, cycloalkyl and heterocycloalkyl may be optionally substituted by one or more groups selected from (C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub>)alkyl, R<com:Sup>A< / com:Sup>O(C<com:Sub>1< / com:Sub>- <com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math>)alkylene, <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>haloalkyl, oxo, <com:Math><semantics>RAO−<annotation encoding="application / x-tex">R^AO_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>heterocycloalkyl-<com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>alkyl, heteroaryl, aryl optionally substituted by halo, R<com:Sup>C< / com:Sup>O-, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N-, -NHC(O)R<com:Sup>C< / com:Sup>, <com:Math><semantics>−C(O)N(RARB)<annotation encoding="application / x-tex">-C(O)N(R^AR^B)< / annotation>< / semantics>< / com:Math>, halo, <com:Math><semantics>−SO2N(RARB)<annotation encoding="application / x-tex">-SO_2N(R^AR^B)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−O(RAO(C1−C4)alkylene−N(RARB)<annotation encoding="application / x-tex">-O(R^AO(C_1-C_4)alkylene-N(R^AR^B)< / annotation>< / semantics>< / com:Math>, aryl-<com:Math><semantics>−(C1−C4)alkylene−N(RARB)<annotation encoding="application / x-tex">-(C_1-C_4)alkylene-N(R^AR^B)< / annotation>< / semantics>< / com:Math> <com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math>)alkyl-, <com:Math><semantics>−C(O)RA<annotation encoding="application / x-tex">-C(O)R^A< / annotation>< / semantics>< / com:Math>, R<com:Sup>A< / com:Sup> and R<com:Sup>B< / com:Sup> are at each occurrence independently H or selected from the group consisting of <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkyl-, aryl, <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> haloalkyl, or R<com:Sup>A< / com:Sup> and R<com:Sup>B< / com:Sup> may form together with the nitrogen atom to which they are attached a 6 membered saturated heterocyclic monocyclic ring system optionally containing a further heteroatom which is nitrogen or oxygen, which may be optionally substituted by <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math>alkyl- and oxo; R<com:Sup>C< / com:Sup> is H or selected from the group consisting of (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N-, aryl-(C<com:Sub>1< / com:Sub>- C<com:Sub>4< / com:Sub>)alkyl-, Y is selected from the group consisting of -OR<com:Sup>D< / com:Sup>, R<com:Sup>C< / com:Sup>SO<com:Sub>2< / com:Sub>-, halo, -NHSO<com:Sub>2< / com:Sub>R<com:Sup>C< / com:Sup>, heteroaryl, (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)heterocycloalkyl, wherein any of such heteroaryl and heterocycloalkyl may be optionally substituted by one or more groups selected from <com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math>alkyl, <com:Math><semantics>−C(O)N(RARB)<annotation encoding="application / x-tex">-C(O)N(R^AR^B)< / annotation>< / semantics>< / com:Math>; J is H or selected from the group consisting of <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>−ORC<annotation encoding="application / x-tex">-OR^C< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>𝑹𝑫<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{D}}< / annotation>< / semantics>< / com:Math> is H or (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl. In a still preferred embodiment, the invention refers to a compound of formula (I) as defined above [Image disponible dans le document PDF, Image available in the PDF document] (I) wherein Z is selected from the group consisting of heteroaryl and aryl, wherein any of such heteroaryl and aryl may be optionally substituted by one or more groups selected from <com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math>alkyl, halo, CN, <com:Math><semantics>(RARB)NC(O)<annotation encoding="application / x-tex">(R^AR^B)NC(O)< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>haloalkyl, <com:Math><semantics>RAO<annotation encoding="application / x-tex">R^AO< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>(RARB)N(C1−C6)<annotation encoding="application / x-tex">(R^AR^B)N(C_1-C_6)< / annotation>< / semantics>< / com:Math> C<com:Sub>6< / com:Sub>)alkylene-, (C<com:Sub>3< / com:Sub>-C<com:Sub>7< / com:Sub>)cycloalkyl-, R<com:Sup>C< / com:Sup>SO<com:Sub>2< / com:Sub>-, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N-; <com:Math><semantics>𝑹1<annotation encoding="application / x-tex">\mathbf{R}_1< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>𝑯<annotation encoding="application / x-tex">\mathbf{H}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>𝑹2<annotation encoding="application / x-tex">\mathbf{R}_2< / annotation>< / semantics>< / com:Math> is selected from the group consisting of <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl, heteroaryl<com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkyl-, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>heterocycloalkyl-<com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>alkyl, heteroaryl-<com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>hydroxyalkyl, aryl-(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>- <com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math>)alkyl-, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>heterocycloalkyl, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>cycloalkyl-<com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>alkyl-, <com:Math><semantics>(RARB)N(C1−C6)<annotation encoding="application / x-tex">(R^AR^B)N(C_1-C_6)< / annotation>< / semantics>< / com:Math> C<com:Sub>6< / com:Sub>)alkylene-; R<com:Sup>A< / com:Sup>O(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkylene, wherein any of such alkyl, alkylene, aryl, heteroaryl, cycloalkyl and heterocycloalkyl may be optionally substituted by one or more groups selected from (C<com:Sub>1< / com:Sub>- C<com:Sub>3< / com:Sub>)alkyl, R<com:Sup>A< / com:Sup>O(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkylene-, (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)haloalkyl, oxo, R<com:Sup>A< / com:Sup>O-, (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)heterocycloalkyl- (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl, heteroaryl, aryl optionally substituted by halo, R<com:Sup>C< / com:Sup>O-, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N-, -NHC(O)R<com:Sup>C< / com:Sup>, -C(O)N(R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>), halo, -SO<com:Sub>2< / com:Sub>N(R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>), -O(R<com:Sup>A< / com:Sup>O(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkylene-N(R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>), <com:Math><semantics>aryl−(C1−C4)alkyl−,−C(O)RA;<annotation encoding="application / x-tex">aryl-(C_1-C_4)alkyl-, -C(O)R^A;< / annotation>< / semantics>< / com:Math> <com:Math><semantics>𝑹𝑨<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{A}}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>𝑹𝑩<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{B}}< / annotation>< / semantics>< / com:Math> are at each occurrence independently H or selected from the group consisting of <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkyl-, aryl, <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> haloalkyl, or R<com:Sup>A< / com:Sup> and R<com:Sup>B< / com:Sup> may form together with the nitrogen atom to which they are attached a 6 membered saturated heterocyclic monocyclic ring system optionally containing a further heteroatom which is nitrogen or oxygen, which may be optionally substituted by <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math>alkyl- and oxo; <com:Math><semantics>𝑹𝑪<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{C}}< / annotation>< / semantics>< / com:Math> is H or selected from the group consisting of <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>(𝑹𝑨𝑹𝑩)<annotation encoding="application / x-tex">(\mathbf{R}^{\mathbf{A}}\mathbf{R}^{\mathbf{B}})< / annotation>< / semantics>< / com:Math>N-, aryl-<com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> C<com:Sub>4< / com:Sub>)alkyl-, Y is selected from the group consisting of -OR<com:Sup>D< / com:Sup>, R<com:Sup>C< / com:Sup>SO<com:Sub>2< / com:Sub>, halo, -NHSO<com:Sub>2< / com:Sub>R<com:Sup>C< / com:Sup>, heteroaryl, (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)heterocycloalkyl, wherein any of such heteroaryl and heterocycloalkyl may be optionally substituted by one or more groups selected from (C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub>)alkyl, - <com:Math><semantics>C(O)N(RARB);<annotation encoding="application / x-tex">C(O)N(R^AR^B);< / annotation>< / semantics>< / com:Math> J is H or selected from the group consisting of <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>ORC<annotation encoding="application / x-tex">OR^C< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>𝑹𝑫<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{D}}< / annotation>< / semantics>< / com:Math> is H or (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl. In a further preferred embodiment, the invention is addressed to compound of formula (I) wherein Z is H or selected from the group consisting of <com:Math><semantics>(RARB)N<annotation encoding="application / x-tex">(R^AR^B)N< / annotation>< / semantics>< / com:Math>-, heteroaryl, preferably thiadiazolyl, thiazolyl, pyrazolyl, pyridazyl, oxadiazolyl, pyridinyl, pyrimidinyl, aryl, preferably phenyl, R<com:Sup>A< / com:Sup>O-, wherein R<com:Sup>A< / com:Sup> is H, each of said heteroaryl and aryl may be optionally substituted by one or more groups selected from methyl, halo, preferably fluorine and chlorine, CN, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)NC(O)-, wherein R<com:Sup>A< / com:Sup> and R<com:Sup>B< / com:Sup> are at each occurrence independently H or methyl, C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)haloalkyl, preferably trifluoromethyl and difluoromethyl, R<com:Sup>A< / com:Sup>O-, wherein R<com:Sup>A< / com:Sup> is H or selected from methyl, trifluoromethyl and difluoromethyl, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkylene-, wherein R<com:Sup>A< / com:Sup> and R<com:Sup>B< / com:Sup> are methyl, cyclopropyl, R<com:Sup>C< / com:Sup>SO<com:Sub>2< / com:Sub>-, wherein R<com:Sup>C< / com:Sup> is methyl, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N- wherein R<com:Sup>A< / com:Sup> and R<com:Sup>B< / com:Sup> are independently H and methyl; <com:Math><semantics>𝑹1<annotation encoding="application / x-tex">\mathbf{R}_1< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>𝑯<annotation encoding="application / x-tex">\mathbf{H}< / annotation>< / semantics>< / com:Math>; R<com:Sub>2< / com:Sub> is selected from the group consisting of heteroaryl(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math>)alkyl-, preferably <com:Math><semantics>([1,2,4]<annotation encoding="application / x-tex">([1,2,4]< / annotation>< / semantics>< / com:Math>triazolo<com:Math><semantics>[4,3−a]<annotation encoding="application / x-tex">[4,3-a]< / annotation>< / semantics>< / com:Math>pyrimidin-3- yl)methyl, (triazolyl)methyl, (triazolyl)ethyl, (imidazo[1,2-a]pyrimidinyl)methyl, (pyrimidinyl)ethyl, (pyrimidinyl)methyl, (pyrazolyl)methyl, (pyridazinyl)methyl, (pyridazinyl)ethyl (oxadiazolyl)methyl, (oxadiazolyl)propyl, (pyridinyl)methyl, (pyridinyl)ethyl, (oxadiazolyl)ethyl, (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)heterocycloalkyl-(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl, preferably (piperidinyl)methyl, (tetrazolyl)methyl, (morpholinyl)ethyl, heteroaryl(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math>)hydroxyalkyl-, preferably (oxadiazolyl)methanol, <com:Math><semantics>(C3−C8)<annotation encoding="application / x-tex">(C_3-C_8)< / annotation>< / semantics>< / com:Math>cycloalkyl<com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>alkyl-, preferably (cyclopropyl)methyl, aryl-(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkyl-, preferably (phenyl)methyl, <com:Math><semantics>(RARB)N(C1−C6)<annotation encoding="application / x-tex">(R^AR^B)N(C_1-C_6)< / annotation>< / semantics>< / com:Math>alkylene-, preferably dimethylaminobuthyl, dimethylaminopropyl, each of said aryl, heteroaryl, cycloalkyl and heterocycloalkyl is optionally further substituted by one or more groups selected from (C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub>)alkyl, preferably methyl and ethyl, trifluoromethyl, OXO, chlorine, R<com:Sup>A< / com:Sup>O-, wherein R<com:Sup>A< / com:Sup> is selected from the group of trifluoroethyl, difluoroethyl, methyl and ethyl, (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)heterocycloalkyl-(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl-, preferably (piperidinyl)methyl, (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)heterocycloalkyl, preferably piperazinyl optionally further substituted by methyl, heteroaryl, preferably pyridinyl, -NHC(O)R<com:Sup>C< / com:Sup>, wherin R<com:Sup>C< / com:Sup> is methyl, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N-, wherein R<com:Sup>A< / com:Sup> and R<com:Sup>B< / com:Sup> are methyl, R<com:Sup>C< / com:Sup>O-, wherein R<com:Sup>C< / com:Sup> is methyl, -C(O)N(R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>); wherein R<com:Sup>A< / com:Sup> is H and R<com:Sup>B< / com:Sup> is methyl; Y is selected from the group consisting of -ORD, RCSO2, halo, -NHSO2RC, heteroaryl wherein any of such heteroaryl may be optionally substituted by one or more groups selected from <com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math>alkyl, <com:Math><semantics>−C(O)N(RARB)<annotation encoding="application / x-tex">-C(O)N(R^AR^B)< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>𝑹𝑫<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{D}}< / annotation>< / semantics>< / com:Math> is (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl, preferably methyl; J is selected from the group consisting of (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl, preferably methyl, <com:Math><semantics>−ORC<annotation encoding="application / x-tex">-OR^{C}< / annotation>< / semantics>< / com:Math> wherein <com:Math><semantics>RC<annotation encoding="application / x-tex">R^{C}< / annotation>< / semantics>< / com:Math> is H or <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>alkyl, preferably methyl. According to specific embodiments, the invention refers to at least one compound as listed in the Table 4 below and pharmaceutical acceptable salts thereof. Table 4: List of preferred compounds having Formula (I) [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] In a further preferred embodiment, the invention is addressed to compound of formula (I) wherein Z is aryl, wherein any of such aryl may be optionally substituted by one or more groups selected from (C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub>)alkyl, halo, CN, <com:Math><semantics>𝑹1<annotation encoding="application / x-tex">\mathbf{R}_1< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>𝑯<annotation encoding="application / x-tex">\mathbf{H}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>𝑹𝟐<annotation encoding="application / x-tex">\mathbf{R_2}< / annotation>< / semantics>< / com:Math> is selected from the group consisting of heteroaryl(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkyl-, (C<com:Sub>3< / com:Sub>- C<com:Sub>8< / com:Sub>)heterocycloalkyl-(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl, (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)heterocycloalkyl, (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)cycloalkyl-(C<com:Sub>1< / com:Sub>- C<com:Sub>6< / com:Sub>)alkyl-, wherein any of such alkyl, heteroaryl may be optionally substituted by one or more groups selected from (C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub>)alkyl, (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)haloalkyl, oxo, R<com:Sup>A< / com:Sup>O-, aryl, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N- and halo; <com:Math><semantics>𝑹𝑨<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{A}}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>𝑹𝑩<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{B}}< / annotation>< / semantics>< / com:Math> are at each occurrence independently H or selected from the group consisting of <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math> alkyl-, <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math> haloalkyl; Y is selected from the group consisting of -OR<com:Sup>D< / com:Sup>, R<com:Sup>C< / com:Sup>SO<com:Sub>2< / com:Sub>, halo and -NHSO<com:Sub>2< / com:Sub>R<com:Sup>C< / com:Sup>, heteroaryl, heterocycloalkyl, wherein any of such heteroaryl may be optionally substituted by one or more groups selected from <com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>−C(O)N(RARB)<annotation encoding="application / x-tex">-C(O)N(R^AR^B)< / annotation>< / semantics>< / com:Math>; J is H or selected from the group consisting of OR<com:Sup>C< / com:Sup>; <com:Math><semantics>𝑹𝑪<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{C}}< / annotation>< / semantics>< / com:Math> is H, or selected form the group consisting of (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl, (<com:Math><semantics>𝑹𝑨𝑹𝑩<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{A}}\mathbf{R}^{\mathbf{B}}< / annotation>< / semantics>< / com:Math>)N-; <com:Math><semantics>𝑹𝑫<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{D}}< / annotation>< / semantics>< / com:Math> is H or (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl. According to a preferred embodiment, the invention refers to at least one compound of Table 5, selected from: Table 5: List of preferred compounds having Formula (I) [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] In a further preferred embodiment, the invention is addressed to compound of formula (I) wherein Z is heteroaryl wherein any of such heteroaryl may be optionally substituted by one or more groups selected from (C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub>)alkyl, halo, CN, (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)haloalkyl; <com:Math><semantics>𝑹1<annotation encoding="application / x-tex">\mathbf{R}_1< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>𝑯<annotation encoding="application / x-tex">\mathbf{H}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>𝑹2<annotation encoding="application / x-tex">\mathbf{R}_2< / annotation>< / semantics>< / com:Math> is selected from the group consisting of heteroaryl(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math>)alkyl-, wherein any of such alkyl, heteroaryl may be optionally substituted by one or more groups selected from (C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub>)alkyl, (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)haloalkyl and -oxo; <com:Math><semantics>𝒀<annotation encoding="application / x-tex">\mathbf{Y}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−ORD<annotation encoding="application / x-tex">-OR^D< / annotation>< / semantics>< / com:Math>; J is H; <com:Math><semantics>𝑹𝑫<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{D}}< / annotation>< / semantics>< / com:Math> is (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl. According to a preferred embodiment, the invention refers to at least one compound 5 of Table 6, selected from: Table 6: List of preferred compounds having Formula (I) [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] In a further preferred embodiment, the invention is directed to a compound of formula (I) as defined above, wherein Y is -OR<com:Sup>D< / com:Sup>, represented by formula (Ia) [Image disponible dans le document PDF, Image available in the PDF document] (Ia) wherein Z is selected from the group consisting of aryl, wherein any of such aryl may be optionally substituted by one or more groups selected from halo; <com:Math><semantics>𝑹1<annotation encoding="application / x-tex">\mathbf{R}_1< / annotation>< / semantics>< / com:Math> is H; <com:Math><semantics>𝑹2<annotation encoding="application / x-tex">\mathbf{R}_2< / annotation>< / semantics>< / com:Math> is selected from the group consisting of heteroaryl(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math>)alkyl-, wherein any of such heteroaryl may be optionally substituted by one or more groups selected from (C<com:Sub>1< / com:Sub>- C<com:Sub>3< / com:Sub>)alkyl, C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)haloalkyl; R<com:Sup>A< / com:Sup> and R<com:Sup>B< / com:Sup> are at each occurrence independently H or selected from the group consisting of <com:Math><semantics>(C1−C4)<annotation encoding="application / x-tex">(C_1-C_4)< / annotation>< / semantics>< / com:Math>alkyl-; <com:Math><semantics>𝑹𝑪<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{C}}< / annotation>< / semantics>< / com:Math> is at each occurrence H or selected from the group consisting of (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl; R<com:Sup>D< / com:Sup> is selected in the group consisting of H, (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl, (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)heterocycloalkyl- <com:Math><semantics>(C1−C6)<annotation encoding="application / x-tex">(C_1-C_6)< / annotation>< / semantics>< / com:Math>alkyl-, <com:Math><semantics>RCOC(O)(C1−C4)<annotation encoding="application / x-tex">R^COC(O)(C_1-C_4)< / annotation>< / semantics>< / com:Math>alkylene-, <com:Math><semantics>(RARB)N(C1−C6)<annotation encoding="application / x-tex">(R^AR^B)N(C_1-C_6)< / annotation>< / semantics>< / com:Math>alkylene-, <com:Math><semantics>(C3−<annotation encoding="application / x-tex">(C_3-< / annotation>< / semantics>< / com:Math> C<com:Sub>8< / com:Sub>)heterocycloalkyl, R<com:Sup>C< / com:Sup>O(C1-C4)alkylene-, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N(O)C(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkylene-, (C<com:Sub>3< / com:Sub>- C<com:Sub>8< / com:Sub>)cycloalkyl-(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl-, wherein any of such heterocycloalkly may be optionally substituted by one or more groups selected from <com:Math><semantics>(C1−C3)<annotation encoding="application / x-tex">(C_1-C_3)< / annotation>< / semantics>< / com:Math> alkyl; J is H. In a further preferred embodiment, the invention is addressed to compound of formula (Ia) wherein Z is H or selected from the group consisting of aryl, preferably phenyl, each of said aryl may be optionally substituted by one or more groups selected from halo, preferably fluorine, <com:Math><semantics>𝑹1<annotation encoding="application / x-tex">\mathbf{R}_1< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>𝑯<annotation encoding="application / x-tex">\mathbf{H}< / annotation>< / semantics>< / com:Math>; R<com:Sub>2< / com:Sub> is selected from the group consisting of heteroaryl(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics>< / com:Math>)alkyl-, (pyrimidinyl)ethyl, (pyridazinyl)methyl, each of said heteroaryl is optionally further substituted by one or more groups selected from (C<com:Sub>1< / com:Sub>-C<com:Sub>3< / com:Sub>)alkyl, preferably methyl trifluoromethyl, <com:Math><semantics>𝑹𝑫<annotation encoding="application / x-tex">\mathbf{R}^{\mathbf{D}}< / annotation>< / semantics>< / com:Math> is H or selected in the group consisting of, (C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl, preferably methyl, propyl, (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)heterocycloalkyl-(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl-, preferably (azetidinyl)methyl, (morpholinyl)methyl, (morpholinyl)ethyl, (oxetanyl)methyl, <com:Math><semantics>RCOC(O)(C1−C4)<annotation encoding="application / x-tex">R^{C}OC(O)(C_1-C_4)< / annotation>< / semantics>< / com:Math>alkylene-, wherein <com:Math><semantics>RC<annotation encoding="application / x-tex">R^{C}< / annotation>< / semantics>< / com:Math> is selected form the group of H and ethyl, (R<com:Sup>A< / com:Sup>R<com:Sup>B< / com:Sup>)N(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkylene-, preferably dimethylaminopropyl, (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)heterocycloalkyl, preferably tetrahydropyranyl, R<com:Sup>C< / com:Sup>O(C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub>)alkylene-, preferably selected from the group of methoxyethyl, propanolyl, <com:Math><semantics>(RARB)N(O)C(C1−C4)<annotation encoding="application / x-tex">(R^AR^B)N(O)C(C_1-C_4)< / annotation>< / semantics>< / com:Math>alkylene-, preferably dimethylacetylamide, tetrahydrofuranyl, (C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub>)cycloalkyl-(C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub>)alkyl-, preferably (cyclopropyl)methyl, each of said heterocycloalkyl may be optionally substituted by one or more groups selected from methyl, ethyl and propyl; J is H. According to specific embodiments, the invention provides at least one compound listed in the Table 7 below and pharmaceutical acceptable salts thereof. Table 7: List of preferred compounds having Formula (Ia) [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] The compounds of formula (I) including all the compounds or at least one of the here above listed can be generally prepared according to the procedure outlined in detail in the Schemes shown below using generally known methods. Scheme 1 [Image disponible dans le document PDF, Image available in the PDF document] In one embodiment of the present invention, compound (IA) may be prepared according to SCHEME 1 from compound (II). Compound (II) was prepared following the procedure described in J.Med Chem., 2015, 58 (8), 3548-3571. Compound (III) may be prepared from Compound (II) by a deoxyamination reaction mediated by coupling reagents like PyBOP with a suitable amine (Reag.1). Compound (IA) may be prepared from Compound (III) by a metal-catalyzed cross coupling reactions like Stille or Suzuki or similars as described in "Transition Metals for Organic Synthesis", 2nd Ed, 1, 2004 with a suitable reagent like (Reag. 2). Alternatevely Compound (V) may be prepared from Compound (III) by metal- catalyzed Miyaura borylation reaction. Compound (IA) may be prepared from Compound (V) by a metal-catalyzed cross coupling reactions like Stille, Suzuki or similar as described in "Transition Metals for Organic Synthesis", 2nd Ed, 1, 2004 with a suitable organohalogen compound like (Reag. 3). In another embodiment, compound (IV) was prepared starting from compound (II) by a metal-catalyzed cross coupling reactions like Stille, Suzuki or similars as described in "Transition Metals for Organic Synthesis", 2nd Ed, 1, 2004 with a suitable Organometallic reagent like (Reag.2). Compound (IA) may be prepared from Compound (V) by deoxyamination reaction mediated by reagents like PyBOP or similar with a suitable amine (Reag.1). Some compounds (IA) may contain a protected hydroxyl or amino group which were then removed under well known procedures. Scheme 2 [Image disponible dans le document PDF, Image available in the PDF document] In another embodiment of the present invention, compound (IB) may be prepared according to SCHEME 2 from compounds (VI). Compound (VII) may be prepared from Compound (VI) by means of a quinazoline ring construction reaction mediated by suitable reagents like triethylorthoacetate or similar. Compound (VIII) may be prepared from Compound (VII) by metal-catalyzed cross coupling reactions like Stille, Suzuki or similar ones with suitable organometallic reagents (Reag.2) like, for example, organoboron compounds. Compounds (IB) may be prepared from compound (VIII) by deoxyamination reaction mediated by reagents like PyBOP or similar in the presence of a suitable amine (Reag. 1). Some compounds (IB) may contain a protected hydroxyl or amino group which were then removed under well known procedures. Scheme 3 [Image disponible dans le document PDF, Image available in the PDF document] In another embodiment of the present invention, compound (IC) may be prepared according to SCHEME 3 from compound (IX). Compound (X) may be prepared from Compound (IX) by metal-catalyzed cross coupling reactions like Stille, Suzuki or similar ones with suitable organometallic reagents (Reag.2) like, for example, organoboron compounds. Compound (XI) may be prepared from Compound (X) by Halogenation with suitable reagents like Bromine, NBS, NIS, Iodine, iodonium salts or similar. Compound (XII) may be prepared from Compound (XI) by hydrolysis in a basic or acidic medium. Compound (XIII) may be prepared from Compound (XII) by quinazoline ring construction reaction with suitable reagents like formamide or similars. Compound (XIV) may be prepared from Compound (XIII) by deoxyamination reaction mediated by reagents like PyBOP or similar in the presence of a suitable amine (Reag.1). Compound (IC) may be prepared from Compound (XIV) by metal-catalyzed cross coupling reactions like Stille, Suzuki or similar ones with suitable organometallic reagents (Reag. 6) like, for example, organoboron compounds. Some compounds (IC) may contain a protected hydroxyl or amino group which were then removed under well known procedures. Compound (IK) may be prepared from Compound (XIV) by amination reactions in the presence of a suitable reagent like, for example, methanesulfonamide. Some compounds (IK) may contain a protected hydroxyl or amino group which were then removed under well known procedures. Scheme 4 [Image disponible dans le document PDF, Image available in the PDF document] In another embodiment of the present invention, compounds (ID) may be prepared according to SCHEME 4 from compounds (IA). Compound (XV) may be prepared from Compound (IA) by means of dealkylation reactions mediated by strong Lewis acids like BBr<com:Sub>3< / com:Sub> or similar. Compounds (ID) were prepared from compounds (XV) by alkylation with a suitable alkylating agent (Reag. 4) like, alkyl chlorides, bromides, iodides, mesylates, tosylates or similar. Alternatively, compounds (ID) may be prepared from compounds (XV) and a suitable alcohol by Mitsunobu-like reactions mediated, for example, by DEAD / PPh3, DIAD / PPh<com:Sub>3< / com:Sub> or CMT. Some compounds (ID) may contain a protected hydroxyl or amino group which were then removed under well-known procedures. Scheme 5 [Image disponible dans le document PDF, Image available in the PDF document] In another embodiment of the present invention, compound (IE) may be prepared according to SCHEME 5 from compounds (XVI). Compound (XVII) may be prepared from Compound (XVI) by deoxyamination reaction mediated by reagents like PyBOP or similar in the presence of a suitable amine (Reag. 1). Compounds (IE) were prepared from Compounds (XVII) by metal-catalyzed cross coupling reactions like Stille, Suzuki or similar ones with suitable organometallic reagents (Reag. 2) like, for example, organoboron compounds. Some compounds (IE) may contain a protected hydroxyl or amino group which were then removed under well known procedures. Scheme 6 [Image disponible dans le document PDF, Image available in the PDF document] In another embodiment of the present invention, compound (IF) and (IG) may be prepared according to SCHEME 6 from compounds (XIII). Compound (XVIII) may be prepared from Compound (XIII) by metal catalyzed sulfenylation reaction with a suitable sulfinate (Reag. 5) like, for example, sodium methanesulfinate. Compound (IF) may be prepared from Compound (XVIII) by deoxyamination reaction mediated by reagents like PyBOP or similar in the presence of a suitable amine (Reag. 1). Some compounds (IF) may contain a protected hydroxyl or amino group which were then removed under well known procedures. In another embodiment of the present invention Compound (XIX) may be prepared from Compound (XVIII) by amination with tributylborate and (aminooxy)sulfonic acid as described in Tetr. Lett. 1994, 39, 7201 Compound (IG) may be prepared from Compound (XIX) by deoxyamination reaction mediated by reagents like PyBOP or similar in the presence of a suitable amine (Reag. 1). Some compounds (IG) may contain a protected hydroxyl or amino group which were then removed under well known procedures. Scheme 7 [Image disponible dans le document PDF, Image available in the PDF document] In another embodiment of the present invention, compound (IH) and (IJ) may be prepared according to SCHEME 7 from compounds (VI). Compound (XX) may be prepared from Compound (VI) by quinazoline ring construction reaction with suitable reagents like Urea or similars. Compound (XXI) may be prepared from Compound (XX) by metal-catalyzed cross coupling reactions like Stille, Suzuki or similar ones with suitable organometallic reagents (Reag. 2) like, for example, organoboron compounds. Compound (XXII) may be prepared from Compound (XXI) by chlorination reaction with suitable reagents like phosphorous oxychloride or similar. Compound (XXIII) may be prepared from Compound (XXII) by amination reaction in the presence of a suitable amine (Reag. 1). Compound (IH) may be prepared from Compound (XXIII) by hydrolisys with a suitable reagent like, for example, acetic acid. Some compounds (IH) may contain a protected hydroxyl or amino group which were then removed under well known procedures. In another embodiment of the present invention Compound (IJ) may be prepared from Compound (XXIII) by reaction with alkoxides, like, for example, Sodium Methoxide. Some compounds (IJ) may contain a protected hydroxyl or amino group which were then removed under well known procedures. In a specific aspect the present invention relates to compounds of formula (Ib) [Image disponible dans le document PDF, Image available in the PDF document] (Ib) wherein R<com:Sub>3< / com:Sub> is OH or halo, R<com:Sub>4< / com:Sub> is H or OH; R<com:Sub>5< / com:Sub> is halo or -OMe; <com:Math><semantics>𝑹6<annotation encoding="application / x-tex">\mathbf{R}_6< / annotation>< / semantics>< / com:Math> is halo or <com:Math><semantics>Z<annotation encoding="application / x-tex">Z< / annotation>< / semantics>< / com:Math>; Z is as defined above. In a further aspect the present invention relates to the use of compounds of formula (Ib) as intermediate in the preparation of compounds of formula (I) as above described. The compounds of the present invention have surprisingly been found to effectively inhibit P2X<com:Sub>3< / com:Sub> receptor and said compounds are useful for the treatment of respiratory disease. In one embodiment, representative compounds of formula (I) of the present invention have surprisingly been found to effectively and selectively inhibit P2X<com:Sub>3< / com:Sub> receptor and said compounds are useful for the treatment of respiratory disease avoiding adverse effect, such as loss of taste response. In a preferred embodiment, the compound of formula (I) are selective P2X<com:Sub>3< / com:Sub> antagonist wherein the selective P2X<com:Sub>3< / com:Sub> antagonist is at least 10-fold selective for P2X<com:Sub>3< / com:Sub> homomeric receptor antagonism versus <com:Math><semantics>P2X2 / 3<annotation encoding="application / x-tex">P2X_{2 / 3}< / annotation>< / semantics>< / com:Math> heteromeric receptor antagonism. In a further preferred embodiment, the selective P2X<com:Sub>3< / com:Sub> antagonist is at least 30-fold selective for P2X<com:Sub>3< / com:Sub> homomeric receptor antagonism versus P2X<com:Sub>2 / 3< / com:Sub> heteromeric receptor antagonism. In a further preferred embodiment, the selective P2X<com:Sub>3< / com:Sub> antagonist is at least 50-fold selective for P2X<com:Sub>3< / com:Sub> homomeric receptor antagonism versus P2X<com:Sub>2 / 3< / com:Sub> heteromeric receptor antagonism. The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in admixture with one or more pharmaceutically acceptable carrier or excipient, either alone or in combination with one or more further active ingredient. In one aspect, the invention refers to a compound of formula (I) according to the invention for use as a medicament. In a further aspect, the invention refers to the use of a compound of formula (I) of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of disorders associated with P2X<com:Sub>3< / com:Sub> receptors mechanism, preferably for the treatment of respiratory diseases. Preferably, the invention refers to a compound of formula (I) for use in the prevention and / or treatment of respiratory diseases, preferably cough, sub-acute or chronic cough, treatment-resistant cough, idiopathic chronic cough, post-viral cough, iatrogenic cough, asthma, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and cough associated with respiratory diseases such as COPD, asthma and bronchospasm. More preferably, the invention refers to a compounds of formula (I) for use in the prevention and / or treatment of chronic cough and cough associated with respiratory diseases such as COPD, asthma and bronchospasm. The invention also provides a method for the prevention and / or treatment of disorders associated with P2X<com:Sub>3< / com:Sub> receptors mechanisms, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the invention. In particular the invention refers to a method for the prevention and / or treatment wherein the disorder is cough, sub-acute or chronic cough, treatment-resistant cough, idiopathic chronic cough, post-viral cough, iatrogenic cough, asthma, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and cough associated with respiratory diseases such as COPD, asthma and bronchospasm, wherein said method comprises the administration of a proper amount of a compound of formula (I) to a patient in the need thereof. In a further preferred embodiment, the disorder is chronic cough. The methods of treatment of the invention comprise administering a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof. As used herein, "safe and effective amount" in reference to a compound of formula (I) or a pharmaceutically acceptable salt thereof or other pharmaceutically-active agent means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects and it can nevertheless be routinely determined by the skilled artisan. The compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. Typical daily dosages may vary depending upon the particular route of administration chosen. The invention also provides pharmaceutical compositions of compounds of formula (I) in admixture with one or more pharmaceutically acceptable carrier or excipient, for example those described in Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., N.Y., U.S.A. Administration of the compounds of the invention and their pharmaceutical compositions may be accomplished according to patient needs, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternally and by infusion) and by inhalation. Preferably the compounds of the present invention may be administered orally or by inhalation. Various solid oral dosage forms can be used for administering compounds of the invention including such solid forms as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders. The compounds of the invention can be administered alone or combined with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and known excipients, including suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like. Time release capsules, tablets and gels are also advantageous in administering the compounds of the invention. Preferably the compounds of the invention are administered in forms of tablets. Various liquid oral dosage forms can also be used for administering compounds of the invention, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs. Such dosage forms can also contain suitable known inert diluents such as water and suitable known excipients such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and / or suspending the compounds of the invention. The compounds of the invention may be injected, for example, intravenously, in the form of an isotonic sterile solution. For the treatment of the diseases of the respiratory tract, the compounds according to the invention are preferably administered by inhalation. Inhalable preparations include inhalable powders, propellant-containing metering aerosols or propellant-free inhalable formulations. For administration as a dry powder, single- or multi-dose inhalers known from the prior art may be utilized. In that case the powder may be filled in gelatine, plastic or other capsules, cartridges or blister packs or in a reservoir. A diluent or carrier chemically inert to the compounds of the invention, e.g. lactose or any other additive suitable for improving the respirable fraction may be added to the powdered compounds of the invention. Inhalation aerosols containing propellant gas such as hydrofluoroalkanes may contain the compounds of the invention either in solution or in dispersed form. The propellant-driven formulations may also contain other ingredients such as co-solvents, stabilizers and optionally other excipients. The propellant-free inhalable formulations comprising the compounds of the invention may be in form of solutions or suspensions in an aqueous, alcoholic or hydroalcoholic medium and they may be delivered by jet or ultrasonic nebulizers known from the prior art or by soft-mist nebulizers. Preferably, the compound of the present invention are administered orally. The compounds of the invention can be administered as the sole active agent or in combination with other pharmaceutical active ingredients. Preferably, the compound of the present invention can be combined with therapeutic agents or active ingredients useful for the treatment of disease which are related to or mediated by P2X<com:Sub>3< / com:Sub> receptor. The dosages of the compounds of the invention depend upon a variety of factors including among others the particular disease to be treated, the severity of the symptoms, the route of administration, and the like. The invention is also directed to a device comprising a pharmaceutical composition comprising a compound of formula (I) according to the invention, in form of a single- or multi-dose dry powder inhaler or a metered dose inhaler. The various aspects of the invention described in this application are illustrated buy the following examples which are not meant to limit the invention in any way. following examples illustrate the invention. The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given. PREPARATIONS OF INTERMEDIATES AND EXAMPLES Chemical names were generated using the Dotmatics software. In some cases generally accepted names of commercially available reagents were used in place of Dotmatics software generated names. All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art. (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine HCl, <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-1-(6- methylpyridazin-3-yl)ethan-1-amine HCl were prepared accordingly to the procedure described in WO2016 / 091776. Abbreviation – Meaning Et<com:Sub>2< / com:Sub>O: diethyl ether; Et<com:Sub>3< / com:Sub>N: triethyl amine; TEA: triethyl amine; DCC: N,N'-Dicyclohexylcarbodiimide; PyBOP: (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate; DMF: dimethylformamide; EtOAc: Ethyl acetate; RT: room temperature; THF: tetrahydrofuran; DCM: dichloromethane; MeOH: methyl alcohol; EtOH: ethylic alcohol; TFA: Trifluoroacetic acid; LC-MS: Liquid Chromatography / Mass Spectrometry; HPLC: high pressure liquid chromatography; MPLC: medium pressure liquid chromatography; SFC: Supercritical Fluid Chromatography; dppf: 1,1'- Bis( diphenylphosphino) ferrocene; DIEA or DIPEA: N,N-Diisopropylethylamine; MeCN: Acetonitrile; MTBE: tert-Butyl methyl ether; TBDMSCl: tert-Butyl(chloro)dimethylsilane; DMSO: Dimethylsulfoxide; Boc<com:Sub>2< / com:Sub>O: di-tert-butyl dicarbonate; UPLC: Ultra Performance Liquid Chromatography. General Experimental Details and methods Analytical Methods Liquid Chromatography-Mass Spectrometry Method 1 UPLC-MS was performed on a Waters Acquity I-Class with Waters Diode Array Detector coupled to a Waters SQD2 single quadrapole mass spectrometer using an Waters HSS C18 column (1.8 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>m, 100 <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 2.1 mm) being initially held at 5% acetonitrile / water (with 0.1% formic acid in each mobile phase) for 1.2 minutes, followed by a linear gradient of 5-100% within 3.5 minutes and then held at 100% for 1.5 minutes (<com:Math><semantics>F=0.5<annotation encoding="application / x-tex">F = 0.5< / annotation>< / semantics>< / com:Math> mL / min). Method 2 UPLC-MS was performed on a Waters Acquity I-Class with Waters Diode Array Detector coupled to a Waters SQD2 single quadrapole mass spectrometer using an Waters BEH Shield RP18 column (1.7 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>m, 100 <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 2.1 mm) being initially held at 5% acetonitrile / water (with 10 mM ammonium bicarbonate in each mobile phase) for 1.2 minutes, followed by a linear gradient of 5-100% within 3.5 minutes and then held at <com:Math><semantics>100%<annotation encoding="application / x-tex">100\%< / annotation>< / semantics>< / com:Math> for 1.5 minutes (F = 0.5 mL / min). Method 3 UPLC-MS was performed on a Waters DAD + Waters SQD2, single quadrapole UPLC-MS spectrometer using an Acquity UPLC BEH Shield RP18 1.7um 100 x 2.1mm (Plus guard cartridge), maintained at temp column being initially held at 5% acetonitrile / water (with 10 mM ammonium bicarbonate in each mobile phase) for 0.4 minutes, followed by a linear gradient of 5-95% within 6.4 minutes and then held at 95% for 1.2 minutes (<com:Math><semantics>F=0.4 mL / min<annotation encoding="application / x-tex">F = 0.4 \text{ mL / min}< / annotation>< / semantics>< / com:Math>). Method 4 UPLC-MS was performed on a Waters DAD + Waters SQD2, single quadrapole UPLC-MS spectrometer using an Acquity UPLC BEH Shield RP18 1.7um 100 x 2.1mm (Plus guard cartridge), maintained at temp column being initially held at 5% Acetonitrile (Far UV grade) with 0.1% (V / V) formic acid / Water (High purity via PureLab Option unit) with 0.1% formic acid for 0.4 minutes, followed by a linear gradient of 5-95% within 6.4 minutes and then held at 95% for 1.2 minutes (<com:Math><semantics>F=0.4 mL / min<annotation encoding="application / x-tex">F = 0.4 \text{ mL / min}< / annotation>< / semantics>< / com:Math>). Method 5 Aquity UPLC - QDa Mass Spectrometer with a C18-reverse-phase column (50 × 2.1 mm Acquity CSH with 1.7 µm particle size) maintained at 40 °C, elution with A: 95 / 5 water / acetonitrile + 0.05% formic acid; B: 95 / 5 acetonitrile / water + 0.05% formic acid. Gradient: [Image disponible dans le document PDF, Image available in the PDF document] Detection-MS, UV PDA MS ionisation method-Electrospray (positive / negative ion). Aquity UPLC - QDa Mass Spectrometer with a C18-reverse-phase column (50 × 2.1 mm Acquity BEH with 1.7 µm particle size) maintained at 40 °C, elution with A: 95 / 5 water / acetonitrile + 0.05% conc. ammonia; B: 95 / 5 acetonitrile / water + 0.05% conc. ammonia. Gradient: [Image disponible dans le document PDF, Image available in the PDF document] Detection-MS, UV PDA MS ionisation method-Electrospray (positive / negative ion) Method 7 Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific MSQ Pluse quipped with a Kinetex® 2.6 µm XB-C18 (4.6x50mm), 110A maintained at 25 °C, elution with A: 0.1 % v / v water solution of formic acid, B: 0.1 % v / v acetonitrile solution of formic acid Gradient: [Image disponible dans le document PDF, Image available in the PDF document] Detection-MS, UV PDA MS ionisation method-Electrospray (positive / negative ion) NMR <com:Sup>1< / com:Sup>H Nuclear magnetic resonance (NMR) spectroscopy was carried out using a Bruker or Varian instruments operating at 300 or 400 MHz using the stated solvent at around room temperature unless otherwise stated. In all cases, NMR data were consistent with the proposed structures. Characteristic chemical shifts (<com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math>) are given in parts-per- million using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; m, multiplet; br, broad. Preparative reverse-phase HPLC conditions Preparative HPLC purification was performed by reverse phase HPLC using a Waters Fractionlynx preparative HPLC system (2525 pump, 2996 / 2998 UV / VIS detector, 2767 liquid handler) or an equivalent HPLC system such as a Gilson Trilution UV directed system. The Waters 2767 liquid handler acted as both auto-sampler and fraction collector. The columns used for the preparative purification of the compounds were a Waters Sunfire OBD Phenomenex Luna Phenyl Hexyl or Waters Xbridge Phenyl at 10 μm 19 × 150 mm or Waters CSH Phenyl Hexyl, 19 × 150, 5 μm column. Appropriate focused gradients were selected based on acetonitrile and methanol solvent systems under either acidic or basic conditions. The modifiers used under acidic / basic conditions were formic acid or trifluoroacetic acid (0.1% V / V) and ammonium bicarbonate (10 mM) respectively. The purification was controlled by Waters Fractionlynx software through monitoring at 210-400 nm, and triggered a threshold collection value at 260 nm and, when using the Fractionlynx, the presence of target molecular ion as observed under API conditions. Collected fractions were analysed by LCMS (Waters Acquity systems with Waters SQD). Chiral Supercritical Fluid Chromatography (SFC) separation protocol The diastereomeric separation of compounds was achieved by Supercritical Fluid Chromatography (SFC) using a Waters Thar Prep100 preparative SFC system (P200 CO2 pump, 2545 modifier pump, 2998 UV / VIS detector, 2767 liquid handler with Stacked Injection Module). The Waters 2767 liquid handler acted as both auto-sampler and fraction collector. Appropriate isocratic methods were selected based on methanol, ethanol or isopropanol solvent systems under un-modified or basic conditions. The standard SFC method used was modifier, CO2, 100 mL / min, 120 Bar backpressure, 40 °C column temperature. The modifier used under basic conditions was diethylamine <com:Math><semantics>(0.1% V / V)<annotation encoding="application / x-tex">(0.1\% \text{ V / V})< / annotation>< / semantics>< / com:Math>. The modifier used under acidic conditions was either formic acid <com:Math><semantics>(0.1%<annotation encoding="application / x-tex">(0.1\%< / annotation>< / semantics>< / com:Math> <com:Math><semantics>V / V<annotation encoding="application / x-tex">V / V< / annotation>< / semantics>< / com:Math>) or trifluoroacetic acid (0.1% <com:Math><semantics>V / V<annotation encoding="application / x-tex">V / V< / annotation>< / semantics>< / com:Math>). The SFC purification was controlled by Waters Fractionlynx software through monitoring at 210-400 nm and triggered at a threshold collection value, typically 260 nm. Collected fractions were analysed by SFC (Waters / Thar SFC systems with Waters SQD). The fractions that contained the desired product were concentrated by vacuum centrifugation. Supercritical Fluid Chromatography – Mass Spectrometry analytical conditions Method 8 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a Lux Cellulose-3 column with a 15% methyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. Method 9 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a Lux Cellulose-3 column with a 20% methyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. 5 Method 10 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a Lux Cellulose-4 column with a 55% ethyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. Method 11 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a Lux Cellulose-4 column with a 20% iso-propyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. Method 12 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a Lux Cellulose-4 column with a 30% iso-propyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. Method 13 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a Lux Cellulose-4 column with a 50% iso-propyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. Method 14 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a Lux Cellulose-4 column with a 25% methyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. Method 15 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a YMC Amylose-C column with a 15% ethyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. 5 Method 16 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a YMC Amylose-C column with a 25% iso-propyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. Method 17 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a YMC Amylose-C column with a 35% iso-propyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. Method 18 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a YMC Amylose-C column with a 55% iso-propyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. Method 19 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a YMC Amylose-C column with a 15% methyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. Method 20 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a YMC Amylose-C column with a 20% methyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. Method 21 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a YMC Cellulose-C column with a 15% iso-propyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. 5 Method 22 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a YMC Cellulose-C column with a 15% methyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. Method 23 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a YMC Cellulose-C column with a 25% methyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. Method 24 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a YMC Cellulose-SC column with a 55% iso-propyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. Method 25 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a Lux Cellulose-3 column with a 10% methyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. Method 26 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a Lux Cellulose-3 column with a 25% methyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. Method 27 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a Lux Cellulose-3 column with a 30% methyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. 5 Method 28 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a Lux Cellulose-4 column with a 40% iso-propyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. Method 29 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a Lux Cellulose-4 column with a 40% methyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. Method 30 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a Lux Cellulose-4 column with a 50% methyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. Method 31 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a Lux Cellulose-4 column with a 55% iso-propyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. Method 32 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a Lux Cellulose-4 column with a 55% methyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. Method 33 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a YMC Amylose-C column with a 20% ethyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. 5 Method 34 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a YMC Amylose-C column with a 30% iso-propyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. Method 35 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a YMC Amylose-C column with a 30% methyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. Method 36 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a YMC Amylose-C column with a 40% methyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. Method 37 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a YMC Amylose-C column with a 55% methyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. Method 38 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a YMC Cellulose-C column with a 20% methyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. Method 39 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a YMC Cellulose-SC column with a 35% iso-propyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine) isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. 5 Method 40 SFC-MS was performed on a Waters / Thar SFC systems with Waters SQD using a YMC Cellulose-SC column with a 45% iso-propyl alcohol / CO<com:Sub>2< / com:Sub> (with 0.1% diethylamine)isocratic run at 5 mL / min, 120 Bar backpressure, 40 °C column temperature. PREPARATION OF INTERMEDIATES AND EXAMPLES Example 1 6-(4-Fluorophenyl)-8-methoxy-N-(1-(3-methyl-1,2,4-oxadiazol-5- yl)ethyl)quinazolin-4-amine Preparation of Intermediate 1, 2-Amino-5-bromo-3-methoxybenzoic acid hydrobromide [Image disponible dans le document PDF, Image available in the PDF document] A solution of bromine (6.0 g, 1.9 mL, 37.70 mmol) in chloroform (15 mL) was added dropwise over a period of one hour to a suspension of 2-amino-3-methoxybenzoic acid (6.0 g, 35.90 mmol) in chloroform (180 mL) at 0 °C. The reaction was stirred for a further five hours and slowly allowed to warm to room temperature. The solvent was removed in vacuo and the residue was triturated with diethyl ether. The reaction was filtered to give the title compound as a beige solid (11.3 g, 96%). LCMS (Method 4): <com:Math><semantics>[MH+]=247<annotation encoding="application / x-tex">[MH+] = 247< / annotation>< / semantics>< / com:Math> at 4.07 min. Preparation of Intermediate 2 6-Bromo-8-methoxyquinazolin-4-ol [Image disponible dans le document PDF, Image available in the PDF document] A solution 2-amino-5-bromo-3-methoxybenzoic acid hydrobromide (Intermediate 1) (10.0 g, 30.60 mmol) in formamide (40 mL) was heated to 165 °C for 18 hours. After return to room temperature, the reaction was diluted with water (100 mL) and poured into ice water (400 mL) and filtered. The solid was washed with water (200 mL) and diethyl ether (200 mL) to give the title compound as a light brown solid (5.9 g, 76%). LCMS (Method 4): <com:Math><semantics>[MH+]=255<annotation encoding="application / x-tex">[MH+] = 255< / annotation>< / semantics>< / com:Math> at 3.07 min. Preparation of Intermediate 3, 6-(4-Fluorophenyl)-8-methoxyquinazolin-4-ol [Image disponible dans le document PDF, Image available in the PDF document] Nitrogen was bubbled for 5 min through a mixture of 6-bromo-8- methoxyquinazolin-4-ol (Intermediate 2) (1.18 g, 4.63 mmol), 4-fluorophenylboronic acid (710 mg, 5.09 mmol) and cesium carbonate (5.73 g, 17.58 mmol) in 1,4-dioxane (30 mL) and water (7.5) mL), then <com:Math><semantics>[1,1′−<annotation encoding="application / x-tex">[1,1'-< / annotation>< / semantics>< / com:Math> bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (190 mg, 0.23 mmol) was added and the reaction was heated to 110 °C for 5 hours. After return to room temperature, the reaction was diluted with water (20 mL), filtered and the solid was washed with 10% methanol in diethyl ether then with diethyl ether to give the title compound (1.0 g, 80%) as a beige solid. LCMS (Method 5): <com:Math><semantics>[MH+]=271.1<annotation encoding="application / x-tex">[MH+] = 271.1< / annotation>< / semantics>< / com:Math> at 0.81 min. <com:Math><semantics>6−(4−Fluorophenyl)−8−methoxy−N−(1−(3−methyl−1,2,4−oxadiazol−5−<annotation encoding="application / x-tex">6-(4-Fluorophenyl)-8-methoxy-N-(1-(3-methyl-1,2,4-oxadiazol-5-< / annotation>< / semantics>< / com:Math> yl)ethyl)quinazolin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] To a solution of 6-(4-fluorophenyl)-8-methoxyquinazolin-4-ol (Intermediate 3) (100 mg, 0.37 mmol) in N,N-dimethylformamide (2 mL) was successively added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (212 mg, 0.41 mmol) and di-isopropylethylamine (0.32 mL, 1.85 mmol). The resulting mixture was heated to 40 °C and stirred for 20 min, 1-(3-methyl-1,2,4-oxadiazol-5-yl)ethan-1-amine (67 mg, 0.41 mmol) was then added and the heating was maintained at 40 °C for 18 hours. After return to room temperature, the mixture was diluted with ethyl acetate (50 mL) and water (20 mL). The organic phase was washed with brine (2 <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 20 mL), passed through a hydrophobic frit and the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound (43 mg, 31%) as a white solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.85 (d, J = 6.8 Hz, 1 H), 8.49 (s, 1 H), 8.24 (s, 1 H), <com:Math><semantics>7.99<annotation encoding="application / x-tex">7.99< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=5.6<annotation encoding="application / x-tex">J = 5.6< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>8.6<annotation encoding="application / x-tex">8.6< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>2<annotation encoding="application / x-tex">2< / annotation>< / semantics>< / com:Math> H), <com:Math><semantics>7.61<annotation encoding="application / x-tex">7.61< / annotation>< / semantics>< / com:Math> (s, <com:Math><semantics>1<annotation encoding="application / x-tex">1< / annotation>< / semantics>< / com:Math> H), <com:Math><semantics>7.44<annotation encoding="application / x-tex">7.44< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=8.8<annotation encoding="application / x-tex">J = 8.8< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>8.8<annotation encoding="application / x-tex">8.8< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>2<annotation encoding="application / x-tex">2< / annotation>< / semantics>< / com:Math> H), <com:Math><semantics>5.88−5.82<annotation encoding="application / x-tex">5.88-5.82< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(m,1H),4.08(s,3H),2.37(s,3H),1.78(d,J=7.1Hz,3H)<annotation encoding="application / x-tex">(m, 1 H), 4.08 (s, 3 H), 2.37 (s, 3 H), 1.78 (d, J = 7.1 Hz, 3 H)< / annotation>< / semantics>< / com:Math>. LCMS (Method 4): [MH+] <com:Math><semantics>=375<annotation encoding="application / x-tex">= 375< / annotation>< / semantics>< / com:Math> at 3.29 min. The compounds reported in the table below were synthesised following the same procedure described for the preparation of 6-(4-Fluorophenyl)-8-methoxy-N-(1-(3- methyl-1,2,4-oxadiazol-5-yl)ethyl)quinazolin-4-amine. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Example 114 N-(((1r,4r)-4-Aminocyclohexyl)methyl)-6-(4-fluorophenyl)-8- methoxyquinazolin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] 5 Step 1: Preparation of Benzyl <com:Math><semantics>((1r,4r)−4−(((6−(4−fluorophenyl)−8−<annotation encoding="application / x-tex">((1r,4r)-4-(((6-(4-fluorophenyl)-8-< / annotation>< / semantics>< / com:Math> methoxyquinazolin-4-yl)amino)methyl)cyclohexyl)carbamate [Image disponible dans le document PDF, Image available in the PDF document] To a solution of 6-(4-fluorophenyl)-8-methoxyquinazolin-4-ol (Intermediate 3) (80 mg, 0.30 mmol) in N,N-dimethylformamide (2 mL) was successively added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (169 mg, 0.32 mmol) and di-isopropylethylamine (0.32 mL, 1.85 mmol). The resulting mixture was heated to 40 °C and stirred for 20 min, benzyl <com:Math><semantics>((1r,4r)−4−<annotation encoding="application / x-tex">((1r,4r)-4-< / annotation>< / semantics>< / com:Math> (aminomethyl)cyclohexyl)carbamate (93 mg, 0.36 mmol) was then added and the heating was maintained at 40 °C for 18 hours. After return to room temperature, the mixture was diluted with ethyl acetate (50 mL) and water (20 mL). The organic phase was washed with brine (2 × 20 mL), passed through a hydrophobic frit and the solvent was removed in vacuo. The residue was used directly in the next step without any further purification. Step 2: Preparation of <com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-(((1<com:Math><semantics>r<annotation encoding="application / x-tex">r< / annotation>< / semantics>< / com:Math>,4<com:Math><semantics>r<annotation encoding="application / x-tex">r< / annotation>< / semantics>< / com:Math>)-4-aminocyclohexyl)methyl)-6-(4-fluorophenyl)- 8-methoxyquinazolin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] Nitrogen was bubbled for 5 min through a solution of benzyl <com:Math><semantics>((1r,4r)−4−((6−(4−<annotation encoding="application / x-tex">((1r,4r)-4-((6-(4-< / annotation>< / semantics>< / com:Math> fluorophenyl)-8-methoxyquinazolin-4-yl)amino)methyl)cyclohexyl)carbamate (152 mg, 0.30 mmol) in MeOH (3.0 mL) then Pd / C (10%) (31 mg, 0.03 mmol) was added followed by portion wise addition of sodium borohydride (88 mg, 2.36 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction was filtered through Celite® and then loaded onto an SCX cartridge. The cartridge was washed with methanol and the filtrate was collected when eluting with a 7M solution of ammonia in methanol. The solvent was removed in vacuo and the residue was purified by preparative HPLC to give the title compound (2.0 mg, 1.8%) as a brown solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, MeOD) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.45 (s, 1 H), 8.31 (s, 1 H), 7.80 (d, J = 1.6 Hz, 1 H), <com:Math><semantics>7.72−7.68<annotation encoding="application / x-tex">7.72-7.68< / annotation>< / semantics>< / com:Math> (m, 2 H), <com:Math><semantics>7.38<annotation encoding="application / x-tex">7.38< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=1.6<annotation encoding="application / x-tex">J = 1.6< / annotation>< / semantics>< / com:Math> Hz, 1 H), <com:Math><semantics>7.13<annotation encoding="application / x-tex">7.13< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=8.8<annotation encoding="application / x-tex">J = 8.8< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>8.8<annotation encoding="application / x-tex">8.8< / annotation>< / semantics>< / com:Math> Hz, 2 H), <com:Math><semantics>3.98<annotation encoding="application / x-tex">3.98< / annotation>< / semantics>< / com:Math> (s, 3 H), <com:Math><semantics>3.41<annotation encoding="application / x-tex">3.41< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=7.0<annotation encoding="application / x-tex">J = 7.0< / annotation>< / semantics>< / com:Math> Hz, 2 H), <com:Math><semantics>2.95−2.86<annotation encoding="application / x-tex">2.95-2.86< / annotation>< / semantics>< / com:Math> (m, 1 H), <com:Math><semantics>1.97−1.87<annotation encoding="application / x-tex">1.97-1.87< / annotation>< / semantics>< / com:Math> (m, 4 H), <com:Math><semantics>1.80−1.70<annotation encoding="application / x-tex">1.80-1.70< / annotation>< / semantics>< / com:Math> (m, 1 H), <com:Math><semantics>1.32−1.03<annotation encoding="application / x-tex">1.32-1.03< / annotation>< / semantics>< / com:Math> (m, 4 H). LCMS (Method 4): [MH+] = 381 at 2.43 min. Intermediate 4 <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-6-Bromo-8-methoxy-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-(1-(6-methylpyridazin-3-yl)ethyl)quinazolin-4- amine [Image disponible dans le document PDF, Image available in the PDF document] To a solution of 6-bromo-8-methoxyquinazolin-4-ol (Intermediate 2) (65 mg, 0.27 mmol) in N,N-dimethylformamide (1.5 mL) was successively added (benzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate (139 mg, 0.27 mmol) and di- isopropylethylamine (0.2 mL, 0.81 mmol). The resulting mixture was heated to 60 °C for one hour then <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-1-<com:Math><semantics>(6<annotation encoding="application / x-tex">(6< / annotation>< / semantics>< / com:Math>-methylpyridazin-3-yl)ethan-1-amine <com:Math><semantics>(65 mg,0.27 mmol)<annotation encoding="application / x-tex">(65 \text{ mg}, 0.27 \text{ mmol})< / annotation>< / semantics>< / com:Math> was added and the heating was maintained at 60 °C for 18 hours. After return to room temperature, the reaction mixture was directly concentrated onto silica gel and purified by chromatography on silica gel eluting with 0-100% (10% MeOH in ethyl acetate) in ethyl acetate to give the title compound as a beige solid (100 mg, quantitative yield). LCMS (Method 4): <com:Math><semantics>[MH+]=374<annotation encoding="application / x-tex">[MH+] = 374< / annotation>< / semantics>< / com:Math> at 2.42 min. The following intermediates reported in the table below were synthesised following the same procedure described for the preparation of <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-6-Bromo-8-methoxy-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(1−(6−<annotation encoding="application / x-tex">(1-(6-< / annotation>< / semantics>< / com:Math> methylpyridazin-3-yl)ethyl)quinazolin-4-amine (Intermediate 4): [Image disponible dans le document PDF, Image available in the PDF document] Example 115 5 8-Methoxy-6-(5-methyl-1,3,4-thiadiazol-2-yl)-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] Step 1: Preparation of 8-methoxy-N-((6-methylpyridazin-3-yl)methyl)-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] Nitrogen was bubbled for 5 min through a mixture of 6-bromo-8-methoxy-N-((6- methylpyridazin-3-yl)methyl)quinazolin-4-amine (Intermediate 6) (250 mg, 0.69 mmol), bis-(pinacolato)diboron (194 mg, 0.76 mmol), [1,1'-bis-(diphenylphosphino)- ferrocene]dichloropalladium(II) (25 mg, 0.03 mmol) and potassium acetate (204 mg, 2.08 mmol) in 1,4-dioxane (15.0 mL). The mixture was heated at 90 °C for 18 hours. After return to room tempearature, the reaction was filtered through Celite® and the solvent was removed in vacuo. The residue was taken on to the next step without further purification. Step 2: Preparation of 8-methoxy-6-(5-methyl-1,3,4-thiadiazol-2-yl)-N-((6- methylpyridazin-3-yl)methyl)quinazolin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] Nitrogen was bubbled for 5 min through a mixture of 2-bromo-5-methyl-1,3,4- thiadiazole (34 mg, 0.19 mmol), 8-methoxy-N-((6-methylpyridazin-3-yl)methyl)-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-amine (70 mg, 0.17 mmol), potassium carbonate (36 mg, 0.26 mmol) and water (0.5 mL) in 1,4-dioxane (4.0 mL), then tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.02 mmol) was added. The resulting mixture was heated to 95 °C for 16 hours. After return to room temperature, the reaction was filtered through Celite®, rinced with ethyl acetate (20 mL). The organic phases were combined, passed through a hydrophobic frit and the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound as an off-white solid (21.0 mg, 32%). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 9.31 (dd, J = 5.8, 5.8 Hz, 1 H), 8.47 (s, 1 H), 8.44 <com:Math><semantics>(d,J=1.7Hz,1H),7.80(d,J=1.4Hz,1H),7.58(d,J=8.7Hz,1H),7.51(d,J=8.7Hz,1H),7.51(d,J=8.7Hz,1H),7.51(d,J=8.7Hz,1H),7.51(d,J=8.7Hz,1H),7.51(d,J=8.7Hz,1H),7.51(d,<annotation encoding="application / x-tex">(d, J = 1.7 Hz, 1 H), 7.80 (d, J = 1.4 Hz, 1 H), 7.58 (d, J = 8.7 Hz, 1 H), 7.51 (d, J = 8.7 Hz, 1 H), 7.51 (d, J = 8.7 Hz, 1 H), 7.51 (d, J = 8.7 Hz, 1 H), 7.51 (d, J = 8.7 Hz, 1 H), 7.51 (d, J = 8.7 Hz, 1 H), 7.51 (d,< / annotation>< / semantics>< / com:Math> Hz, 1 H), <com:Math><semantics>5.03<annotation encoding="application / x-tex">5.03< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=5.8<annotation encoding="application / x-tex">J = 5.8< / annotation>< / semantics>< / com:Math> Hz, 2 H), <com:Math><semantics>4.03<annotation encoding="application / x-tex">4.03< / annotation>< / semantics>< / com:Math> (s, 3 H), <com:Math><semantics>2.84<annotation encoding="application / x-tex">2.84< / annotation>< / semantics>< / com:Math> (s, 3 H), <com:Math><semantics>2.60<annotation encoding="application / x-tex">2.60< / annotation>< / semantics>< / com:Math> (s, 3 H). LCMS (Method 3): <com:Math><semantics>[MH+]=380<annotation encoding="application / x-tex">[MH+] = 380< / annotation>< / semantics>< / com:Math> at 2.13 min. The following compounds reported in the table below were prepared according to the same procedure described for the preparation of 8-methoxy-6-(5-methyl-1,3,4- thiadiazol-2-yl)-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Example 140 8-Methoxy-N-((6-methylpyridazin-3-yl)methyl)-6-(5-methylthiazol-2- yl)quinazolin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] - Step 1: Preparation of 6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-8-methoxy-N-((6- methylpyridazin-3-yl)methyl)quinazolin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] Nitrogen was bubbled for 5 min through a mixture of 6-bromo-8-methoxy-N-((6- methylpyridazin-3-yl)methyl)quinazolin-4-amine (Intermediate 6) (100 mg, 0.28 mmol), bis(neopentyl glycolato)diboron (66 mg, 0.29 mmol), <com:Math><semantics>[1,1]<annotation encoding="application / x-tex">[1,1]< / annotation>< / semantics>< / com:Math>- bis(diphenylphosphino)ferrocene]-dichloropalladium (II) complex with dichloromethane (10 mg, 0.02 mmol) and potassium acetate (54 mg, 0.55 mmol) in 1,4-dioxane (3.0 mL). The mixture was heated to 100 °C for 3 hours. After return to room temperature, the mixture was taken on to the next step as a 1,4-dioxane solution without further purification. Step 2: Preparation of 8-methoxy-N-((6-methylpyridazin-3-yl)methyl)-6-(5- methylthiazol-2-yl)quinazolin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] To the above solution of 6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-8-methoxy-N- ((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine (100 mg, 0.28 mmol) was added aqueous caesium carbonate (181 mg, 0.56 mmol, 0.4 mL), 2-bromo-5-methylthiazole (64 mg, 0.28 mmol) and tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.02 mmol). The resulting mixture was heated to 95 °C for 16 hours. After return to room temperature, the mixture was filtered through Celite® and the filter cake rinsed with ethyl acetate (<com:Math><semantics>2×10<annotation encoding="application / x-tex">2 \times 10< / annotation>< / semantics>< / com:Math> mL). The organic phases were washed with saturated aqueous ammonium chloride (10 mL), passed through a hydrophobic frit and the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound as an off-white solid (25 mg, 24%). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 9.24 (dd, J = 5.7, 5.7 Hz, 1 H), 8.43 (s, 1 H), 8.37 <com:Math><semantics>(d,J=1.5Hz,1H),7.75(d,J=1.5Hz,1H),7.68(d,J=1.1Hz,1H),7.57(d,J=8.7Hz,1H)<annotation encoding="application / x-tex">(d, J = 1.5 Hz, 1 H), 7.75 (d, J = 1.5 Hz, 1 H), 7.68 (d, J = 1.1 Hz, 1 H), 7.57 (d, J = 8.7 Hz, 1 H)< / annotation>< / semantics>< / com:Math> Hz, 1 H), <com:Math><semantics>7.50<annotation encoding="application / x-tex">7.50< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=8.7<annotation encoding="application / x-tex">J = 8.7< / annotation>< / semantics>< / com:Math> Hz, 1 H), <com:Math><semantics>5.02<annotation encoding="application / x-tex">5.02< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=5.8<annotation encoding="application / x-tex">J = 5.8< / annotation>< / semantics>< / com:Math> Hz, 2 H), <com:Math><semantics>4.00<annotation encoding="application / x-tex">4.00< / annotation>< / semantics>< / com:Math> (s, 3 H), <com:Math><semantics>2.60<annotation encoding="application / x-tex">2.60< / annotation>< / semantics>< / com:Math> (s, 3 H), 2.50 (s, 3 H). LCMS (Method 3): <com:Math><semantics>[MH+]=379<annotation encoding="application / x-tex">[MH+] = 379< / annotation>< / semantics>< / com:Math> at 3.20 min. The following compounds reported in the table below were prepared according to the same procedure described for the preparation of 8-methoxy-N-((6-methylpyridazin- 3-yl)methyl)-6-(5-methylthiazol-2-yl)quinazolin-4-amine: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Example 163 8-Methoxy-6-(1-methyl-1H-pyrazol-4-yl)-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] 5 To a solution of 6-bromo-8-methoxy-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine (Intermediate 6) (100 mg, 0.28 mmol) in 1,4-dioxane (2.0 mL) was added 1-methyl-4-(tributylstannyl)-1H-pyrazole (124 mg, 0.33 mmol) and tetrakis(triphenylphosphine)palladium(0) (32 mg, 0.03 mmol). The resulting mixture was heated to 80 °C for 18 h. After return to room temperature, the reaction was filtered through Celite®. The Celite® cake was rinsed with ethyl acetate <com:Math><semantics>(2×20 mL)<annotation encoding="application / x-tex">(2 \times 20 \text{ mL})< / annotation>< / semantics>< / com:Math>. Combined organic phases were washed with 1 N aqueous potassium fluoride (10 mL), filtered through a hydrophobic frit and the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound as an off-white solid (6.7 mg, 7%). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.83 (dd, J = 5.8, 5.8 Hz, 1 H), 8.36 (s, 1 H), 8.27 <com:Math><semantics>(s,1H),8.09(d,J=1.5Hz,1H),8.02(s,1H),7.55(d,J=8.7Hz,1H),7.52−7.46(m,T)<annotation encoding="application / x-tex">(s, 1 H), 8.09 (d, J = 1.5 Hz, 1 H), 8.02 (s, 1 H), 7.55 (d, J = 8.7 Hz, 1 H), 7.52-7.46 (m, T)< / annotation>< / semantics>< / com:Math> <com:Math><semantics>2 H<annotation encoding="application / x-tex">2 \text{ H}< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>5.03 (d, J=5.8 Hz, 2 H)<annotation encoding="application / x-tex">5.03 \text{ (d, J} = 5.8 \text{ Hz, 2 H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>3.98 (s, 3 H)<annotation encoding="application / x-tex">3.98 \text{ (s, 3 H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>3.92 (s, 3 H)<annotation encoding="application / x-tex">3.92 \text{ (s, 3 H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>2.60 (s, 3 H)<annotation encoding="application / x-tex">2.60 \text{ (s, 3 H)}< / annotation>< / semantics>< / com:Math>. LCMS (Method 3): <com:Math><semantics>[MH+]=362<annotation encoding="application / x-tex">[MH+] = 362< / annotation>< / semantics>< / com:Math> at 2.64 min. The following compound reported in the table below was prepared according to the same procedure described for the preparation of 8-Methoxy-6-(1-methyl-1H-pyrazol-4- yl)-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine: [Image disponible dans le document PDF, Image available in the PDF document] Example 164 6-(4-Fluoro-3-methylphenyl)-8-methoxy-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] To a solution of 6-bromo-8-methoxy-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine (Intermediate 6) (70 mg, 0.19 mmol) in 1,4-dioxane (4.0 mL) was added 4-fluoro-3-methylphenylboronic acid (33 mg, 0.21 mmol), tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.02 mmol), potassium carbonate (36 mg, 0.26 mmol) and water (0.5 mL). The resulting mixture was heated to 95 °C for 18 h. After return to room temperature, the reaction was filtered through Celite®. The Celite® cake was rinsed with ethyl acetate (2 × 20 mL). Combined organic phases were washed with brine (2 × 20 mL), filtered through a hydrophobic frit and the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound as an off-white solid (18 mg, 24%). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO) d 9.03 (dd, J=5.8, 5.8 Hz, 1H), 8.41 (s, 1H), 8.15 (d, J=1.8 Hz, 1H), 7.82 (dd, J=2.0, 7.4 Hz, 1H), 7.77 - 7.72 (m, 1H), 7.57 - 7.49 (m, 3H), 7.31 (dd, J=9.1, 9.1 Hz, 1H), 5.03 (d, J=5.8 Hz, 2H), 4.03 (s, 3H), 2.60 (s, 3H), 2.37 (d, <com:Math><semantics>J=1.8Hz,3H<annotation encoding="application / x-tex">J=1.8 Hz, 3H< / annotation>< / semantics>< / com:Math>). LCMS (Method 4): <com:Math><semantics>[MH+]=390<annotation encoding="application / x-tex">[MH+] = 390< / annotation>< / semantics>< / com:Math> at 3.12 min. The following compounds reported in the table below were prepared according to the same procedure described for the preparation of 6-(4-Fluoro-3-methylphenyl)-8- methoxy-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Example 176a 6-(4-Fluoro-2-methoxyphenyl)-8-methoxy-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] To a solution of 6-bromo-8-methoxy-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine (intermediate 6) (70 mg, 0.19 mmol) in 1,2- dimethoxyethane (3.0 mL) was added (4-fluoro-2-methoxyphenyl)boronic acid (41 mg, 0.24 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with dichloromethane (8.2 mg, 0.01 mmol), caesium carbonate (130 mg, 0.40 mmol) and water (0.3 mL). The resulting mixture was heated to 95 °C for 18 h. After return to room temperature, the reaction was filtered through Celite®. The Celite® cake was rinsed with ethyl acetate (2 <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 20 mL). Combined organic phases were washed with brine (2 <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 20 mL), filtered through a hydrophobic frit and the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound as an off-white solid (35 mg, 45%). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.92 (dd, J = 5.8, 5.8 Hz, 1 H), 8.41 (s, 1 H), 7.91 <com:Math><semantics>(d,J=1.5Hz,1H),7.54−7.46(m,3H),7.37(d,J=1.4Hz,1H),7.10(dd,J=2.4,11.5)<annotation encoding="application / x-tex">(d, J = 1.5 Hz, 1 H), 7.54-7.46 (m, 3 H), 7.37 (d, J = 1.4 Hz, 1 H), 7.10 (dd, J = 2.4, 11.5)< / annotation>< / semantics>< / com:Math> Hz, 1 H), <com:Math><semantics>6.97−6.91<annotation encoding="application / x-tex">6.97-6.91< / annotation>< / semantics>< / com:Math> (m, 1 H), <com:Math><semantics>4.99<annotation encoding="application / x-tex">4.99< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=5.6<annotation encoding="application / x-tex">J = 5.6< / annotation>< / semantics>< / com:Math> Hz, 2 H), <com:Math><semantics>3.93<annotation encoding="application / x-tex">3.93< / annotation>< / semantics>< / com:Math> (s, 3 H), <com:Math><semantics>3.84<annotation encoding="application / x-tex">3.84< / annotation>< / semantics>< / com:Math> (s, 3 H), <com:Math><semantics>2.59<annotation encoding="application / x-tex">2.59< / annotation>< / semantics>< / com:Math> (s, 3 H). LCMS (Method 3): <com:Math><semantics>[MH+]=406<annotation encoding="application / x-tex">[MH+] = 406< / annotation>< / semantics>< / com:Math> at 3.97 min. The following compounds reported in the table below were prepared via adaptation of the above procedure starting from appropriate intermediate reported in table. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Example 183 (R)-6-(4-Fluorophenyl)-8-methoxy-2-methyl-N-(1-(2- (trifluoromethyl)pyrimidin-5 yl)ethyl)quinazolin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] 5 Step 1: Preparation of 6-bromo-8-methoxy-2-methylquinazolin-4-ol [Image disponible dans le document PDF, Image available in the PDF document] To a solution of 2-amino-5-bromo-3-methoxybenzoic acid hydrobromide (0.5 g, 1.53 mmol) (Intermediate 1) in N,N-dimethylformamide (5mL) was successively added 1-hydroxybenzotriazole hydrate (0.23 g, 1.68 mmol), N-(3-Dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (0.32 g, 1.68 mmol) and N,N-diisopropylethylamine (0.29 mL, 1.68 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction was then cooled to 0 °C and 28% aqueous ammonium hydroxide solution (1.5 mL) was added dropwise and the reaction was allowed to warm to room temperature overnight. The reaction was concentrated under reduced pressure and the residue was dissolved in triethyl orthoacetate (3.4 mL, 18.36 mmol), acetic acid (0.84 mL, 14.69 mmol) was added dropwise and the reaction was heated to 120 °C for 2 hours. The reaction was then cooled and concentrated. The crude residue was triturated with iso- propanol and filtered to give the title compound as an off-white solid (0.10 g, 30%). LCMS (Method 3): <com:Math><semantics>[MH+]=268 / 270<annotation encoding="application / x-tex">[MH+] = 268 / 270< / annotation>< / semantics>< / com:Math> at 3.28 min. Step 2: Preparation of 6-(4-fluorophenyl)-8-methoxy-2-methylquinazolin-4-ol [Image disponible dans le document PDF, Image available in the PDF document] Nitrogen was bubbled for 5 min through a mixture of 6-bromo-8-methoxy-2- methylquinazolin-4-ol (0.10 g, 0.37 mmol), 4-fluorophenylboronic acid (57 mg, 0.409 mmol), cesium carbonate (0.46 g, 1.41 mmol), water (0.5 mL) in 1,4-dioxane (2 mL), then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (15 mg, 0.0186 mmol) was added. The reaction was heated to 120 °C for 4 hours. After return to room temperature, the reaction was diluted with water (10 mL) and ethyl acetate (10 mL), the reaction was then filtered and the collected solid was washed with water (10 mL) and diethyl ether (10 mL) to give the title compound as a grey solid (0.10 g, 94%). LCMS (Method 3): <com:Math><semantics>[MH+]=285<annotation encoding="application / x-tex">[MH+] = 285< / annotation>< / semantics>< / com:Math> at 3.59 min. Step 3: Preparation of <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-6-(4-fluorophenyl)-8-methoxy-2-methyl-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-(1-(2- (trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] To a solution of 6-(4-Fluorophenyl)-8-methoxy-2-methylquinazolin-4-ol (100 mg, 0.35 mmol) in N,N-dimethylformamide (2 mL) was successively added (benzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate (201 mg, 0.39 mmol) and di- isopropylethylamine (0.31 mL, 1.76 mmol). The resulting mixture was heated to 40 °C and stirred for 20 min, (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethan-1-amine (88 mg, 0.387 mmol) was then added and the heating was maintained at 40 °C for 4 hours. After return to room temperature, the reaction was directly purified by preparative HPLC to give the title compound (15.1 mg, 9%). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 9.22 (s, 2 H), 8.55 (d, J = 6.8 Hz, 1 H), 8.18 (s, 1 H), <com:Math><semantics>7.95<annotation encoding="application / x-tex">7.95< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=5.6<annotation encoding="application / x-tex">J = 5.6< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>8.6<annotation encoding="application / x-tex">8.6< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>2<annotation encoding="application / x-tex">2< / annotation>< / semantics>< / com:Math> H), <com:Math><semantics>7.51<annotation encoding="application / x-tex">7.51< / annotation>< / semantics>< / com:Math> (s, <com:Math><semantics>1<annotation encoding="application / x-tex">1< / annotation>< / semantics>< / com:Math> H), <com:Math><semantics>7.42<annotation encoding="application / x-tex">7.42< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=8.7<annotation encoding="application / x-tex">J = 8.7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>8.7<annotation encoding="application / x-tex">8.7< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>2<annotation encoding="application / x-tex">2< / annotation>< / semantics>< / com:Math> H), <com:Math><semantics>5.73<annotation encoding="application / x-tex">5.73< / annotation>< / semantics>< / com:Math>- <Formule mathématique disponible dans le document PDF, Math available in the PDF document>5.66 \text{ (m, 1 H)}, 4.03 \text{ (s, 3 H)}, 2.46 \text{ (s, 3 H)}, 1.78 \text{ (d, J} = 7.1 Hz, 3 H)}. LCMS (Method 4): <com:Math><semantics>[MH+]=458<annotation encoding="application / x-tex">[MH+] = 458< / annotation>< / semantics>< / com:Math> at 4.97 min. Example 184 (R)-6-(4-Fluorophenyl)-8-methoxy-4-((1-(2-(trifluoromethyl)pyrimidin-5- yl)ethyl)-amino)-quinazolin-2-ol [Image disponible dans le document PDF, Image available in the PDF document] = Step 1: Preparation of 6-bromo-8-methoxyquinazoline-2,4-diol [Image disponible dans le document PDF, Image available in the PDF document] A mixture of 2-amino-5-bromo-3-methoxybenzoic acid hydrobromide (Intermediate 1) (1.0 g, 3.06 mmol) and urea (1.84 g, 30.58 mmol) was heated to 170 °C for 18 hours. After return to room temperature, the reaction was diluted with water (50 mL) and filtered. The collected solid was washed with water (20 mL) and diethyl ether (20 mL) to give the title compound as a light brown solid (0.7 g, 84%) which was taken on to the next step without further purification. LCMS (Method 4): <com:Math><semantics>[MH+]=271<annotation encoding="application / x-tex">[MH+] = 271< / annotation>< / semantics>< / com:Math> at 3.17 min. Step 2: Preparation of 2,4-dichloro-6-(4-fluorophenyl)-8-methoxyquinazoline [Image disponible dans le document PDF, Image available in the PDF document] Nitrogen was bubbled for 5 min through a mixture of 6-bromo-8- methoxyquinazoline-2,4-diol (0.5 g, 1.84 mmol), 4-fluorophenylboronic acid (284 mg, 2.03 mmol), cesium carbonate (2.28 g, 7.01 mmol) and water (2.5 mL) in 1,4-dioxane (10.0 mL), then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (75 mg, 0.09 mmol) was added. The resulting mixture was heated to 120 °C for 4 hours. After return to room temperature, the solvent was removed in vacuo. The residue was dry loaded onto silica gel and purified by chromatography on silica gel, eluting with 0-5% methanol in dichloromethane to give 160 mg of a crude product. This product (68 mg) was suspended in phosphorus oxychloride (1 mL, 10.73 mmol) and N,N- diisopropylethylamine (0.026 mL, 0.147 mmol) was added dropwise followed by a drop of N,N-dimethylformamide. The solution was then heated to 130 °C for 18 hours. After return to room temperature, the solvent was removed in vacuo. The residue was taken up with H<com:Sub>2< / com:Sub>O (10 mL) and stirred for one hour at room temperature. The reaction was filtered to give the title compound as an off-white solid (44 mg, 65%). LCMS (Method 4): <com:Math><semantics>[MH+]=323<annotation encoding="application / x-tex">[MH+] = 323< / annotation>< / semantics>< / com:Math> at 5.76 min. Step 3: Preparation of <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-6-(4-fluorophenyl)-8-methoxy-4-((1-(2- (trifluoromethyl)pyrimidin-5-yl)ethyl)-amino)-quinazolin-2-ol [Image disponible dans le document PDF, Image available in the PDF document] A mixture of 2,4-dichloro-6-(4-fluorophenyl)-8-methoxyquinazoline (44 mg, 0.13 mmol), (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethan-1-amine (35 mg, 0.13 mmol) and N,N-diisopropylethylamine (0.046 mL, 0.27 mmol) in dichloromethane (2 mL) was stirred at room temperature for 2 hours. The reaction was then diluted with H<com:Sub>2< / com:Sub>O (10 mL) and extracted with dichloromethane (3 <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 30 mL). The combined organic phases were passed through a hydrophobic frit and concentrated in vacuo. The residue was dissolved in acetic acid (2 mL) and heated to 70 °C for 2 hours. After return to room temperature, the reaction was concentrated in vacuo and the residue was purified by preparative HPLC to give the title compound as an off-white solid (6.1 mg, 10%). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 10.04 (s, 1 H), 9.15 (s, 2 H), 8.68 (d, J = 7.2 Hz, 1 H), <com:Math><semantics>8.04<annotation encoding="application / x-tex">8.04< / annotation>< / semantics>< / com:Math> (s, 1 H), <com:Math><semantics>7.87−7.82<annotation encoding="application / x-tex">7.87-7.82< / annotation>< / semantics>< / com:Math> (m, 2 H), <com:Math><semantics>7.48<annotation encoding="application / x-tex">7.48< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=1.4<annotation encoding="application / x-tex">J = 1.4< / annotation>< / semantics>< / com:Math> Hz, 1 H), <com:Math><semantics>7.36<annotation encoding="application / x-tex">7.36< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=8.9<annotation encoding="application / x-tex">J = 8.9< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>8.9<annotation encoding="application / x-tex">8.9< / annotation>< / semantics>< / com:Math> Hz, 2 H), <com:Math><semantics>5.66−5.60<annotation encoding="application / x-tex">5.66-5.60< / annotation>< / semantics>< / com:Math> (m, 1 H), <com:Math><semantics>3.97<annotation encoding="application / x-tex">3.97< / annotation>< / semantics>< / com:Math> (s, 3 H), <com:Math><semantics>1.71<annotation encoding="application / x-tex">1.71< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=7.2<annotation encoding="application / x-tex">J = 7.2< / annotation>< / semantics>< / com:Math> Hz, 3 H). LCMS (Method 4): <com:Math><semantics>[MH+]=460<annotation encoding="application / x-tex">[MH+] = 460< / annotation>< / semantics>< / com:Math> at 4.5 min. Example 185 (R)-6-(4-Fluorophenyl)-2,8-dimethoxy-N-(1-(2-(trifluoromethyl)pyrimidin-5- yl)ethyl)quinazolin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] A mixture of 2,4-dichloro-6-(4-fluorophenyl)-8-methoxyquinazoline (143 mg, 0.44) mmol), (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethan-1-amine (117 mg, 0.44 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.89 mmol) in dichloromethane (5 mL) was stirred at room temperature for 2 hours. The reaction was then diluted with H<com:Sub>2< / com:Sub>O (10 mL) and extracted with dichloromethane (3 <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 30 mL). The combined organic phases were passed through a hydrophobic frit and concentrated in vacuo. The residue was dissolved in methanol (2 mL) and sodium methoxide (25% in methanol) (0.13 mL, 0.58 mmol) was added. The mixture was heated to 80 °C for 2 hours. After return to room temperature, the reaction was concentrated in vacuo and the residue was purified by preparative HPLC to give the title compound as a brown solid (3.5 mg, 3.2%). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 9.17 (s, 2 H), 8.68 (d, J = 6.9 Hz, 1 H), 8.15 (d, J = <com:Math><semantics>1.8 Hz<annotation encoding="application / x-tex">1.8 \text{ Hz}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>1 H<annotation encoding="application / x-tex">1 \text{ H}< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>7.93−7.88 (m, 2 H)<annotation encoding="application / x-tex">7.93-7.88 \text{ (m, 2 H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>7.47 (d, J = 1.5 Hz, 1 H)<annotation encoding="application / x-tex">7.47 \text{ (d, J = 1.5 Hz, 1 H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>7.38 (dd, J = 8.9, 8.9 Hz, 2)<annotation encoding="application / x-tex">7.38 \text{ (dd, J = 8.9, 8.9 Hz, 2)}< / annotation>< / semantics>< / com:Math> H), 5.61 (dd, <com:Math><semantics>J=6.8<annotation encoding="application / x-tex">J = 6.8< / annotation>< / semantics>< / com:Math>, 6.8 Hz, 1 H), 3.99 (s, 3 H), 3.83 (s, 3 H), 1.73 (d, <com:Math><semantics>J=7.2<annotation encoding="application / x-tex">J = 7.2< / annotation>< / semantics>< / com:Math> Hz, 3 H). LCMS (Method 4): <com:Math><semantics>[MH+]=474<annotation encoding="application / x-tex">[MH+] = 474< / annotation>< / semantics>< / com:Math> at 3.87 min. Example 186 <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-6-(4-Fluorophenyl)-8-iodo-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-(1-(2-(trifluoromethyl)pyrimidin-5- 5 yl)ethyl)quinazolin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] Step 1: Preparation of methyl 4-amino-4'-fluoro-[1,1'-biphenyl]-3-carboxylate [Image disponible dans le document PDF, Image available in the PDF document] Nitrogen was bubbled for 5 min through a mixture of methyl 2-amino-5- bromobenzoate (2.00 g, 8.69 mmol), 4-fluorophenylboronic acid, pinacol ester (2.90 g, 12.04 mmol), potassium phosphate tribasic (3.69 g, 17.39 mmol), water (3.5 mL) in N,N- dimethylformamide (10.5) mL), then <com:Math><semantics>[1,1′−<annotation encoding="application / x-tex">[1,1'-< / annotation>< / semantics>< / com:Math> bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (710 mg, 0.87 mmol) was added. The resulting mixture was heated to 100 °C for 1.25 hours. After return to room temperature, the reaction was diluted with water (100 mL) and diethyl ether (100 mL) and the organic phase was separated. The aqueous phase was extracted further with diethyl ether (100 mL) and then Ethyl acetate (100 mL). The organic phases were combined, washed with water (100 mL), dried over MgSO<com:Sub>4< / com:Sub> and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel eluting with 5-35% Ethyl acetate in cyclohexane to give the title compound as an off- white solid <com:Math><semantics>(2.08g,97%)<annotation encoding="application / x-tex">(2.08 g, 97\%)< / annotation>< / semantics>< / com:Math>. <com:Sup>1< / com:Sup>H NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.06 (d, J = 2.3 Hz, 1 H), 7.50-7.44 (m, 3 H), 7.08 <com:Math><semantics>(dd,J=8.7,8.7Hz,2H),6.74(d,J=8.6Hz,1H),5.78(s,2H),3.90(s,3H).<annotation encoding="application / x-tex">(dd, J = 8.7, 8.7 Hz, 2 H), 6.74 (d, J = 8.6 Hz, 1 H), 5.78 (s, 2 H), 3.90 (s, 3 H).< / annotation>< / semantics>< / com:Math> Step 2: Preparation of methyl 4-amino-4'-fluoro-5-iodo-[1,1'-biphenyl]-3- carboxylate [Image disponible dans le document PDF, Image available in the PDF document] To a solution of methyl 4-amino-4'-fluoro-[1,1'-biphenyl]-3-carboxylate (2.08 g, 8.48 mmol) in dichloromethane (25 mL) was added bis(pyridine)iodonium tetrafluoroborate (4.73 g, 12.72 mmol) and TFA (2.1 mL, 27.42 mmol). The resulting mixture was stirred at room temperature for 2 days. HPLC analysis showed 70 % conversion and further bis(pyridine)iodonium tetrafluoroborate (1.25 g, 3.36 mmol) was added and the stirring was maintained for a further 2.5 hours. The reaction was diluted with dichloromethane (25 mL) and cautiously treated with a solution of NaHCO<com:Sub>3< / com:Sub> (7 g, 83 mmol) in water (100 mL). The aqueous layer was collected and further extracted with dichloromethane (<com:Math><semantics>2×25<annotation encoding="application / x-tex">2 \times 25< / annotation>< / semantics>< / com:Math> mL). The organic phases were combined, washed with an 8 % sodium thiosulphate aqueous solution (100 mL), filtered through a hydrophobic frit and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel eluting with 0–25% Ethyl acetate in cyclohexane to give the title compound as an off- white solid (2.71 g, 86%). <com:Sup>1< / com:Sup>H NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>): δ 8.10-8.07 (m, 1 H), 8.04-8.00 (m, 1 H), 7.46-7.41 <com:Math><semantics>(m,2H),7.09(dd,J=8.6,8.6Hz,2H),6.48−6.37(m,2H),3.91(s,3H).<annotation encoding="application / x-tex">(m, 2 H), 7.09 (dd, J = 8.6, 8.6 Hz, 2 H), 6.48-6.37 (m, 2 H), 3.91 (s, 3 H).< / annotation>< / semantics>< / com:Math> Step 3: Preparation of 4-amino-4'-fluoro-5-iodo-[1,1'-biphenyl]-3-carboxylic acid [Image disponible dans le document PDF, Image available in the PDF document] To a solution of methyl 4-amino-4'-fluoro-5-iodo-[1,1'-biphenyl]-3-carboxylate (2.59 g, 6.98 mmol) in 1,4-dioxane (25 mL) and water (5 mL) was added lithium hydroxide monohydrate (1.75 g, 41.87 mmol). The mixture was stirred at room temperature for 18 hours. The reaction was diluted with water (100 mL) and diethyl ether (100 mL) and separated. The aqueous phase was acidified with 1N HCl (45 mL) to pH = 1 and extracted with dichloromethane (<com:Math><semantics>3×50<annotation encoding="application / x-tex">3 \times 50< / annotation>< / semantics>< / com:Math> mL). The organic phases were combined, filtered through a hydrophobic frit and the solvent was removed in vacuo to give the title compound as an off-white solid (2.39 g, 96%). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 13.17 (s, 1 H), 8.18 (d, J = 2.0 Hz, 1 H), 8.09 (d, J <com:Math><semantics>=2.3 Hz,1 H,7.65 (dd, J=5.4,8.5 Hz,2 H,7.27 (dd, J=8.8,8.8 Hz,2 H),6.84 (s, 2)<annotation encoding="application / x-tex">= 2.3 \text{ Hz}, 1 \text{ H}, 7.65 \text{ (dd, J} = 5.4, 8.5 \text{ Hz}, 2 \text{ H}, 7.27 \text{ (dd, J} = 8.8, 8.8 \text{ Hz}, 2 \text{ H}), 6.84 \text{ (s, 2)}< / annotation>< / semantics>< / com:Math> H). Step 4: Preparation of 6-(4-fluorophenyl)-8-iodoquinazolin-4(3H)-one [Image disponible dans le document PDF, Image available in the PDF document] A solution of 4-amino-4'-fluoro-5-iodo-[1,1'-biphenyl]-3-carboxylic acid (2.39 g, 6.69 mmol) in formamide (4 mL) was heated to 130 °C for 16 hours. After return to room temperature, the reaction was diluted with water (20 mL) and stirred for 20 minutes before filtering. The solid was washed with water <com:Math><semantics>(3×5 mL)<annotation encoding="application / x-tex">(3 \times 5 \text{ mL})< / annotation>< / semantics>< / com:Math> then 10% MeOH in diethyl ether <com:Math><semantics>(3×5 mL)<annotation encoding="application / x-tex">(3 \times 5 \text{ mL})< / annotation>< / semantics>< / com:Math> to give the title compound as an off-white solid (2.14 g, 87%). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO): δ 12.57 (s, 1 H), 8.66 (s, 1 H), 8.36 (s, 1 H), 8.28 (s, 1 H), <com:Math><semantics>7.89<annotation encoding="application / x-tex">7.89< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=5.6<annotation encoding="application / x-tex">J = 5.6< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>7.8<annotation encoding="application / x-tex">7.8< / annotation>< / semantics>< / com:Math> Hz, 2 H), <com:Math><semantics>7.38<annotation encoding="application / x-tex">7.38< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=8.6<annotation encoding="application / x-tex">J = 8.6< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>8.6<annotation encoding="application / x-tex">8.6< / annotation>< / semantics>< / com:Math> Hz, 2 H). Step 5: Preparation of <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-6-(4-fluorophenyl)-8-iodo-N-(1-(2- (trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] To a solution of 6-(4-fluorophenyl)-8-iodoquinazolin-4-(3H)-one (1.14 g, 3.11 mmol) in N,N-dimethylformamide (10 mL) was successively added (benzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate (2.03 g, 1.25 mmol) and di- isopropylethylamine (2.7 mL, 15.57 mmol). The resulting mixture was heated to 45 °C for one hour then (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethan-1-amine hydrochloride (0.96 g, 4.2 mmol) was added and the heating was maintained at 45 °C for 2 hours. After return to room temperature, the mixture was diluted with ethyl acetate (75 mL) and water (175 mL). The organic phase was washed with brine (2 × 20 mL), passed through a hydrophobic frit and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel eluting with 0–15% ethyl acetate in dichloromethane to give the title compound as an off-white solid (1.27 g, 75%). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 9.18 (s, 2 H), 8.88 (d, J = 6.9 Hz, 1 H), 8.71 (d, J <com:Math><semantics>=1.8 Hz,1 H,8.67 (d, J=1.8 Hz,1 H),8.51 (s, 1 H),7.95−7.90 (m, 2 H),7.40 (dd, J=1.8 Hz,1 H)<annotation encoding="application / x-tex">= 1.8 \text{ Hz}, 1 \text{ H}, 8.67 \text{ (d, J} = 1.8 \text{ Hz}, 1 \text{ H}), 8.51 \text{ (s, 1 H)}, 7.95-7.90 \text{ (m, 2 H)}, 7.40 \text{ (dd, J} = 1.8 \text{ Hz}, 1 \text{ H})< / annotation>< / semantics>< / com:Math> <com:Math><semantics>8.9,8.9 Hz,2 H<annotation encoding="application / x-tex">8.9, 8.9 \text{ Hz}, 2 \text{ H}< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>5.73−5.67 (m, 1 H)<annotation encoding="application / x-tex">5.73-5.67 \text{ (m, 1 H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>1.75 (d, J=7.2 Hz,3 H)<annotation encoding="application / x-tex">1.75 \text{ (d, J} = 7.2 \text{ Hz}, 3 \text{ H)}< / annotation>< / semantics>< / com:Math>. The following compound reported in the table below was prepared via adaptation of the above procedure using the appropriate amine. [Image disponible dans le document PDF, Image available in the PDF document] Example 188 <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-6-(4-fluorophenyl)-8-(methylsulfonyl)-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-(1-(2- (trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] Step 1: Preparation of 6-(4-fluorophenyl)-8-(methylsulfonyl)quinazolin-4(3H)-one [Image disponible dans le document PDF, Image available in the PDF document] To a solution of 6-(4-fluorophenyl)-8-iodoquinazolin-4-(3H)-one (200 mg, 0.546 mmol) in dry DMSO (1.5 mL), sodium methanesulfinate (67 mg, 0.655 mmol) was added followed by copper(I) iodide (10.40 mg, 0.055 mmol) and L-proline (13 mg, 0.109 mmol). The reaction was heated to 110 °C and stirred for 18h. A second addition of all reagents led to complete consumption of the starting material. The reaction mixture was cooled to RT and loaded onto column. Purification by RP flash chromatography (Biotage Isolera, C8 40 g cartridge, gradient elution from 0 to 80% B in A; A: water / MeCN 95:5 + 0.1% HCOOH, B: MeCN / water 95:5 + 0.1% HCOOH) yielded the titled compound (52 mg, 0.163 mmol, 30%) as white powder. LCMS (Method 5): 0.81 min, 319 [M+H]+. Step 2: Preparation of <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-6-(4-fluorophenyl)-8-(methylsulfonyl)-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-(1-(2- (trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] To a suspension of 6-(4-fluorophenyl)-8-(methylsulfonyl)quinazolin-4(3H)-one (52 mg, 0.163 mmol) in DMF (1 mL), (7-azabenzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate (94 mg, 0.180 mmol) and di- isopropylethylamine (0.086 mL, 0.490 mmol) were added followed after 10 min by (R)- 1-(2-(trifluoromethyl)pyrimidin-5-yl)ethan-1-amine HCl (56 mg, 0.245 mmol). The resulting mixture was stirred at RT for 16h. Purification by RP flash chromatography (Biotage Isolera, Ultra SNAP 30g cartridge, gradient elution from 0 to 90% of B in A; A: water / MeCN 95:5 + 0.1% HCOOH, B: MeCN / water 95:5 + 0.1% HCOOH) yielded impure titled compound. A second purification by flash chromatography (Biotage Isolera, KP-NH 28g cartridge, gradient elution from 5% to 100% EtOAc in heptane) yielded the titled compound (20 mg, 0.041 mmol, 25 % yield) as pale yellow powder. LCMS (Method 5): 1.14 min, 492 [M+H]+. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> ppm 9.16 (s, 2 H), 9.04 (br d, J = 6.61 Hz, 1 H), <com:Math><semantics>8.97<annotation encoding="application / x-tex">8.97< / annotation>< / semantics>< / com:Math> (s, 1 H), <com:Math><semantics>8.58<annotation encoding="application / x-tex">8.58< / annotation>< / semantics>< / com:Math> (s, 1 H), <com:Math><semantics>8.53<annotation encoding="application / x-tex">8.53< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=1.76<annotation encoding="application / x-tex">J = 1.76< / annotation>< / semantics>< / com:Math> Hz, 1 H), <com:Math><semantics>7.89<annotation encoding="application / x-tex">7.89< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=8.60<annotation encoding="application / x-tex">J = 8.60< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>5.29<annotation encoding="application / x-tex">5.29< / annotation>< / semantics>< / com:Math> Hz, 2 H), <com:Math><semantics>7.41<annotation encoding="application / x-tex">7.41< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=8.82<annotation encoding="application / x-tex">J = 8.82< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>2<annotation encoding="application / x-tex">2< / annotation>< / semantics>< / com:Math> H), <com:Math><semantics>5.60−5.70<annotation encoding="application / x-tex">5.60 - 5.70< / annotation>< / semantics>< / com:Math> (m, <com:Math><semantics>1<annotation encoding="application / x-tex">1< / annotation>< / semantics>< / com:Math> H), <com:Math><semantics>3.53<annotation encoding="application / x-tex">3.53< / annotation>< / semantics>< / com:Math> (s, <com:Math><semantics>3<annotation encoding="application / x-tex">3< / annotation>< / semantics>< / com:Math> H), <com:Math><semantics>1.72<annotation encoding="application / x-tex">1.72< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=7.28<annotation encoding="application / x-tex">J = 7.28< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>3<annotation encoding="application / x-tex">3< / annotation>< / semantics>< / com:Math> H). The following compound reported in the table below was prepared via adaptation of the above procedure using the appropriate amine. [Image disponible dans le document PDF, Image available in the PDF document] Example 190 <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(6<annotation encoding="application / x-tex">(6< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(4<annotation encoding="application / x-tex">(4< / annotation>< / semantics>< / com:Math>-fluorophenyl)-<com:Math><semantics>4<annotation encoding="application / x-tex">4< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>((1<annotation encoding="application / x-tex">((1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(2<annotation encoding="application / x-tex">(2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(trifluoromethyl)pyrimidin−<math>5<annotation encoding="application / x-tex">(trifluoromethyl)pyrimidin-5< / annotation>< / semantics>< / com:Math>- 5 yl)ethyl)amino)quinazolin-8-yl)methanesulfonamide [Image disponible dans le document PDF, Image available in the PDF document] To a solution of <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-6-(4-fluorophenyl)-8-iodo-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-(1-(2- (trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine (60 mg, 0.111 mmol) in 1,4- Dioxane (1.5 mL), methanesulfonamide (14 mg, 0.145 mmol), copper(I) iodide (2.119 mg, 0.011 mmol), L-proline (2.56 mg, 0.022 mmol) and potassium carbonate (46 mg, 0.334 mmol) were added. The resulting mixture was heated to 150 °C for 6h. The reaction was diluted with DCM and water was added. The two phases were separated, the aqueous layer was extracted with DCM (2 x 10 mL) and the combined organic phase was filtered through a PhaseSeparator tube. Volatiles were removed under reduced pressure. Purification by RP flash chromatography (Biotage Isolera, Ultra SNAP 30g cartridge, gradient elution from 5% to 100% of B in A; A: water / MeCN 95:5 + 0.1% HCOOH, B: MeCN / water 95:5 + 0.1% HCOOH) yielded the titled compound (9 mg, 0.018 mmol, 16 % yield) as pale beige powder. LCMS (Method 5): 1.17 min, 507 [M+H]+. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) δ ppm 9.14 (s, 3 H), 8.71 - 8.86 (m, 1 H), 8.47 (s, 1 H), 8.36 (br s, 1 H), 7.95 (s, 1 H), 7.81 (br dd, <com:Math><semantics>J=8.16<annotation encoding="application / x-tex">J = 8.16< / annotation>< / semantics>< / com:Math>, 5.73 Hz, 2 H), 7.37 (br t, <com:Math><semantics>J=<annotation encoding="application / x-tex">J =< / annotation>< / semantics>< / com:Math> 8.71 Hz, 2 H), 5.66 (br s, 1 H), 3.12 (s, 3 H), 1.71 (br d, <com:Math><semantics>J=7.06<annotation encoding="application / x-tex">J = 7.06< / annotation>< / semantics>< / com:Math> Hz, 3 H). The following compound reported in the table below was prepared via adaptation of the above procedure. [Image disponible dans le document PDF, Image available in the PDF document] Example 192 (R)-6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidin-5- yl)ethyl)amino)quinazoline-8-sulfonamide [Image disponible dans le document PDF, Image available in the PDF document] _ Step 1: Preparation of 6-(4-fluorophenyl)-4-oxo-3,4-dihydroquinazoline-8- sulfonamide [Image disponible dans le document PDF, Image available in the PDF document] To a suspension of 6-(4-fluorophenyl)-8-(methylsulfonyl)quinazolin-4(3H)-one (167 mg, 0.525 mmol) in dry THF (2 mL), cooled to 0 °C, lithium diisopropylamide 2.0 M in THF heptane ethylbenzene (1.049 mL, 2.099 mmol) was added. The reaction was warmed to RT and stirred for 30 min until complete dissolution. To the resulting orange solution, tributylborane 1.0 M in THF (2.62 mL, 2.62 mmol) was added and the reaction was heated to 64 °C and stirred for 12h. A solution of (aminoxy)sulfonic acid (208 mg, 1.836 mmol) and potassium acetate (232 mg, 2.361 mmol) in water (2 mL) was added and the resulting mixture stirred at 65 °C for 6h. Volatiles were removed under reduced pressure. The crude was taken up with DMF and purified by RP flash chromatography (Biotage Isolera, Ultra SNAP C18 60g cartridge, gradient elution from 0 to 80% of B in A; A: water / MeCN 95:5 + 0.1% HCOOH, B: MeCN / water 95:5 + 0.1% HCOOH). An unseparable mixture of titled compound and starting material was isolated and used as such in the next step. Step 2: Preparation of <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidin- 5-yl)ethyl)amino)quinazoline-8-sulfonamide [Image disponible dans le document PDF, Image available in the PDF document] To a suspension of the crude 6-(4-fluorophenyl)-4-hydroxyquinazoline-8- sulfonamide (40 mg, 0.125 mmol) in DMF (1.5 mL), (benzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate (78 mg, 0.150 mmol) and di- isopropylethylamine (0.066 mL, 0.376 mmol) were added followed after 5 min by (R)-1- (2-(trifluoromethyl)pyrimidin-5-yl)ethan-1-amine (36 mg, 0.188 mmol). The resulting mixture was stirred at RT for 12h. The reaction was diluted with DCM and quenched with water. The two phases were separated and the aqueous layer was extracted once with DCM. Combined organic phase was filtered through a PhaseSeparator tube and volatiles removed under reduced pressure. Purification by flash chromatography (Biotage Isolera, Ultra SNAP 25g cartridge, gradient elution from 5% to 100% EtOAc in heptane) yielded impure titled compound. Second purification by flash chromatography (Biotage Isolera, SNAP NH 28g cartridge, gradient elution from 5% to 100% EtOAc in heptane) yielded the titled compound (4 mg, 8.12 µmol, 6.48 % yield) as white powder. LCMS (Method 5): 1.08 min, 493 [M+H]+. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) δ ppm 9.15 (s, 2 H), 9.01 (br s, 1 H), 8.88 (br d, J <com:Math><semantics>=1.98 Hz,1 H<annotation encoding="application / x-tex">= 1.98 \text{ Hz}, 1 \text{ H}< / annotation>< / semantics>< / com:Math>), 8.54 (s, 1 H), 8.42 - 8.49 (m, 1 H), 7.81 - 7.96 (m, 2 H), 7.40 (br t, J = 8.82 Hz, 2 H), 7.21 (br s, 2 H), 5.67 (br d, <com:Math><semantics>J=6.84<annotation encoding="application / x-tex">J = 6.84< / annotation>< / semantics>< / com:Math> Hz, 1 H), 1.72 (d, <com:Math><semantics>J=7.06<annotation encoding="application / x-tex">J = 7.06< / annotation>< / semantics>< / com:Math> Hz, 3 H). Example 193 <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-6-(4-fluorophenyl)-8-(1-methyl-<com:Math><semantics>1H<annotation encoding="application / x-tex">1H< / annotation>< / semantics>< / com:Math>-pyrazol-4-yl)-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-(1-(2- (trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] Nitrogen was bubbled for 15 min through a mixture of <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-6-<com:Math><semantics>(4<annotation encoding="application / x-tex">(4< / annotation>< / semantics>< / com:Math>-Fluorophenyl)-8- iodo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine (100 mg, 0.18 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (52 mg, 0.25 mmol), cesium fluoride (85 mg, 0.56 mmol), water (0.5 mL) in N,N-dimethylformamide (2.0 mL), then tetrakis(triphenylphosphine)palladium(0) (21 mg, 0.02 mmol) was added. The resulting mixture was heated to 95 °C for 16 hours. After return to room temperature, the reaction was diluted with water (6 mL) and extracted with ethyl acetate (3 <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3 mL). The combined organic phases were filtered through a hydrophobic frit and the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound as an off-white solid (63 mg, 69%). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 9.24 (s, 2 H), 8.76 (d, J = 6.8 Hz, 1 H), 8.71 (s, 1 H), <com:Math><semantics>8.59−8.54<annotation encoding="application / x-tex">8.59-8.54< / annotation>< / semantics>< / com:Math> (m, 2 H), <com:Math><semantics>8.39<annotation encoding="application / x-tex">8.39< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=1.5<annotation encoding="application / x-tex">J = 1.5< / annotation>< / semantics>< / com:Math> Hz, 1 H), <com:Math><semantics>8.35<annotation encoding="application / x-tex">8.35< / annotation>< / semantics>< / com:Math> (s, 1 H), <com:Math><semantics>8.03<annotation encoding="application / x-tex">8.03< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=5.4<annotation encoding="application / x-tex">J = 5.4< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>8.7<annotation encoding="application / x-tex">8.7< / annotation>< / semantics>< / com:Math> Hz, 2 H), 7.45 (dd, <com:Math><semantics>J=8.8<annotation encoding="application / x-tex">J = 8.8< / annotation>< / semantics>< / com:Math>, 8.8 Hz, 2 H), 5.80-5.71 (m, 1 H), 3.97 (s, 3 H), 1.80 (d, <com:Math><semantics>J=7.1<annotation encoding="application / x-tex">J = 7.1< / annotation>< / semantics>< / com:Math> Hz, 3 H). LCMS (Method 3): <com:Math><semantics>[MH+]=494<annotation encoding="application / x-tex">[MH+] = 494< / annotation>< / semantics>< / com:Math> at 5.1 min. The following compounds reported in the table below were prepared according to the same procedure described for the preparation of <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-6-(4-fluorophenyl)-8-(1-methyl- 1H-pyrazol-4-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Example 198 <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)amino)- quinazolin-8-ol [Image disponible dans le document PDF, Image available in the PDF document] - To a solution of 6-(4-fluorophenyl)-8-methoxy-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-[(1<com:Math><semantics>R<annotation encoding="application / x-tex">R< / annotation>< / semantics>< / com:Math>)-1-[2-(trifluoromethyl)- pyrimidin-5-yl]ethyl]quinazolin-4-amine (490 mg, 1.11 mmol) in chloroform (8 mL) at 0 °C was added dropwise boron tribromide (0.32 mL, 3.32 mmol). The reaction was then allowed to warm to room temperature and was heated to 65 °C for 18 hours. After return to room temperature, the reaction was cooled down in an ice-bath and quenched with methanol (2 mL). The solvent was removed in vacuo. The residue was diluted with ethyl acetate (50 mL) and washed with saturated aqueous NaHCO<com:Sub>3< / com:Sub> solution (50 mL). The aqueous layer was then extracted with ethyl acetate <com:Math><semantics>(2×20 mL)<annotation encoding="application / x-tex">(2 \times 20 \text{ mL})< / annotation>< / semantics>< / com:Math>. The organic phases were combined, passed through a hydrophobic frit and the solvent was removed in vacuo to give the title compound as a grey solid (416 mg, 88%). <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 9.18 (s, 2 H), 8.65 (d, J = 7.0 Hz, 1 H), 8.46 (s, 1 H), <com:Math><semantics>8.09<annotation encoding="application / x-tex">8.09< / annotation>< / semantics>< / com:Math> (s, 1 H), <com:Math><semantics>7.86<annotation encoding="application / x-tex">7.86< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=5.5<annotation encoding="application / x-tex">J = 5.5< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>8.7<annotation encoding="application / x-tex">8.7< / annotation>< / semantics>< / com:Math> Hz, 2 H), <com:Math><semantics>7.45<annotation encoding="application / x-tex">7.45< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=1.3<annotation encoding="application / x-tex">J = 1.3< / annotation>< / semantics>< / com:Math> Hz, 1 H), <com:Math><semantics>7.37<annotation encoding="application / x-tex">7.37< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=1.3<annotation encoding="application / x-tex">J = 1.3< / annotation>< / semantics>< / com:Math> Hz, 1 H), <com:Math><semantics>7.37<annotation encoding="application / x-tex">7.37< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=1.3<annotation encoding="application / x-tex">J = 1.3< / annotation>< / semantics>< / com:Math> Hz, 1 H), <com:Math><semantics>7.37<annotation encoding="application / x-tex">7.37< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=1.3<annotation encoding="application / x-tex">J = 1.3< / annotation>< / semantics>< / com:Math> Hz, 1 H), <com:Math><semantics>7.37<annotation encoding="application / x-tex">7.37< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=1.3<annotation encoding="application / x-tex">J = 1.3< / annotation>< / semantics>< / com:Math> Hz, 1 H), <com:Math><semantics>7<annotation encoding="application / x-tex">7< / annotation>< / semantics>< / com:Math> 8.8, 8.8 Hz, 2 H), 5.71-5.67 (m, 1 H), 1.75 (d, <com:Math><semantics>J=7.0 Hz<annotation encoding="application / x-tex">J = 7.0 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 3 H). OH not observed. The following compounds were prepared via adaptations of the above procedure starting from substrate reported in table. [Image disponible dans le document PDF, Image available in the PDF document] Example 200 <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-6-(4-Fluorophenyl)-8-((tetrahydro-<com:Math><semantics>2H<annotation encoding="application / x-tex">2H< / annotation>< / semantics>< / com:Math>-pyran-4-yl)oxy)-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-(1-(2- (trifluoromethyl) pyrimidin-5-yl)ethyl)quinazolin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] Nitrogen was bubbled for 5 min through a mixture of <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-6-(4-fluorophenyl)-4-((1- (2-(trifluoromethyl)pyrimidin-5-yl)ethyl)amino)quinazolin-8-ol (40 mg, 0.01 mmol), tetrahydro-4-pyranol (10 mg, 0.102 mmol) and cyanomethyltributylphosphorane (1 M in toluene, 0.14 mL, 0.14 mmol) in toluene (3.0 mL). The mixture was heated to 100 °C for 72 hours. After return to room temperature, the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound (17 mg, 38%) as an off white solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 9.18 (s, 2 H), 8.64 (d, J = 7.0 Hz, 1 H), 8.44 (s, 1 H), <com:Math><semantics>8.23<annotation encoding="application / x-tex">8.23< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=1.6<annotation encoding="application / x-tex">J = 1.6< / annotation>< / semantics>< / com:Math> Hz, 1 H), <com:Math><semantics>7.94−7.89<annotation encoding="application / x-tex">7.94-7.89< / annotation>< / semantics>< / com:Math> (m, 2 H), <com:Math><semantics>7.65<annotation encoding="application / x-tex">7.65< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=1.6<annotation encoding="application / x-tex">J = 1.6< / annotation>< / semantics>< / com:Math> Hz, 1 H), <com:Math><semantics>7.39<annotation encoding="application / x-tex">7.39< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=1.6<annotation encoding="application / x-tex">J = 1.6< / annotation>< / semantics>< / com:Math> Hz, 1 H), <com:Math><semantics>7.39<annotation encoding="application / x-tex">7.39< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=1.6<annotation encoding="application / x-tex">J = 1.6< / annotation>< / semantics>< / com:Math> Hz, 1 H), <com:Math><semantics>7.39<annotation encoding="application / x-tex">7.39< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=1.6<annotation encoding="application / x-tex">J = 1.6< / annotation>< / semantics>< / com:Math> Hz, 1 H), <com:Math><semantics>7.39<annotation encoding="application / x-tex">7.39< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=1.6<annotation encoding="application / x-tex">J = 1.6< / annotation>< / semantics>< / com:Math> Hz, 1 H), <com:Math><semantics>7.39<annotation encoding="application / x-tex">7.39< / annotation>< / semantics>< / com:Math> 8.8, 8.8 Hz, 2 H), 5.71-5.66 (m, 1 H) 5.02-4.94 (m, 1 H), 3.96-3.88 (m, 2 H), 3.51 (dd, J <com:Math><semantics>=9.7,9.7 Hz,2 H<annotation encoding="application / x-tex">= 9.7, 9.7 \text{ Hz}, 2 \text{ H}< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>2.07−2.00 (m, 2 H)<annotation encoding="application / x-tex">2.07-2.00 \text{ (m, 2 H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>1.74 (d, J=7.0 Hz,5 H<annotation encoding="application / x-tex">1.74 \text{ (d, J} = 7.0 \text{ Hz}, 5 \text{ H}< / annotation>< / semantics>< / com:Math>). LCMS (Method 3): <com:Math><semantics>[MH+]=514<annotation encoding="application / x-tex">[MH+] = 514< / annotation>< / semantics>< / com:Math> at 3.79 min. Example 201 <com:Math><semantics>6−(4−fluorophenyl)−8−[(3R)−oxolan−3−yl]oxy−N−(1R)−1−[2−yl]oxy<annotation encoding="application / x-tex">6-(4-fluorophenyl)-8-{[(3R)-oxolan-3-yl]oxy}-N-{(1R)-1-[2-yl]oxy}< / annotation>< / semantics>< / com:Math> (trifluoromethyl)pyrimidin-5-yllethyl}quinazolin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] Potassium carbonate (47.7 mg, 0.345 mmol) was added to a mixture of (R)-6-(4- fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)amino)quinazolin-8-ol (64.4 mg, 0.150 mmol) and (S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (41.8 mg, 0.172 mmol) in DMF (Volume: 3 ml). Stirring went on at 60 °C for 16 h. The reaction mixture was allowed to cool down to rt, then it was quenched by the addition of formic acid (0.017 ml, 0.450 mmol). Purification by RP chromatography (Biotage Isolera, 30 g C18 cartridge, gradient elution from 100:0 to 50:50 A / B, A: water / acetonitrile 95:5 + 0.1% HCOOH, B: acetonitrile:water 95:5 +0.1% HCOOH) then DP chromatography (Biotage Isolera, 11 g NH cartridge, gradient elution from 0 to 40% ethyl acetate in dichloromethane) yielded 6-(4-fluorophenyl)-8-(((R)-tetrahydrofuran-3-yl)oxy)-N-((R)- 1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine (8.3 mg, 0.017 mmol, 11.08 % yield) as a white powder. LCMS (Method 5): Method 5 0.74 min, 500.0 [M+H]+, CSH method 2 min. 1H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> ppm 9.16 (s, 2 H), 8.61 (d, J=6.6 Hz, 1 H), 8.42 (s, 1 H), 8.21 (d, J=1.3 Hz, 1 H), 7.84 - 8.01 (m, 2 H), 7.51 (d, J=1.3 Hz, 1 H), 7.38 (t, J=8.8 Hz, 2 H), 5.67 (t, J=7.0 Hz, 1 H), 5.35 - 5.50 (m, 1 H), 3.85 - 4.04 (m, 3 H), 3.79 (d, J=4.4 Hz, 1 H), 2.19 - 2.37 (m, 1 H), 2.03 - 2.17 (m, 1 H), 1.72 (d, J=7.0 Hz, 3 H). The following compounds were prepared via adaptations of the above procedures starting from substrate reported in table. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Example 214 2-[6-(4-fluorophenyl)-4-[(6-methylpyridazin-3-yl)methylamino]quinazolin-8- yl]oxyacetic acid, sodium salt [Image disponible dans le document PDF, Image available in the PDF document] NaOH (10.5 mg, 0.26 mmol) was added to ethyl 2-[6-(4-fluorophenyl)-4-[(6- methylpyridazin-3-yl)methylamino]quinazolin-8-yl]oxyacetate (117 mg, 0.26 mmol) (Example 211) in MeOH (2.2 mL). The mixture was stirred at rt for 3 days then diluted with diethyl ether and filtered to leave 2-[6-(4-fluorophenyl)-4-[(6-methylpyridazin-3- yl)methylamino]quinazolin-8-yl]oxyacetic acid sodium salt (87 mg, 75 % yield) as a white powder. Example 215 8-(azetidin-3-ylmethoxy)-6-(4-fluorophenyl)-N-[(6-methylpyridazin-3- yl)methyl]quinazolin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] Cesium carbonate (360 mg, 1.1 mmol) was added to a mixture of Example 186A (200 mg, 0.55 mmol) and N-Boc-3-(Iodomethyl)azetidine (247 mg, 0.72 mmol) in DMF (Volume: 3 ml). Stirring went on at 25 °C for 48 h. The crude material was purified by chromatography. The intermediate Boc-protected amine (150 mg, 0.28 mmol) was treated with 8N HCl in MeOH at RT for 3 days to leave 8-(azetidin-3-ylmethoxy)-6-(4- fluorophenyl)-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine (122 mg, 87 % yield) as a white powder. LCMS (Method 7):: 2.24 min, [M+H]+ 431.1Se1 6min <com:Sup>1< / com:Sup>H NMR (300 MHz, METHANOL-d4) δ ppm 8.80 (s, 1 H), 8.49 (d, J=8.80 Hz, 1 H), 8.37 (d, J=1.28 Hz, 1 H), 8.31 (br d, J=8.44 Hz, 1 H), 7.90 - 7.97 (m, 3 H), 7.33 (t, J=8.71 Hz, 2 H), 5.43 (s, 2 H), 4.60 (d, J=4.95 Hz, 2 H), 4.34 (dd, J=8.44, 3.48 Hz, 4 H), 2.89 (s, 3 H) The following compounds were prepared via adaptations of the above procedures starting from substrate reported in table. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Example 220 6-(4-fluorophenyl)-8-[(1-methylazetidin-3-yl)methoxy]-N-[(6- methylpyridazin-3-yl)methyl]quinazolin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] 8-(azetidin-3-ylmethoxy)-6-(4-fluorophenyl)-N-[(6-methylpyridazin-3- yl)methyl]quinazolin-4-amine (Example 215) (50 mg, 0.1 mmol) was reacted with Sodium carbonate (31.6 mg, 0.3 mmol) dimethylsulfate (247 mg, 0.72 mmol) in DMF (1.65 mL). Stirring went on at 25 °C for 18 h. The crude material was purified by chromatography to leave 6-(4-fluorophenyl)-8-((1-methylazetidin-3-yl)methoxy)-N-((6- methylpyridazin-3-yl)methyl)quinazolin-4-amine (1.9 mg, 4 % yield) as a white powder LCMS (Method 7): LCMS (Method 7): 2.09 min, [M+H]+ 445.1 <com:Sup>1< / com:Sup>H NMR (300 MHz, DMSO-d<com:Sub>6< / com:Sub>) <com:Sup>1< / com:Sup>H NMR (300 MHz, CHLOROFORM-d) δ ppm 8.71 (s, 1 H), 7.73 (br s, 1 H), 7.54 - 7.63 (m, 3 H), 7.51 (d, J=8.80 Hz, 1 H), 7.35 - 7.41 (m, 1 H), 7.33 (s, 1 H), 7.11 - 7.22 (m, 2 H), 5.09 (d, J=3.85 Hz, 2 H), 4.42 (d, J=6.24 Hz, 2 H), 3.63 - 3.70 (m, 2 H), 3.34 - 3.56 (m, 2 H), 3.06 - 3.30 (m, 1 H), 2.75 (s, 3 H), 2.53 (s, 3 H) The following compounds were prepared via adaptations of the above procedures starting from substrate reported in table. [Image disponible dans le document PDF, Image available in the PDF document] Example 223 and Example 224 <com:Math><semantics>((R)−8−methoxy−6−(3−methyl−1H−pyrazol−1−yl)−N−(1−(2−methyl−1H−pyrazol−1−yl)−N−(1−(2−methyl−1H−pyrazol−1−yl)−N−(1−(2−methyl−1H−pyrazol−1−yl)−N−(1−(2−methyl−1H−pyrazol−1−yl)−N−(1−(2−methyl−1H−pyrazol−1−yl)−N−(1−(2−methyl−1<annotation encoding="application / x-tex">((R)-8-methoxy-6-(3-methyl-1H-pyrazol-1-yl)-N-(1-(2-methyl-1H-pyrazol-1-yl)-N-(1-(2-methyl-1H-pyrazol-1-yl)-N-(1-(2-methyl-1H-pyrazol-1-yl)-N-(1-(2-methyl-1H-pyrazol-1-yl)-N-(1-(2-methyl-1H-pyrazol-1-yl)-N-(1-(2-methyl-1< / annotation>< / semantics>< / com:Math> (trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine (Ex. 223) and (<com:Math><semantics>R<annotation encoding="application / x-tex">R< / annotation>< / semantics>< / com:Math>)-8- methoxy-6-(5-methyl-1H-pyrazol-1-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5- yl)ethyl)quinazolin-4-amine (Ex. 224) [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Example 223 Example 224 Nitrogen was bubbled for 5 min through a mixture of <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-6-bromo-8-methoxy-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>- (1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine (107 mg, 0.25 mmol), copper (I) iodide (2.4 mg, 0.01 mmol) and potassium carbonate (73 mg, 0.53 mmol). 5- Methyl-1H-pyrazole (20 mg, 0.25 mmol) and <com:Math><semantics>(rac)<annotation encoding="application / x-tex">(rac)< / annotation>< / semantics>< / com:Math>-(+)-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>,<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>'-dimethyl-1,2- cyclohexanediamine (3.6 mg, 0.03 mmol) in toluene (0.5 mL) were added and the reaction mixture was heated to 115 °C for 72 hours. After return to room temperature, the reaction was filtered through Celite® and the filter cake rinsed with toluene <com:Math><semantics>(2×5 mL)<annotation encoding="application / x-tex">(2 \times 5 \text{ mL})< / annotation>< / semantics>< / com:Math>. The organic phases were filtered through a hydrophobic frit and the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compounds. The structure of each regioisomer (Example 223 and Example 224) was confirmed by <com:Sup>1< / com:Sup>H NMR studies. Example 223: 33 mg, 30%, off-white solid <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 9.18 (s, 2 H), 8.59 (d, J = 7.0 Hz, 1 H), 8.52 (d, J = <com:Math><semantics>2.4 Hz<annotation encoding="application / x-tex">2.4 \text{ Hz}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>1 H<annotation encoding="application / x-tex">1 \text{ H}< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>8.39 (s, 1 H)<annotation encoding="application / x-tex">8.39 \text{ (s, } 1 \text{ H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>8.23 (d, J=2.1 Hz<annotation encoding="application / x-tex">8.23 \text{ (d, } J = 2.1 \text{ Hz}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>1 H)<annotation encoding="application / x-tex">1 \text{ H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>7.69 (d, J=2.0 Hz<annotation encoding="application / x-tex">7.69 \text{ (d, } J = 2.0 \text{ Hz}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>1 H)<annotation encoding="application / x-tex">1 \text{ H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>6.46 (d, J=2.0 Hz<annotation encoding="application / x-tex">6.46 \text{ (d, } J = 2.0 \text{ Hz}< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>=2.3 Hz,1 H<annotation encoding="application / x-tex">= 2.3 \text{ Hz}, 1 \text{ H}< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>5.69−5.63 (m, 1 H),4.01 (s, 3 H),2.35 (s, 3 H),1.74 (d, J=7.1 Hz, 3 H).<annotation encoding="application / x-tex">5.69-5.63 \text{ (m, 1 H)}, 4.01 \text{ (s, 3 H)}, 2.35 \text{ (s, 3 H)}, 1.74 \text{ (d, J} = 7.1 \text{ Hz, 3 H)}.< / annotation>< / semantics>< / com:Math> LCMS (Method 3): <com:Math><semantics>[MH+]=430<annotation encoding="application / x-tex">[MH+] = 430< / annotation>< / semantics>< / com:Math> at 3.30 min. Example 224: 6 mg, 6%, off-white solid <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 9.16 (s, 2 H), 8.64 (d, J = 7.0 Hz, 1 H), 8.08 (d, J <com:Math><semantics>=2.0 Hz,1 H),7.65 (d, J=1.6 Hz,1 H),7.39 (d, J=2.0 Hz,1 H),6.77 (s, 1 H),6.37 (s, 1 H)<annotation encoding="application / x-tex">= 2.0 \text{ Hz}, 1 \text{ H}), 7.65 \text{ (d, J} = 1.6 \text{ Hz}, 1 \text{ H}), 7.39 \text{ (d, J} = 2.0 \text{ Hz}, 1 \text{ H}), 6.77 \text{ (s, 1 H)}, 6.37 \text{ (s, 1 H)}< / annotation>< / semantics>< / com:Math> 1 H), 5.69-5.64 (m, 1 H), 3.97 (s, 3 H), 2.43 (s, 3 H), 1.70 (d, J = 7.1 Hz, 3 H). LCMS (Method 3): <com:Math><semantics>[MH+]=430<annotation encoding="application / x-tex">[MH+] = 430< / annotation>< / semantics>< / com:Math> at 3.18 min. Example 225 and Example 226 <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-8-Methoxy-6-(4-methyl-<com:Math><semantics>1H<annotation encoding="application / x-tex">1H< / annotation>< / semantics>< / com:Math>-imidazol-1-yl)-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-(1-(2- (trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine (Ex. 225) and (<com:Math><semantics>R<annotation encoding="application / x-tex">R< / annotation>< / semantics>< / com:Math>)-8- methoxy-6-(5-methyl-1H-imidazol-1-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5- yl)ethyl)quinazolin-4-amine (Ex. 226) [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Example 225 Example 226 Nitrogen was bubbled for 5 min through a mixture of <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-6-bromo-8-methoxy-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>- (1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine (214 mg, 0.50 mmol), copper (I) iodide (5.0 mg, 0.02 mmol) and caesium carbonate (145 mg, 1.05 mmol). 5- Methyl-1H-imidaozle (50 mg, 0.60 mmol) and <com:Math><semantics>(rac)<annotation encoding="application / x-tex">(rac)< / annotation>< / semantics>< / com:Math>-(+)-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>,<com:Math><semantics>N′<annotation encoding="application / x-tex">N'< / annotation>< / semantics>< / com:Math>-dimethyl-1,2- cyclohexanediamine (3.6 mg, 0.03 mmol) in N,N-dimethylformamide (0.3 mL) were added and the reaction mixture was heated to 115 °C for 72 hours. After return to room temperature, the reaction was filtered through Celite® and the filter cake rinsed with N,N- dimethylformamide (<com:Math><semantics>2×3<annotation encoding="application / x-tex">2 \times 3< / annotation>< / semantics>< / com:Math> mL). The organic phases were filtered through a hydrophobic frit and the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compounds. The structure of each regioisomer Example 225 and Example 226 was confirmed by <com:Sup>1< / com:Sup>H NMR. Example 225: 18 mg, 8%, off-white solid <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 9.17 (s, 2 H), 8.50 (d, J = 6.7 Hz, 1 H), 8.41 (s, 1 H), <com:Math><semantics>8.32<annotation encoding="application / x-tex">8.32< / annotation>< / semantics>< / com:Math> (s, 1 H), <com:Math><semantics>8.09<annotation encoding="application / x-tex">8.09< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=1.9<annotation encoding="application / x-tex">J = 1.9< / annotation>< / semantics>< / com:Math> Hz, 1 H), <com:Math><semantics>7.62<annotation encoding="application / x-tex">7.62< / annotation>< / semantics>< / com:Math> (s, 1 H), <com:Math><semantics>7.53<annotation encoding="application / x-tex">7.53< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=2.1<annotation encoding="application / x-tex">J = 2.1< / annotation>< / semantics>< / com:Math> Hz, 1 H), <com:Math><semantics>5.69<annotation encoding="application / x-tex">5.69< / annotation>< / semantics>< / com:Math>- <com:Math><semantics>5.63 (m, 1 H),4.01 (s, 3 H),2.23 (s, 3 H),1.74 (d, J=7.2 Hz, 3 H).LCMS (Method 4)<annotation encoding="application / x-tex">5.63 \text{ (m, 1 H)}, 4.01 \text{ (s, 3 H)}, 2.23 \text{ (s, 3 H)}, 1.74 \text{ (d, J} = 7.2 \text{ Hz, 3 H)}. LCMS \text{ (Method 4)}< / annotation>< / semantics>< / com:Math>: <com:Math><semantics>[MH+]=430 at 4.01 min.<annotation encoding="application / x-tex">[MH+] = 430 \text{ at } 4.01 \text{ min.}< / annotation>< / semantics>< / com:Math> Example 226: 14 mg, 7%, off-white solid <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO): δ 9.40 (s, 1H), 9.33 (s, 1 H), 9.18 (s, 2 H), 8.70 (s, 1 H), <com:Math><semantics>8.26<annotation encoding="application / x-tex">8.26< / annotation>< / semantics>< / com:Math> (s, 1 H), <com:Math><semantics>7.74<annotation encoding="application / x-tex">7.74< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=1.5<annotation encoding="application / x-tex">J = 1.5< / annotation>< / semantics>< / com:Math> Hz, 1 H), <com:Math><semantics>7.65<annotation encoding="application / x-tex">7.65< / annotation>< / semantics>< / com:Math> (s, 1 H), <com:Math><semantics>5.77<annotation encoding="application / x-tex">5.77< / annotation>< / semantics>< / com:Math> (q, <com:Math><semantics>J=7.0<annotation encoding="application / x-tex">J = 7.0< / annotation>< / semantics>< / com:Math> Hz, 1 H), <com:Math><semantics>4.04<annotation encoding="application / x-tex">4.04< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(s,3H),2.31(s,3H),1.77−1.72(m,3H).LCMS(Method3):[MH+]=430at2.23<annotation encoding="application / x-tex">(s, 3 H), 2.31 (s, 3 H), 1.77-1.72 (m, 3 H). LCMS (Method 3): [MH+] = 430 at 2.23< / annotation>< / semantics>< / com:Math> min. Example 227 <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-8-Methoxy-6-(4-methyl-<com:Math><semantics>1H<annotation encoding="application / x-tex">1H< / annotation>< / semantics>< / com:Math>-pyrazol-1-yl)-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-(1-(2- (trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] Nitrogen was bubbled for 5 min through a mixture of <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-6-bromo-8-methoxy-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>- (1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine (107 mg, 0.25 mmol), copper (I) iodide (2.4 mg, 0.01 mmol), 4-methyl-1H-pyrazole (25 mg, 0.30 mmol) and potassium carbonate <com:Math><semantics>(73 mg,0.53)<annotation encoding="application / x-tex">(73 \text{ mg}, 0.53)< / annotation>< / semantics>< / com:Math> mmol). <com:Math><semantics>(rac)<annotation encoding="application / x-tex">(rac)< / annotation>< / semantics>< / com:Math>-(+)-<com:Math><semantics>N,N′<annotation encoding="application / x-tex">N,N'< / annotation>< / semantics>< / com:Math>-dimethyl-1,2- cyclohexanediamine (3.6 mg, 0.03 mmol) in toluene (0.5 mL) was added and the reaction mixture was heated to 115 °C for 72 hours. After return to room temperature, the reaction was filtered through Celite® and the filter cake was rinsed with toluene <com:Math><semantics>(2×5 mL)<annotation encoding="application / x-tex">(2 \times 5 \text{ mL})< / annotation>< / semantics>< / com:Math>. The organic phases were filtered through a hydrophobic frit and the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound (4 mg, 6%) as an off white solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO): δ 9.20 (s, 2 H), 8.67 (s, 1 H), 8.49 (s, 1 H), 8.45 (s, 1 H), <com:Math><semantics>7.94<annotation encoding="application / x-tex">7.94< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=1.5<annotation encoding="application / x-tex">J = 1.5< / annotation>< / semantics>< / com:Math> Hz, 1 H), <com:Math><semantics>7.74<annotation encoding="application / x-tex">7.74< / annotation>< / semantics>< / com:Math> (s, 1 H), <com:Math><semantics>5.83<annotation encoding="application / x-tex">5.83< / annotation>< / semantics>< / com:Math> (q, <com:Math><semantics>J=6.9<annotation encoding="application / x-tex">J = 6.9< / annotation>< / semantics>< / com:Math> Hz, 1 H), <com:Math><semantics>4.13<annotation encoding="application / x-tex">4.13< / annotation>< / semantics>< / com:Math> (s, 3 H), 2.17 (s, 3 H), 1.80 (d, <com:Math><semantics>J=7.2 Hz<annotation encoding="application / x-tex">J = 7.2 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 3 H). LCMS (Method 3): [MH+] = 430 at 4.42 min. Intermediate 8 6-bromo-N-((6-methylpyridin-3-yl)methyl)quinazolin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] A mixture of 6-bromo-4-chloroquinazoline (1 g, 4.11 mmol), (6-methylpyridin-3- yl)methanamine (0.500 g, 4.09 mmol) and triethylamine (3 ml, 21.52 mmol) in 1,4- Dioxane / DMF 5:1 (Volume: 12 ml) was stirred at 100 °C for 16 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (Biotage Isolere, 55 g NH cartridge, gradient elution from 0 to 50% Acetone in heptane) yielded 6-bromo-N-((6-methylpyridin-3-yl)methyl)quinazolin-4-amine (1.35 g, 4.10 mmol, 100 % yield) as a pale yellow powder. LCMS (Method 6): <com:Math><semantics>0.82 min<annotation encoding="application / x-tex">0.82 \text{ min}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>m / z328.8[M]+and330.8[M+2]+,<annotation encoding="application / x-tex">m / z 328.8 [M] + and 330.8 [M+2] +,< / annotation>< / semantics>< / com:Math> The following intermediates were synthesised via adaptations of the same procedure by reacting suitable amines with substrate reported in the table. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Example 228 6-(5-methylpyridin-2-yl)-N-((6-methylpyridin-3-yl)methyl)quinazolin-4- amine [Image disponible dans le document PDF, Image available in the PDF document] Tetrakis(triphenylphosphine)palladium(0) (70.2 mg, 0.061 mmol) was added to a mixture of 6-bromo-N-((6-methylpyridin-3-yl)methyl)quinazolin-4-amine (Intermediate 8) (100 mg, 0.304 mmol) and 5-methyl-2-(tributylstannyl)pyridine (0.315 ml, 0.911 mmol) in DMF (Volume: 2 ml). Stirring went on for 16 h at 80 °C. Purification by DP chromatography (Biotage Isolera, 28 g NH cartridge, gradient elution from 0 to 100% EtOAC in dichloromethane in 20 CV) yielded 6-(5-methylpyridin-2-yl)-N-((6- methylpyridin-3-yl)methyl)quinazolin-4-amine (69.8 mg, 0.204 mmol, 67.3 % yield) as a white powder. LCMS: 0.33 min, 341.9 m / z [M+H]+, CSH 2 min. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) d ppm 9.02 (t, J=5.7 Hz, 1 H), 8.93 - 8.96 (m, 1 H), 8.55 - 8.58 (m, 1 H), 8.49 - 8.54 (m, 2 H), 8.48 (s, 1 H), 8.00 - 8.09 (m, 1 H), 7.73 - 7.82 (m, 2 H), 7.66 - 7.72 (m, 1 H), 7.16 - 7.22 (m, 1 H), 4.76 - 4.82 (m, 2 H), 2.43 (s, 3 <com:Math><semantics>H<annotation encoding="application / x-tex">H< / annotation>< / semantics>< / com:Math>), 2.37 (s, 3 <com:Math><semantics>H<annotation encoding="application / x-tex">H< / annotation>< / semantics>< / com:Math>). The following compounds were synthesised via adaptation of the above procedure using the appropriate stannane reagent and starting from substrate reported in table: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Example 234 6-(4-fluorophenyl)-N2,N2-dimethyl-N4-(1-(3-methyl-1,2,4-oxadiazol-5- yl)ethyl)quinazoline-2,4-diamine [Image disponible dans le document PDF, Image available in the PDF document] 5 A solution of 2-chloro-6-(4-fluorophenyl)-N-(1-(3-methyl-1,2,4-oxadiazol-5- yl)ethyl)quinazolin-4-amine (Example 223) (80 mg, 0.208 mmol) and dimethylamine 2.0 M in THF (0.625 ml, 1.251 mmol) in 1,4-dioxane (Volume: 3 ml) was stirred at 100 °C for 16 h. The reaction mixture was partitioned between saturated aqueous ammonium chloride and dichloromethane. The organic layer was concentrated under reduced pressure. Purification by DP chromatography (Biotage Isolera, 10 g KP-Sil cartridge, gradient elution from 0 to 70% [dichloromethane / MeOH 9:1] in dichloromethane in 15 CV) yielded6-(4-fluorophenyl)-N2,N2-dimethyl-N4-(1-(3-methyl-1,2,4-oxadiazol-5- yl)ethyl)quinazoline-2,4-diamine (73.5 mg, 0.187 mmol, 90 % yield) as a pale yellow powder. LCMS: 0.71 min, m / z 393.0 [M+H]+, Method 5 acidic method. 1H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> ppm 8.51 - 8.84 (m, 1 H), 8.45 (d, J=1.8 Hz, 1 H), 7.81 (dd, J=8.8, 5.7 Hz, 3 H), 7.32 (t, J=8.8 Hz, 3 H), 5.45 - 5.55 (m, 1 H), 3.02 (s, 6 H), 2.30 (s, 3 H), 1.72 (d, J=7.0 Hz, 3 H). The following compounds were synthesised via adaptation of the above procedure. Example 237 was obtained using the same reaction conditions as Example 235, Example 238 was was obtained using the same reaction conditions as Example 236 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Example 239 6-(4-fluorophenyl)-2-methyl-N-((6-methylpyridazin-3-yl)methyl)quinazolin- 4-amine [Image disponible dans le document PDF, Image available in the PDF document] Pd(dppf)Cl<com:Sub>2< / com:Sub> · CH<com:Sub>2< / com:Sub>Cl<com:Sub>2< / com:Sub> (11.86 mg, 0.015 mmol) was added to a mixture of 6-bromo- 2-methyl-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine (Intermediate 9) (50 mg, 0.145 mmol), (4-fluorophenyl)boronic acid (30.5 mg, 0.218 mmol) and potassium phosphate (61.7 mg, 0.291 mmol) in DMF / water 2:1 (Volume: 3 ml). Stirring went on for 16 h at 80 °C. Purification by RP chromatography (Biotage Isolera, 30 g C18 cartridge, gradient elution from 0 to 65% B in A, A: water / acetonitrile 95:5 + 0.1% conc ammonia, B: acetonitrile:water 95:5 +0.1% conc ammonia in 20 CV) then by RP chromatography (Biotage Isolera, 30 g C18 cartridge, gradient elution from 0 to 50% B in A, A: water / acetonitrile 95:5 + 0.1% HCOOH, B: acetonitrile:water 95:5 +0.1% HCOOH in 15 CV) yielded 6-(4-fluorophenyl)-2-methyl-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine (35.9 mg, 0.100 mmol, 68.8 % yield) as an off-white powder. LCMS (Method 5): 0.53 min, m / z 360 [M+H]+,. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.17 - 13.22 (bs, 1 H), 9.00 (br. s., 1 H), 8.60 (d, J=1.8 Hz, 1 H), 8.07 (dd, J=8.8, 1.8 Hz, 1 H), 7.87 (dd, J=8.8, 5.7 Hz, 2 H), 7.69 (d, J=8.3 Hz, 1 H), 7.46 - 7.61 (m, 2 H), 7.35 (t, J=8.8 Hz, 2 H), 5.03 (d, J=5.3 Hz, 2 H), 2.59 (s, 3 H), 2.43 (s, 3 H). The following intermediates were synthesised via adaptations of the same procedure starting from suitable intermediates reported in table. Example 246 was obtained with the same conditions used for Example 245. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Example 249 N-((3,5-difluoropyridin-2-yl)methyl)-6-(4-fluorophenyl)quinazolin-4-amine hydrochloride [Image disponible dans le document PDF, Image available in the PDF document] DIPEA (0.15 mL, 0.861 mmol) was added to a mixture of 6-bromo-4- chloroquinazoline (100 mg, 0.411 mmol) and (3,5-difluoropyridin-2-yl)methanamine hydrochloride (74.2 mg, 0.411 mmol) in DMF (Volume: 2 ml). Stirring went on for 6 h at 80 °C. Upon completion of conversion of starting materials to 6-bromo-N-((3,5- difluoropyridin-2-yl)methyl)quinazolin-4-amine, water (1 mL) was added to the reaction mixture followed by 4-fluorophenylboronic acid (86 mg, 0.614 mmol), potassium phosphate (174 mg, 0.818 mmol) and Pd(dppf)Cl<com:Sub>2< / com:Sub> · CH<com:Sub>2< / com:Sub>Cl<com:Sub>2< / com:Sub> (33.5 mg, 0.041 mmol). Stirring went on for 16 h at 80 °C. The mixture was allowed to cool down to rt, then formic acid (150 µL, 3.98 mmol) was added. Purification by RP chromatography (Biotage Isolera, 30 g C18 cartridge, gradient elution from 100:0 to 65:35 A / B, A: water / acetonitrile 95:5 + 0.1% HCOOH, B: acetonitrile:water 95:5 +0.1% HCOOH in 15 CV) yielded <com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-((3,5-difluoropyridin-2-yl)methyl)-6-(4-fluorophenyl)quinazolin-4- amine hydrochloride (98.4 mg, 0.244 mmol, 59.5 % yield) as an off-white powder. LCMS (Method 5): : 0.67 min, 366.9 m / z [M+H]+, <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) δ ppm 10.82 (br s, 1 H), 8.92 - 9.00 (m, 1 H), 8.84 - 8.91 (m, 1 H), 8.44 - 8.50 (m, 1 H), 8.34 - 8.44 (m, 1 H), 7.98 - 8.07 (m, 1 H), 7.87 - 7.97 (m, 3 H), 7.43 (t, J=8.88 Hz, 2 H), 5.13 (br d, J=5.26 Hz, 2 H). Example 250 6-(4-fluorophenyl)-N-methyl-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl) quinazolin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] To a solution of 6-(4-fluorophenyl)-N-(1-(3-methyl-1,2,4-oxadiazol-5- yl)ethyl)quinazolin-4-amine (30 g, 0.086 mmol) in DMF (1 mL), cooled to 0 °C, NaH (6.07 mg, 0.240 mmol) was added and the reaction stirred for 30 min before adding MeI (10.74 µL, 0.172 mmol). After 20h, the crude mixture was directly loaded onto column and purified by RP flash chromatography (Biotage Isolera, 12 g C18 cartridge, gradient elution from 0 to 80% B in A; A: water / MeCN 95:5 + 0.1% HCOOH, B: MeCN / water 95:5 + 0.1% HCOOH) yielded the titled compound (16 mg, 0.044 mmol, 51.3 % yield) as pale beige powder. LCMS (Method 5): 0.57 min, 364.0 [M+H]+. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> <com:Math><semantics>□<annotation encoding="application / x-tex">\Box< / annotation>< / semantics>< / com:Math>ppm 8.33 (d, J=2.2 Hz, 1 H), 8.08 (s, 1 H), 7.98 (dd, J=8.4, 2.2 Hz, 1 H), 7.69 - 7.77 (m, 2 H), 7.51 (d, J=8.8 Hz, 1 H), 7.32 (t, J=8.8 Hz, 2 H), 5.72 (d, J=6.6 Hz, 1 H), 3.63 (s, 3 H), 2.31 (s, 3 H), 1.53 (d, J=7.1 Hz, 3 H). Example 251 (R)-6-(3,3-difluoropyrrolidin-1-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5- yl)ethyl)quinazolin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] To a suspension of <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-6-bromo-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(1−(2−(trifluoromethyl)pyrimidin−5−<annotation encoding="application / x-tex">(1-(2-(trifluoromethyl)pyrimidin-5-< / annotation>< / semantics>< / com:Math> yl)ethyl)quinazolin-4-amine (40 mg, 0.100 mmol) in Toluene (1.5 mL), 3,3- difluoropyrrolidine hydrochloride (36 mg, 0.251 mmol) and cesium carbonate (82 mg, 0.251 mmol) were added, followed by <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-(+)-2,2'-bis(diphenylphoshino)-1,1'- binaphthyl (13 mg, 0.020 mmol) and tris(dibenylideneacetone)dipalladium (0) (9.20 mg, 10.05 μmol). The resulting mixture was heated to 100 °C and stirred for 7h. The mixture was cooled to RT and filtered. Volatiles were removed under reduced pressure. Purification by RP flash chromatography (Biotage Isolera, 30 g C18 cartridge, gradient elution from 0 to 90% B in A; A: water / MeCN 95:5 + 0.1% HCOOH, B: MeCN / water 95:5 + 0.1% HCOOH) yielded impure product. A second purification by flash chromatography (Biotage Isolera, 11 g NH cartridge, gradient elution from 5% to 100% EtOAc in heptane) yielded the titled compound (21 mg, 4.95 μmol, 5 % yield) as white powder. LCMS (Method 5): 0.68 min, 425.0 [M+H]+. <com:Math><semantics>1<annotation encoding="application / x-tex">^{1}< / annotation>< / semantics>< / com:Math>H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 2H), 8.31 (d, J=7.06 Hz, 1H), 8.27 (s, 1H), 7.55-7.62 (m, 3H), 5.66 (quin, J=6.89 Hz, 1H), 3.76 (t, J=13.89 Hz, 2H), 3.51 (t, J=7.06 Hz, 2H), 2.39-2.49 (m, 2H), 1.72 (d, J=7.06 Hz, 3H). The following Examples were synthesised via adaptations of the above procedure. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] The following compounds reported in the table below were obtained as single isomers by chiral preparative SFC purification of the appropriate racemic mixture hereinabove described. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Intermediate 15 6-bromo-8-methoxy-4-((2-(trimethylsilyl)ethoxy)methoxy)quinazoline [Image disponible dans le document PDF, Image available in the PDF document] 6-Bromo-8-methoxyquinazolin-4-ol (200 mg, 0.78 mmol) (intermediate 2) was dissolved in N,N-dimethylformamide (10 mL) and the reaction mixture cooled to 0 °C. Sodium hydride (60% dispersion in mineral oil, 38 mg, 0.94 mmol) was added portion- wise and the reaction mixture stirred for 30 min. (2-Chloromethoxyethyl)trimethylsilane (0.21 ml, 1.18 mmol) was then added dropwise. The reaction was then stirred at 0 °C for 1 hour and then allowed to warm to room temperature. The reaction mixture was quenched with water (5 mL) and partitioned with ethyl acetate (15 mL). The phases were separated and the aqueous layer washed with ethyl acetate <com:Math><semantics>(2×10 mL)<annotation encoding="application / x-tex">(2 \times 10 \text{ mL})< / annotation>< / semantics>< / com:Math>. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel, eluting with <com:Math><semantics>0−40%<annotation encoding="application / x-tex">0-40\%< / annotation>< / semantics>< / com:Math> ethyl acetate in cyclohexane to give the title compound (181 mg, 60%) as a colourless solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, CDCl3): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.17 (s, 1 H), 8.04 (d, J = 2.0 Hz, 1 H), 7.3 (d, J = <com:Math><semantics>2.0 Hz<annotation encoding="application / x-tex">2.0 \text{ Hz}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>1 H<annotation encoding="application / x-tex">1 \text{ H}< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>5.43 (s, 2 H)<annotation encoding="application / x-tex">5.43 \text{ (s, } 2 \text{ H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>4.02 (s. 3 H)<annotation encoding="application / x-tex">4.02 \text{ (s. } 3 \text{ H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>3.66 (m, J=4.1 Hz<annotation encoding="application / x-tex">3.66 \text{ (m, } J = 4.1 \text{ Hz}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>2 H)<annotation encoding="application / x-tex">2 \text{ H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>0.95 (m, J=4.1 Hz<annotation encoding="application / x-tex">0.95 \text{ (m, } J = 4.1 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 2 H)), <com:Math><semantics>0.02<annotation encoding="application / x-tex">0.02< / annotation>< / semantics>< / com:Math> (s, 9 H). LCMS (Method 3): [MH+] = 385 at 5.24 min. Intermediate 16 8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-((2- (trimethylsilyl)ethoxy) methoxy)quinazoline [Image disponible dans le document PDF, Image available in the PDF document] Nitrogen was bubbled for 10 minutes through a mixture of 6-bromo-8-methoxy-4- ((2-(trimethylsilyl)ethoxy)methoxy)quinazoline (190 mg, 0.49 mmol), bis(pinacolato)diboron (150 mg, 0.59 mmol) and potassium acetate (97 mg, 0.99 mmol) in 1,4-dioxane (5 mL), then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36 mg, 0.05 mmol) was added. The reaction mixture was then heated at 95 °C for 2 hours. After this time the reaction was cooled to room temperature and filtered through Celite®. The title compound was used directly as a solution in 1,4-dioxane, assuming a quantitative yield. Intermediate 17 6-(5-Fluoropyridin-2-yl)-8-methoxy-4-((2-(trimethylsilyl)ethoxy)-methoxy)- quinazoline [Image disponible dans le document PDF, Image available in the PDF document] To 8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-((2- (trimethylsilyl) ethoxy)methoxy) quinazoline (330 mg, 0.78 mmol) was added 2-bromo- 5-fluropyridine (137 mg, 0.78 mmol), cesium carbonate (508 mg, 1.56 mmol), 1,4- dioxane (8 mL) and water (1 mL). Nitrogen was bubbled through the reaction mixture for 10 minutes before tetrakis(triphenylphosphine)palladium(0) (90 mg, 0.078 mmol) was added. The reaction was then heated at 90 °C for 16 hours. After this time the reaction mixture was cooled to room temperature, filtered through Celite® and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 0 <com:Math><semantics>−60%<annotation encoding="application / x-tex">-60\%< / annotation>< / semantics>< / com:Math> ethyl acetate in cyclohexane to give the title compound (226 mg, 72%) as a pale yellow solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.76 (d, J = 2.4 Hz, 1 H), 8.46 (s, 1 H), 8.42 (d, J <com:Math><semantics>=1.7 Hz,1 H<annotation encoding="application / x-tex">= 1.7 \text{ Hz}, 1 \text{ H}< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>8.30 (dd, J=9.1 Hz,4.4 Hz,1 H<annotation encoding="application / x-tex">8.30 \text{ (dd, J} = 9.1 \text{ Hz}, 4.4 \text{ Hz}, 1 \text{ H}< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>8.06 (d, J=1.7 Hz,1 H)<annotation encoding="application / x-tex">8.06 \text{ (d, J} = 1.7 \text{ Hz}, 1 \text{ H})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>7.91 (dt, J=1.7 Hz)<annotation encoding="application / x-tex">7.91 \text{ (dt, J} = 1.7 \text{ Hz})< / annotation>< / semantics>< / com:Math> 2.4, 9.1Hz, 1 H), 5.44 (s, 2 H), 4.06 (s, 3 H), 3.64 (t, <com:Math><semantics>J=8.1<annotation encoding="application / x-tex">J = 8.1< / annotation>< / semantics>< / com:Math>Hz, 2 H), 0.97 (t, <com:Math><semantics>J=8.1<annotation encoding="application / x-tex">J = 8.1< / annotation>< / semantics>< / com:Math> Hz, 2 H), <com:Math><semantics>0.01<annotation encoding="application / x-tex">0.01< / annotation>< / semantics>< / com:Math> (s, 9 H). LCMS (Method 3): [MH+] = <com:Math><semantics>402<annotation encoding="application / x-tex">402< / annotation>< / semantics>< / com:Math> at <com:Math><semantics>5.43<annotation encoding="application / x-tex">5.43< / annotation>< / semantics>< / com:Math> min. The following intermediates reported in the table below were synthesised following the same procedure described for the preparation of 6-(5-Fluoropyridin-2-yl)-8-methoxy- 4-((2-(trimethylsilyl)ethoxy)-methoxy)-quinazoline (Intermediate 17): [Image disponible dans le document PDF, Image available in the PDF document] Intermediate 23 6-(5-fluoropyridin-2-yl)-8-methoxyquinazolin-4-ol [Image disponible dans le document PDF, Image available in the PDF document] 6-(5-Fluoropyridin-2-yl)-8-methoxy-4-((2- (trimethylsilyl)ethoxy)methoxy)quinazoline (225 mg, 0.56 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (0.21 mL, 2.81 mmol). The reaction mixture was stirred for 16 hours. The reaction mixture was concentrated in vacuo to yield the title compound (142 mg, 93%) as a pale orange solid. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO): <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8,76 (d, J = 2.4 Hz, 1 H), 8.39 (d, J = 1.7 Hz, 1 H), <com:Math><semantics>8.29<annotation encoding="application / x-tex">8.29< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=9.0<annotation encoding="application / x-tex">J = 9.0< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>4.6<annotation encoding="application / x-tex">4.6< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>1<annotation encoding="application / x-tex">1< / annotation>< / semantics>< / com:Math> H), <com:Math><semantics>8.13<annotation encoding="application / x-tex">8.13< / annotation>< / semantics>< / com:Math> (s, <com:Math><semantics>1<annotation encoding="application / x-tex">1< / annotation>< / semantics>< / com:Math> H) <com:Math><semantics>8.05<annotation encoding="application / x-tex">8.05< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=1.7<annotation encoding="application / x-tex">J = 1.7< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>1<annotation encoding="application / x-tex">1< / annotation>< / semantics>< / com:Math> H), <com:Math><semantics>7.92<annotation encoding="application / x-tex">7.92< / annotation>< / semantics>< / com:Math> (dt, <com:Math><semantics>J=1.7<annotation encoding="application / x-tex">J = 1.7< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>1<annotation encoding="application / x-tex">1< / annotation>< / semantics>< / com:Math> H), <com:Math><semantics>1.92<annotation encoding="application / x-tex">1.92< / annotation>< / semantics>< / com:Math> (dt, <com:Math><semantics>J=1.7<annotation encoding="application / x-tex">J = 1.7< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>1<annotation encoding="application / x-tex">1< / annotation>< / semantics>< / com:Math> H), <com:Math><semantics>1.92<annotation encoding="application / x-tex">1.92< / annotation>< / semantics>< / com:Math> (dt, <com:Math><semantics>J=1.7<annotation encoding="application / x-tex">J = 1.7< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>1<annotation encoding="application / x-tex">1< / annotation>< / semantics>< / com:Math> H), <com:Math><semantics>1.92<annotation encoding="application / x-tex">1.92< / annotation>< / semantics>< / com:Math> (dt, <com:Math><semantics>J=1.7<annotation encoding="application / x-tex">J = 1.7< / annotation>< / semantics>< / com:Math> <com:Math><semantics>=2.4,9.1<annotation encoding="application / x-tex">= 2.4, 9.1< / annotation>< / semantics>< / com:Math>Hz, 1 H), <com:Math><semantics>5.69<annotation encoding="application / x-tex">5.69< / annotation>< / semantics>< / com:Math> (br s, 1 H), <com:Math><semantics>4.06<annotation encoding="application / x-tex">4.06< / annotation>< / semantics>< / com:Math> (s, 3 H). LCMS (Method 3): [MH+] <com:Math><semantics>=272<annotation encoding="application / x-tex">= 272< / annotation>< / semantics>< / com:Math> at 3.08 min. The following intermediates reported in the table below were synthesised following the same procedure described for the preparation of 6-(5-fluoropyridin-2-yl)-8- 5 methoxyquinazolin-4-ol (Intermediate 23): [Image disponible dans le document PDF, Image available in the PDF document] Example 315 <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-6-(5-fluoropyridin-2-yl)-8-methoxy-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-(1-(5-methyl-1,2,4-oxadiazol-3- yl)ethyl)quinazolin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] Example 325 <com:Math><semantics>(S)<annotation encoding="application / x-tex">(S)< / annotation>< / semantics>< / com:Math>-6-<com:Math><semantics>(5<annotation encoding="application / x-tex">(5< / annotation>< / semantics>< / com:Math>-fluoropyridin-2-yl)-8-methoxy-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(1<annotation encoding="application / x-tex">(1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(5<annotation encoding="application / x-tex">(5< / annotation>< / semantics>< / com:Math>-methyl-1,2,4-oxadiazol-3- yl)ethyl)quinazolin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] Step 1: Preparation of 4-Chloro-6-(5-fluoropyridin-2-yl)-8-methoxyquinazoline [Image disponible dans le document PDF, Image available in the PDF document] 8-Methoxy-6-(5-fluoropyridin-2-yl)quinazolin-4-ol (750 mg, 2.81 mmol) was suspended in thionyl chloride (4.1 mL, 56.12 mmol) and DMF (0.0005 mL, 0.006 mmol) was added. The reaction mixture was heated at 95 °C for 4 hours. The reaction was cooled to room temperature and the solvent was removed in vacuo to give 4-chloro-6-(5- fluoropyridin-2-yl)-8-methoxyquinazoline (800 mg, 98%). The crude residue was taken on directly to the next step without further purification. Step 2: Preparation of <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-6-(5-fluoropyridin-2-yl)-8-methoxy-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-(1-(5-methyl- 1,2,4-oxadiazol-3-yl)ethyl)quinazolin-4-amine and [Image disponible dans le document PDF, Image available in the PDF document] and <com:Math><semantics>(S)<annotation encoding="application / x-tex">(S)< / annotation>< / semantics>< / com:Math>-6-<com:Math><semantics>(5<annotation encoding="application / x-tex">(5< / annotation>< / semantics>< / com:Math>-fluoropyridin-2-yl)-8-methoxy-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(1<annotation encoding="application / x-tex">(1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(5<annotation encoding="application / x-tex">(5< / annotation>< / semantics>< / com:Math>-methyl-1,2,4-oxadiazol-3- yl)ethyl)quinazolin-4-amine [Image disponible dans le document PDF, Image available in the PDF document] To a mixture of 4-chloro-6-(5-fluoropyridin-2-yl)-8-methoxyquinazoline (100 mg, 0.367 mmol) and N,N-diisopropylethylamine (0.32 mL, 1.84 mmol) in 1,4-dioxane (5 mL) was added (R)-1-(5-methyl-1,2,4-oxadiazol-3-yl)ethan-1-amine (93 mg, 0.735 mmol). The resulting mixture was stirred at 50 °C for 5 days. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (25 mg, 19%) as an off white solid. Example 315 <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-6-(5-fluoropyridin-2-yl)-8-methoxy-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-(1-(5-methyl-1,2,4-oxadiazol-3- yl)ethyl)quinazolin-4-amine: <com:Sup>1< / com:Sup>H NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 8.57 (s, 1 H), 8.54 (d, J=3.8 Hz, 1 H), 7.88 (s, 2 H), 7.69 (s, 1 H), 7.54 (ddd, J=8.6, 8.6, 2.9 Hz, 1 H), 6.82 (s, 1 H), 5.92 - 5.84 (m, 1 H), 4.13 (s, 3 H), 2.65 (s, 3 H), 1.77 (d, J=6.1 Hz, 3 H). LCMS (Method 3): <com:Math><semantics>[MH+]=381<annotation encoding="application / x-tex">[MH+] = 381< / annotation>< / semantics>< / com:Math> at 2.90 min. Chiral analysis (Method 31) at 2.24 min. Example 325 <com:Math><semantics>(S)<annotation encoding="application / x-tex">(S)< / annotation>< / semantics>< / com:Math>-6-<com:Math><semantics>(5<annotation encoding="application / x-tex">(5< / annotation>< / semantics>< / com:Math>-fluoropyridin-2-yl)-8-methoxy-<com:Math><semantics>N<annotation encoding="application / x-tex">N< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(1<annotation encoding="application / x-tex">(1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(5<annotation encoding="application / x-tex">(5< / annotation>< / semantics>< / com:Math>-methyl-1,2,4-oxadiazol-3- yl)ethyl)quinazolin-4-amine Chiral analysis (Method 31) at 0.58 min. The following compounds reported in the table below were prepared according to the same procedure described for the preparation of <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math>-6-(5-fluoropyridin-2-yl)-8- methoxy-N-(1-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl)quinazolin-4-amine. Some compounds were further purified by preparative chiral SFC to obtain the pure enantiomers. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] PHARMACOLOGICAL ACTIVITY OF THE COMPOUNDS OF THE INVENTION. In vitro Electrophysiology Assay for P2X<com:Sub>3< / com:Sub> Cells expressing P2X<com:Sub>3< / com:Sub> receptors were grown according to standard practice and maintained at 37 °C in a 5% humidified CO<com:Sub>2< / com:Sub> atmosphere. The cells were seeded into T175 flask 2 days prior to the day of the assay and dissociated from the flasks using TrypLE when grown to confluence of 80-90%. The dissociated cells were resuspended in serum free media at a cell density of <com:Math><semantics>3x106<annotation encoding="application / x-tex">3x10^6< / annotation>< / semantics>< / com:Math> cells / ml and loaded onto the Sophion Qube automated patch-clamp system. The extracellular assay buffer contained 145 mM NaCl, 4 mM KCl, 2 mM CaCl<com:Sub>2< / com:Sub>, 1 mM MgCl<com:Sub>2< / com:Sub>, 10 mM HEPES, and 10 mM glucose at pH 7.4. The intracellular assay solution contained 140 mM CsF, 10 mM NaCl, 10 mM EGTA, 10 mM HEPES at pH 7.2. Agonist stock solutions were prepared in H<com:Sub>2< / com:Sub>O and diluted in bath solution prior to use. All antagonists were prepared as 10 mM stock solutions in DMSO and diluted in bath solution prior to use. All experiments were performed under the whole- cell patch clamp configuration at room temperature with 384 individual cells being voltage clamped at -60 mV simultaneously on the Sophion Qube instrument. Two baseline responses were established with the application of <com:Math><semantics>α,β<annotation encoding="application / x-tex">\alpha,\beta< / annotation>< / semantics>< / com:Math>-MeATP (800 nM), with the subsequent agonist applications being washed out using extracellular assay buffer containing 0.5 U / ml apyrase. Following the second agonist application, antagonist was incubated in the absence of <com:Math><semantics>α,β<annotation encoding="application / x-tex">\alpha,\beta< / annotation>< / semantics>< / com:Math>-MeATP for 10 minutes. After antagonist preincubation, 800 nM <com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>-MeATP and antagonist were co-administered to determine the inhibitory effect of the antagonist. One concentration of an antagonist was assessed against a single cell, with different concentrations of the antagonist applied to other cells on the 384 recording substrate. The control P2X<com:Sub>3< / com:Sub> current amplitude was taken from the peak current amplitude from the second agonist response prior to preincubation with antagonist. The peak P2X<com:Sub>3< / com:Sub> current amplitude in the presence of antagonist was used to calculate the inhibitory effect at each concentration of the antagonist according to the following equation: Percentage inhibition of <com:Math><semantics>P2X3=(P2X3 control peak amplitude-P2X3 antagonist<annotation encoding="application / x-tex">P2X_3 = (P2X_3 \text{ control peak amplitude-} P2X_3 \text{ antagonist}< / annotation>< / semantics>< / com:Math> peak amplitude) / P2X<com:Sub>3< / com:Sub> control peak amplitude)*100 Concentration-response curves were constructed from ten different concentrations with each concentration of antagonist tested on at least two individual cells. The concentration of the antagonist to inhibit P2X<com:Sub>3< / com:Sub> current by 50% (IC<com:Sub>50< / com:Sub>) was determined by fitting the data with the following equation: [Image disponible dans le document PDF, Image available in the PDF document] Where 'a' is minimum response, 'b' is maximum response, 'c' is IC<com:Sub>50< / com:Sub> and 'd' is Hill slope. The results for individual compounds are provided below in Table 8 and are expressed as range of activity. Table 8 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] wherein the compounds are classified in term of potency with respect to their inhibitory activity on P2X<com:Sub>3< / com:Sub> according to the following classification criterion: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] In vitro Electrophysiology Assay for P2X2 / 3 Representative compound of the present invention have been also tested for P2X<com:Sub>2 / 3< / com:Sub> receptor. The same assay protocol was used for the P2X<com:Sub>2 / 3< / com:Sub> assay as the P2X<com:Sub>3< / com:Sub> assay with two modifications: 1) 10 µM ATP was used as the agonist; and 2) the mean current amplitude was measured seven seconds after the application of agonist. The results of Table 9 indicate that representative compounds of the present inve...

Claims

1. A compound of formula (I) [Image disponible dans le document PDF, Image available in the PDF document] (I) wherein Z is (C 3 -C 8 )heterocycloalkyl, (R A R B )N-, heteroaryl, or aryl, wherein any of such heteroaryl, heterocycloalkyl and aryl may be optionally substituted by one or more groups each independently (C 1 -C 3 )alkyl-, halo, CN, ( R A R B ) N C ( O ) (R^AR^B)NC(O) -, ( C 1 − C 6 ) (C_1-C_6) haloalkyl-, R A O R^AO -, ( R A R B ) N ( C 1 − C 6 ) (R^AR^B)N(C_1-C_6) alkylene-, ( C 3 − C 6 ) (C_3-C_6) C 7 )cycloalkyl-, R C SO 2 -, or (R A R B )N-; 𝑹 1 \mathbf{R}_1 is H or (C 1 -C 4 )alkyl; 𝑹 𝟐 \mathbf{R_2} is ( C 1 − C 6 ) (C_1-C_6) alkyl-, heteroaryl ( C 1 − C 4 ) (C_1-C_4) alkyl-, ( C 3 − C 8 ) (C_3-C_8) heterocycloalkyl- ( C 1 − C 4 ) (C_1-C_4) alkyl-, ( C 3 − C 8 ) (C_3-C_8) heterocycloalkyl- ( C 1 − C 4 ) (C_1-C_4) alkyl-, ( C 3 − C 8 ) (C_3-C_8) heterocycloalkyl- ( C 1 − C 4 ) (C_1-C_4) alkyl-, ( C 3 − C 8 ) (C_3-C_8) heterocyc C 6 )alkyl-, heteroaryl-(C 1 -C 6 )hydroxyalkyl-, (C 3 -C 8 )heterocycloalkyl, (C 3 - C 8 C_8 )cycloalkyl- ( C 1 − C 6 ) (C_1-C_6) alkyl-, aryl- ( C 1 − C 4 ) (C_1-C_4) alkyl-, ( R A R B ) N ( C 1 − C 6 ) (R^AR^B)N(C_1-C_6) alkylene-, (R A R B )N(O)C(C 1 -C 4 )alkylene- or R A O(C 1 -C 4 )alkylene- wherein any of such alkyl, alkylene, aryl, heteroaryl and heterocycloalkyl may be optionally substituted by one or more of (C 1 -C 3 )alkyl, R A O(C 1 -C 4 )alkylene-, (C 1 - C 6 C_6 )haloalkyl, halo, oxo, R A O R^AO -, ( C 3 − C 8 ) (C_3-C_8) heterocycloalkyl- ( C 1 − C 6 ) (C_1-C_6) alkyl-, heteroaryl, ( R A R B ) N − , (R^AR^B)N-, -NHC(O) R C R^{C} , -C(O)N( R A R B R^{A}R^{B} ), -SO 2 N( R A R B R^{A}R^{B} ), -O(C 1 -C 4 )alkylene- N(R A R B ), aryl optionally substituted by halo, -OR C , aryl-(C 1 -C 4 )alkyl-, or -C(O)R A ; 257 𝑹 𝑨 \mathbf{R}^{\mathbf{A}} and 𝑹 𝑩 \mathbf{R}^{\mathbf{B}} are at each occurrence independently H, (C 1 -C 4 )alkyl-, (C 3 - C 8 C_8 )cycloalkyl-, or ( C 1 C_1 - C 6 C_6 ) haloalkyl, or R A and R B may form together with the nitrogen atom to which they are attached a 5 or 6 membered saturated heterocyclic monocyclic ring system optionally containing a further heteroatom which is nitrogen or oxygen, which may be optionally substituted by one or more groups each independently ( C 1 − C 4 ) (C_1-C_4) alkyl and oxo; 𝑹 𝑪 \mathbf{R}^{\mathbf{C}} is at each occurrence H, ( C 1 − C 6 ) (C_1-C_6) alkyl, ( 𝑹 𝑨 𝑹 𝑩 ) (\mathbf{R}^{\mathbf{A}}\mathbf{R}^{\mathbf{B}}) N-, or aryl- ( C 1 − C 4 ) (C_1-C_4) alkyl-; Y is -OR D , R C SO 2 , halo, -NHSO 2 R C , heteroaryl, or (C 3 -C 8 )heterocycloalkyl, wherein any of such heteroaryl and heterocycloalkyl may be optionally substituted by one or more groups each independently ( C 1 − C 3 ) (C_1-C_3) alkyl, or − C ( O ) N ( R A R B ) -C(O)N(R^AR^B) ; 𝑹 𝑫 \mathbf{R}^{\mathbf{D}} is H, (C 1 -C 6 )alkyl, (C 3 -C 8 )heterocycloalkyl-(C 1 -C 6 )alkyl-, 𝑹 𝑪 \mathbf{R}^{\mathbf{C}} OC(O)(C 1 - C 4 C_4 )alkylene-, ( C 3 C_3 - C 6 C_6 )alkylene-, ( C 3 C_3 - C 8 C_8 )heterocycloalkyl, ( C 3 C_3 - C 8 C_8 )cycloalkyl-( C 1 C_1 - C 6 C_6 )alkyl-, R C O ( C 1 R^CO(C_1 - C 4 C_4 )alkylene-, or ( R A R B ) N ( O ) C ( C 1 (R^AR^B)N(O)C(C_1 - C 4 )alkylene-, wherein any of such heterocycloalkyl may be optionally substituted by one or more groups reach independently (C 1 -C 3 )alkyl-; J is H, ( C 1 − C 6 ) (C_1-C_6) alkyl, ( R A R B ) N (R^AR^B)N -, ( C 1 − C 6 ) (C_1-C_6) haloalkyl, − O R C -OR^C or halo.

2. The compound of formula I according to claim 1, wherein the compound is: (R)-6-(4-Fluorophenyl)-8-methoxy-N-(1-(6-methylpyridazin-3- yl)ethyl)quinazolin-4-amine, 6-(4-Fluorophenyl)-8-methoxy-N-((2-(trifluoromethyl)pyrimidin-5- yl)methyl)quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] yl)ethyl)quinazolin-4-amine, 258 N-([1,2,4]Triazolo[4,3-a]pyrimidin-3-ylmethyl)-6-(4-fluorophenyl)-8- methoxyquinazolin-4-amine, 6-[[[6-(4-Fluorophenyl)-8-methoxy-quinazolin-4-yl]amino]methyl]-1H- pyridin-2-one, 6-(4-Fluorophenyl)-8-methoxy-N-[(1-methyl-4- piperidyl)methyl]quinazolin-4-amine, (R)-5-(1-((6-(4-fluorophenyl)-8-methoxyquinazolin-4-yl)amino)ethyl)-2- (trifluoromethyl)pyridine 1-oxide formate, 8-Methoxy-N-((6-methylpyridazin-3-yl)methyl)-6-(5-methylpyridin-2- yl)quinazolin-4-amine, 8-Methoxy-N-[(6-methylpyridazin-3-yl)methyl]-6-(5-methylpyrimidin-2- yl)quinazolin-4-amine, 8-Methoxy-N-((6-methylpyridazin-3-yl)methyl)-6-(5-methylthiazol-2- yl)quinazolin-4-amine, (R)-5-(1-((8-Methoxy-6-(5-methyl-1,3,4-thiadiazol-2-yl)quinazolin-4- yl)amino)ethyl)-2-(trifluoromethyl)pyridine 1-oxide, 8-Methoxy-6-(5-methylpyrimidin-2-yl)-N-[(1R)-1-[2- (trifluoromethyl)pyrimidin-5-yl]ethyl]quinazolin-4-amine, 6-(5-Fluoropyrimidin-2-yl)-8-methoxy-N-[(1R)-1-[2- (trifluoromethyl)pyrimidin-5-yl]ethyl]quinazolin-4-amine, 6-(5-Fluoro-2-pyridyl)-8-methoxy-N-[(1R)-1-[2-(trifluoromethyl)pyrimidin- 5-yl]ethyl]quinazolin-4-amine, 8-Methoxy-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-6-(5- methylpyrimidin-2-yl)quinazolin-4-amine, 8-Methoxy-6-(1-methylpyrazol-3-yl)-N-[(1R)-1-(6-methylpyridazin-3- yl)ethyl]quinazolin-4-amine, 259 6-(5-Fluoro-2-pyridyl)-8-methoxy-N-[(1R)-1-(6-methylpyridazin-3- yl)ethyl]quinazolin-4-amine, 6-(5-Chloropyridin-2-yl)-8-methoxy-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine, (R)-6-(4-fluorophenyl)-8-methoxy-N-(1-(2-(trifluoromethyl)pyrimidin-5- yl)ethyl)quinazolin-4-amine, 6-(4-fluorophenyl)-8-methoxy-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine, (R)-6-(4-Fluorophenyl)-8-methoxy-4-((1-(2-(trifluoromethyl)pyrimidin- 5yl)ethyl)-amino)-quinazolin-2-ol, 6-(4-fluorophenyl)-8-(2-methoxyethoxy)-N-[(6-methylpyridazin-3- yl)methyl]quinazolin-4-amine, 6-(4-fluorophenyl)-N-[(6-methylpyridazin-3-yl)methyl]-8-(oxetan-3- ylmethoxy)quinazolin-4-amine, 6-(4-fluorophenyl)-N-[(6-methylpyridazin-3-yl)methyl]-8-tetrahydropyran- 4-yloxy-quinazolin-4-amine, 2-[6-(4-fluorophenyl)-4-[(6-methylpyridazin-3-yl)methylamino]quinazolin- 8-yl]oxyacetic acid, sodium salt, 6-(4-fluorophenyl)-N-[(6-methylpyridazin-3-yl)methyl]-8-pyrrolidin-3- yloxy-quinazolin-4-amine, 6-(4-fluorophenyl)-N-[(6-methylpyridazin-3-yl)methyl]-8-(morpholin-2- ylmethoxy)quinazolin-4-amine, Single enantiomer 1 of 6-(4-fluorophenyl)-8-methoxy-N-(1-(3- (trifluoromethyl)-1,2,4-oxadiazol-5-yl)ethyl)quinazolin-4-amine Single enantiomer 2 of 6-(4-fluorophenyl)-8-methoxy-N-(1-(3- (trifluoromethyl)-1,2,4-oxadiazol-5-yl)ethyl)quinazolin-4-amine, Single enantiomer 1 of 2-((6-(4-fluorophenyl)-8-methoxyquinazolin-4- yl)amino)-2-(3-methyl-1,2,4-oxadiazol-5-yl)ethan-1-ol, Single enantiomer 2 of 2-((6-(4-fluorophenyl)-8-methoxyquinazolin-4- yl)amino)-2-(3-methyl-1,2,4-oxadiazol-5-yl)ethan-1-ol, Single enantiomer 1 of 6-(4-fluorophenyl)-8-methoxy-N-(1-(5-methyl-1,3,4- thiadiazol-2-yl)ethyl)quinazolin-4-amine, Single enantiomer 2 of 6-(4-fluorophenyl)-8-methoxy-N-(1-(5-methyl-1,3,4- thiadiazol-2-yl)ethyl)quinazolin-4-amine, Single enantiomer 1 of 6-(4-fluorophenyl)-8-methoxy-N-(1-(3-methyl-1,2,4- oxadiazol-5-yl)ethyl)quinazolin-4-amine, Single enantiomer 2 of 6-(4-fluorophenyl)-8-methoxy-N-(1-(3-methyl-1,2,4- oxadiazol-5-yl)ethyl)quinazolin-4-amine, 6-(3,5-Difluoropyridin-2-yl)-8-methoxy-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine, 6-(3-Fluoro-5-methyl-2-pyridyl)-8-methoxy-N-[(6-methylpyridazin-3- yl)methyl] quinazolin-4-amine, 6-(5-Ethylthiazol-2-yl)-8-methoxy-N-[(6-methylpyridazin-3- yl)methyl]quinazolin-4-amine, (R)-8-methoxy-6-(1-methyl-1H-1,2,4-triazol-3-yl)-N-(1-(2- (trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine, (R)-8-methoxy-6-(1-methyl-1H-pyrazol-3-yl)-N-(1-(2- (trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine, (R)-8-methoxy-6-(1-methyl-1H-1,2,4-triazol-3-yl)-N-(1-(6- methylpyridazin-3-yl)ethyl)quinazolin-4-amine, (R)-6-(5-fluoropyridin-2-yl)-8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazol-3- yl)ethyl)quinazolin-4-amine, 261 [Image disponible dans le document PDF, Image available in the PDF document] methylpyridin-2-yl)quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] pyridyl)quinazolin-4-amine, 6-(5-fluoro-2-pyridyl)-8-methoxy-N-[(1R)-1-(5-methyl-1,3,4-oxadiazol-2- yl)ethyl]quinazolin-4-amine, 8-methoxy-N-[(1R)-1-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]-6-(5-methyl-2- pyridyl)quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] methylpyrimidin-2-yl)quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] methylpyrimidin-2-yl)quinazolin-4-amine.

3. A compound, wherein the compound is: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] yl)quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] (trifluoromethyl)quinazolin-4-amine, N-((6-methylpyridazin-3-yl)methyl)-6-(5-methylpyridin-2-yl)quinazolin-4- amine, N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)-6-(5-methylthiazol-2- yl)quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] yl)ethyl)quinazolin-4-amine, N2-cyclopropyl-6-(4-fluorophenyl)-N4-(1-(3-methyl-1,2,4-oxadiazol-5- yl)ethyl)quinazoline-2,4-diamine, [Image disponible dans le document PDF, Image available in the PDF document] morpholinoquinazolin-4-amine, 2-((2-(cyclopropylamino)-6-(4-fluorophenyl)quinazolin-4- yl)amino)propanamide, N-cyclopropyl-2-((2-(cyclopropylamino)-6-(4-fluorophenyl)quinazolin-4- yl)amino)propanamide, [Image disponible dans le document PDF, Image available in the PDF document] yl)methyl)quinazolin-4-amine, N-((6-methylpyridin-3-yl)methyl)-6-(5-methylthiophen-2-yl)quinazolin-4- amine, [Image disponible dans le document PDF, Image available in the PDF document] N-((6-methylpyridazin-3-yl)methyl)-6-(2-methylpyrimidin-5-yl)quinazolin- 4-amine, [Image disponible dans le document PDF, Image available in the PDF document] yl)ethyl)quinazolin-4-amine, 263 6-(4-fluorophenyl)-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)quinazolin-4- amine, 2-(4-(((6-methylpyridin-3-yl)methyl)amino)quinazolin-6-yl)benzonitrile, 2-(4-(((6-methylpyridin-3-yl)methyl)amino)quinazolin-6-yl)benzamide, 6-(4-fluorophenyl)-N-((6-methylpyridin-3-yl)methyl)quinazolin-4-amine formate, 6-(4-fluorophenyl)-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine, N-((3,5-difluoropyridin-2-yl)methyl)-6-(4-fluorophenyl)quinazolin-4-amine hydrochloride, 6-(4-fluorophenyl)-N-methyl-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl) quinazolin-4-amine, ( R ) − 6 − ( 3 , 3 ) (R)-6-(3,3) difluoropyrrolidin-1-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5- yl)ethyl)quinazolin-4-amine, (R)-6-morpholino-N-(1-(2-(trifluoromethyl)pyrimidin-5- yl)ethyl)quinazolin-4-amine, (R)-1-methyl-4-(4-((1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)amino) quinazolin-6-yl)piperazin-2-one, N-((6-methylpyridazin-3-yl)methyl)-6-morpholinoquinazolin-4-amine, Single enantiomer 1 of 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol- 5-yl)ethyl]quinazolin-4-amine, Single enantiomer 2 of 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol- 5-yl)ethyl]quinazolin-4-amine, Single enantiomer 1 of N2-cyclopropyl-6-(4-fluorophenyl)-N4-[1-(3-methyl- 1,2,4-oxadiazol-5-yl)ethyl]quinazoline-2,4-diamine, Single enantiomer 2 of N2-cyclopropyl-6-(4-fluorophenyl)-N4-[1-(3-methyl- 1,2,4-oxadiazol-5-yl)ethyl]quinazoline-2,4-diamine, Single enantiomer 1 of 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol- 5-yl)ethyl]-2-morpholino-quinazolin-4-amine, Single enantiomer 2 of 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol- 5-yl)ethyl]-2-morpholino-quinazolin-4-amine, Single enantiomer 1 of 6-(4-fluorophenyl)-N2,N2-dimethyl-N4-[1-(3- methyl-1,2,4-oxadiazol-5-yl)ethyl]quinazoline-2,4-diamine, or Single enantiomer 2 of 6-(4-fluorophenyl)-N2,N2-dimethyl-N4-[1-(3- methyl-1,2,4-oxadiazol-5-yl)ethyl]quinazoline-2,4-diamine.

4. The compound of formula I according to claim 1, [Image disponible dans le document PDF, Image available in the PDF document] (I) wherein Z is heteroaryl or aryl, wherein any of such heteroaryl or aryl may be optionally substituted by one or more groups each independently (C 1 -C 3 )alkyl, halo, CN, (R A R B )NC(O)-, ( C 1 − (C_1- C 6 )haloalkyl, R A O-, (R A R B )N(C 1 -C 6 )alkylene-, (C 3 -C 7 )cycloalkyl-, R C SO 2 -, or ( R A R B ) N (R^AR^B)N -; 𝑹 1 \mathbf{R}_1 is H or ( C 1 − C 4 ) (C_1-C_4) alkyl, 𝑹 𝟐 \mathbf{R_2} is ( C 1 − C 6 ) (C_1-C_6) alkyl, heteroaryl ( C 1 − C 4 ) (C_1-C_4) alkyl-, ( C 3 − C 8 ) (C_3-C_8) heterocycloalkyl- ( C 1 − C 4 ) (C_1-C_4) alkyl- C 6 )alkyl, heteroaryl- ( C 1 − C 6 ) (C_1-C_6) hydroxyalkyl, aryl- ( C 1 − C 4 ) (C_1-C_4) alkyl-, ( C 3 − (C_3- C 8 )heterocycloalkyl, (C 3 -C 8 )cycloalkyl-(C 1 -C 6 )alkyl-, (R A R B )N(C 1 -C 6 )alkylene-; or R A O ( C 1 − C 4 ) R^AO(C_1-C_4) alkylene, wherein any of such alkyl, alkylene, aryl, heteroaryl, cycloalkyl or heterocycloalkyl may be optionally substituted by one or more groups each independently (C 1 - C 3 )alkyl, R A O ( C 1 − C 4 ) R^{A}O(C_{1}-C_{4}) alkylene, ( C 1 − C 6 ) (C_{1}-C_{6}) haloalkyl, oxo, R A O R^{A}O -, ( C 3 − (C_3- C 8 )heterocycloalkyl-(C 1 -C 6 )alkyl, heteroaryl, aryl optionally substituted by halo, R C O R^{C}O -, ( R A R B ) N (R^{A}R^{B})N -, − N H C ( O ) R C -NHC(O)R^{C} , − C ( O ) N ( R A R B ) -C(O)N(R^{A}R^{B}) , halo, − S O 2 N ( R A R B ) -SO_{2}N(R^{A}R^{B}) , − O ( R A O ( C 1 − C 1 ) ) -O(R^{A}O(C_{1}-C_{1})) C 4 C_4 )alkylene-N( R A R B R^AR^B ), aryl-( C 1 C_1 - C 4 C_4 )alkyl-, or -C(O) R A R^A , 𝑹 𝑨 \mathbf{R}^{\mathbf{A}} and 𝑹 𝑩 \mathbf{R}^{\mathbf{B}} are at each occurrence independently H, (C 1 -C 4 )alkyl-, aryl, (C 1 - C 6 ) or haloalkyl, or R A and R B may form together with the nitrogen atom to which they are attached a 6 membered saturated heterocyclic monocyclic ring system optionally containing a further heteroatom which is nitrogen or oxygen, which may be optionally substituted by (C 1 -C 4 )alkyl- or oxo; 𝑹 𝑪 \mathbf{R}^{\mathbf{C}} is H, ( C 1 − C 6 ) (C_1-C_6) alkyl, ( 𝑹 𝑨 𝑹 𝑩 ) (\mathbf{R}^{\mathbf{A}}\mathbf{R}^{\mathbf{B}}) N-, or aryl- ( C 1 − C 4 ) (C_1-C_4) alkyl-, Y is -OR D , R C SO 2 -, halo, -NHSO 2 R C , heteroaryl, or (C 3 -C 8 )heterocycloalkyl, wherein any of such heteroaryl and heterocycloalkyl may be optionally substituted by one or more groups each independently ( C 1 − C 3 ) (C_1-C_3) alkyl, or − C ( O ) N ( R A R B ) -C(O)N(R^AR^B) ; J is H, ( C 1 − C 6 ) (C_1-C_6) alkyl, or − O R C -OR^C , 𝑹 𝑫 \mathbf{R}^{\mathbf{D}} is H or (C 1 -C 6 )alkyl.

5. The compound of formula I according to claim 1, [Image disponible dans le document PDF, Image available in the PDF document] (I) wherein Z is heteroaryl or aryl, wherein any of such heteroaryl or aryl may be optionally substituted by one or more groups each independently ( C 1 − C 3 ) (C_1-C_3) alkyl, halo, CN, ( R A R B ) N C ( O ) (R^AR^B)NC(O) -, ( C 1 − C 3 ) (C_1-C_3) C 6 )haloalkyl, R A O-, (R A R B )N(C 1 -C 6 )alkylene-, (C 3 -C 7 )cycloalkyl-, R C SO 2 -, or ( R A R B ) N (R^AR^B)N -; 𝑹 1 \mathbf{R}_1 is H, 𝑹 𝟐 \mathbf{R_2} is ( C 1 − C 6 ) (C_1-C_6) alkyl, heteroaryl ( C 1 − C 4 ) (C_1-C_4) alkyl-, ( C 3 − C 8 ) (C_3-C_8) heterocycloalkyl- ( C 1 − C 4 ) (C_1-C_4) alkyl- C 6 )alkyl, heteroaryl- ( C 1 − C 6 ) (C_1-C_6) hydroxyalkyl, aryl- ( C 1 − C 4 ) (C_1-C_4) alkyl-, ( C 3 − (C_3- C 8 )heterocycloalkyl, (C 3 -C 8 )cycloalkyl-(C 1 -C 6 )alkyl-, (R A R B )N(C 1 -C 6 )alkylene-, or R A O ( C 1 − C 4 ) R^AO(C_1-C_4) alkylene, wherein any of such alkyl, alkylene, aryl, heteroaryl, cycloalkyl or heterocycloalkyl may be optionally substituted by one or more groups each independently (C 1 - C 3 )alkyl, R A O ( C 1 − C 4 ) R^{A}O(C_{1}-C_{4}) alkylene, ( C 1 − C 6 ) (C_{1}-C_{6}) haloalkyl, oxo, R A O R^{A}O -, ( C 3 − (C_3- C 8 )heterocycloalkyl-(C 1 -C 6 )alkyl, heteroaryl, aryl optionally substituted by halo, R C O − R^{C}O- , ( R A R B ) N − (R^{A}R^{B})N- , − N H C ( O ) R C -NHC(O)R^{C} , − C ( O ) N ( R A R B ) -C(O)N(R^{A}R^{B}) , halo, − S O 2 N ( R A R B ) -SO_{2}N(R^{A}R^{B}) , − O ( R A O ( C 1 − C 1 ) ) -O(R^{A}O(C_{1}-C_{1})) C 4 C_4 )alkylene-N( R A R B R^AR^B ), aryl-( C 1 C_1 - C 4 C_4 )alkyl-, or -C(O) R A R^A , 𝑹 𝑨 \mathbf{R}^{\mathbf{A}} and 𝑹 𝑩 \mathbf{R}^{\mathbf{B}} are at each occurrence independently H, (C 1 -C 4 )alkyl-, aryl, or ( C 1 − C 6 ) (C_1-C_6) haloalkyl, or R A and R B may form together with the nitrogen atom to which they are attached a 6 membered saturated heterocyclic monocyclic ring system optionally containing a further heteroatom which is nitrogen or oxygen, which may be optionally substituted by one or more ( C 1 − C 4 ) (C_1-C_4) alkyl- and / or oxo; [Image disponible dans le document PDF, Image available in the PDF document] Y is -OR D , R C SO 2 -, halo, -NHSO 2 R C , heteroaryl, or (C 3 -C 8 )heterocycloalkyl, wherein any of such heteroaryl or heterocycloalkyl may be optionally substituted by one or more groups each independently ( C 1 − C 3 ) (C_1-C_3) alkyl, or − C ( O ) N ( R A R B ) -C(O)N(R^AR^B) ; J is H, ( C 1 − C 6 ) (C_1-C_6) alkyl, or − O R C -OR^C , 𝑹 𝑫 \mathbf{R}^{\mathbf{D}} is H or (C 1 -C 6 )alkyl.

6. The compound of formula I according to claim 4 or 5, wherein the compound is: [Image disponible dans le document PDF, Image available in the PDF document] (trifluoromethyl)pyrimidin-5 yl)ethyl)quinazolin-4-amine, (R)-6-(4-Fluorophenyl)-8-methoxy-4-((1-(2-(trifluoromethyl)pyrimidin-5- yl)ethyl)-amino)-quinazolin-2-ol, (R)-6-(4-Fluorophenyl)-2,8-dimethoxy-N-(1-(2-(trifluoromethyl)pyrimidin- 5-yl)ethyl)quinazolin-4-amine, 6-(4-Fluorophenyl)-8-methoxy-N-(1-(3-methyl-1,2,4-oxadiazol-5- yl)ethyl)quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] yl)methyl)quinazolin-4-amine, N-((6-(Difluoromethoxy)pyridin-3-yl)methyl)-6-(4-fluorophenyl)-8- methoxyquinazolin-4-amine, (R)-6-(4-Fluorophenyl)-8-methoxy-N-(1-(6-methylpyridazin-3- yl)ethyl)quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] yl)methyl)quinazolin-4-amine, 4-(((6-(4-Fluorophenyl)-8-methoxyquinazolin-4-yl)amino)methyl)-1- methylpyridin-2(1H)-one, N-((2-(Dimethylamino)pyrimidin-5-yl)methyl)-6-(4-fluorophenyl)-8- methoxyquinazolin-4-amine, N-((5-Chloropyrimidin-2-yl)methyl)-6-(4-fluorophenyl)-8- methoxyquinazolin-4-amine, 268 5-(((6-(4-Fluorophenyl)-8-methoxyquinazolin-4-yl)amino)methyl)-N- methylpicolinamide, 6-(4-Fluorophenyl)-8-methoxy-N-((2-methylpyrimidin-5- yl)methyl)quinazolin-4-amine, N-(1-(3-Ethyl-1,2,4-oxadiazol-5-yl)ethyl)-6-(4-fluorophenyl)-8- methoxyquinazolin-4-amine, 6-(4-Fluorophenyl)-8-methoxy-N-(1-(6-methoxypyridin-3- yl)ethyl)quinazolin-4-amine, 6-(4-Fluorophenyl)-8-methoxy-N-(1-(3-(trifluoromethyl)-1,2,4-oxadiazol-5- yl)ethyl)quinazolin-4-amine, 6-(4-Fluorophenyl)-8-methoxy-N-(1-(6-methylpyridin-3- yl)ethyl)quinazolin-4-amine, 2-((6-(4-Fluorophenyl)-8-methoxyquinazolin-4-yl)amino)-2-(3-methyl- 1,2,4-oxadiazol-5-yl)ethan-1-ol, 6-(4-Fluorophenyl)-8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazol-3- yl)ethyl)quinazolin-4-amine, N-(Cyclopropylmethyl)-6-(4-fluorophenyl)-8-methoxyquinazolin-4-amine, 6-(4-Fluorophenyl)-8-methoxy-N-(1-(5-methyl-1,3,4-oxadiazol-2- yl)ethyl)quinazolin-4-amine, 6-(4-Fluorophenyl)-8-methoxy-N-((2-(trifluoromethyl)pyrimidin-5- yl)methyl)quinazolin-4-amine, 6-(4-Fluorophenyl)-8-methoxy-N-((6-(trifluoromethyl)pyridin-3- yl)methyl)quinazolin-4-amine, 6-(4-Fluorophenyl)-8-methoxy-N-(1-(5-methyl-1,3,4-thiadiazol-2- yl)ethyl)quinazolin-4-amine, 6-(4-Fluorophenyl)-N-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)ethyl)-8- methoxyquinazolin-4-amine, N-((6-(Dimethylamino)pyridin-3-yl)methyl)-6-(4-fluorophenyl)-8- methoxyquinazolin-4-amine, 6-(4-Fluorophenyl)-8-methoxy-N-[[5-(trifluoromethyl)-3- pyridyl]methyl]quinazolin-4-amine, 3-((6-(4-Fluorophenyl)-8-methoxyquinazolin-4- yl)amino)tetrahydrothiophene 1,1-dioxide, 6-(4-Fluorophenyl)-8-methoxy-N-((tetrahydro-2H-pyran-4- yl)methyl)quinazolin-4-amine, Single enantiomer 1 of 3-((6-(4-Fluorophenyl)-8-methoxyquinazolin-4- yl)amino)tetrahydrothiophene 1,1-dioxide, Single enantiomer 2 of 3-((6-(4-Fluorophenyl)-8-methoxyquinazolin-4- yl)amino)tetrahydrothiophene 1,1-dioxide, N-(5-(((6-(4-Fluorophenyl)-8-methoxyquinazolin-4- yl)amino)methyl)pyridin-2-yl)acetamide, 6-(4-Fluorophenyl)-8-methoxy-N-(2-(6-methylpyridin-3- yl)ethyl)quinazolin-4-amine, 6-(4-Fluorophenyl)-8-methoxy-N-(1-methylpiperidin-4-yl)quinazolin-4- amine, N1-(6-(4-Fluorophenyl)-8-methoxyquinazolin-4-yl)-N3,N3- dimethylpropane-1,3-diamine, (S)-2-((6-(4-Fluorophenyl)-8-methoxyquinazolin-4-yl)amino)-2-(6- methoxypyridin-3-yl)ethan-1-ol, 6-(4-Fluorophenyl)-8-methoxy-N-((6-morpholinopyridazin-3- yl)methyl)quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] yl)methyl)quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] yl)propyl)quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] pyridyl]methyl]quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] yl)methyl)quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] yl)methyl)quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] yl)amino)ethyl)morpholin-3-one, [Image disponible dans le document PDF, Image available in the PDF document] yl)methyl)quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] yl)methyl)quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] yl)methyl)quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] methoxyquinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] yl)methyl)quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] methoxyquinazolin-4-amine, N-([1,2,4]Triazolo[4,3-a]pyrimidin-3-ylmethyl)-6-(4-fluorophenyl)-8- methoxyquinazolin-4-amine, 3-(((6-(4-Fluorophenyl)-8-methoxyquinazolin-4-yl)amino)methyl)-6- methylpyridin-2(1H)-one, 6-(4-Fluorophenyl)-8-methoxy-N-((3-(pyridin-4-yl)-1,2,4-oxadiazol-5- yl)methyl)quinazolin-4-amine, 6-(4-Fluorophenyl)-8-methoxy-N-((3-(piperidin-1-ylmethyl)-1,2,4- oxadiazol-5-yl)methyl)quinazolin-4-amine, 6-(4-Fluorophenyl)-8-methoxy-N-((1-methyl-1H-1,2,3-triazol-4- yl)methyl)quinazolin-4-amine, 6-(4-Fluorophenyl)-8-methoxy-N-((6-(4-methylpiperazin-1-yl)pyridin-3- yl)methyl)quinazolin-4-amine, 6-(4-Fluorophenyl)-8-methoxy-N-((4-(trifluoromethyl)pyridin-3- yl)methyl)quinazolin-4-amine, 6-(4-Fluorophenyl)-8-methoxy-N-((2-(trifluoromethyl)pyridin-3- yl)methyl)quinazolin-4-amine, N-((5,6-Dimethylpyridin-3-yl)methyl)-6-(4-fluorophenyl)-8- methoxyquinazolin-4-amine, 6-(4-Fluorophenyl)-8-methoxy-N-[(1-methylimidazol-2- yl)methyl]quinazolin-4-amine, 6-(4-Fluorophenyl)-8-methoxy-N-(2-phenylcyclopropyl)quinazolin-4- amine, N-[(3-Chloro-4-pyridyl)methyl]-6-(4-fluorophenyl)-8-methoxy-quinazolin- 4-amine, 2-(3-Chloro-4-pyridyl)-2-[[6-(4-fluorophenyl)-8-methoxy-quinazolin-4- yl]amino]ethanol, 272 N-[(3S,4R)-4-Ethoxytetrahydrofuran-3-yl]-6-(4-fluorophenyl)-8-methoxy- quinazolin-4-amine, N-[(1,1-Dioxothian-4-yl)methyl]-6-(4-fluorophenyl)-8-methoxy-quinazolin- 4-amine, 4-[[6-(4-Fluorophenyl)-8-methoxy-quinazolin-4-yl]amino]-1-methyl- piperidin-2-one, 6-[[[6-(4-Fluorophenyl)-8-methoxy-quinazolin-4-yl]amino]methyl]-1H- pyridin-2-one, 3-[[[6-(4-Fluorophenyl)-8-methoxy-quinazolin-4-yl]amino]methyl]-1,4- dihydro-1,2,4-triazol-5-one, N-[[1-(4-Chlorophenyl)cyclopropyl]methyl]-6-(4-fluorophenyl)-8-methoxy- quinazolin-4-amine, (5R)-5-[[[6-(4-Fluorophenyl)-8-methoxy-quinazolin-4- yl]amino]methyl]pyrrolidin-2-one, (1S)-2-[[6-(4-Fluorophenyl)-8-methoxy-quinazolin-4-yl]amino]-1-phenyl- ethanol, N'-[6-(4-Fluorophenyl)-8-methoxy-quinazolin-4-yl]-N,N-dimethyl-1-(4- pyridyl)ethane-1,2-diamine, (2S)-2-[[6-(4-fluorophenyl)-8-methoxy-quinazolin-4-yl]amino]-4-methyl- pentanamide, 6-(4-Fluorophenyl)-8-methoxy-N-(2H-tetrazol-5-ylmethyl)quinazolin-4- amine, 6-(4-Fluorophenyl)-8-methoxy-N-[(2-methylindazol-6- yl)methyl]quinazolin-4-amine, N-[2-[4-(Dimethylamino)phenyl]ethyl]-6-(4-fluorophenyl)-8-methoxy- quinazolin-4-amine, 273 4-[[[6-(4-Fluorophenyl)-8-methoxy-quinazolin-4-yl]amino]methyl]-N,N- dimethyl-benzenesulfonamide, 6-(4-Fluorophenyl)-8-methoxy-N-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin- 6-yl)quinazolin-4-amine, N-[(1R,5S)-8-Benzyl-8-azabicyclo[3.2.1]octan-3-yl]-6-(4-fluorophenyl)-8- methoxy-quinazolin-4-amine, N-[[4-[2-(dimethylamino)ethoxy]phenyl]methyl]-6-(4-fluorophenyl)-8- methoxy-quinazolin-4-amine, 6-(4-Fluorophenyl)-8-methoxy-N-(3-pyrrolidin-1-ylpropyl)quinazolin-4- amine, (1S,2R)-1-[[6-(4-Fluorophenyl)-8-methoxy-quinazolin-4-yl]amino]indan-2- ol, 6-(4-Fluorophenyl)-8-methoxy-N-[(4-methyl-2,3-dihydro-1,4-benzoxazin- 7-yl)methyl]quinazolin-4-amine, N-[(6-Chloroimidazo[1,2-a]pyridin-2-yl)methyl]-6-(4-fluorophenyl)-8- methoxy-quinazolin-4-amine, N-[(4-Benzyloxyphenyl)methyl]-6-(4-fluorophenyl)-8-methoxy-quinazolin- 4-amine, N-[(1-Benzylazetidin-3-yl)methyl]-6-(4-fluorophenyl)-8-methoxy- quinazolin-4-amine, 6-(4-Fluorophenyl)-8-methoxy-N-[[(2R)-tetrahydrofuran-2- yl]methyl]quinazolin-4-amine, N-[Cyclohexyl(phenyl)methyl]-6-(4-fluorophenyl)-8-methoxy-quinazolin- 4-amine, 3-(3-Chlorophenyl)-3-[[6-(4-fluorophenyl)-8-methoxy-quinazolin-4- yl]amino]propan-1-ol, 274 6-(4-Fluorophenyl)-8-methoxy-N-[(1-methylbenzimidazol-5- yl)methyl]quinazolin-4-amine, 6-(4-Fluorophenyl)-8-methoxy-N-[2-(4-methylpiperazin-1-yl)-1-phenyl- ethyl]quinazolin-4-amine, 6-(4-Fluorophenyl)-8-methoxy-N-[(1S)-1-methyl-2-pyrrolidin-1-yl- ethyl]quinazolin-4-amine, 6-(4-Fluorophenyl)-8-methoxy-N-[(1-methylindazol-7- yl)methyl]quinazolin-4-amine, 6-(4-Fluorophenyl)-8-methoxy-N-[(1-methylazetidin-3- yl)methyl]quinazolin-4-amine, (1R,2S)-1-[[6-(4-Fluorophenyl)-8-methoxy-quinazolin-4-yl]amino]indan-2- ol, 3-[[6-(4-Fluorophenyl)-8-methoxy-quinazolin-4-yl]amino]-1-methyl- pyrrolidin-2-one, 6-(4-Fluorophenyl)-8-methoxy-N-(1-tetrahydropyran-4-ylethyl)quinazolin- 4-amine, N-[[3-Chloro-5-(trifluoromethyl)-2-pyridyl]methyl]-6-(4-fluorophenyl)-8- methoxy-quinazolin-4-amine, 1-[4-[[[6-(4-Fluorophenyl)-8-methoxy-quinazolin-4-yl]amino]methyl]-1- piperidyl]ethanone, 2,2-Difluoro-3-[[6-(4-fluorophenyl)-8-methoxy-quinazolin-4- yl]amino]propan-1-ol, 6-(4-Fluorophenyl)-8-methoxy-N-(2-piperazin-1-ylethyl)quinazolin-4- amine, 6-(4-Fluorophenyl)-8-methoxy-N-(pyrrolidin-3-ylmethyl)quinazolin-4- amine, 6-(4-Fluorophenyl)-8-methoxy-N-(pyrrolidin-2-ylmethyl)quinazolin-4- amine, 6-(4-Fluorophenyl)-8-methoxy-N-(1-methyl-2-morpholino- ethyl)quinazolin-4-amine, (S)-6-(4-Fluorophenyl)-8-methoxy-N-((tetrahydrofuran-2- yl)methyl)quinazolin-4-amine, 6-(4-Fluorophenyl)-8-methoxy-N-((1-methylpyrrolidin-3- yl)methyl)quinazolin-4-amine, N1,N1-Diethyl-N3-(6-(4-fluorophenyl)-8-methoxyquinazolin-4-yl)propane- 1,3-diamine, (R)-6-(4-Fluorophenyl)-8-methoxy-N-(1-methylpiperidin-3-yl)quinazolin-4- amine, 6-(4-Fluorophenyl)-8-methoxy-N-((1-methylpiperidin-2- yl)methyl)quinazolin-4-amine, 6-(4-Fluorophenyl)-8-methoxy-N-(2-(1-methylazetidin-3- yl)ethyl)quinazolin-4-amine, 2-[[6-(4-Fluorophenyl)-8-methoxy-quinazolin-4-yl]amino]-2- tetrahydropyran-4-yl-ethanol formate, 6-(4-Fluorophenyl)-8-methoxy-N-[(1-methyl-4- piperidyl)methyl]quinazolin-4-amine, 6-(4-Fluorophenyl)-8-methoxy-N-[(1-methylindazol-4- yl)methyl]quinazolin-4-amine, (R)-5-(1-((6-(4-fluorophenyl)-8-methoxyquinazolin-4-yl)amino)ethyl)-2- (trifluoromethyl)pyridine 1-oxide formate, 6-(4-fluorophenyl)-8-methoxy-N-(2-morpholinoethyl)quinazolin-4-amine, 276 N-(((1r,4r)-4-Aminocyclohexyl)methyl)-6-(4-fluorophenyl)-8- methoxyquinazolin-4-amine, 8-Methoxy-6-(5-methyl-1,3,4-thiadiazol-2-yl)-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine, 8-Methoxy-N-((6-methylpyridazin-3-yl)methyl)-6-(5-methylpyridin-2- yl)quinazolin-4-amine, 6-(8-Methoxy-4-(((6-methylpyridazin-3-yl)methyl)amino)quinazolin-6- yl)nicotinonitrile, 6-(5-(Difluoromethyl)pyridin-2-yl)-8-methoxy-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine, 6-(8-Methoxy-4-(((6-methylpyridazin-3-yl)methyl)amino)quinazolin-6- yl)pyridin-3-ol, 6-(5-(Difluoromethoxy)pyridin-2-yl)-8-methoxy-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine, 8-Methoxy-N-((6-methylpyridazin-3-yl)methyl)-6-(5- (methylsulfonyl)pyridin-2-yl)quinazolin-4-amine, 6-(8-Methoxy-4-(((6-methylpyridazin-3-yl)methyl)amino)quinazolin-6- yl)nicotinamide, 6-(8-Methoxy-4-(((6-methylpyridazin-3-yl)methyl)amino)quinazolin-6-yl)- N-methylnicotinamide, 8-Methoxy-N-((6-methylpyridazin-3-yl)methyl)-6-(5- (trifluoromethoxy)pyridin-2-yl)quinazolin-4-amine, 6-[5-(Dimethylamino)-2-pyridyl]-8-methoxy-N-[(6-methylpyridazin-3- yl)methyl]quinazolin-4-amine, 6-(5-Cyclopropylpyridin-2-yl)-8-methoxy-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine, 277 6-(5-Chloropyridin-2-yl)-8-methoxy-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine, 8-Methoxy-N-((6-methylpyridazin-3-yl)methyl)-6-(6-methylpyridin-3- yl)quinazolin-4-amine, 8-Methoxy-6-(5-methyl-1,3,4-oxadiazol-2-yl)-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine, 8-Methoxy-6-(1-methyl-1H-pyrazol-3-yl)-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine, 6-(1,5-Dimethyl-1H-pyrazol-3-yl)-8-methoxy-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine, 8-Methoxy-6-(6-methoxypyridazin-3-yl)-N-[(6-methylpyridazin-3- yl)methyl]quinazolin-4-amine, 8-Methoxy-6-(6-methylpyridazin-3-yl)-N-[(6-methylpyridazin-3- yl)methyl]quinazolin-4-amine, 8-Methoxy-N-[(6-methylpyridazin-3-yl)methyl]-6-(5-methylpyrimidin-2- yl)quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] yl)methyl]quinazolin-4-amine, 6-(5-Fluoropyrimidin-2-yl)-8-methoxy-N-[(6-methylpyridazin-3- yl)methyl]quinazolin-4-amine, 6-[8-Methoxy-4-[(6-methylpyridazin-3-yl)methylamino]quinazolin-6- yl]pyridazin-3-ol, [Image disponible dans le document PDF, Image available in the PDF document] (trifluoromethyl)pyridin-2-yl)quinazolin-4-amine, 8-Methoxy-6-(5-methoxypyridin-2-yl)-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine, 278 8-Methoxy-N-((6-methylpyridazin-3-yl)methyl)-6-(5-methylthiazol-2- yl)quinazolin-4-amine, 8-Methoxy-N-((6-methylpyridazin-3-yl)methyl)-6-(4- (trifluoromethyl)thiazol-2-yl)quinazolin-4-amine, 6-(1,3-Dimethyl-1H-pyrazol-4-yl)-8-methoxy-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine, 8-Methoxy-N-((6-methylpyridazin-3-yl)methyl)-6-(4-methylthiazol-2- yl)quinazolin-4-amine, 8-Methoxy-N-((6-methylpyridazin-3-yl)methyl)-6-(2-methylthiazol-5- yl)quinazolin-4-amine, (R)-5-(1-((8-Methoxy-6-(5-methyl-1,3,4-thiadiazol-2-yl)quinazolin-4- yl)amino)ethyl)-2-(trifluoromethyl)pyridine 1-oxide, (R)-8-Methoxy-6-(5-methyl-1,3,4-thiadiazol-2-yl)-N-(1-(6- methylpyridazin-3-yl)ethyl)quinazolin-4-amine, (R)-8-Methoxy-6-(5-methyl-1,3,4-thiadiazol-2-yl)-N-(1-(2- (trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine, 8-Methoxy-6-(5-methylpyrimidin-2-yl)-N-[(1R)-1-[2- (trifluoromethyl)pyrimidin-5-yl]ethyl]quinazolin-4-amine, 6-(5-Fluoropyrimidin-2-yl)-8-methoxy-N-[(1R)-1-[2- (trifluoromethyl)pyrimidin-5-yl]ethyl]quinazolin-4-amine, 6-(5-Fluoro-2-pyridyl)-8-methoxy-N-[(1R)-1-[2-(trifluoromethyl)pyrimidin- 5-yl]ethyl]quinazolin-4-amine, 8-Methoxy-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-6-(5- methylpyrimidin-2-yl)quinazolin-4-amine, 8-Methoxy-6-(1-methylpyrazol-3-yl)-N-[(1R)-1-(6-methylpyridazin-3- yl)ethyl]quinazolin-4-amine, 279 6-[5-(Difluoromethyl)-2-pyridyl]-8-methoxy-N-[(1R)-1-(6- methylpyridazin-3-yl)ethyl]quinazolin-4-amine, 8-Methoxy-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-6-(5-methyl-2- pyridyl)quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] yl)ethyl]quinazolin-4-amine, 8-Methoxy-6-(3-methylisothiazol-5-yl)-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine, ( R ) (R) -8-methoxy-6- ( 5 (5 -methylpyridin-2-yl)-N- ( 1 (1 - ( 2 (2 - (trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine, ( R ) (R) -8-methoxy-6- ( 5 (5 -methylthiazol-2-yl)-N- ( 1 (1 - ( 2 (2 - (trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine, (R)-8-methoxy-4-((1-(2-(trifluoromethyl)pyrimidin-5- yl)ethyl)amino)quinazolin-6-ol, (R)-8-methoxy-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4- amine, 8-Methoxy-N-((6-methylpyridazin-3-yl)methyl)-6-(5- (trifluoromethyl)thiazol-2-yl)quinazolin-4-amine, 8-Methoxy-6-(1-methyl-1H-pyrazol-4-yl)-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine, 6-(4,5-Dimethylthiazol-2-yl)-8-methoxy-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine, 6-(4-Fluoro-3-methylphenyl)-8-methoxy-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine, 6-(2,4-Difluorophenyl)-8-methoxy-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine, 280 6-(4-Fluoro-3-methoxyphenyl)-8-methoxy-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine, 6-(4-Fluoro-2-methylphenyl)-8-methoxy-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine, 6-(4-Fluoro-2-(trifluoromethyl)phenyl)-8-methoxy-N-((6-methyl)pyridazin- 3-yl)methyl)quinazolin-4-amine, 6-(3-Fluorophenyl)-8-methoxy-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine, 6-(2,4-Difluorophenyl)-8-methoxy-N-[(1R)-1-(6-methylpyridazin-3- yl)ethyl]quinazolin-4-amine, 6-[4-[(Dimethylamino)methyl]phenyl]-8-methoxy-N-[(6-methylpyridazin- 3-yl)methyl]quinazolin-4-amine formate, 4-[8-Methoxy-4-[(6-methylpyridazin-3-yl)methylamino]quinazolin-6-yl]- N,N-dimethyl-benzamide, 6-[4-(Dimethylamino)phenyl]-8-methoxy-N-[(6-methylpyridazin-3- yl)methyl]quinazolin-4-amine, 8-Methoxy-6-(4-methoxyphenyl)-N-[(6-methylpyridazin-3- yl)methyl]quinazolin-4-amine, Single enantiomer 1 of 6-(4-fluorophenyl)-8-methoxy-N-(1-(3-methyl-1,2,4- oxadiazol-5-yl)ethyl)quinazolin-4-amine, Single enantiomer 2 of 6-(4-fluorophenyl)-8-methoxy-N-(1-(3-methyl-1,2,4- oxadiazol-5-yl)ethyl)quinazolin-4-amine,6-(3,4-Difluorophenyl)-8-methoxy-N- ((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine, 6-(4-Fluoro-2-methoxyphenyl)-8-methoxy-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine, 281 8-Methoxy-N-((6-methylpyridazin-3-yl)methyl)-6-(2,4,6- trifluorophenyl)quinazolin-4-amine, 2-(8-Methoxy-4-(((6-methylpyridazin-3-yl)methyl)amino)quinazolin-6-yl)- 5-methylbenzonitrile, 5-Fluoro-2-(8-methoxy-4-(((6-methylpyridazin-3- yl)methyl)amino)quinazolin-6-yl)benzonitrile, 5-Fluoro-2-(8-methoxy-4-(((6-methylpyridazin-3- yl)methyl)amino)quinazolin-6-yl)phenol, (R)-6-(4-fluorophenyl)-8-methoxy-N-(1-(2-(trifluoromethyl)pyrimidin-5- yl)ethyl)quinazolin-4-amine, 6-(4-fluorophenyl)-8-methoxy-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine, (R)-6-(4-Fluorophenyl)-8-methoxy-2-methyl-N-(1-(2- (trifluoromethyl)pyrimidin-5 yl)ethyl)quinazolin-4-amine, (R)-6-(4-Fluorophenyl)-8-methoxy 4-((1-(2 (trifluoromethyl)pyrimidin-5 yl)ethyl)-amino)-quinazolin-2-ol, 6-(4-fluorophenyl)-8-iodo-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4- amine, 6-(4-fluorophenyl)-N-((6-methylpyridazin-3-yl)methyl)-8- (methylsulfonyl)quinazolin-4-amine, (R)-N-(6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidin-5- yl)ethyl)amino)quinazolin-8-yl)methanesulfonamide, N-(6-(4-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-8- yl)methanesulfonamide, (R)-6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidin-5- yl)ethyl)amino)quinazoline-8-sulfonamide, (R)-6-(4-fluorophenyl)-8-(1-methyl-1H-pyrazol-4-yl)-N-(1-(2- (trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine, (R)-6-(4-Fluorophenyl)-8-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-N-(1- (2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine, (R)-6-(4-Fluorophenyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-8- (1,3,5-trimethyl-1H-pyrazol-4-yl)quinazolin-4-amine, (R)-6-(4-Fluorophenyl)-8-(pyridin-4-yl)-N-(1-(2- (trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine, (R)-4-(6-(4-Fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidin-5- yl)ethyl)amino)quinazolin-8-yl)-N,N-dimethylbenzamide, (R)-6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidin-5- yl)ethyl)amino)-quinazolin-8-ol, 6-(4-fluorophenyl)-4-(((6-methylpyridazin-3-yl)methyl)amino)quinazolin-8- ol, ( ( R ) − 8 − m e t h o x y − 6 − ( 3 − m e t h y l − 1 H − p y r a z o l − 1 − y l ) − N − ( 1 − ( 2 − m e t h y l − 1 H − p y r a z o l − 1 − y l ) − N − ( 1 − ( 2 − m e t h y l − 1 H − p y r a z o l − 1 − y l ) − N − ( 1 − ( 2 − m e t h y l − 1 H − p y r a z o l − 1 − y l ) − N − ( 1 − ( 2 − m e t h y l − 1 H − p y r a z o l − 1 − y l ) − N − ( 1 − ( 2 − m e t h y l − 1 H − p y r a z o l − 1 − y l ) − N − ( 1 − ( 2 − m e t h y l − 1 ((R)-8-methoxy-6-(3-methyl-1H-pyrazol-1-yl)-N-(1-(2-methyl-1H-pyrazol-1-yl)-N-(1-(2-methyl-1H-pyrazol-1-yl)-N-(1-(2-methyl-1H-pyrazol-1-yl)-N-(1-(2-methyl-1H-pyrazol-1-yl)-N-(1-(2-methyl-1H-pyrazol-1-yl)-N-(1-(2-methyl-1 (trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine, (R)-8-methoxy-6-(5-methyl-1H-pyrazol-1-yl)-N-(1-(2- (trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine, (R)-8-Methoxy-6-(4-methyl-1H-imidazol-1-yl)-N-(1-(2- (trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine, (R)-8-methoxy-6-(5-methyl-1H-imidazol-1-yl)-N-(1-(2- (trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine, (R)-8-Methoxy-6-(4-methyl-1H-pyrazol-1-yl)-N-(1-(2- (trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine, Single enantiomer 1 of 6-(4-fluorophenyl)-8-methoxy-N-(1-(3- (trifluoromethyl)-1,2,4-oxadiazol-5-yl)ethyl)quinazolin-4-amine, Single enantiomer 2 of 6-(4-fluorophenyl)-8-methoxy-N-(1-(3- (trifluoromethyl)-1,2,4-oxadiazol-5-yl)ethyl)quinazolin-4-amine, Single enantiomer 1 6-(4-fluorophenyl)-8-methoxy-N-(1-(6-methylpyridin- 3-yl)ethyl)quinazolin-4-amine, Single enantiomer 2 6-(4-fluorophenyl)-8-methoxy-N-(1-(6-methylpyridin- 3-yl)ethyl)quinazolin-4-amine, Single enantiomer 1 6-(4-fluorophenyl)-8-methoxy-N-(1-(5-methyl-1,2,4- oxadiazol-3-yl)ethyl)quinazolin-4-amine, Single enantiomer 2 6-(4-fluorophenyl)-8-methoxy-N-(1-(5-methyl-1,2,4- oxadiazol-3-yl)ethyl)quinazolin-4-amine, Single enantiomer 1 of 6-(4-fluorophenyl)-8-methoxy-N-(1-(5-methyl-1,3,4- oxadiazol-2-yl)ethyl)quinazolin-4-amine, Single enantiomer 2 of 6-(4-fluorophenyl)-8-methoxy-N-(1-(5-methyl-1,3,4- oxadiazol-2-yl)ethyl)quinazolin-4-amine, Single enantiomer 1 of 6-(4-fluorophenyl)-8-methoxy-N-(1-(6- methoxypyridin-3-yl)ethyl)quinazolin-4-amine, Single enantiomer 2 of 6-(4-fluorophenyl)-8-methoxy-N-(1-(6- methoxypyridin-3-yl)ethyl)quinazolin-4-amine, Single enantiomer 1 of 2-((6-(4-fluorophenyl)-8-methoxyquinazolin-4- yl)amino)-2-(3-methyl-1,2,4-oxadiazol-5-yl)ethan-1-ol, Single enantiomer 2 of 2-((6-(4-fluorophenyl)-8-methoxyquinazolin-4- yl)amino)-2-(3-methyl-1,2,4-oxadiazol-5-yl)ethan-1-ol, Single enantiomer 1 of N-(1-(3-ethyl-1,2,4-oxadiazol-5-yl)ethyl)-6-(4- fluorophenyl)-8-methoxyquinazolin-4-amine, Single enantiomer 2 of N-(1-(3-ethyl-1,2,4-oxadiazol-5-yl)ethyl)-6-(4- fluorophenyl)-8-methoxyquinazolin-4-amine, 284 Single enantiomer 1 of N-(1-cyclopropylethyl)-6-(4-fluorophenyl)-8- methoxyquinazolin-4-amine, Single enantiomer 2 of N-(1-cyclopropylethyl)-6-(4-fluorophenyl)-8- methoxyquinazolin-4-amine, Single enantiomer of N3-(6-(4-fluorophenyl)-8-methoxyquinazolin-4-yl)- N1,N1-dimethylbutane-1,3-diamine, Single enantiomer 2 of N3-(6-(4-fluorophenyl)-8-methoxyquinazolin-4-yl)- N1,N1-dimethylbutane-1,3-diamine, Single enantiomer 1 of 6-(4-fluorophenyl)-N-[1-(3-isopropyl-1,2,4- oxadiazol-5-yl)ethyl]-8-methoxy-quinazolin-4-amine, Single enantiomer 2 of 6-(4-fluorophenyl)-N-[1-(3-isopropyl-1,2,4- oxadiazol-5-yl)ethyl]-8-methoxy-quinazolin-4-amine, Single enantiomer 1 of 6-(4-fluorophenyl)-8-methoxy-N-[2-methyl-1-(3- methyl-1,2,4-oxadiazol-5-yl)propyl]quinazolin-4-amine, Single enantiomer 2 of 6-(4-fluorophenyl)-8-methoxy-N-[2-methyl-1-(3- methyl-1,2,4-oxadiazol-5-yl)propyl]quinazolin-4-amine, Single enantiomer 1 of 6-(4-fluorophenyl)-8-methoxy-N-(1-(5-methyl-1,3,4- thiadiazol-2-yl)ethyl)quinazolin-4-amine, Single enantiomer 2 of 6-(4-fluorophenyl)-8-methoxy-N-(1-(5-methyl-1,3,4- thiadiazol-2-yl)ethyl)quinazolin-4-amine, (R)-6-(4-Fluorophenyl)-8-iodo-N-(1-(2-(trifluoromethyl)pyrimidin-5- yl)ethyl)quinazolin-4-amine, (R)-6-(4-fluorophenyl)-8-(methylsulfonyl)-N-(1-(2- (trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine, 6-(4-Fluorophenyl)-8-methoxy-N-(1-(3-(pyridin-4-yl)-1,2,4-oxadiazol-5- yl)ethyl)quinazolin-4-amine, 6-(4-fluorophenyl)-8-methoxy-N-(2-(3-methyl-1,2,4-oxadiazol-5-yl)propan- 2-yl)quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] methoxyquinazolin-4-amine, (S)-6-(4-fluorophenyl)-8-methoxy-N-(1-(5-methyl-4H-1,2,4-triazol-3- yl)ethyl)quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] yl)methyl)quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] yl)methyl] quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] yl)ethyl)quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] methylpyridazin-3-yl)ethyl)quinazolin-4-amine, (R)-6-(5-fluoropyridin-2-yl)-8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazol-3- yl)ethyl)quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] methylpyridin-2-yl)quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] pyridyl)quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] yl)ethyl]quinazolin-4-amine, 286 8-methoxy-N-[(1R)-1-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]-6-(5-methyl-2- pyridyl)quinazolin-4-amine, 2-((8-methoxy-6-(5-methylpyrimidin-2-yl)quinazolin-4-yl)amino)-2-(3- methyl-1,2,4-oxadiazol-5-yl)ethan-1-ol, 6-(5-fluoro-2-pyridyl)-8-methoxy-N-[1-[6-(trifluoromethyl)pyridazin-3- yl]ethyl]quinazolin-4-amine, 6-(5-fluoropyridin-2-yl)-8-methoxy-N-(1-(5-methyl-1,3,4-oxadiazol-2- yl)ethyl)quinazolin-4-amine, 6-(5-fluoropyridin-2-yl)-8-methoxy-N-(1-(5-methyl-1,3,4-thiadiazol-2- yl)ethyl)quinazolin-4-amine, 8-methoxy-N-[(1R)-1-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]-6-(5- methylpyrimidin-2-yl)quinazolin-4-amine, (S)-6-(5-fluoropyridin-2-yl)-8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazol-3- yl)ethyl)quinazolin-4-amine, or 8-Methoxy-N-[(1S)-1-(6-methylpyridazin-3-yl)ethyl]-6-(5- methylpyrimidin-2-yl)quinazolin-4-amine.

7. The compound of formula (I) according to claim 1, wherein Y is -OR D , represented by formula (Ia) [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (Ia) wherein Z is aryl, 287 wherein any of such aryl may be optionally substituted by one or more groups that are halo; 𝑹 1 \mathbf{R}_1 is H, 𝑹 𝟐 \mathbf{R_2} is heteroaryl(C 1 -C 4 )alkyl-, wherein any of such heteroaryl may be optionally substituted by one or more groups that are each independently ( C 1 − C 3 ) (C_1-C_3) alkyl, or C 1 − C 6 ) C_1-C_6) haloalkyl; 𝑹 𝑨 \mathbf{R}^{\mathbf{A}} and 𝑹 𝑩 \mathbf{R}^{\mathbf{B}} are at each occurrence independently H or ( C 1 − C 4 ) (C_1-C_4) alkyl-; 𝑹 𝑪 \mathbf{R}^{\mathbf{C}} is at each occurrence H or (C 1 -C 6 )alkyl; R D is H, (C 1 -C 6 )alkyl, (C 3 -C 8 )heterocycloalkyl-(C 1 -C 6 )alkyl-, R C OC(O)(C 1 - C 4 C_4 )alkylene-, ( R A R B ) N ( C 1 − C 6 ) (R^AR^B)N(C_1-C_6) alkylene-, ( C 3 − C 8 ) (C_3-C_8) heterocycloalkyl, R C O ( C 1 − C 6 ) R^CO(C_1-C_6) C4)alkylene-, ( R A R B ) N ( O ) C ( C 1 − C 4 ) (R^AR^B)N(O)C(C_1-C_4) alkylene-, or ( C 3 − C 8 ) (C_3-C_8) cycloalkyl- ( C 1 − C 6 ) (C_1-C_6) alkyl-, wherein any of such heterocycloalkyl may be optionally substituted by one or more groups that are each independently ( C 1 − C 3 ) (C_1-C_3) alkyl; and J is H.

8. The compound of formula I according to claim 1, wherein the compound is: (R)-6-(4-Fluorophenyl)-8-((tetrahydro-2H-pyran-4-yl)oxy)-N-(1-(2- (trifluoromethyl) pyrimidin-5-yl)ethyl)quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] (trifluoromethyl)pyrimidin-5-yl]ethyl}quinazolin-4-amine, 6-(4-fluorophenyl)-8-isopropoxy-N-[(6-methylpyridazin-3- yl)methyl]quinazolin-4-amine, 8-(cyclopropylmethoxy)-6-(4-fluorophenyl)-N-[(6-methylpyridazin-3- yl)methyl]quinazolin-4-amine, 2-[6-(4-fluorophenyl)-4-[(6-methylpyridazin-3-yl)methylamino]quinazolin- 8-yl]oxyethanol, 288 2-[6-(4-fluorophenyl)-4-[(6-methylpyridazin-3-yl)methylamino]quinazolin- 8-yl]oxy-N,N-dimethyl-acetamide, 6-(4-fluorophenyl)-8-(2-methoxyethoxy)-N-[(6-methylpyridazin-3- yl)methyl]quinazolin-4-amine, 6-(4-fluorophenyl)-N-[(6-methylpyridazin-3-yl)methyl]-8-(oxetan-3- ylmethoxy)quinazolin-4-amine, 6-(4-fluorophenyl)-N-[(6-methylpyridazin-3-yl)methyl]-8-tetrahydropyran- 4-yloxy-quinazolin-4-amine, [Image disponible dans le document PDF, Image available in the PDF document] morpholinoethoxy)quinazolin-4-amine, 6-(4-fluorophenyl)-8-[(1-methyl-4-piperidyl)oxy]-N-[(6-methylpyridazin-3- yl)methyl]quinazolin-4-amine, 8-[3-(dimethylamino)propoxy]-6-(4-fluorophenyl)-N-[(6-methylpyridazin- 3-yl)methyl]quinazolin-4-amine, ethyl [Image disponible dans le document PDF, Image available in the PDF document] yl)methylamino]quinazolin-8-yl]oxyacetate, [Image disponible dans le document PDF, Image available in the PDF document] yl)methyl]quinazolin-4-amine, 2-[6-(4-fluorophenyl)-4-[(6-methylpyridazin-3-yl)methylamino]quinazolin- 8-yl]oxyacetic acid, sodium salt, 8-(azetidin-3-ylmethoxy)-6-(4-fluorophenyl)-N-[(6-methylpyridazin-3- yl)methyl]quinazolin-4-amine, 6-(4-fluorophenyl)-N-[(6-methylpyridazin-3-yl)methyl]-8-pyrrolidin-3- yloxy-quinazolin-4-amine, 6-(4-fluorophenyl)-N-[(6-methylpyridazin-3-yl)methyl]-8-(morpholin-2- ylmethoxy)quinazolin-4-amine, 8-(azetidin-3-yloxy)-6-(4-fluorophenyl)-N-[(6-methylpyridazin-3- yl)methyl]quinazolin-4-amine, 6-(4-fluorophenyl)-N-[(6-methylpyridazin-3-yl)methyl]-8-(4- piperidyloxy)quinazolin-4-amine, 6-(4-fluorophenyl)-8-[(1-methylazetidin-3-yl)methoxy]-N-[(6- methylpyridazin-3-yl)methyl]quinazolin-4-amine, 6-(4-fluorophenyl)-8-[(4-methylmorpholin-2-yl)methoxy]-N-[(6- methylpyridazin-3-yl)methyl]quinazolin-4-amine, 6-(4-fluorophenyl)-N-[(6-methylpyridazin-3-yl)methyl]-8-(1- methylpyrrolidin-3-yl)oxy-quinazolin-4-amine, (R)-2-((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidin-5- yl)ethyl)amino)quinazolin-8-yl)oxy)acetamide, ( R ) (R) -2-((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidin-5- yl)ethyl)amino)quinazolin-8-yl)oxy)-1-(pyrrolidin-1-yl)ethan-1-one, (R)-N,N-diethyl-2-((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidin- 5-yl)ethyl)amino)quinazolin-8-yl)oxy)acetamide, 6-(4-fluorophenyl)-N-[(6-methylpyridazin-3-yl)methyl]-8-[(3S)-pyrrolidin- 3-yl]oxy-quinazolin-4-amine, or 6-(4-fluorophenyl)-N-[(6-methylpyridazin-3-yl)methyl]-8-[(3R)-pyrrolidin- 3-yl]oxy-quinazolin-4-amine.

9. A pharmaceutical composition comprising the compound as defined in any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, either alone or in combination with another one or more active ingredient, in admixture with one or more pharmaceutically acceptable diluent, carrier or excipient.

10. The pharmaceutical composition according to claim 9 for oral administration.

11. A compound according to any one of claims 1 to 8 or a pharmaceutical composition according to claim 9 or 10 for use to treat a disease wherein P2X 3 receptors are involved.

12. A compound according to any one of claims 1 to 8 or a pharmaceutical composition according to claim 9 or 10 for use to prevent and / or treat a respiratory disease.

13. The compound or the pharmaceutical composition for use according to claim 12, wherein the respiratory disease comprises cough, sub-acute or chronic cough, treatment-resistant cough, idiopathic chronic cough, post-viral cough, iatrogenic cough, asthma, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) or cough associated with a respiratory disease.

14. The compound or the pharmaceutical composition for use according to claim 13, wherein the respiratory disease is cough associated with COPD, asthma or bronchospasm.

15. The compound or the pharmaceutical composition according to claim 14 for use to treat chronic cough.

16. A compound of formula Ib [Image disponible dans le document PDF, Image available in the PDF document] (Ib) wherein R 3 is OH or halo, R 4 is H or OH, R 5 is -OMe, R 6 R_6 is Z Z , Z is (C 3 -C 8 )heterocycloalkyl, (R A R B )N-, heteroaryl, or aryl, wherein any of such heteroaryl, heterocycloalkyl and aryl may be optionally substituted by one or more groups each independently (C 1 -C 3 )alkyl-, halo, CN, ( R A R B ) N C ( O ) (R^AR^B)NC(O) -, ( C 1 − C 6 ) (C_1-C_6) haloalkyl-, R A O R^AO -, ( R A R B ) N ( C 1 − C 6 ) (R^AR^B)N(C_1-C_6) alkylene-, ( C 3 − C 6 ) (C_3-C_6) C 7 )cycloalkyl-, R C SO 2 -, or (R A R B )N-.

17. Use of the compound of formula (Ib) as defined in claim 16, as an intermediate in the preparation of the compound of formula (I) as defined in any one of claims 1 to 8.

18. Use of the compound as defined in any one of claims 1 to 8 or the pharmaceutical composition according to claim 9 or 10, to treat a disease wherein a P2X 3 receptor is involved.

19. Use of the compound as defined in any one of claims 1 to 8 or the pharmaceutical composition as defined in claim 9 or 10, to prevent and / or to treat a respiratory disease.

20. The use according to claim 19, wherein the respiratory disease comprises cough, sub-acute or chronic cough, treatment-resistant cough, idiopathic chronic cough, post-viral cough, iatrogenic cough, asthma, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) or cough associated with a respiratory disease.

21. The use of claim 20, wherein the respiratory disease is cough associated with COPD, asthma or bronchospasm.

22. The use of claim 20 or 21, where the cough comprises chronic cough.

23. Use of the compound as defined in any one of claims 1 to 8 or the pharmaceutical composition as defined in claim 9 or 10, in the manufacture of a medicament for treating a disease wherein a P2X 3 receptor is involved.

24. Use of the compound as defined in any one of claims 1 to 8 or the pharmaceutical composition as defined in claim 9 or 10, in the manufacture of a medicament for preventing and / or treating a respiratory disease.

25. The use of claim 24, wherein the respiratory disease comprises cough, sub-acute or chronic cough, treatment-resistant cough, idiopathic chronic cough, post-viral cough, iatrogenic cough, asthma, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) or a cough associated with a respiratory disease.

26. The use of claim 25, wherein the respiratory disease is cough associated with COPD, asthma or bronchospasm.

27. The use of claim 26, wherein the cough is chronic cough.