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  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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  • A61K31/5375—1,4-Oxazines, e.g. morpholine
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  • C07D239/72—Quinazolines; Hydrogenated quinazolines
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  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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  • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
  • C07F5/02—Boron compounds

Definitions

• the present invention relates to compounds inhibiting P2X purinoceptor 3 (hereinafter P2X 3 inhibitors); particularly the invention relates to compounds that are amino quinazoline derivatives, methods of preparing such compounds, pharmaceutical compositions containing them and therapeutic use thereof.
• P2X 3 inhibitors compounds inhibiting P2X purinoceptor 3
• the invention relates to compounds that are amino quinazoline derivatives, methods of preparing such compounds, pharmaceutical compositions containing them and therapeutic use thereof.
• 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 1 , P2X 2 , P2X 3 , P2X 4 , P2X 5 , and P2X 7 channels and heteromeric P2X 2/3 and P2X 1/5 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.
• 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
• the P2X 3 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 3 purinoceptor: Brain Res Mol Brain Res.1997;47(1–2):59–66).
• P2X 3 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 3 receptors and coexpression with P2X2 receptors during rat embryonic neurogenesis. J Comp Neurol 443(4):368–3822002)
• P2X 3 antagonists have been proposed for the treatment of diabetic neuropathic pain (Guo J et al: Contributions of purinergic P2X 3 receptors within the midbrain periaqueductal gray to diabetes-induced neuropathic pain, J Physiol Sci Jan;65(1):99-104 2015).
• P2X 3 and P2X 2/3 channels play an important role in the development of articular hyperalgesia of arthritic joints (Teixeira JM et al: P2X 3 and P2X 2/3 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 3 are also a potential target for therapeutic 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 3 antagonists may improve recovery of erectile function (Li CL et al: Effects of intracavernous injection of P2X 3 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 3 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).
• P2X 3 are expressed by airway afferent nerves and mediate hypersensitivity of the cough reflex, which is dramatically reduced by the oral P2X 3 antagonist, AF-219 (Abdulqawi et al: P2X 3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study, Lancet 385, 1198-205, 2015).
• AF-219 Abdulqawi et al: P2X 3 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 P2X 2/3 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 3 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 3 receptor immunoreactive nerves in rat taste buds, Neuroreport, 10(5):1107-11, 1999).
• WO2017058645 (Afferent Pharmaceuticals INC) discloses the use of diaminopyrimidine P2X 3 /P2X 2/3 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.
• amino quinazoline derivatives are not disclosed.
• WO2017011729 discloses the use of cromolyn or a pharmaceutically acceptable salt thereof and P2X 3 and/or a P2X 2/3 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 3 receptor and to pharmaceutical compositions containing such compounds, and the use of compounds for the treatment of several disorders, including the respiratory diseases.
• WO2016084922 (Shionogi), discloses triazine derivatives compounds having a novel P2X 3 and/or P2X 2/3 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 discloses 2-cyanophenyl fused heterocyclic compounds of the class tetrahydropyrido[4,3-d]pyrimidines and pharmaceutical compositions comprising such compounds.
• WO2010033168 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 3 receptor and/ or P2X 2/3 receptor antagonists.
• 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 invention.
• WO2008000645 (Roche) discloses tetrazole substituted arylamides compounds antagonists of P2X 3 and/or P2X 2/3 receptors, useful for the treatment of genitourinary, pain, gastrointestinal and respiratory diseases, conditions and disorders.
• the present invention refers to compounds of formula (I)
• Z is selected from the group consisting of (C 3 -C 8 )heterocycloalkyl, (R A R B )N-, heteroaryl, aryl, wherein any of such alkyl, heteroaryl, heterocycloalky and aryl may be optionally substituted by one or more groups selected from (C 1 -C 3 )alkyl-, halo, CN, (R A R B )NC(O)-, (C 1 -C 6 )haloalkyl-, R A O-, (R A R B )N(C 1 -C 6 )alkylene-, (C3-C7)cycloalkyl-, R C SO2-, (R A R B )N-;
• R 1 is H or (C 1 -C 4 )alkyl
• R 2 is selected from the group consisting of (C 1 -C 6 )alkyl-, heteroaryl(C 1 -C 4 )alkyl-, (C 3 -C 8 )heterocycloalkyl-(C 1 -C 6 )alkyl-, heteroaryl-(C 1 -C 6 )hydroxyalkyl-, (C 3 -C 8 )heterocycloalkyl, (C 3 -C 8 )cycloalkyl-(C 1 -C 6 )alkyl-, aryl-(C 1 -C 4 )alkyl-, (R A R B )N(C 1 -C 6 )alkylene-, (R A R B )N(O)C(C 1 -C 4 )alkylene-, R A O(C 1 -C 4 )alkylene- wherein any of such alkyl, alkylene,
• 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 selected (C 1 -C 4 )alkyl and oxo;
• R C is at each occurrence H or selected from the group consisting of (C 1 -C 6 )alkyl, (R A R B )N-, aryl-(C 1 -C 4 )alkyl-;
• R D is selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 3 -C 8 )heterocycloalkyl-(C 1 -C 6 )alkyl-, R C OC(O)(C 1 -C 4 )alkylene-, (R A R B )N(C 1 -C 6 )alkylene-, (C 3 -C 8 )heterocycloalkyl, (C 3 -C 8 )cycloalkyl-(C 1 -C 6 )alkyl-, R C O(C 1 -C4)alkylene-, (R A R B )N(O)C(C 1 -C 4 )alkylene-, wherein any of such heterocycloalkyl may be optionally substituted by one or more groups selected from (C 1 -C 3 )alkyl;
• J is H or selected from the group consisting of (C 1 -C 6 )alkyl, (R A R B )N-, (C 1 -C 6 ) haloalkyl, -OR C and halo.
• the invention refers to a pharmaceutical composition
• 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.
• the invention provides a compound of formula (I) for the use as a medicament.
• the invention provides the use of a compound of formula (I) for use in treatment of any disease wherein the P2X 3 receptors are involved.
• the invention 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.
• 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.
• the invention refers to a compound of formula Ib
• R 3 is OH or halo
• R 4 is H or OH
• R 5 is halo or -OMe
• R 6 is halo or Z
• the invention refers to the use of compound of formula (Ib) as intermediate in the preparation of compounds of formula (I).
• Z is selected from the group consisting of (C 3 -C 8 )heterocycloalkyl, (R A R B )N-, heteroaryl, aryl, wherein any of such alkyl, heteroaryl, heterocycloalky and aryl may be optionally substituted by one or more groups selected from (C 1 -C 3 )alkyl-, halo, CN, (R A R B )NC(O)-, (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 SO2-, (R A R B )N-;
• R 1 is H or (C 1 -C 4 )alkyl
• R 2 is selected from the group consisting of (C 1 -C 6 )alkyl-, heteroaryl(C 1 -C 4 )alkyl-, (C 3 -C 8 )heterocycloalkyl-(C 1 -C 6 )alkyl-, heteroaryl-(C 1 -C 6 )hydroxyalkyl-, (C 3 -C 8 )heterocycloalkyl, (C 3 -C 8 )cycloalkyl-(C 1 -C 6 )alkyl-, aryl-(C 1 -C 4 )alkyl-, (R A R B )N(C 1 -C 6 )alkylene-, (R A R B )N(O)C(C 1 -C 4 )alkylene-, R A O(C 1 -C 4 )alkylene- wherein any of such alkyl, alkylene, aryl, heteroaryl and heterocycloalkyl may be optionally substituted
• R A and R B are at each occurrence independently H or selected from the group consisting of (C 1 -C 4 )alkyl-, (C 3 -C 8 )cycloalkyl, (C 1 -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 selected (C 1 -C 4 )alkyl and oxo;
• R C is at each occurrence H or selected from the group consisting of (C 1 -C 6 )alkyl, (R A R B )N-, aryl-(C 1 -C 4 )alkyl-;
• J is H or selected from the group consisting of (C 1 -C 6 )alkyl, (R A R B )N-, (C 1 -C 6 ) haloalkyl, -OR C and halo.
• pharmaceutically acceptable salts 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.
• (C x -C y )alkylene wherein x and y are integers, refers to a C x -C y alkyl radical having in total two unsatisfied valencies, such as a divalent methylene radical.
• the terms“(C 1 -C 6 ) hydroxyalkyl” or“(C 1 -C 6 ) aminoalkyl” refer to the above defined“(C 1 -C 6 ) 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.
• aminoalkyl encompasses alkyl groups (i.e.“(C 1 -C 6 ) alkyl” groups) substituted by one or more amino group (- NR A R B ).
• alkyl groups i.e.“(C 1 -C 6 ) alkyl” groups
• aminoalkyl is a mono-aminoalkyl group such as R A R B N- (C 1 -C 6 ) alkyl.
• heteroatom e.g. N, S or O
• (C x -C y ) cycloalkyl refers to saturated cyclic hydrocarbon groups containing the indicated number of ring carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.
• 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.
• 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.
• 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.
• bicyclic heterocyclic systems included within the scope of the term are fused, spiro and bridged bicyclic systems.
• Said heterocycloalkyl i.e. heterocyclic radical or group
• 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 x -C y ) 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.
• heterocycle radicals are tetrahydrothiophene 1,1-dioxide, 3,3-difluoropyrrolidinyl, 1-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 1-piperidinyl, 1- piperazinyl, 4-morpholinyl.
• “Aryloxyl” and“Aryl (C 1 -C 6 ) alkoxyl” likewise“heteroAryloxyl” and“Heteroaryl (C 1 -C 6 ) 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.
• aryl (C 1 -C 6 ) 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.
• heteroaryl (C x -C y )alkyl or“aryl (C x -C y )alkyl” refers to an heteroaryl or aryl ring linked to a straight-chained or branched alkyl groups having from x to y carbon atoms.
• ring system refers to mono- or bicyclic or polycyclic ring systems which may be saturated, partially unsaturated or unsaturated, such as aryl, (C 3 -C 10 ) cycloalkyl, (C 3 -C 6 ) heterocycloalkyl or heteroaryl.
• said heterocycle radicals are 1-pyrrolidinyl, 1-piperidinyl, 1- piperazinyl, 4-morpholinyl
• the carbonyl group is herein represented as -C(O)-
• 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 2 - might be also represented as -S(O) 2 - to disambiguate e.g. with respect to the sulfinic group -S(O)O-.
• 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.
• acidic groups such as COOH groups
• physiological cation salts may be present as well, for instance including alkaline or alkaline earth metal ions.
• the compounds according to the invention 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).
• Z is selected from the group consisting of heteroaryl, aryl, (R A R B )N-, (C 3 - C 8 )heterocycloalkyl, wherein any of such heteroaryl, aryl and heterocycloalkyl may be optionally substituted by one or more groups selected from (C 1 -C 3 )alkyl, halo, CN, (R A R B )NC(O)-; R 1 is H or (C 1 -C 4 )alkyl;
• R 2 is selected from the group consisting of heteroaryl(C 1 -C 4 )alkyl-, (R A R B )N(O)C(C 1 -C 4 )alkylene-, wherein any of such heteroaryl may be optionally substituted by one or more groups selected from (C 1 -C 3 )alkyl, halo, (C 1 -C 6 ) haloalkyl;
• J is H or selected from the group consisting of (C 1 -C 4 )alkyl, (R A R B )N-, halo, (C 1 - C 6 )haloalkyl.
• 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 (C 1 -C 3 )alkyl and halo;
• R 1 is H
• R 2 is selected from the group consisting of (C 3 -C 8 )heterocycloalkyl-(C 1 -C 6 )alkyl-, preferably (piperidinyl)methyl; heteroaryl(C 1 -C 4 )alkyl-, preferably (pyridinyl)methyl, (pyridinyl)ethyl, (pyridazinyl)methyl, (pyridazinyl)ethyl (pyrimidinyl)methyl, (pyrimidinyl)ethyl, (oxadiazolyl)ethyl, (thiadiazolyl)ethyl ([1,2,4]triazolo[4,3- a]pyrimidin-3-yl)methyl, and
• any of such alkyl, heteroaryl and heterocycloalkyl may be optionally substituted by one or more groups selected from (C 1 -C 3 )alkyl, (C 1 -C 6 )haloalkyl and -OH;
• Y is selected from the group consisting of H and -OR D , R D is at each occurrence selected from the group consisting of
• (C 1 -C 6 )alkyl preferably methyl
• (C 3 -C 8 )heterocycloalkyl preferably tetrahydropyranyl, pyrrolidinyl, and R C O(C 1 -C 4 )alkylene-, preferably methoxyethyl;
• R C is at each occurrence selected from the group consisting of H and (C 1 -C 6 )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)
• 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 A R B (R A R B )N-, wherein R A and R B 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
• R 1 is H or methyl
• R 2 is selected from the group consisting of
• heteroaryl(C 1 -C4)alkyl- preferably (pyridinyl)methyl, (pyridazyl)methyl, (pyrimidinyl)ethyl, (oxadiazolyl)ethyl
• RARB N(O)C(C 1 -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
• R A and R B 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.
• 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)
• 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 (C 1 -C 3 )alkyl and halo;
• R1 is H
• R2 is selected from the group consisting of heteroaryl(C 1 -C4)alkyl-, wherein any of such heteroaryl may be optionally substituted by one or more groups selected from (C 1 -C 3 )alkyl and (C 1 -C 6 ) haloalkyl;
• Y is H
• J is H or halo.
• the invention refers to at least one compound of Table 3, selected from: Table 3: List of preferred compounds having Formula (I)
• Z is selected from the group consisting of heteroaryl and aryl
• any of such heteroaryl and aryl may be optionally substituted by one or more groups selected from (C 1 -C 3 )alkyl, halo, CN, (R A R B )NC(O)-, (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 -, (R A R B )N-;
• R 1 is H or (C 1 -C 4 )alkyl
• R 2 is selected from the group consisting of (C 1 -C 6 )alkyl, heteroaryl(C 1 -C 4 )alkyl-, (C 3 -C 8 )heterocycloalkyl-(C 1 -C 6 )alkyl, heteroaryl-(C 1 -C 6 )hydroxyalkyl, aryl-(C 1 - C 4 )alkyl-, (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-; R A O(C 1 -C 4 )alkylene,
• any of such alkyl, alkylene, aryl, heteroaryl, cycloalkyl and heterocycloalkyl may be optionally substituted by one or more groups selected from (C 1 -C 3 )alkyl, R A O(C 1 - C 4 )alkylene, (C 1 -C 6 )haloalkyl, oxo, R A O-, (C 3 -C 8 )heterocycloalkyl-(C 1 -C 6 )alkyl, heteroaryl, aryl optionally substituted by halo, R C O-, (R A R B )N-, -NHC(O)R C , - C(O)N(R A R B ), halo, -SO 2 N(R A R B ), -O(R A O(C 1 -C 4 )alkylene-N(R A R B ), aryl-(C 1 - C 4 )alkyl-, -C(O
• R C is H or selected from the group consisting of (C 1 -C 6 )alkyl, (R A R B )N-, aryl-(C 1 - C 4 )alkyl-,
• Y is selected from the group consisting of -OR D , R C SO 2 -, halo, -NHSO 2 R C , heteroaryl, (C 3 -C 8 )heterocycloalkyl,
• any of such heteroaryl and heterocycloalkyl may be optionally substituted by one or more groups selected from (C 1 -C 3 )alkyl, -C(O)N(R A R B );
• J is H or selected from the group consisting of (C 1 -C 6 )alkyl, -OR C ,
• R D is H or (C 1 -C 6 )alkyl.
• the invention refers to a compound of formula (I) as defined above
• 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 1 -C 3 )alkyl, halo, CN, (R A R B )NC(O)-, (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 -, (R A R B )N-;
• R 1 is H
• R 2 is selected from the group consisting of (C 1 -C 6 )alkyl, heteroaryl(C 1 -C 4 )alkyl-, (C 3 -C 8 )heterocycloalkyl-(C 1 -C 6 )alkyl, heteroaryl-(C 1 -C 6 )hydroxyalkyl, aryl-(C 1 - C 4 )alkyl-, (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-; R A O(C 1 -C 4 )alkylene,
• any of such alkyl, alkylene, aryl, heteroaryl, cycloalkyl and heterocycloalkyl may be optionally substituted by one or more groups selected from (C 1 - C 3 )alkyl, R A O(C 1 -C 4 )alkylene-, (C 1 -C 6 )haloalkyl, oxo, R A O-, (C 3 -C 8 )heterocycloalkyl- (C 1 -C 6 )alkyl, heteroaryl, aryl optionally substituted by halo, R C O-, (R A R B )N-, - NHC(O)R C , -C(O)N(R A R B ), halo, -SO 2 N(R A R B ), -O(R A O(C 1 - C 4 )alkylene-N(R A R B ), aryl-(C 1 -C 4 )alkyl-, -C(
• R A and R B are at each occurrence independently H or selected from the group consisting of (C 1 -C 4 )alkyl-, aryl, (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 (C 1 -C 4 )alkyl- and oxo;
• R C is H or selected from the group consisting of (C 1 -C 6 )alkyl, (R A R B )N-, aryl-(C 1 - C 4 )alkyl-,
• Y is selected from the group consisting of -OR D , R C SO 2 , halo, -NHSO 2 R C , heteroaryl, (C 3 -C 8 )heterocycloalkyl, wherein any of such heteroaryl and heterocycloalkyl may be optionally substituted by one or more groups selected from (C 1 -C 3 )alkyl, - C(O)N(R A R B );
• J is H or selected from the group consisting of (C 1 -C 6 )alkyl, OR C ;
• R D is H or (C 1 -C 6 )alkyl.
• Z is H or selected from the group consisting of (R A R B )N-,
• heteroaryl preferably thiadiazolyl, thiazolyl, pyrazolyl, pyridazyl, oxadiazolyl, pyridinyl, pyrimidinyl,
• aryl preferably phenyl
• R A O-, wherein R A is H
• each of said heteroaryl and aryl may be optionally substituted by one or more groups selected from
• halo preferably fluorine and chlorine
• R A R B NC(O)-, wherein R A and R B are at each occurrence independently H or methyl,
• C 1 -C 6 )haloalkyl preferably trifluoromethyl and difluoromethyl
• R A O-, wherein R A is H or selected from methyl, trifluoromethyl and difluoromethyl,
• R C SO 2 -, wherein R C is methyl
• R A R B (R A R B )N- wherein R A and R B are independently H and methyl;
• R 1 is H
• heteroaryl(C 1 -C 6 )hydroxyalkyl- preferably (oxadiazolyl)methanol
• aryl-(C 1 -C 4 )alkyl- preferably (phenyl)methyl
• R A R B N(C 1 -C 6 )alkylene-, preferably dimethylaminobuthyl, dimethylaminopropyl,
• each of said aryl, heteroaryl, cycloalkyl and heterocycloalkyl is optionally further substituted by one or more groups selected from
• (C 1 -C 3 )alkyl preferably methyl and ethyl
• R A is selected from the group of trifluoroethyl, difluoroethyl, methyl and ethyl,
• heteroaryl preferably pyridinyl
• R C O-, wherein R C is methyl
• Y is selected from the group consisting of -OR D , R C SO 2 , halo, -NHSO 2 R C , heteroaryl wherein any of such heteroaryl may be optionally substituted by one or more groups selected from (C 1 -C 3 )alkyl, -C(O)N(R A R B ); R D is (C 1 -C 6 )alkyl, preferably methyl;
• J is selected from the group consisting of
• (C 1 -C 6 )alkyl preferably methyl
• Z is aryl, wherein any of such aryl may be optionally substituted by one or more groups selected from (C 1 -C 3 )alkyl, halo, CN,
• R 2 is selected from the group consisting of heteroaryl(C 1 -C 4 )alkyl-, (C3- C8)heterocycloalkyl-(C 1 -C 6 )alkyl, (C 3 -C 8 )heterocycloalkyl, (C 3 -C 8 )cycloalkyl-(C 1 - C6)alkyl-, wherein any of such alkyl, heteroaryl may be optionally substituted by one or more groups selected from (C 1 -C 3 )alkyl, (C 1 -C 6 )haloalkyl, oxo, R A O-, aryl, (R A R B )N- and halo; R A and R B are at each occurrence independently H or selected from the group consisting of (C 1 -C 4 )alkyl-, (C 1 -C 6 ) haloalkyl;
• Y is selected from the group consisting of -OR D , R C SO 2 , halo and -NHSO 2 R C , heteroaryl, heterocycloalkyl, wherein any of such heteroaryl may be optionally substituted by one or more groups selected from (C 1 -C 3 )alkyl, -C(O)N(R A R B );
• J is H or selected from the group consisting of OR C ;
• R C is H, or selected form the group consisting of (C 1 -C 6 )alkyl, (R A R B )N-;
• R D is H or (C 1 -C 6 )alkyl.
• the invention refers to at least one compound of Table 5, selected from: Table 5: List of preferred compounds having Formula (I)
• Z is heteroaryl wherein any of such heteroaryl may be optionally substituted by one or more groups selected from (C 1 -C 3 )alkyl, halo, CN, (C 1 -C 6 )haloalkyl;
• R 1 is H
• the invention is directed to a compound of formula (I) as defined above, wherein Y is -OR D , represented by formula (Ia)
• 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;
• R 1 is H
• R 2 is selected from the group consisting of heteroaryl(C 1 -C 4 )alkyl-, wherein any of such heteroaryl may be optionally substituted by one or more groups selected from (C 1 -C 3 )alkyl, C 1 -C 6 )haloalkyl;
• R A and R B are at each occurrence independently H or selected from the group consisting of (C 1 -C 4 )alkyl-;
• R C is at each occurrence H or selected from the group consisting of (C 1 -C 6 )alkyl
• R D is selected in the group consisting of H, (C 1 -C 6 )alkyl, (C 3 -C 8 )heterocycloalkyl-(C 1 -C 6 )alkyl-, R C OC(O)(C 1 -C 4 )alkylene-, (R A R B )N(C 1 -C 6 )alkylene-, (C 3 -C 8 )heterocycloalkyl, R C O(C 1 -C4)alkylene-, (R A R B )N(O)C(C 1 -C 4 )alkylene-, (C 3 -C 8 )cycloalkyl-(C 1 -C 6 )alkyl-, wherein any of such heterocycloalkly may be optionally substituted by one or more groups selected from (C 1 - C 3 )alkyl
• 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,
• R 2 is selected from the group consisting of
• heteroaryl(C 1 -C 4 )alkyl- (pyrimidinyl)ethyl, (pyridazinyl)methyl,
• each of said heteroaryl is optionally further substituted by one or more groups selected from
• (C 1 -C 3 )alkyl preferably methyl
• R D is H or selected in the group consisting of,
• (C 1 -C 6 )alkyl preferably methyl, propyl
• R C OC(O)(C 1 -C 4 )alkylene-, wherein R C is selected form the group of H and ethyl, (R A R B )N(C 1 -C 6 )alkylene-, preferably dimethylaminopropyl,
• R C O(C 1 -C 4 )alkylene-, preferably selected from the group of methoxyethyl, propanolyl,
• 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)
• 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).
• 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).
• 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.
• compound (IB) may be prepared according to SCHEME 2 from compounds (VI).
• Some compounds (IB) may contain a protected hydroxyl or amino group which were then removed under well known procedures.
• 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 (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.
• Compound (XV) may be prepared from Compound (IA) by means of dealkylation reactions mediated by strong Lewis acids like BBr 3 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.
• a suitable alkylating agent Reag.4
• compounds (ID) may be prepared from compounds (XV) and a suitable alcohol by Mitsunobu-like reactions mediated, for example, by DEAD/PPh3, DIAD/PPh 3 or CMT.
• 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.
• 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.
• a suitable sulfinate Reag. 5
• 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.
• 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.
• 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 (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.
• 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.
• R 3 is OH or halo
• R 5 is halo or -OMe
• 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 3 receptor and said compounds are useful for the treatment of respiratory disease.
• representative compounds of formula (I) of the present invention have surprisingly been found to effectively and selectively inhibit P2X 3 receptor and said compounds are useful for the treatment of respiratory disease avoiding adverse effect, such as loss of taste response.
• the compound of formula (I) are selective P2X 3 antagonist wherein the selective P2X 3 antagonist is at least 10-fold selective for P2X 3 homomeric receptor antagonism versus P2X 2/3 heteromeric receptor antagonism.
• the selective P2X 3 antagonist is at least 30-fold selective for P2X 3 homomeric receptor antagonism versus P2X 2/3 heteromeric receptor antagonism.
• the selective P2X 3 antagonist is at least 50-fold selective for P2X 3 homomeric receptor antagonism versus P2X 2/3 heteromeric receptor antagonism.
• the present invention also provides a pharmaceutical composition
• 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.
• the invention refers to a compound of formula (I) according to the invention for use as a medicament.
• 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 3 receptors mechanism, preferably for the treatment of respiratory diseases.
• 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.
• 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
• 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 3 receptors mechanisms, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the invention.
• 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.
• 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.
• the compounds of the present invention may be administered orally or by inhalation.
• 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.
• 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.
• 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.
• 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.
• 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 3 receptor.
• 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.
• TEA triethyl amine
• DCC N,N'-Dicyclohexylcarbodiimide
• TFA Trifluoroacetic acid
• DIEA or DIPEA N,N-Diisopropylethylamine
• 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 ⁇ m 19 ⁇ 150 mm or Waters CSH Phenyl Hexyl, 19 ⁇ 150, 5 ⁇ m column.
• 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).
• SFC Supercritical Fluid Chromatography
• 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 oC column temperature.
• the modifier used under basic conditions was diethylamine (0.1% V/V).
• the modifier used under acidic conditions was either formic acid (0.1% V/V) or trifluoroacetic acid (0.1% V/V).
• 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 2 (with 0.1% diethylamine) isocratic run at 5 mL/min, 120 Bar backpressure, 40 oC column temperature.
• 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 2 (with 0.1% diethylamine) isocratic run at 5 mL/min, 120 Bar backpressure, 40 oC column temperature.
• 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 2 (with 0.1% diethylamine) isocratic run at 5 mL/min, 120 Bar backpressure, 40 oC column temperature.
• 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 2 (with 0.1% diethylamine) isocratic run at 5 mL/min, 120 Bar backpressure, 40 oC column temperature.
• 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 2 (with 0.1% diethylamine) isocratic run at 5 mL/min, 120 Bar backpressure, 40 oC column temperature.
• 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 2 (with 0.1% diethylamine) isocratic run at 5 mL/min, 120 Bar backpressure, 40 oC column temperature.
• 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 2 (with 0.1% diethylamine) isocratic run at 5 mL/min, 120 Bar backpressure, 40 oC column temperature.
• 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 2 (with 0.1% diethylamine) isocratic run at 5 mL/min, 120 Bar backpressure, 40 oC column temperature.
• 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 2 (with 0.1% diethylamine) isocratic run at 5 mL/min, 120 Bar backpressure, 40 oC column temperature.
• 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 2 (with 0.1% diethylamine) isocratic run at 5 mL/min, 120 Bar backpressure, 40 oC column temperature.
• 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 2 (with 0.1% diethylamine) isocratic run at 5 mL/min, 120 Bar backpressure, 40 oC column temperature.
• 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 2 (with 0.1% diethylamine) isocratic run at 5 mL/min, 120 Bar backpressure, 40 oC column temperature.
• 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 2 (with 0.1% diethylamine) isocratic run at 5 mL/min, 120 Bar backpressure, 40 oC column temperature.
• 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 2 (with 0.1% diethylamine) isocratic run at 5 mL/min, 120 Bar backpressure, 40 oC column temperature.
• 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 2 (with 0.1% diethylamine) isocratic run at 5 mL/min, 120 Bar backpressure, 40 oC column temperature.
• 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 2 (with 0.1% diethylamine) isocratic run at 5 mL/min, 120 Bar backpressure, 40 oC column temperature.
• 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 2 (with 0.1% diethylamine) isocratic run at 5 mL/min, 120 Bar backpressure, 40 oC column temperature.
• 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 2 (with 0.1% diethylamine) isocratic run at 5 mL/min, 120 Bar backpressure, 40 oC column temperature.
• 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 2 (with 0.1% diethylamine) isocratic run at 5 mL/min, 120 Bar backpressure, 40 oC column temperature.
• 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 2 (with 0.1% diethylamine) isocratic run at 5 mL/min, 120 Bar backpressure, 40 oC column temperature.
• 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 2 (with 0.1% diethylamine) isocratic run at 5 mL/min, 120 Bar backpressure, 40 oC column temperature.
• 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 2 (with 0.1% diethylamine) isocratic run at 5 mL/min, 120 Bar backpressure, 40 oC column temperature.
• 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 2 (with 0.1% diethylamine) isocratic run at 5 mL/min, 120 Bar backpressure, 40 oC column temperature.
• 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 2 (with 0.1% diethylamine) isocratic run at 5 mL/min, 120 Bar backpressure, 40 oC column temperature.
• 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 2 (with 0.1% diethylamine) isocratic run at 5 mL/min, 120 Bar backpressure, 40 oC column temperature.
• 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 2 (with 0.1% diethylamine) isocratic run at 5 mL/min, 120 Bar backpressure, 40 oC column temperature.
• 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 2 (with 0.1% diethylamine) isocratic run at 5 mL/min, 120 Bar backpressure, 40 oC column temperature.
• 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 2 (with 0.1% diethylamine) isocratic run at 5 mL/min, 120 Bar backpressure, 40 oC column temperature.
• Step 1 Preparation of Benzyl ((1r,4r)-4-(((6-(4-fluorophenyl)-8- methoxyquinazolin-4-yl)amino)methyl)cyclohexyl)carbamate
• Step 2 Preparation of N-(((1r,4r)-4-aminocyclohexyl)methyl)-6-(4-fluorophenyl)- 8-methoxyquinazolin-4-amine Nitrogen was bubbled for 5 min through a solution of benzyl ((1r,4r)-4-(((6-(4- 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).
• 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
• Step 2 Preparation of 8-methoxy-6-(5-methyl-1,3,4-thiadiazol-2-yl)-N-((6- methylpyridazin-3-yl)methyl)quinazolin-4-amine
• 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
• Step 2 Preparation of 8-methoxy-N-((6-methylpyridazin-3-yl)methyl)-6-(5- methylthiazol-2-yl)quinazolin-4-amine
• Example 176a 6-(4-Fluoro-2-methoxyphenyl)-8-methoxy-N-((6-methylpyridazin-3- yl)methyl)quinazolin-4-amine
• 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 4 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 (2.08 g, 97%).
• Step 2 Preparation of methyl 4-amino-4'-fluoro-5-iodo-[1,1'-biphenyl]-3- carboxylate
• dichloromethane 25 mL
• bis(pyridine)iodonium tetrafluoroborate 4.73 g, 12.72 mmol
• TFA 2.1 mL, 27.42 mmol
• Step 3 Preparation of 4-amino-4'-fluoro-5-iodo-[1,1'-biphenyl]-3-carboxylic acid
• 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.
• Step 4 Preparation of 6-(4-fluorophenyl)-8-iodoquinazolin-4(3H)-one
• 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 oC 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 (3 ⁇ 5 mL) then 10% MeOH in diethyl ether (3 ⁇ 5 mL) to give the title compound as an off-white solid (2.14 g, 87%).
• Step 5 Preparation of (R)-6-(4-fluorophenyl)-8-iodo-N-(1-(2- (trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine
• 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).
• Step 2 Preparation of (R)-6-(4-fluorophenyl)-8-(methylsulfonyl)-N-(1-(2- (trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine
• Step 1 Preparation of 6-(4-fluorophenyl)-4-oxo-3,4-dihydroquinazoline-8- sulfonamide
• Step 2 Preparation of (R)-6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidin- 5-yl)ethyl)amino)quinazoline-8-sulfonamide
• 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.
• Example 223 and Example 224 ((R)-8-methoxy-6-(3-methyl-1H-pyrazol-1-yl)-N-(1-(2- (trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine (Ex. 223) and (R)-8- methoxy-6-(5-methyl-1H-pyrazol-1-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5- yl)ethyl)quinazolin-4-amine (Ex.224)
• LCMS (Method 3): [MH+] 430 at 3.30 min.
• LCMS (Method 3): [MH+] 430 at 3.18 min.
• Example 225 and Example 226 (R)-8-Methoxy-6-(4-methyl-1H-imidazol-1-yl)-N-(1-(2- (trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine (Ex.225) and (R)-8- methoxy-6-(5-methyl-1H-imidazol-1-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5- yl)ethyl)quinazolin-4-amine (Ex.226)
• LCMS (Method 4): [MH+] 430 at 4.01 min.
• LCMS (Method 3): [MH+] 430 at 2.23 min.
• Example 228 6-(5-methylpyridin-2-yl)-N-((6-methylpyridin-3-yl)methyl)quinazolin-4- amine 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.
• 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
• Example 246 was obtained with the same conditions used for Example 245.
• Example 249 N-((3,5-difluoropyridin-2-yl)methyl)-6-(4-fluorophenyl)quinazolin-4-amine hydrochloride 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.
• Example 250 6-(4-fluorophenyl)-N-methyl-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl) quinazolin-4-amine
• 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 ⁇ L, 0.172 mmol).
• 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 (2 ⁇ 10 mL). 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 0– 40% ethyl acetate in cyclohexane to give the title compound (181 mg, 60%) as a colourless solid.
• Step 2 Preparation of (R)-6-(5-fluoropyridin-2-yl)-8-methoxy-N-(1-(5-methyl- 1,2,4-oxadiazol-3-yl)ethyl)quinazolin-4-amine and F N
• Cells expressing P2X3 receptors were grown according to standard practice and maintained at 37 °C in a 5% humidified CO2 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 3x10 6 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 CaCl2, 1 mM MgCl2, 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 H2O 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 a,b-MeATP (800 nM), with the subsequent agonist applications being washed out using extracellular assay buffer containing 0.5 U/ml apyrase.
• antagonist was incubated in the absence of a,b-MeATP for 10 minutes. After antagonist preincubation, 800 nM a,b-MeATP and antagonist were co-administered to determine the inhibitory effect of the antagonist.
• 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 3 current amplitude was taken from the peak current amplitude from the second agonist response prior to preincubation with antagonist.
• the peak P2X 3 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:
• Concentration-response curves were constructed from ten different concentrations with each concentration of antagonist tested on at least two individual cells.
• concentration of the antagonist to inhibit P2X 3 current by 50% (IC 50 ) was determined by fitting the data with the following equation:
• Representative compound of the present invention have been also tested for P2X2/3 receptor.
• Step 1 Synthesis of 6-bromo-4-((6-methylpyridin-3-yl)methoxy)pyrido[2,3- d]pyrimidine
• 6-Bromopyrido[2,3-d]pyrimidin-4(3H)-one (202 mg, 0.89 mmol) (Intermediate 1), 5- hydroxymethyl-2-methylpyridine (110 mg, 0.89 mmol) and triphenylphosphine (328 mg, 1.25 mmol) were stirred in dry THF (7 mL) and a solution of diisopropyl azodicarboxylate (229 mL, 1.16 mmol) in dry THF (3 mL) was added dropwise and stirred at room temperature for 6 hours. The reaction was filtered and the precipitate was washed with (2:1) DCM/MeOH (20 mL). The filtrates were combined and the solvent was removed in vacuo.
• Step 2 Synthesis of 6-(4-fluorophenyl)-4-[(6-methyl-3- pyridyl)methoxy]pyrido[2,3-d]pyrimidine
• Nitrogen gas was bubbled through a mixture of 6-bromo-4-((6-methylpyridin-3- yl)methoxy)pyrido[2,3- d]pyrimidine (84 mg, 0.254 mmol), 4-fluorophenylboronic acid, pinacol ester (76 mg, 0.342 mmol) and cesium fluoride (116 mg, 0.761 mmol) in DMF (1 mL) and water (0.3 mL). After 5 min, tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol) was added and the resulting mixture was heated at 95 oC for 16 hours.

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