Amino quinazoline derivatives as p2x3 inhibitors

Abstract

To provide a compound for inhibiting P2X purinoceptor 3.SOLUTION: The present invention provides a compound that is an amino quinazoline derivative represented by the following formula (I), a method of producing such a compound, a pharmaceutical composition including the same, and a therapeutic use thereof. The compound may be useful in the treatment of many disorders associated with P2X3 receptor mechanisms, such as respiratory diseases including cough, asthma, idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (COPD).SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to compounds that inhibit the P2X purinoceptor 3 (hereinafter referred to as P2X3 inhibitors); in particular, the present invention relates to compounds that are aminoquinazoline derivatives, methods for producing such compounds, pharmaceutical compositions containing them, and their therapeutic uses.

[0002] The compounds of the present invention may be useful for the treatment of many disorders related to the P2X3 receptor mechanism, such as respiratory diseases including cough, asthma, idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (COPD).

Background Art

[0003] P2X receptors are cell surface ion channels activated by extracellular adenosine 5-triphosphate (ATP). The P2X receptor family is a trimeric assembly composed of seven different subunit subtypes (P2X1-7) that assemble as homomeric and heteromeric channels. All subunits share a common topology including an intracellular terminus, two transmembrane helices that form an ion channel, and a large extracellular domain containing an ATP binding site. Homomeric P2X1, P2X2, P2X3, P2X4, P2X5, and P2X7 channels and heteromeric P2X 2 / 3 and P2X 1 / 5Channels have been fully characterized after heterologous expression. P2X receptors are widely distributed, and functional responses are seen in neurons, glial cells, epithelium, endothelium, bone, muscle, and hematopoietic tissues. In smooth muscle, P2X receptors respond to ATP released from sympathetic motor nerves (e.g., during ejaculation). In sensory nerves, they are involved in the initiation of afferent signals in several organs (e.g., bladder, intestine) and play an important role in the perception of tissue damage and inflammatory stimuli. A paracrine role for ATP signaling via P2X receptors may exist in the neurohypophysis, duct glands, airway epithelium, kidney, bone, and hematopoietic 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 receptor subtypes varies according to sensitivity to ATP and small molecule antagonists (K Kaczmarek-Hajek et al: Molecular and functional properties of P2X receptors - recent progress and persisting challenges; Purinergic Signalling 8:375-417, 2012).

[0004] In humans, P2X3 receptors have been reported at the mRNA level in the heart and spinal cord and at the protein level in DRG, intestine (intramural plexus neurons), bladder (urothelium and urothelial endothelium), and dental pulp (Garcia-Guzman M et al: Molecular characterization and pharmacological properties of the human P2X3 purinoceptor: Brain Res Mol Brain Res. 1997; 47(1-2):59-66).

[0005] The neurophysiological role of the P2X3 receptor in airway sensory nerve function is similar to its role in 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 given rise to hypotheses regarding the involvement of the P2X3 receptor in symptoms of airway dysfunction, including cough and bronchial hyperresponsiveness (Ford AP: In pursuit of P2X3 antagonists: novel therapeutics for chronic pain 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). The P2X3 subunit also coexists in many neurons, particularly within the DRG, inferior ganglion, nucleus of the solitary tract, and taste buds (Cheung KK, Burnstock G: Localization of P2X3 receptors and coexpression with P2X2 receptors during rat embryonic neurogenesis. J Comp Neurol 443(4):368-382 2002).

[0006] P2X3 antagonists have been proposed for the treatment of painful diabetic neuropathy (Guo J et al: Contributions of purinergic P2X3 receptors within the midbrain periaqueductal gray to diabetes-induced neuropathic pain, J Physiol Sci Jan;65(1):99-104 2015).

[0007] P2X3 and P2X 2 / 3Channels play an important role in the development of arthritic joint hyperalgesia (Teixeira JM et al: P2X3 and P2X2 / 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).

[0008] P2X3 is also a potential target for the treatment of bladder pain. They have also been proposed as analgesic targets for treating ureteral colic and facilitating the passage of ureteral stones (Canda AE et al: Physiology and pharmacology of the human ureter: basis for current and future treatments, Urol Int. 78(4):289-98, 2007).

[0009] P2X3 overexpression is involved in the reduction of recurrence-free survival in patients with hepatocellular carcinoma, identifying P2X3 as a potential therapeutic target (Maynard JP et al: P2X3 purinergic receptor overexpression is associated with poor recurrence-free survival in hepatocellular carcinoma patients Oncotarget Dec 1;6(38):41162-79, 2015).

[0010] P2X3 antagonists have been suggested to have the potential to improve the recovery of erectile function (Li CL et al: Effects of intracavernous injection of P2X3 and NK1 receptor antagonists on erectile dysfunction induced by spinal cord transection in rats, Andrologia. Feb;47(1):25-9, 2015).

[0011] ATP enhances citric acid-induced and histamine-induced cough in preclinical models, and this effect can be reduced by P2X3 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).

[0012] The therapeutic promise of P2X3 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 P2X3 receptors in respiratory and urological disorders, Front Cell Neurosci, Dec 19;7:267, 2013). P2X3 is expressed by airway sensory nerves and mediates cough reflex hypersensitivity, which is dramatically reduced by the oral P2X3 antagonist, AF-219 (Abdulqawi et al: P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study, Lancet 385, 1198-205, 2015).

[0013] ATP is an important neurotransmitter in the taste system that acts mainly via P2X 2 / 3 heteromeric receptors. Consequently, taste function disturbances can be an unintended result of clinical trials for pain, chronic cough, and other conditions using purinergic P2X3 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 P2X3 receptor immunoreactive nerves in rat taste buds, Neuroreport, 10(5):1107-11, 1999).

[0014] P2X3 and / or P2X 2 / 3 As inhibitors, a variety of compounds have been described in the literature.

[0015] International Publication No. 2017058645 (Afferent Pharmaceuticals INC) discloses the use of a diamino pyrimidine P2X3 / P2X antagonist for the treatment of disorders including cough, chronic cough, and cough impulse, including cough associated with respiratory diseases or disorders, by administering an effective amount of the disclosed compound. However, aminoquinazoline derivatives are not disclosed. 2 / 3 However, aminoquinazoline derivatives are not disclosed.

[0016] International Publication No. 2017011729 (Patara Pharma LLC) discloses the use of cromolyn or a pharmaceutically acceptable salt thereof and a P2X3 and / or P2X receptor antagonist as an antitussive for the treatment of lung diseases and conditions. 2 / 3 International Publication No. 2017011729 (Patara Pharma LLC) discloses the use of cromolyn or a pharmaceutically acceptable salt thereof and a P2X3 and / or P2X receptor antagonist as an antitussive for the treatment of lung diseases and conditions.

[0017] International Publication No. 2016091776 (Evotec AG) discloses 1,3-thiazol-2-yl substituted benzamide compounds that inhibit the P2X3 receptor, pharmaceutical compositions containing such compounds, and the use of the compounds for the treatment of several disorders including respiratory diseases.

[0018] International Publication No. 2016088838 (Shionogi & Co., Ltd.) discloses novel purine derivative compounds having P2X3 and / or P2X receptor antagonistic activity. 2 / 3 International Publication No. 2016088838 (Shionogi & Co., Ltd.) discloses novel purine derivative compounds having P2X3 and / or P2X receptor antagonistic activity.

[0019] International Publication No. 2016084922 (Shionogi & Co., Ltd.) discloses novel triazine derivative compounds having P2X3 and / or P2X receptor antagonistic activity. 2 / 3 International Publication No. 2016084922 (Shionogi & Co., Ltd.) discloses novel triazine derivative compounds having P2X3 and / or P2X receptor antagonistic activity.

[0020] International Publication No. 2008 / 123963 (Renovis) relates to fused heterocyclic compounds of tetrahydropyrido[4,3-d]pyrimidines and pharmaceutical compositions containing such compounds. Methods for preventing and / or treating several disorders, such as neurodegenerative disorders, pain, asthma, autoimmune disorders, by administering the disclosed compounds are also provided.

[0021] International Publication No. 2008 / 130481 (Renovis) discloses 2-cyanophenyl fused heterocyclic compounds of tetrahydropyrido[4,3-d]pyrimidines and pharmaceutical compositions containing such compounds.

[0022] International Publication No. 2010 / 033168 (Renovis) relates to a series of benzamides substituted with phenyl or pyridyl, and more specifically, P2X3 receptor and / or P2X 2 / 3 receptor antagonists, which are considered useful for the treatment of diseases related to P2X purinergic receptors. However, pyridopyrimidine derivatives are not disclosed.

[0023] International Publication No. 2009 / 110985 (Renovis) relates to phenyl and pyridyl substituted benzamide compounds and pharmaceutical compositions containing such compounds, excluding thiazole substituted benzamides, which are different compounds from the compounds of the present invention.

[0024] International Publication No. 2008 / 000645 (Roche) discloses P2X3 and / or P2X 2 / 3 receptor tetrazole substituted arylamide compound antagonists useful for the treatment of urogenital, pain, gastrointestinal and respiratory diseases, conditions and disorders.

[0025] Despite the prior art cited above, there remains a need for novel aminoquinazoline compounds having a selective action preferably on the P2X3 receptor, for the treatment of diseases related to the P2X3 receptor, for example, particularly in respiratory diseases.

[0026] It should be noted that the prior art does not describe or suggest the aminokynazoline derivative compound of the present invention of general formula (I) which solves the above-mentioned necessity.

Summary of the Invention

[0027] The present invention relates to formula (I)

Chemical formula

[0028] In a second aspect, the present invention refers to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, alone or in combination with one or more other active ingredients, as a mixture with one or more pharmaceutically acceptable carriers or excipients.

[0029] In a third aspect, the present invention provides a compound of formula (I) for use as a medicament.

[0030] In a further aspect, the present invention provides the use of a compound of formula (I) for use in the treatment of any disease in which the P2X3 receptor is involved.

[0031] In a further aspect, the present invention relates to a compound of formula (I) for use in the prevention and / or treatment of cough, subacute or chronic cough, treatment-resistant cough, idiopathic chronic cough, post-viral infection 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.

[0032] In a further aspect, the present invention relates to formula Ib

Chemical formula

[0033] In a further aspect, the present invention refers to the use of a compound of formula (Ib) as an intermediate in the manufacture of a compound of formula (I).

[0034] Detailed Description of the Invention The present invention relates to formula (I)

Chemical formula

[0035] Definition As used herein, the term "pharmaceutically acceptable salt" refers to derivatives of the compounds of formula (I), wherein the parent compound, if present, is appropriately modified by converting any free acid or basic group with any base or acid to the corresponding addition salt which has conventionally been intended to be pharmaceutically acceptable.

[0036] Accordingly, suitable examples of said salts include inorganic or organic acid addition salts of basic residues such as amino groups, and inorganic or organic base addition salts of acidic residues such as carboxyl groups.

[0037] Cations of inorganic bases that can be suitably used for producing salts include ions of alkali metals or alkaline earth metals such as potassium, sodium, calcium or magnesium.

[0038] Compounds obtained by reacting the main compounds that function as bases with inorganic or organic acids to form salts include, for example, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, succinic acid and citric acid.

[0039] As used herein, the term "halogen" or "halogen atom" includes fluorine, chlorine, bromine and iodine atoms, preferably chlorine or fluorine.

[0040] The term "(C x -C y )alkyl" wherein x and y are integers refers to a straight-chain or branched-chain alkyl group having from x to y carbon atoms. Thus, when x is 1 and y is 6, for example, said term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl.

[0041] As used herein, the term "(C x -C y )alkylene" wherein x and y are integers refers to a C having an overall valence of 2 such as a divalent methylene radicalx -C y refers to an alkyl group.

[0042] The expression “(C x -C y ) haloalkyl” means the “C x -C y alkyl” group defined above, where one or more hydrogen atoms are replaced by one or more halogen atoms, which may be the same or different.

[0043] Therefore, examples of the “(C x -C y ) haloalkyl” group include halogenated, polyhalogenated, and fully halogenated alkyl groups in which all hydrogen atoms are replaced by halogen atoms, such as trifluoromethyl or difluoromethyl, trifluoroethyl groups.

[0044] As synonyms, the terms “(C1-C6) hydroxyalkyl” or “(C1-C6) aminoalkyl” mean the “(C1-C6) alkyl” group defined above, in which one or more hydrogen atoms are replaced by one or more hydroxy groups (OH) or amino groups, respectively. Examples of these include hydroxymethyl, aminomethyl, dimethylaminopropyl, etc.

[0045] In this specification, unless otherwise indicated, aminoalkyl includes an alkyl group (i.e., a “(C1-C6) alkyl” group) substituted with one or more amino groups (-NR A R B ). Therefore, examples of aminoalkyl are monoaminoalkyl groups such as R A R B N-(C1-C6) alkyl.

[0046] For the substituents R A and R B defined above and below, R A and R BWhen they combine with the nitrogen atom to form a 5- to 6-membered heterocyclic radical as a unit, at least one further ring carbon atom in the heterocyclic radical may optionally be substituted with at least one heteroatom (e.g., N, S, or O) and / or may have an -oxo(=O) substituent. It is understood that the heterocyclic radical may optionally be further substituted at any available position in the ring, i.e., on a carbon atom or on any heteroatom available for substitution. Substitution on a carbon atom includes spiro disubstitution and substitution on two adjacent carbon atoms, thus forming a further 5- to 6-membered heterocyclic ring in either case. Examples of the heterocyclic radical are 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-methylpiperazinyl, piperazin-4-yl-2-one, 4-morpholinyl, morpholinyl-3-one, 1-(piperazin-1-yl)ethenone.

[0047] The term “(C x -C y )cycloalkyl” refers to a saturated cyclic hydrocarbon group containing the indicated number of ring carbon atoms. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.

[0048] The term “aryl” refers to a monocyclic carbon ring system having 6 atoms, wherein the ring is aromatic. Examples of suitable aryl monocyclic ring systems include, for example, phenyl.

[0049] The term “heteroaryl” refers to a monocyclic or bicyclic aromatic radical containing one or more heteroatoms selected from S, N, and O, including two such monocyclic rings covalently fused, or one such monocyclic ring and one monocyclic aryl ring. Examples of suitable 5-, 6-membered heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, tetrazolyl, and triazinyl.

[0050] The term "heterocyclyl" or "heterocyclic" relates to saturated monocyclic, bicyclic or tricyclic non-aromatic radicals containing one or more heteroatoms selected from S, N and O. In the case of bicyclic heterocyclic systems, fused, spiro and bridged bicyclic systems are included within the scope of the term.

[0051] The term "(C x -C y )heterocycloalkyl", where x and y are integers, refers to a saturated or partially unsaturated monocyclic (C x -C y )cycloalkyl group in which at least one carbon atom is substituted by at least one heteroatom (e.g., N, S or O) or has an -oxo (=O) substituent. The said heterocycloalkyl (i.e., heterocyclic radical or group) may optionally be further substituted at available positions in the ring, i.e., on a carbon atom or on any heteroatom available for substitution. Substitution on a carbon atom includes spiro disubstitution and substitution on two adjacent carbon atoms, thus forming in either case a further 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 tetrahydropyridinyl, tetrahydrothiophenyl, azetidinyl, oxetanyl, tetrahydropyranyl, pyranyl, 2H- or 4H-pyranyl, dihydro- or tetrahydrofuranyl, dihydroisoxazolyl, pyrrolidin-2-one-yl, dihydropyrrolyl radical, etc.

[0052] Specific examples of said heterocyclic radicals are tetrahydrothiophene 1,1-dioxide, 3,3-difluoropyrrolidinyl, 1-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-morpholinyl.

[0053] The expressions “aryloxyl” and “aryl(C1-C6)alkoxyl”, as well as “heteroaryloxyl” and “heteroaryl(C1-C6)alkoxyl”, refer to an aryl or heteroaryl group bonded via an oxygen bridge and a bonded aryl-alkoxyl or heteroaryl-alkoxyl group. Examples of such groups are phenyloxy, benzyloxy and pyridyloxy, respectively.

[0054] The term “aryl(C1-C6)alkyl” refers to an aryl ring bonded to a straight-chain or branched alkyl group having 1 to 6 carbon atoms, for example, a phenylmethyl (i.e., benzyl), phenylethyl or phenylpropyl group.

[0055] The term (C z -C k )heterocycloalkyl-(C x -C y )alkyl refers to a heterocyclic ring bonded to a straight-chain or branched alkyl group having x to y carbon atoms.

[0056] Similarly, the term “heteroaryl(C x -C y )alkyl” or “aryl(C x -C y )alkyl” refers to a heteroaryl or aryl ring bonded to a straight-chain or branched alkyl group having x to y carbon atoms.

[0057] The expression “ring system” refers to a monocyclic or bicyclic or polycyclic ring system, aryl, (C3-C 10 )cycloalkyl, (C3-C6)heterocycloalkyl or heteroaryl, which may be saturated, partially unsaturated or unsaturated.

[0058] The terms "group", "radical", "fragment" or "substituent" are synonymous and are intended to denote a functional group or a molecular fragment that can be attached to a bond or to another fragment or molecule. Thus, by way of example, a "heterocyclic radical" as used herein refers to a monocyclic or bicyclic saturated or partially saturated heterocyclic moiety (group, radical), preferably a 4- to 11-membered monocyclic radical, wherein at least one additional ring carbon atom in said heterocyclic radical may optionally be substituted with at least one additional heteroatom independently selected from N, S or O, and / or may have an -oxo (=O) substituent, and said heterocyclic radical may further optionally form an additional 5- to 6-membered cyclic or heterocyclic, saturated, partially saturated or aromatic ring by spiro-disubstitution and substitution on two adjacent or vicinal atoms. Examples of said heterocyclic radicals are 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, etc.

[0059] A line ("-") that does not exist between two letters or symbols is meant to represent a point of attachment for a substituent. When represented schematically, the point of attachment in a cyclic functional group is indicated by a point ("·") located at one of the available ring atoms when the functional group is capable of attachment to a bond or to another fragment of the molecule.

[0060] The oxo moiety is represented as (O) as an alternative to other common representations, e.g., (=O). Thus, for general formulae, a carbonyl group is represented herein as -C(O)-, and in general, a group in parentheses is a side group and is not included in the chain, and the parentheses are used to avoid ambiguity in linear chemical formulae when considered useful; for example, the sulfonyl group -SO2- may be represented as -S(O)2- to avoid ambiguity with respect to, for example, the sulfinyl group -S(O)O-.

[0061] When a basic amino group or a quaternary ammonium group is present in the compound of formula I, there may always be present a physiologically acceptable anion selected from chloride, bromide, iodide, trifluoroacetate, formate, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p-toluenesulfonate, pamoate and naphthalenedisulfonate. Similarly, in the presence of an acidic group such as a COOH group, the corresponding physiological cation salts are also present, for example, containing alkali metal or alkaline earth metal ions.

[0062] When containing one or more stereocenters, it is clear that the compounds of formula (I) can exist as optical stereoisomers.

[0063] When the compounds according to the invention have at least one stereocenter, as a result they can exist as enantiomers. When the compounds according to the invention have two or more stereocenters, they can exist as diastereoisomers. All such single enantiomers, diastereoisomers and mixtures thereof in any proportion are included within the scope of the invention. The absolute configuration (R) or (S) for a carbon with a stereocenter is assigned based on the Cahn-Ingold-Prelog nomenclature rules based on the priority of the groups.

[0064] The present invention further relates to deuterated derivatives of the corresponding compounds of formula (I).

[0065] All preferred groups or embodiments for the compounds of formula I described above and hereinafter can be combined with each other and applied with the necessary modifications.

[0066] In a preferred embodiment, the present invention relates to formula (I) as defined above

Chemical formula

[0067] In another preferred embodiment, the present invention provides Z is selected from the group consisting of heteroaryl and aryl, wherein any of said heteroaryl and aryl may optionally be substituted with one or more groups selected from (C1-C3) alkyl and halo; R1 is H; R2 is selected from the group consisting of (C3-C8) heterocycloalkyl-(C1-C6) alkyl-, preferably (piperidinyl) methyl; heteroaryl(C1-C4) 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, wherein any of said alkyl, heteroaryl and heterocycloalkyl may optionally be substituted with one or more groups selected from (C1-C3) alkyl, (C1-C6) haloalkyl and -OH; Y is selected from the group consisting of H and -OR D and R D in each case is (C1-C6) alkyl, preferably methyl, (C3-C8) heterocycloalkyl-(C1-C6) alkyl-, preferably (oxetanyl) methyl, (morpholinyl) methyl, R C OC(O)(C1-C4) alkylene-, preferably -CH2C(O)OH; (C3-C8) heterocycloalkyl, preferably tetrahydropyranyl, pyrrolidinyl, and R C O(C1-C4) alkylene-, preferably methoxyethyl and is selected from the group consisting of; J in each case is H and -OR C and is preferably selected from the group consisting of H or -OH; R C in each case is selected from the group consisting of H and (C1-C6) alkyl, relates to a compound of formula (I).

[0068] According to a preferred embodiment, the present invention refers to at least one of the compounds listed in Table 1 below and pharmaceutically acceptable salts thereof. Table 1: List of Preferred Compounds Having Formula (I)

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

[0069] In a further preferred embodiment, the present invention Z is heteroaryl, preferably pyrimidinyl, thiazolyl, pyridinyl, thiophenyl, aryl, preferably phenyl, R A and R B together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated heterocyclic monocyclic ring system containing an additional heteroatom which is oxygen or nitrogen, said heterocyclic radical being optionally further substituted with one or more oxo, methyl and fluorine (R A R B )N-, and being selected from the group consisting of; any of said heteroaryl and aryl is optionally methyl, fluorine, R C R C selected from the group consisting of fluorine, -OH, and SO2 and RA and R B is H (R A R B )N-, CN, R A and R B is H (R A R B )NC(O)- and may be further substituted with one or more groups selected from the group consisting of: R1 is H or methyl; R2 is heteroaryl(C1-C4)alkyl-, preferably (pyridinyl)methyl, (pyridazinyl)methyl, (pyrimidinyl)ethyl, (oxadiazolyl)ethyl (R A R B )N(O)C(C1-C4)alkylene-, preferably R A R B is selected from the group consisting of those where R is H, cyclopropyl; Y is H; J is H or halo, preferably chlorine, (C1-C4)alkyl, preferably methyl, (C1-C6)haloalkyl preferably trifluoromethyl, R A and R B in each case are independently H, cyclopropyl and methyl, or R A and R B together with the nitrogen atom to which they are attached form a 6-membered saturated heterocyclic monocyclic ring system containing an additional heteroatom which is oxygen, (R A R B )N- and are selected from the group consisting of, a compound of formula (I).

[0070] According to a preferred embodiment, the present invention refers to at least one of the compounds listed in Table 2 below and pharmaceutically acceptable salts thereof. Table 2: List of Preferred Compounds Having Formula (I) [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0071] In a further preferred embodiment, the present invention Z is H or is selected from the group consisting of heteroaryl and aryl, where any said heteroaryl and aryl may optionally be substituted with one or more groups selected from (C1-C3) alkyl and halo; R 1 is H; R 2 is selected from the group consisting of heteroaryl (C1-C4) alkyl-, where any said heteroaryl may optionally be substituted with one or more groups selected from (C1-C3) alkyl and (C1-C6) haloalkyl; Y is H; relates to a compound of formula (I) where J is H or halo.

[0072] According to a preferred embodiment, the present invention refers to at least one of the compounds of Table 3, selected from the following. Table 3: List of Preferred Compounds Having Formula (I) [Table 3-1] [Table 3-2]

[0073] In a preferred embodiment, the present invention relates to formula (I)

Chemical formula

[0074] In a further preferred embodiment, the invention relates to formula (I) as defined above [Chemical formula] [wherein, Z is selected from the group consisting of heteroaryl and aryl, wherein any said heteroaryl and aryl may optionally be (C1-C3)alkyl, halo, CN, (R A R B )NC(O)-, (C1-C6)haloalkyl, R A O-, (R A R B )N(C1-C6)alkylene-, (C3-C7)cycloalkyl-, R C SO2-, (R A R B )N-; and is optionally substituted with one or more groups selected from the following; R1 is H; R2 is selected from the group consisting of (C1-C6)alkyl, heteroaryl(C1-C4)alkyl-, (C3-C8)heterocycloalkyl-(C1-C6)alkyl, heteroaryl-(C1-C6)hydroxyalkyl, aryl-(C1-C4)alkyl-, (C3-C8)heterocycloalkyl, (C3-C8)cycloalkyl-(C1-C6)alkyl-, (R A R B )N(C1-C6)alkylene-; R A O(C1-C4)alkylene; where any said alkyl, alkylene, aryl, heteroaryl, cycloalkyl and heterocycloalkyl may optionally be (C1-C3)alkyl, R O(C1-C4)alkylene-, (C1-C6)haloalkyl, oxo, R A O-, (C3-C8)heterocycloalkyl-(C1-C6)alkyl, heteroaryl, aryl optionally substituted with halo, R A O-, (R C O-; (R A R B )N-, -NHC(O)R C -, -C(O)N(R A R B )-, halo, -SO2N(RA R B )、 -O(R A O(C1-C4) alkylene-N(R A R B )、 aryl-(C1-C4) alkyl-, -C(O)R A and may be substituted with one or more groups selected from: R A and R B in each case is independently H, or is selected from the group consisting of (C1-C4) alkyl-, aryl, (C1-C6) haloalkyl, or R A and R B together with the nitrogen atom to which they are attached may form a 6-membered saturated heterocyclic monocyclic ring system optionally containing an additional heteroatom which may be substituted with (C1-C4) alkyl- and oxo and which may be nitrogen or oxygen; R C is H, or is selected from the group consisting of (C1-C6) alkyl, (R A R B )N-, aryl-(C1-C4) alkyl-; Y is -OR D 、R C SO2, halo, -NHSO2R C 、 heteroaryl, (C3-C8) heterocycloalkyl, where any said heteroaryl and heterocycloalkyl may optionally be substituted with one or more groups selected from (C1-C3) alkyl, -C(O)N(R A R B ); J is H, or is selected from the group consisting of (C1-C6) alkyl, OR C ; R D is H or (C1-C6) alkyl〕 refers to a compound of.

[0075] In a further preferred embodiment, the present invention provides that Z is H, or (R A R B)N- heteroaryl, preferably thiazolyl, thiazolyl, pyrazolyl, pyridazinyl, oxadiazolyl, pyridinyl, pyrimidinyl, aryl, preferably phenyl, R A R where R is H A O- selected from the group consisting of: each of said heteroaryl and aryl may optionally be methyl, halo, preferably fluorine and chlorine, CN, R A and R B are each independently H or methyl in each case (R A R B )NC(O)-, C1-C6) haloalkyl, preferably trifluoromethyl and difluoromethyl, R A where R is H or selected from methyl, trifluoromethyl and difluoromethyl R A O-, R A and R B are methyl (R A R B )N(C1-C6) alkylene-, cyclopropyl, R C where R is methyl R C SO2-, R A and R B are independently H and methyl (R A R B )N- optionally substituted with one or more groups selected from; R1 is H; R2 is Heteroaryl(C1-C4)alkyl-, preferably ([1,2,4]triazolo[4,3-a]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, (C3-C8)heterocycloalkyl-(C1-C6)alkyl, preferably (piperidinyl)methyl, (tetrazolyl)methyl, (morpholinyl)ethyl, Heteroaryl(C1-C6)hydroxyalkyl-, preferably (oxadiazolyl)methanol, (C3-C8)cycloalkyl(C1-C6)alkyl-, preferably (cyclopropyl)methyl, Aryl-(C1-C4)alkyl-, preferably (phenyl)methyl, (R A R B )N(C1-C6)alkylene-, preferably dimethylaminobutyl, dimethylaminopropyl selected from the group consisting of, each of said aryl, heteroaryl, cycloalkyl and heterocycloalkyl may optionally, (C1-C3)alkyl, preferably methyl and ethyl, trifluoromethyl, oxo, chlorine, R A wherein R is selected from the group consisting of trifluoroethyl, difluoroethyl, methyl and ethyl and R A O-, (C3-C8)heterocycloalkyl-(C1-C6)alkyl-, preferably (piperidinyl)methyl, (C3-C8)heterocycloalkyl, preferably piperazinyl optionally further substituted with methyl, heteroaryl, preferably pyridinyl, RC -NHC(O)R where R is methyl C , R A and R B is methyl (R A R B )N- R C is methyl R C O- R A is H and R B is methyl -C(O)N(R A R B ) may be further substituted with one or more groups selected from the group consisting of; Y is -OR D , R C SO2, halo, -NHSO2R C , heteroaryl, where any said heteroaryl may optionally be substituted with one or more groups selected from (C1-C3)alkyl, -C(O)N(R A R B ) R D is (C1-C6)alkyl, preferably methyl; J is (C1-C6)alkyl, preferably methyl, R C is H or (C1-C6)alkyl, preferably methyl -OR C selected from the group consisting of, relates to a compound of formula (I).

[0076] According to certain embodiments, the present invention refers to at least one of the compounds listed in Table 4 below and pharmaceutically acceptable salts thereof. Table 4: List of Preferred Compounds Having Formula (I)

Table 4-1

Table 4-2

Table 4-3

Table 4-4

Table 4-5

Table 4-6

Table 4-7

Table 4-8

Table 4-9

Table 4-10

Table 4-11

Table 4-12

Table 4-13

Table 4-14

Table 4-15

Table 4-16

Table 4-17

Table 4-18

Table 4-19

Table 4-20

Table 4-21

Table 4-22

Table 4-23

Table 4-24

Table 4-25

Table 4-26

Table 4-27

Table 4-28

Table 4-29

Table 4-30

Table 4-31

Table 4-32

[0077] In a further preferred embodiment, the present invention is Z is aryl, where any of said aryl may optionally be substituted with one or more groups selected from (C1-C3)alkyl, halo, CN, R1 is H; R2 is selected from the group consisting of heteroaryl(C1-C4)alkyl-, (C3-C8)heterocycloalkyl-(C1-C6)alkyl, (C3-C8)heterocycloalkyl, (C3-C8)cycloalkyl-(C1-C6)alkyl-, wherein any said alkyl, heteroaryl may optionally be substituted with one or more groups selected from (C1-C3)alkyl, (C1-C6)haloalkyl, oxo, R A O-, aryl, (R A R B )N- and halo; R A and R B are each independently H or selected from the group consisting of (C1-C4)alkyl-, (C1-C6)haloalkyl; Y is -OR D R C SO2, halo and -NHSO2R C , heteroaryl, heterocycloalkyl, wherein any said heteroaryl may optionally be substituted with one or more groups selected from (C1-C3)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 from the group consisting of (C1-C6)alkyl, (R A R B )N-; R D is H or (C1-C6)alkyl, relates to a compound of formula (I).

[0078] According to a preferred embodiment, the present invention refers to at least one compound of Table 5 selected from the following. Table 5: List of preferred compounds having formula (I)

Table 5-1

Table 5-2

Table 5-3

Table 5-4

Table 5-5

Table 5-6

Table 5-7

Table 5-8

[0079] In a further preferred embodiment, the present invention is wherein Z is heteroaryl, where any said heteroaryl may optionally be substituted with one or more groups selected from (C1-C3)alkyl, halo, CN, (C1-C6)haloalkyl; R1 is H; R2 is selected from the group consisting of heteroaryl(C1-C4)alkyl-, where any said alkyl, heteroaryl may optionally be substituted with one or more groups selected from (C1-C3)alkyl, (C1-C6)haloalkyl and -oxo; Y is -OR D ; J is H; R D is (C1-C6)alkyl, relates to a compound of formula (I).

[0080] According to a preferred embodiment, the present invention refers to at least one compound of Table 6 selected from the following. Table 6: List of preferred compounds having formula (I)

Table 6-1

Table 6-2

Table 6-3

Table 6-4

Table 6-5

[0081] In a further preferred embodiment, the invention provides that Y is -OR D of formula (Ia)

Chemical formula

[0082] In a further preferred embodiment, the present invention Z is H, or aryl, preferably phenyl selected from the group consisting of each of said aryl may optionally be halo, preferably fluorine substituted with one or more groups selected from R1 is H; R2 is selected from the group consisting of heteroaryl(C1-C4)alkyl-, (pyrimidinyl)ethyl, (pyridazinyl)methyl, each of said heteroaryl may optionally be (C1-C3)alkyl, preferably methyl trifluoromethyl further substituted with one or more groups selected from R D is H, or (C1-C6)alkyl, preferably methyl, propyl, (C3-C8)heterocycloalkyl-(C1-C6)alkyl-, preferably (azetidinyl)methyl, (morpholinyl)methyl, (morpholinyl)ethyl, (oxetanyl)methyl, R C R selected from the group consisting of H and ethyl C -OC(O)(C1-C4)alkylene-, (R A R B )N(C1-C6)alkylene-, preferably dimethylaminopropyl, (C3-C8) Heterocycloalkyl, preferably tetrahydropyranyl, R C O(C1-C4) alkylene-, preferably methoxyethyl, propanolyl, (R A R B )N(O)C(C1-C4) alkylene-, preferably dimethylacetylamide, tetrahydrofuranyl, (C3-C8) cycloalkyl-(C1-C6) alkyl-, preferably (cyclopropyl)methyl selected from the group consisting of each of said heterocycloalkyl may optionally be substituted with one or more groups selected from methyl, ethyl and propyl; where J is H, relates to a compound of formula (Ia).

[0083] According to a particular embodiment, the present invention provides at least one of the compounds listed in Table 7 below and at least one of their pharmaceutically acceptable salts. Table 7: List of preferred compounds having formula (Ia)

Table 7-1

Table 7-2

Table 7-3

Table 7-4

Table 7-5

[0084] Compounds of formula (I) containing all or at least one of the compounds listed above can generally be prepared using known methods according to the methods detailed in the scheme shown below.

[0085] Scheme 1

Chem.

[0086] Compound (III) can be prepared from compound (II) by a deoxygenative amination reaction mediated by a coupling agent such as PyBOP using a suitable amine (reagent 1).

[0087] Compound (IA) can be prepared from compound (III) by a metal-catalyzed cross-coupling reaction such as a Stille or Suzuki coupling or a similar reaction described in "Transition Metals for Organic Synthesis", 2nd Ed, 1, 2004 using a suitable reagent such as (reagent 2).

[0088] Alternatively, compound (V) can be prepared from compound (III) by a metal-catalyzed Miyaura borylation reaction.

[0089] Compound (IA) can be prepared from compound (V) by a metal-catalyzed cross-coupling reaction such as a Stille or Suzuki coupling or a similar reaction described in "Transition Metals for Organic Synthesis", 2nd Ed, 1, 2004 using a suitable organic halogen compound such as (reagent 3).

[0090] In another embodiment, compound (IV) was prepared starting from compound (II) by a metal-catalyzed cross-coupling reaction such as a Stille or Suzuki coupling or a similar reaction as described in "Transition Metals for Organic Synthesis", 2nd Ed, 1, 2004 using a suitable organometallic reagent such as (reagent 2).

[0091] Compound (IA) can be prepared from compound (V) by a deoxygenative amination reaction mediated by a reagent such as PyBOP or a similar reagent using a suitable amine (reagent 1).

[0092] Some compounds (IA) may contain protected hydroxyl or amino groups, which were later deprotected by known methods.

[0093] Scheme 2

Chemical Structure

[0094] Compound (VII) can be prepared from compound (VI) by a method of quinazoline ring construction reaction mediated by a reagent such as triethyl orthoacetate or a similar reagent.

[0095] Compound (VIII) can be prepared from compound (VII) by a metal-catalyzed cross-coupling reaction such as a Stille or Suzuki coupling reaction or a similar reaction using a suitable organometallic reagent (reagent 2) such as an organoboron compound.

[0096] Compound (IB) can be prepared from compound (VIII) by a deoxygenative amination reaction mediated by a reagent such as PyBOP or a similar reagent in the presence of a suitable amine (reagent 1).

[0097] Some compounds (IB) may contain protected hydroxyl or amino groups, which were then removed by known methods.

[0098] Scheme 3

Chemical Structure

[0099] The compound (X) can be prepared from the compound (IX) by a metal-catalyzed cross-coupling reaction such as a Stille or Suzuki coupling reaction or a similar reaction using a suitable organometallic reagent (Reagent 2) such as an organoboron compound.

[0100] The compound (XI) can be prepared from the compound (X) by halogenation using a suitable reagent such as bromine, NBS, NIS, iodine, an iodonium salt or a similar reagent.

[0101] The compound (XII) can be prepared from the compound (XI) by hydrolysis in a basic or acidic medium.

[0102] The compound (XIII) can be prepared from the compound (XII) by a quinazoline ring construction reaction using a suitable reagent such as formamide or a similar reagent.

[0103] The compound (XIV) can be prepared from the compound (XIII) by a deoxygenative amination reaction mediated by a reagent such as PyBOP or a similar reagent in the presence of a suitable amine (Reagent 1).

[0104] The compound (IC) can be prepared from the compound (XIV) by a metal-catalyzed cross-coupling reaction such as a Stille or Suzuki coupling reaction or a similar reaction using a suitable organometallic reagent (Reagent 6) such as an organoboron compound. Some compounds (IC) may contain protected hydroxyl or amino groups, which are then removed by known methods.

[0105] The compound (IK) can be prepared from the compound (XIV) by amination in the presence of a suitable reagent such as methanesulfonamide. Some compounds (IK) may contain protected hydroxyl or amino groups, which are then removed by known methods.

[0106] Scheme 4

Chem.

[0107] Compound (XV) can be prepared from compound (IA) by a method of dealkylation reaction mediated by a strong Lewis acid such as BBr3 or a similar reagent.

[0108] Compound (ID) was prepared from compound (XV) by alkylation using a suitable alkylating agent (reagent 4) such as alkyl chloride, bromide, iodide, mesylate, tosylate or a similar reagent.

[0109] Alternatively, compound (ID) can be prepared from compound (XV) and a suitable alcohol by Mitsunobu-type reaction mediated by DEAD / PPh3, DIAD / PPh3 or CMT.

[0110] Some compounds (ID) may contain protected hydroxyl or amino groups, which were then removed by known methods.

[0111] Scheme 5

Chem.

[0112] Compound (XVII) can be prepared from compound (XVI) by a deoxygenative amination reaction mediated by a reagent such as PyBOP or a similar reagent in the presence of a suitable amine (reagent 1).

[0113] Compound (IE) can be prepared from compound (XVII) by a Stille, Suzuki coupling or similar metal-catalyzed cross-coupling reaction or similar reaction using a suitable organometallic reagent (reagent 2), such as an organoboron compound, for example.

[0114] Some compounds (IE) may contain protected hydroxyl or amino groups, which are then removed by known methods.

[0115] Scheme 6

Chemical Structure

[0116] Compound (XVIII) can be prepared from compound (XIII) by metal-catalyzed sulfenylation using a suitable sulfinate (reagent 5), such as sodium methanesulfinate, for example.

[0117] Compound (IF) can be prepared from compound (XVIII) by a deoxygenative amination reaction mediated by a reagent such as PyBOP or a similar reagent in the presence of a suitable amine (reagent 1). Some compounds (IF) may contain protected hydroxyl or amino groups, which are then removed by known methods.

[0118] In another embodiment of the present invention, compound (XIX) can be prepared from compound (XVIII) by amination using tributyl borate and (aminooxy)sulfonic acid as described in Tetr. Lett. 1994, 39, 7201.

[0119] Compound (IG) can be prepared from compound (XIX) by a deoxygenative amination reaction mediated by a reagent such as PyBOP or a similar reagent in the presence of a suitable amine (reagent 1).

[0120] Some compounds (IG) may contain protected hydroxyl or amino groups, which were then removed by known methods.

[0121] Scheme 7

Chemical Structure

[0122] Compound (XX) can be prepared from compound (VI) by a quinazoline ring construction reaction using a suitable reagent such as urea or a similar reagent.

[0123] Compound (XXI) can be prepared from compound (XX) by a metal-catalyzed cross-coupling reaction such as a Stille or Suzuki coupling reaction or a similar reaction using a suitable organometallic reagent (Reagent 2), for example, an organoboron compound.

[0124] Compound (XXII) can be prepared from compound (XXI) by a chlorination reaction using a suitable reagent such as phosphorus oxychloride or a similar reagent.

[0125] Compound (XXIII) can be prepared from compound (XXII) by an amination reaction in the presence of a suitable amine (Reagent 1).

[0126] Compound (IH) can be prepared from compound (XXIII) by hydrolysis using a suitable reagent such as acetic acid, for example.

[0127] Some compounds (IH) may contain protected hydroxyl or amino groups, which were then removed by known methods.

[0128] In another embodiment of the present invention, compound (IJ) can be prepared from compound (XXIII) by a reaction using an alkoxide with sodium methoxide, for example.

[0129] Some compounds (IJ) may contain protected hydroxyl or amino groups, which were then removed by known methods.

[0130] In certain embodiments, the present invention relates to a compound of formula (Ib)

Chemical formula

[0131] In a further embodiment, the present invention relates to the use of a compound of formula (Ib) as an intermediate in the manufacture of a compound of formula (I) as described above.

[0132] The compounds of the present invention have surprisingly been found to efficiently inhibit the P2X3 receptor, and said compounds are effective in the treatment of respiratory diseases.

[0133] In certain embodiments, the representative compounds of formula (I) of the present invention have surprisingly been found to efficiently and selectively inhibit the P2X3 receptor, and said compounds are useful in the treatment of respiratory diseases and avoid adverse effects such as loss of taste response.

[0134] In a preferred embodiment, the compound of formula (I) is a selective P2X3 antagonist, where said selective P2X3 antagonist is at least 10-fold selective for P2X3 homomeric receptor antagonism over P2X 2 / 3 heteromeric receptor antagonism.

[0135] In a more preferred embodiment, said selective P2X3 antagonist is P2X 2 / 3It is at least 30-fold selective for P2X3 homomeric receptor antagonism over heteromeric receptor antagonism.

[0136] In a further preferred embodiment, said selective P2X3 antagonist is P2X 2 / 3 It is at least 50-fold selective for P2X3 homomeric receptor antagonism over heteromeric receptor antagonism.

[0137] The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, mixed with one or more pharmaceutically acceptable carriers or excipients, alone or in combination with one or more additional active ingredients.

[0138] In one aspect, the present invention refers to a compound of formula (I) according to the present invention for use as a medicament.

[0139] In a further aspect, the present invention refers to the use of a compound of formula (I) according to the present invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disorder associated with the P2X3 receptor mechanism, preferably for the treatment of a respiratory disease.

[0140] Preferably, the present invention refers to a compound of formula (I) for use in the prevention and / or treatment of a respiratory disease, preferably cough, subacute or chronic cough, treatment-resistant cough, idiopathic chronic cough, post-viral infection 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.

[0141] More preferably, the present invention refers to a compound 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.

[0142] The present invention also provides a method for preventing and / or treating a disorder associated with the P2X3 receptor mechanism, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention.

[0143] In particular, the present invention relates to a method for preventing and / or treating a disorder which is a cough, subacute or chronic cough, treatment-resistant cough, idiopathic chronic cough, post-viral infection 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, which comprises administering to a patient in need of treatment an appropriate amount of a compound of formula (I).

[0144] In a further preferred embodiment, the disorder is chronic cough.

[0145] The treatment method of the present invention comprises administering to a patient in need of treatment a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. As used herein, the "safe and effective amount" in reference to a compound of formula (I) or a pharmaceutically acceptable salt thereof or other pharmaceutically active substance means an amount sufficient to treat the condition of the patient but low enough to avoid serious side effects, although notwithstanding that, the amount is determined as per the definition by those skilled in the art. The compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered once or according to an administration regimen in which various doses are administered at different time intervals over a predetermined period. The typical daily dosage can vary depending on the particular route of administration selected.

[0146] The present invention provides a pharmaceutical composition of a compound of formula (I) in a mixture with one or more pharmaceutically acceptable carriers or excipients, for example, a pharmaceutical composition as described in Remington’s Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., N.Y., U.S.A.

[0147] Administration of the compounds of the present invention and these pharmaceutical compositions can be achieved, depending on the requirements of the patient, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternal and by infusion) and by inhalation.

[0148] Preferably, the compounds of the present invention can be administered orally or by inhalation.

[0149] A variety of solid oral dosage forms can be used to administer the compounds of the present invention, which include solid forms such as tablets, gel capsules, capsules, caplets, granules, lozenges, and bulk drug powders. The compounds of the present invention can be administered alone or in combination with known excipients including a variety of pharmaceutically acceptable carriers, diluents (e.g., sucrose, mannitol, lactose, starch), and suspending agents, solubilizing agents, buffering agents, binding agents, disintegrating agents, preservatives, coloring agents, flavoring agents, lubricants, etc. Sustained-release capsules, tablets, and gels are also advantageous for the administration of the compounds of the present invention.

[0150] Preferably, the compounds of the present invention are administered in the form of tablets.

[0151] A variety of liquid oral dosage forms can also be used to administer the compounds of the present invention, which include aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs. Such dosage forms also include suitable known inert diluents such as water and suitable known excipients such as preservatives, wetting agents, sweetening agents, flavoring agents, and substances for emulsifying and / or suspending the compounds of the present invention. The compounds of the present invention can be administered, for example, intravenously, in the form of an isotonic sterile solution.

[0152] For the treatment of respiratory tract diseases, the compounds according to the present invention are preferably administered by inhalation.

[0153] Inhalable formulations include inhalable powders, metered aerosols containing propellants, or propellant-free inhalable formulations.

[0154] For administration as a dry powder, single or multiple dose inhalers known in the art can be utilized. In that case, the powder can be filled into gelatin, plastic, or other capsules, cartridges, or blister packs, or can be present in a reservoir.

[0155] A chemically inert diluent or carrier for the compounds of the present invention, such as lactose or any other additive suitable for improving the inhalation fraction, is added to the powdered compounds of the present invention.

[0156] An inhalation aerosol agent containing a propellant gas such as hydrofluoroalkane contains the compounds of the present invention in solution or in a dispersed form. The propellant-driven formulations may also contain other components such as co-solvents, stabilizers and optionally other excipients.

[0157] Inhalable formulations containing the compounds of the present invention and free of propellants can be in the form of solutions or suspensions in aqueous, alcoholic or hydroalcoholic media, and they can be delivered by jet or ultrasonic nebulizers or soft mist nebulizers known in the art.

[0158] Preferably, the compounds of the present invention are administered orally.

[0159] The compounds of the present invention can be administered as a single active substance or in combination with other pharmaceutically active ingredients.

[0160] Preferably, the compounds of the present invention can be combined with a therapeutic agent or active ingredient useful for the treatment of diseases associated with or mediated by the P2X3 receptor.

[0161] The dosage of the compounds of the present invention depends on a variety of factors including, inter alia, the particular disease being treated, the severity of the symptoms, the route of administration, etc.

[0162] The present invention also relates to a device in the form of a single-dose or multi-dose dry powder inhaler or metered-dose inhaler containing a pharmaceutical composition comprising a compound of formula (I) according to the present invention.

[0163] The present invention also relates to a device in the form of a single-dose or multi-dose dry powder inhaler or metered-dose inhaler containing a pharmaceutical composition comprising a compound of formula (I) according to the present invention.

[0164] Examples of conducting the experiments described in this specification are helpful for demonstrating the present invention, and the present invention is not limited to the illustrated examples.

Example

[0165] Production of Intermediates and Example Compounds Chemicals were named using the software of Dotmatics. In some cases, instead of the names assigned by the Dotmatics software, the commonly used names of commercially available reagents were used.

[0166] All reagents for which the synthesis is not described in the experimental section are either commercially available, known compounds, or can be formed by methods known to those skilled in the art.

[0167] According to the method described in International Publication No. WO 2016 / 091776, (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine HCl and (R)-1-(6-methylpyridazin-3-yl)ethan-1-amine HCl were prepared.

[0168] Abbreviations - Meanings Et2O: Diethyl ether; Et3N: Triethylamine; TEA: Triethylamine; 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: Ethyl alcohol; TFA: Trifluoroacetic acid; LC-MS: Liquid Chromatography / Mass Spectrometry; HPLC: High Performance Liquid Chromatography; MPLC: Medium Performance 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: Dimethyl Sulfoxide; Boc2O: Di-tert-butyl Dicarbonate; UPLC: Ultra Performance Liquid Chromatography

[0169] Details and Methods of General Experiments Analysis Methods Liquid Chromatography-Mass Spectrometry Method 1 UPLC-MS was performed on a Waters Acquity I-Class equipped with a Waters Diode Array Detector connected to a Waters SQD2 single quadrupole mass spectrometer, using a Waters HSS C18 column (1.8 μm, 100×2.1 mm). First, it was held for 1.2 minutes with 5% acetonitrile / water (each mobile phase containing 0.1% formic acid), then a linear gradient of 5 - 100% was applied within 3.5 minutes, and then maintained at 100% for 1.5 minutes (F = 0.5 mL / min).

[0170] Method 2 UPLC-MS was performed using a Waters Acquity I-Class equipped with a Waters Diode Array Detector connected to a Waters SQD2 single quadrupole mass spectrometer, with a Waters BEH Shield RP18 column (1.7 μm, 100×2.1 mm). First, it was held at 5% acetonitrile / water (containing 10 mM ammonium bicarbonate in each mobile phase) for 1.2 minutes, then a linear gradient of 5 - 100% was applied within 3.5 minutes, and then held at 100% for 1.5 minutes (F = 0.5 mL / min).

[0171] Method 3 UPLC-MS was performed using a Waters DAD + Waters SQD2, single quadrupole UPLC-MS spectrometer, with an Acquity UPLC BEH Shield RP18 1.7 μm 100×2.1 mm (Plus guard cartrige). The column temperature was maintained, and it was held at 5% acetonitrile / water (containing 10 mM ammonium bicarbonate in each mobile phase) for 0.4 minutes, then a linear gradient of 5 - 95% was applied within 6.4 minutes, and then held at 95% for 1.2 minutes (F = 0.4 mL / min).

[0172] Method 4 UPLC-MS was performed using a Waters DAD + Waters SQD2, single quadrupole UPLC-MS spectrometer, with an Acquity UPLC BEH Shield RP18 1.7 μm 100×2.1 mm (Plus guard cartrige) maintained at the column temperature. First, it was held at 5% acetonitrile (Far UV grade) containing 0.1% (V / V) formic acid / water (high purity by PureLab Option unit) containing 0.1% formic acid for 0.4 minutes, then a linear gradient of 5 - 95% was applied within 6.4 minutes, and then maintained at 95% for 1.2 minutes (F = 0.4 mL / min).

[0173] Method 5 Acquity UPLC-QDa mass spectrometer using a C18-reverse phase column (50×2.1 mm Acquity CSH with 1.7 μm particle size) maintained at 40 °C, eluted with A: 95 / 5 water / acetonitrile + 0.05% formic acid; B: 95 / 5 acetonitrile / water + 0.05% formic acid. Gradient:

Table 8

[0174] Method 6 Acquity UPLC-QDa mass spectrometer equipped with a C18 reverse phase column (50×2.1 mm Acquity BEH with 1.7 μm particle size) maintained at 40 °C, eluted with A: 95 / 5 water / acetonitrile + 0.05% concentrated ammonia; B: 95 / 5 acetonitrile / water + 0.05% concentrated ammonia. Gradient:

Table 9

[0175] Method 7 Maintained at 25 °C with Dionex UHPLC Ultimate 3000 equipped with a DAD detector with Kinetex® 2.6 μm XB-C18 (4.6×50 mm), 110A and Thermo Scientific MSQ Pluse, eluted with A: 0.1% v / v aqueous solution of formic acid, B: 0.1% v / v acetonitrile solution of formic acid. Gradient:

Table 10

[0176] NMR 1 1H nuclear magnetic resonance (NMR) spectroscopy was carried out at room temperature using a Bruker or Varian instrument operating at 300 or 400 MHz, using the solvents indicated unless otherwise stated. In all cases, the NMR data were consistent with the presented structure. Characteristic chemical shifts (δ) are given in parts per million using conventional abbreviations for the assignment 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.

[0177] Preparative Reverse-Phase HPLC Conditions Preparative HPLC purification by reverse-phase HPLC was carried out 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 operated as both an autosampler and a fraction collector. The columns used for the preparative purification of the compounds were 10 μm 19 × 150 mm Waters Sunfire OBD Phenomenex Luna Phenyl Hexyl or Waters Xbridge Phenyl, 19 × 150, 5 μm columns. Appropriate predetermined gradients were selected based on acetonitrile and methanol solvent systems under 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 via monitoring at 210 - 400 nm, triggering a threshold collection value at 260 nm, and causing the presence of target molecular ions as observed under API conditions when using Fractionlynx. The recovered fractions were analyzed by LCMS (Waters Acquity system equipped with Waters SQD).

[0178] Chiral Supercritical Fluid Chromatography (SFC) Separation Protocol The diastereomeric separation of the compound was achieved by supercritical fluid chromatography (SFC) using a Waters Thar Prep100 preparative SFC system (equipped with a P200 CO2 pump, a 2545 regulating pump, a 2998 UV / VIS detector, and a 2767 liquid handler with a Stacked Injection Module). The Waters 2767 liquid handler operated as both an autosampler and a fraction collector. Under unmodified or basic conditions, an appropriate isocratic method was selected based on a methanol, ethanol, or isopropanol solvent system. The standard SFC method used was with a modifier, CO2, at 100 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C. The modifier used under basic conditions was diethylamine (0.1% V / V). The modifiers used under acidic conditions were formic acid (0.1% V / V) or trifluoroacetic acid (0.1% V / V). The SFC purification was controlled by Waters Fractionlynx software via monitoring at 210 - 400 nm and typically operated at a threshold collection value of 260 nm. The collected fractions were analyzed by SFC (a Waters / Thar SFC system equipped with a Waters SQD). The fractions containing the desired product were concentrated by vacuum centrifugation.

[0179] Supercritical Fluid Chromatography-Mass Spectrometry Conditions Method 8 SFC - MS was performed isocratically at 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C using 15% methyl alcohol / CO2 (containing 0.1% diethylamine) with a Lux cellulose - 3 column on a Waters / Thar SFC system equipped with a Waters SQD.

[0180] Method 9 SFC - MS was performed isocratically at 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C using 20% methyl alcohol / CO2 (containing 0.1% diethylamine) with a Lux cellulose - 3 column on a Waters / Thar SFC system equipped with a Waters SQD.

[0181] Method 10 SFC-MS was carried out under constant composition conditions at a flow rate of 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C using 55% ethanol / CO2 (containing 0.1% diethylamine) on a Lux cellulose-4 column in a Waters / Thar SFC system equipped with a Waters SQD.

[0182] Method 11 SFC-MS was carried out under constant composition conditions at a flow rate of 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C using 20% isopropyl alcohol / CO2 (containing 0.1% diethylamine) on a Lux cellulose-4 column in a Waters / Thar SFC system equipped with a Waters SQD.

[0183] Method 12 SFC-MS was carried out under constant composition conditions at a flow rate of 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C using 30% isopropyl alcohol / CO2 (containing 0.1% diethylamine) on a Lux cellulose-4 column in a Waters / Thar SFC system equipped with a Waters SQD.

[0184] Method 13 SFC-MS was carried out under constant composition conditions at a flow rate of 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C using 50% isopropyl alcohol / CO2 (containing 0.1% diethylamine) on a Lux cellulose-4 column in a Waters / Thar SFC system equipped with a Waters SQD.

[0185] Method 14 SFC-MS was carried out under constant composition conditions at a flow rate of 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C using 25% methyl alcohol / CO2 (containing 0.1% diethylamine) on a Lux cellulose-4 column in a Waters / Thar SFC system equipped with a Waters SQD.

[0186] Method 15 SFC-MS was carried out under constant composition at a flow rate of 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C using 15% ethyl alcohol / CO2 (containing 0.1% diethylamine) with a YMC Amylose-C column in a Waters / Thar SFC system equipped with a Waters SQD.

[0187] Method 16 SFC-MS was carried out under constant composition at a flow rate of 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C using 25% isopropyl alcohol / CO2 (containing 0.1% diethylamine) with a YMC Amylose-C column in a Waters / Thar SFC system equipped with a Waters SQD.

[0188] Method 17 SFC-MS was carried out under constant composition at a flow rate of 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C using 35% isopropyl alcohol / CO2 (containing 0.1% diethylamine) with a YMC Amylose-C column in a Waters / Thar SFC system equipped with a Waters SQD.

[0189] Method 18 SFC-MS was carried out under constant composition at a flow rate of 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C using 55% isopropyl alcohol / CO2 (containing 0.1% diethylamine) with a YMC Amylose-C column in a Waters / Thar SFC system equipped with a Waters SQD.

[0190] Method 19 SFC-MS was carried out under constant composition at a flow rate of 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C using 15% methyl alcohol / CO2 (containing 0.1% diethylamine) with a YMC Amylose-C column in a Waters / Thar SFC system equipped with a Waters SQD.

[0191] Method 20 SFC-MS was carried out under constant composition conditions at a flow rate of 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C using 20% methyl alcohol / CO₂ (containing 0.1% diethylamine) with a YMC Amylose-C column in a Waters / Thar SFC system equipped with a Waters SQD.

[0192] Method 21 SFC-MS was carried out under constant composition conditions at a flow rate of 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C using 15% isopropyl alcohol / CO₂ (containing 0.1% diethylamine) with a YMC cellulose-C column in a Waters / Thar SFC system equipped with a Waters SQD.

[0193] Method 22 SFC-MS was carried out under constant composition conditions at a flow rate of 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C using 15% methyl alcohol / CO₂ (containing 0.1% diethylamine) with a YMC cellulose-C column in a Waters / Thar SFC system equipped with a Waters SQD.

[0194] Method 23 SFC-MS was carried out under constant composition conditions at a flow rate of 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C using 25% methyl alcohol / CO₂ (containing 0.1% diethylamine) with a YMC cellulose-C column in a Waters / Thar SFC system equipped with a Waters SQD.

[0195] Method 24 SFC-MS was carried out under constant composition conditions at a flow rate of 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C using 55% isopropyl alcohol / CO₂ (containing 0.1% diethylamine) with a YMC cellulose-SC column in a Waters / Thar SFC system equipped with a Waters SQD.

[0196] Method 25 SFC-MS was carried out under constant composition conditions using a Lux cellulose-3 column in a Waters / Thar SFC system equipped with a Waters SQD, with 10% methyl alcohol / CO2 (containing 0.1% diethylamine) at a flow rate of 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C.

[0197] Method 26 SFC-MS was carried out under constant composition conditions using a Lux cellulose-3 column in a Waters / Thar SFC system equipped with a Waters SQD, with 25% methyl alcohol / CO2 (containing 0.1% diethylamine) at a flow rate of 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C.

[0198] Method 27 SFC-MS was carried out under constant composition conditions using a Lux cellulose-3 column in a Waters / Thar SFC system equipped with a Waters SQD, with 30% methyl alcohol / CO2 (containing 0.1% diethylamine) at a flow rate of 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C.

[0199] Method 28 SFC-MS was carried out under constant composition conditions using a Lux cellulose-4 column in a Waters / Thar SFC system equipped with a Waters SQD, with 40% isopropyl alcohol / CO2 (containing 0.1% diethylamine) at a flow rate of 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C.

[0200] Method 29 SFC-MS was carried out under constant composition conditions using a Lux cellulose-4 column in a Waters / Thar SFC system equipped with a Waters SQD, with 40% methyl alcohol / CO2 (containing 0.1% diethylamine) at a flow rate of 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C.

[0201] Method 30 SFC-MS was carried out under constant composition using 50% methyl alcohol / CO2 (containing 0.1% diethylamine) at a flow rate of 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C on a Waters / Thar SFC system equipped with a Waters SQD using a Lux cellulose-4 column.

[0202] Method 31 SFC-MS was carried out under constant composition using 55% isopropyl alcohol / CO2 (containing 0.1% diethylamine) at a flow rate of 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C on a Waters / Thar SFC system equipped with a Waters SQD using a Lux cellulose-4 column.

[0203] Method 32 SFC-MS was carried out under constant composition using 55% methyl alcohol / CO2 (containing 0.1% diethylamine) at a flow rate of 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C on a Waters / Thar SFC system equipped with a Waters SQD using a Lux cellulose-4 column.

[0204] Method 33 SFC-MS was carried out under constant composition using 20% ethyl alcohol / CO2 (containing 0.1% diethylamine) at a flow rate of 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C on a Waters / Thar SFC system equipped with a Waters SQD using a YMC Amylose-C column.

[0205] Method 34 SFC-MS was carried out under constant composition using 30% isopropyl alcohol / CO2 (containing 0.1% diethylamine) at a flow rate of 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C on a Waters / Thar SFC system equipped with a Waters SQD using a YMC Amylose-C column.

[0206] Method 35 SFC-MS was carried out under constant composition conditions using a YMC Amylose-C column in a Waters / Thar SFC system equipped with a Waters SQD, with 30% methyl alcohol / CO2 (containing 0.1% diethylamine) at a flow rate of 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C.

[0207] Method 36 SFC-MS was carried out under constant composition conditions using a YMC Amylose-C column in a Waters / Thar SFC system equipped with a Waters SQD, with 40% methyl alcohol / CO2 (containing 0.1% diethylamine) at a flow rate of 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C.

[0208] Method 37 SFC-MS was carried out under constant composition conditions using a YMC Amylose-C column in a Waters / Thar SFC system equipped with a Waters SQD, with 55% methyl alcohol / CO2 (containing 0.1% diethylamine) at a flow rate of 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C.

[0209] Method 38 SFC-MS was carried out under constant composition conditions using a YMC cellulose-C column in a Waters / Thar SFC system equipped with a Waters SQD, with 20% methyl alcohol / CO2 (containing 0.1% diethylamine) at a flow rate of 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C.

[0210] Method 39 SFC-MS was carried out under constant composition conditions using a YMC cellulose-SC column in a Waters / Thar SFC system equipped with a Waters SQD, with 35% isopropyl alcohol / CO2 (containing 0.1% diethylamine) at a flow rate of 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C.

[0211] Method 40 SFC-MS was carried out under constant composition conditions at 5 mL / min, a back pressure of 120 bar, and a column temperature of 40 °C using 45% isopropyl alcohol / CO2 (containing 0.1% diethylamine) on a Waters / Thar SFC system equipped with a Waters SQD and a YMC cellulose-SC column.

[0212] Production of Intermediates and Example Compounds Example 1 6-(4-Fluorophenyl)-8-methoxy-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)quinazolin-4-amine Production of Intermediate 1, 2-Amino-5-bromo-3-methoxybenzoic acid hydrobromide [Chemical formula] A solution of bromine (6.0 g, 1.9 mL, 37.70 mmol) in chloroform (15 mL) was added dropwise to a suspension of 2-amino-3-methoxybenzoic acid (6.0 g, 35.90 mmol) in chloroform (180 mL) over 1 hour at 0 °C. The reaction mixture was stirred for an additional 5 hours and slowly warmed to room temperature. The solvent was removed in vacuo and the residue was triturated with diethyl ether. The reaction mixture was filtered to afford the title compound as a beige solid (11.3 g, 96%). LCMS (Method 4): [MH + = 247 (4.07 minutes).

[0213] Production of Intermediate 2, 6-Bromo-8-methoxyquinazolin-4-ol [Chemical formula] A solution of 2-amino-5-bromo-3-methoxybenzoic acid hydrobromide (Intermediate 1) (10.0 g, 30.60 mmol) in formamide (40 mL) was heated at 165 °C for 18 hours. After returning to room temperature, the reaction mixture was diluted with water (100 mL), poured into cold water (400 mL), and filtered. The solid was washed with water (200 mL) and diethyl ether (200 mL) to afford the title compound as a light brown solid (5.9 g, 76%). LCMS (Method 4): [MH + = 255 (3.07) minutes.

[0214] Production of Intermediate 3,6-(4-Fluorophenyl)-8-methoxyquinazolin-4-ol

Chemical Structure

[0215] 6-(4-Fluorophenyl)-8-methoxy-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)quinazolin-4-amine

Chemical Structure

[0216] The compounds shown in the following table were synthesized according to a method similar to that described for the preparation of 6-(4-fluorophenyl)-8-methoxy-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)quinazolin-4-amine.

Table 11-1

Table 11-2

Table 11-3

Table 11-4

Table 11-5

Table 11-6

Table 11-7

Table 11-8

Table 11-9

Table 11-10

Table 11-11

Table 11-12

Table 11-13

Table 11-14

Table 11-15

Table 11-16

Table 11-17

Table 11-18

Table 11-19

Table 11-20

Table 11-21

Table 11-22

Table 11-23

Table 11-24

Table 11-25

Table 11-26

Table 11-27

Table 11-28

Table 11-29

[0217] Example 114 N-(((1r,4r)-4-Aminocyclohexyl)methyl)-6-(4-fluorophenyl)-8-methoxyquinazolin-4-amine

Chemical formula

Chemical formula

[0218] Step 2: Preparation of N-(((1r,4r)-4-aminocyclohexyl)methyl)-6-(4-fluorophenyl)-8-methoxyquinazolin-4-amine

Chemical formula

[0219] Intermediate 4 (R)-6-Bromo-8-methoxy-N-(1-(6-methylpyridazin-3-yl)ethyl)quinazolin-4-amine

Chemical Structure

[0220] (R)-6-Bromo-8-methoxy-N-(1-(6-methylpyridazin-3-yl)ethyl)quinazolin-4-amine (Intermediate 4) was synthesized in the same manner as described for the production of the following intermediates shown in the table below. [Table 12]

[0221] Example 115 8-Methoxy-6-(5-methyl-1,3,4-thiadiazol-2-yl)-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine [Chemical formula] Step 1: Production of 8-methoxy-N-((6-methylpyridazin-3-yl)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-amine [Chemical formula] Nitrogen was bubbled through a solution of 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) for 5 minutes. The mixture was stirred at 90 °C for 18 hours. After returning to room temperature, the reaction mixture was filtered through Celite® and the solvent was removed in vacuo. The residue was used in the next step without further purification.

[0222] Step 2: Production of 8-methoxy-6-(5-methyl-1,3,4-thiadiazol-2-yl)-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine [Chemical formula] A solution of 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) was bubbled with nitrogen for 5 minutes, and then tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.02 mmol) was added. The resulting mixture was heated at 95 °C for 16 hours. After returning to room temperature, the reaction mixture was filtered through Celite® and washed 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%). 1 H NMR (400 MHz, DMSO): δ 9.31 (dd, J = 5.8, 5.8 Hz, 1H), 8.47 (s, 1H), 8.44 (d, J = 1.7 Hz, 1H), 7.80 (d, J = 1.4 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H), 5.03 (d, J = 5.8 Hz, 2H), 4.03 (s, 3H), 2.84 (s, 3H), 2.60 (s, 3H). LCMS (method 3): [MH + = 380 (2.13 min).

[0223] The following compounds were prepared in the next steps shown in the table below according to a method similar to that 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.

Table 13-1

Table 13-2

Table 13-3

Table 13-4

Table 13-5

Table 13-6

[0224] Example 140 8-Methoxy-N-((6-methylpyridazin-3-yl)methyl)-6-(5-methylthiazol-2-yl)quinazolin-4-amine

Chemical formula

Chemical formula

[0225] Step 2: Preparation of 8-methoxy-N-((6-methylpyridazin-3-yl)methyl)-6-(5-methylthiazol-2-yl)quinazolin-4-amine

Chemical formula

[0226] The following compounds were prepared in the next steps shown in the table below according to a method similar to that described for the preparation of 8-methoxy-N-((6-methylpyridazin-3-yl)methyl)-6-(5-methylthiazol-2-yl)quinazolin-4-amine.

Table 14-1

Table 14-2

Table 14-3

Table 14-4

Table 14-5

Table 14-6

[0227] Example 163 8-Methoxy-6-(1-methyl-1H-pyrazol-4-yl)-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine

Chemical Structure

[0228] The following compounds were prepared in the following steps shown in the table below according to a method similar to that described for the production of 8-methoxy-6-(1-methyl-1H-pyrazol-4-yl)-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine. [Table 15]

[0229] Example 164 6-(4-Fluoro-3-methylphenyl)-8-methoxy-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine [Chemical formula] 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) were 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 at 95 °C for 18 hours. After returning to room temperature, the reaction mixture was filtered through Celite®. The Celite® cake was washed with ethyl acetate (2 × 20 mL). The 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%). 1 H NMR (400 MHz, DMSO) δ 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, J = 1.8 Hz, 3H). LCMS (Method 4): [MH + = 390 (3.12 minutes).

[0230] The following steps shown in the table below were used to produce the compound according to a method similar to that described for the production of 6-(4-fluoro-3-methylphenyl)-8-methoxy-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine.

Table 16-1

Table 16-2

Table 16-3

[0231] Example 176a 6-(4-Fluoro-2-methoxyphenyl)-8-methoxy-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine

Chemical Structure

[0232] Starting from the appropriate intermediates shown in the table and applying the above method, the following compounds shown in the table were prepared.

Table 17-1

Table 17-2

[0233] Example 183 (R)-6-(4-Fluorophenyl)-8-methoxy-2-methyl-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine

Chemical Structure

Chemical Structure

[0234] Step 2: Preparation of 6-(4-fluorophenyl)-8-methoxy-2-methylquinazolin-4-ol

Chemical Structure

[0235] Project 3: Preparation of (R)-6-(4-Fluorophenyl)-8-methoxy-2-methyl-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine

Chemical Structure

[0236] Example 184 (R)-6-(4-Fluorophenyl)-8-methoxy-4-((1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-amino)-quinazolin-2-ol

Chemical Structure

Chem.

[0237] Process 2: Preparation of 2,4-dichloro-6-(4-fluorophenyl)-8-methoxyquinazoline

Chem.

[0238] Step 3: Preparation of (R)-6-(4-fluorophenyl)-8-methoxy-4-((1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)amino)-quinazolin-2-ol

Chemical Structure

[0239] Example 185 (R)-6-(4-Fluorophenyl)-2,8-dimethoxy-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine

Chemical Structure

[0240] Example 186 (R)-6-(4-Fluorophenyl)-8-iodo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine

Chemical Structure

Chemical Structure

[0241] Step 2: Preparation of methyl 4-amino-4'-fluoro-5-iodo-[1,1'-biphenyl]-3-carboxylate

Chemical formula

[0242] Step 3: Preparation of 4-amino-4'-fluoro-5-iodo-[1,1'-biphenyl]-3-carboxylic acid

Chemical formula

[0243] Step 4: Preparation of 6-(4-fluorophenyl)-8-iodoquinazolin-4(3H)-one

Chemical Structure

[0244] Process 5: Preparation of (R)-6-(4-Fluorophenyl)-8-iodo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine

Chemical Structure

[0245] Using the appropriate amine, the above method was applied to produce the following compounds shown in the table below.

Table 18

[0246] Example 188 (R)-6-(4-Fluorophenyl)-8-(methylsulfonyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine

Chem.

Chem.

[0247] Step 2: Preparation of (R)-6-(4-Fluorophenyl)-8-(methylsulfonyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine

Chem.

[0248] Using appropriate amines, the above method was applied to produce the following compounds shown in the table below.

Table 19

[0249] Example 190 (R)-N-(6-(4-Fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)amino)quinazolin-8-yl)methanesulfonamide

Chemical formula

[0250] The above method was applied to produce the following compounds shown in the table below.

Table 20

[0251] Example 192 (R)-6-(4-Fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)amino)quinazoline-8-sulfonamide

Chemical formula

Chemical formula

[0252] Process 2: Preparation of (R)-6-(4-Fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)amino)quinazoline-8-sulfonamide

Chemical Structure

[0253] Example 193 (R)-6-(4-Fluorophenyl)-8-(1-methyl-1H-pyrazol-4-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine [Chemical Structure] (R)-6-(4-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), and water (0.5 mL) were bubbled with nitrogen for 5 minutes in an N,N-dimethylformamide (2.0 mL) solution, and then tetrakis(triphenylphosphine)palladium(0) (21 mg, 0.02 mmol) was added. The resulting mixture was heated at 95 °C for 16 hours. After returning to room temperature, the reaction was diluted with water (6 mL) and extracted with ethyl acetate (3 × 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%). 1 H NMR (400 MHz, DMSO): δ 9.24 (s, 2H), 8.76 (d, J = 6.8 Hz, 1H), 8.71 (s, 1H), 8.59 - 8.54 (m, 2H), 8.39 (d, J = 1.5 Hz, 1H), 8.35 (s, 1H), 8.03 (dd, J = 5.4, 8.7 Hz, 2H), 7.45 (dd, J = 8.8, 8.8 Hz, 2H), 5.80 - 5.71 (m, 1H), 3.97 (s, 3H), 1.80 (d, J = 7.1 Hz, 3H). LCMS (Method 3): [MH + = 494 (5.1 minutes).

[0254] The following compounds shown in the table below were prepared according to a method similar to that described for the production of (R)-6-(4-fluorophenyl)-8-(1-methyl-1H-pyrazol-4-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine.

Table 21-1

Table 22-1

[0255] Example 198 (R)-6-(4-Fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)amino)-quinazolin-8-ol

Chemical formula

[0256] Starting from the substrates shown in the table, the above method was applied to produce the following compounds. [Table 23]

[0257] Example 200 (R)-6-(4-Fluorophenyl)-8-((tetrahydro-2H-pyran-4-yl)oxy)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine [Chemical formula] (R)-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 toluene solution, 0.14 mL, 0.14 mmol) in toluene (3.0 mL) was bubbled with nitrogen for 5 minutes. The mixture was heated at 100 °C for 72 hours. After returning to room temperature, the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound as an off-white solid (17 mg, 38%). 11H NMR (400 MHz, DMSO): δ 9.18 (s, 2H), 8.64 (d, J = 7.0 Hz, 1H), 8.44 (s, 1H), 8.23 (d, J = 1.6 Hz, 1H), 7.94 - 7.89 (m, 2H), 7.65 (d, J = 1.6 Hz, 1H), 7.39 (dd, J = 8.8, 8.8 Hz, 2H), 5.71 - 5.66 (m, 1H), 5.02 - 4.94 (m, 1H), 3.96 - 3.88 (m, 2H), 3.51 (dd, J = 9.7, 9.7 Hz, 2H), 2.07 - 2.00 (m, 2H), 1.74 (d, J = 7.0 Hz, 5H). LCMS (Method 3): [M+H + = 514 (3.79 minutes).

[0258] Example 201 (R)-4-(2-(1,1-Dioxidothiomorpholino)ethyl)-8-(4-fluorophenyl)-3-oxo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide

Chemical Structure

[0259] Starting from the substrates shown in the table, the above method was applied to produce the following compounds. [Table 24-1] [Table 24-2] [Table 24-3] [Table 24-4] [Table 24-5]

[0260] Example 214 2-[6-(4-Fluorophenyl)-4-[(6-methylpyridazin-3-yl)methylamino]quinazolin-8-yl]oxyacetic acid, sodium salt [Chemical formula] To a solution of 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) was added NaOH (10.5 mg, 0.26 mmol). The mixture was stirred at room temperature for 3 days, then diluted with diethyl ether, filtered, and 2-[6-(4-fluorophenyl)-4-[(6-methylpyridazin-3-yl)methylamino]quinazolin-8-yl]oxyacetic acid sodium salt was obtained as a white powder (87 mg, yield 75%).

[0261] Example 215 8-(Azetidin-3-ylmethoxy)-6-(4-fluorophenyl)-N-[(6-methylpyridazin-3-yl)methyl]quinazolin-4-amine [Chemical formula] To a solution of 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) was added cesium carbonate (360 mg, 1.1 mmol). The mixture was stirred at 25 °C for 48 hours. The crude material was purified. The intermediate Boc-protected amine (150 mg, 0.28 mmol) was treated with a MeOH solution of 8N HCl at room temperature for 3 days to obtain 8-(azetidin-3-ylmethoxy)-6-(4-fluorophenyl)-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine as a white powder (122 mg, yield 87%). LCMS (Method 7):: 2.24 min, [M+H] + 431.1 Se1 6 min 1 H NMR (300 MHz, methanol-d4) δ ppm 8.80 (s, 1H), 8.49 (d, J = 8.80 Hz, 1H), 8.37 (d, J = 1.28 Hz, 1H), 8.31 (brd, J = 8.44 Hz, 1H), 7.90 - 7.97 (m, 3H), 7.33 (t, J = 8.71 Hz, 2H), 5.43 (s, 2H), 4.60 (d, J = 4.95 Hz, 2H), 4.34 (dd, J = 8.44, 3.48 Hz, 4H), 2.89 (s, 3H)

[0262] Starting from the substrates shown in the table, the above method was applied to produce the following compounds. [Table 25-1] [Table 25-2]

[0263] Example 220 6-(4-Fluorophenyl)-8-[(1-methylazetidin-3-yl)methoxy]-N-[(6-methylpyridazin-3-yl)methyl]quinazolin-4-amine [Chemical Structure] 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) and dimethyl sulfate (247 mg, 0.72 mmol) in DMF (1.65 mL). The mixture was stirred at 25 °C for 18 h. The crude material was purified by chromatography to give 6-(4-fluorophenyl)-8-((1-methylazetidin-3-yl)methoxy)-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine as a white powder (1.9 mg, yield 4%). LCMS (Method 7): 2.09 min, [M+H] + 445.1 1 H NMR (300 MHz, DMSO-d6) 1 H NMR (300 MHz, chloroform-d) δ ppm 8.71 (s, 1H), 7.73 (brs, 1H), 7.54 - 7.63 (m, 3H), 7.51 (d, J = 8.80 Hz, 1H), 7.35 - 7.41 (m, 1H), 7.33 (s, 1H), 7.11 - 7.22 (m, 2H), 5.09 (d, J = 3.85 Hz, 2H), 4.42 (d, J = 6.24 Hz, 2H), 3.63 - 3.70 (m, 2H), 3.34 - 3.56 (m, 2H), 3.06 - 3.30 (m, 1H), 2.75 (s, 3H), 2.53 (s, 3H)

[0264] Starting from the substrates shown in the table, the above method was applied to produce the following compounds. [Table 26]

[0265] 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 (Example 223) and (R)-8-methoxy-6-(5-methyl-1H-pyrazol-1-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine (Example 224)

Chemical formula

[0266] Examples 225 and 226 (R)-8-Methoxy-6-(4-methyl-1H-imidazol-1-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine (Example 225) and (R)-8-methoxy-6-(5-methyl-1H-imidazol-1-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine (Example 226)

Chemical formula

[0267] Example 227 (R)-8-Methoxy-6-(4-methyl-1H-pyrazol-1-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine

Chemical formula

[0268] Intermediate 8 6-Bromo-N-((6-methylpyridin-3-yl)methyl)quinazolin-4-amine

Chemical formula

[0269] The following intermediates were synthesized by applying a similar method and reacting the appropriate amine with the substrates shown in the table.

Table 27-1

Table 27-2

[0270] Example 228 6-(5-Methylpyridin-2-yl)-N-((6-methylpyridin-3-yl)methyl)quinazolin-4-amine

Chem.

[0271] Using an appropriate stannane reagent and starting from the substrates shown in the table, the above method was applied to synthesize the following compounds.

Table 28-1

Table 28-2

[0272] Example 234 6-(4-Fluorophenyl)-N2,N2-dimethyl-N4-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)quinazoline-2,4-diamine

Chem.

[0273] Applying the above method, the following compounds were synthesized. The compound of Example 237 was obtained using the same conditions as in Example 235, and the compound of Example 238 was obtained using the same reaction conditions as in Example 236.

Table 29-1

[0274] Example 239 6-(4-Fluorophenyl)-2-methyl-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine [Chemical formula] To a solution of 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) was added Pd(dppf)Cl2·CH2Cl2 (11.86 mg, 0.015 mmol). The mixture was stirred at 80 °C for 16 hours. It was purified by RP chromatography (Biotage Isolera, 30 g C18 cartridge, gradient elution 20 CV with 0 - 65% B in A, A: water / acetonitrile 95:5 + 0.1% concentrated ammonia, B: acetonitrile:water 95:5 + 0.1% concentrated ammonia), and then purified by RP chromatography (Biotage Isolera, 30 g C18 cartridge, gradient elution 15 CV with 0 - 50% B in A, A: water / acetonitrile 95:5 + 0.1% HCOOH, B: acetonitrile:water 95:5 + 0.1% HCOOH) to obtain 6-(4-fluorophenyl)-2-methyl-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine as an off-white powder (35.9 mg, 0.100 mmol, yield 68.8%). LCMS (Method 5): 0.53 min, m / z 360 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ ppm 12.17 - 13.22 (bs, 1H), 9.00 (brs, 1H), 8.60 (d, J = 1.8 Hz, 1H), 8.07 (dd, J = 8.8, 1.8 Hz, 1H), 7.87 (dd, J = 8.8, 5.7 Hz, 2H), 7.69 (d, J = 8.3 Hz, 1H), 7.46 - 7.61 (m, 2H), 7.35 (t, J = 8.8 Hz, 2H), 5.03 (d, J = 5.3 Hz, 2H), 2.59 (s, 3H), 2.43 (s, 3H).

[0275] Starting from the appropriate intermediates shown in the table, the following intermediates were synthesized by applying a similar method. The compound of Example 246 was obtained using the same conditions as those used in Example 245. [Table 30-1] [Table 30-2] [Table 30-3]

[0276] Example 249 N-((3,5-Difluoropyridin-2-yl)methyl)-6-(4-fluorophenyl)quinazolin-4-amine hydrochloride [Chemical formula] To a solution of 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) was added DIPEA (0.15 mL, 0.861 mmol). The mixture was stirred at 80 °C for 6 hours. After the conversion of the starting material to 6-bromo-N-((3,5-difluoropyridin-2-yl)methyl)quinazolin-4-amine was complete, water (1 mL) was added to the reaction mixture, and 4-fluorophenylboronic acid (86 mg, 0.614 mmol), potassium phosphate (174 mg, 0.818 mmol) and Pd(dppf)Cl2·CH2Cl2 (33.5 mg, 0.041 mmol) were added. The mixture was stirred at 80 °C for 16 hours. The mixture was cooled to room temperature, and then formic acid (150 μL, 3.98 mmol) was added. Purification by RP chromatography (Biotage Isolera, 30 g C18 cartridge, gradient elution 15 CV with 100:0 to 65:35 A / B, A: water / acetonitrile 95:5 + 0.1% HCOOH, B: acetonitrile:water 95:5 + 0.1% HCOOH) gave N-((3,5-difluoropyridin-2-yl)methyl)-6-(4-fluorophenyl)quinazolin-4-amine hydrochloride as an off-white powder (98.4 mg, 0.244 mmol, 59.5% yield). LCMS (Method 5):: 0.67 min, 366.9 m / z [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.82 (brs, 1H), 8.92 - 9.00 (m, 1H), 8.84 - 8.91 (m, 1H), 8.44 - 8.50 (m, 1H), 8.34 - 8.44 (m, 1H), 7.98 - 8.07 (m, 1H), 7.87 - 7.97 (m, 3H), 7.43 (t, J = 8.88 Hz, 2H), 5.13 (brd, J = 5.26 Hz, 2H).

[0277] Example 250 6-(4-Fluorophenyl)-N-methyl-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)quinazolin-4-amine [Chemistry] 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) cooled to 0 °C in DMF (1 mL) was added NaH (6.07 mg, 0.240 mmol), and the reaction mixture was stirred for 30 minutes. Then, MeI (10.74 μL, 0.172 mmol) was added. After 20 hours, the crude mixture was directly loaded onto a column and purified by RP flash chromatography (Biotage Isolera, 12 g C18 cartridge, gradient elution 0 - 80% B in A; A: water / MeCN 95:5 + 0.1% HCOOH, B: MeCN / water 95:5 + 0.1% HCOOH) to obtain the title compound as a light beige powder (16 mg, 0.044 mmol, 51.3%). LCMS (Method 5): 0.57 min, 364.0 [M + H] + 。 1 1H NMR (400 MHz, DMSO-d6) δ ppm 8.33 (d, J = 2.2 Hz, 1H), 8.08 (s, 1H), 7.98 (dd, J = 8.4, 2.2 Hz, 1H), 7.69 - 7.77 (m, 2H), 7.51 (d, J = 8.8 Hz, 1H), 7.32 (t, J = 8.8 Hz, 2H), 5.72 (d, J = 6.6 Hz, 1H), 3.63 (s, 3H), 2.31 (s, 3H), 1.53 (d, J = 7.1 Hz, 3H).

[0278] Example 251 (R)-6-(3,3-difluoropyrrolidin-1-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine [Chemistry] A suspension of (R)-6-bromo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine (40 mg, 0.100 mmol) in toluene (1.5 mL) was added with 3,3-difluoropyrrolidine hydrochloride (36 mg, 0.251 mmol) and cesium carbonate (82 mg, 0.251 mmol), and (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (13 mg, 0.020 mmol) and tris(dibenzylideneacetone)dipalladium(0) (9.20 mg, 10.05 μmol) were added. The resulting mixture was heated to 100 °C and stirred for 7 hours. The mixture was cooled to room temperature and filtered. The volatile substances were removed in vacuo. Purification by RP flash chromatography (Biotage Isolera, 30 g C18 cartridge, gradient elution 0 - 90% B in A; A: water / MeCN 95:5 + 0.1% HCOOH, B: MeCN / water 95:5 + 0.1% HCOOH) gave a product containing impurities. A second purification by flash chromatography (Biotage Isolera, 11 g NH cartridge, gradient elution 5% - 100% EtOAc in heptane) gave the title compound as a white powder (21 mg, 4.95 μmol, 5% yield). LCMS (method 5): 0.68 min, 425.0 [M+H] + 。 1 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).

[0279] The following example compounds were synthesized by applying the above method.

Table 31

[0280] By chiral resolution SFC purification of the appropriate racemic mixture, the following compounds shown in the table below were obtained as single isomers.

Table 32-1

Table 32-2

Table 32-3

Table 32-4

Table 32-5

Table 32-6

Table 32-7

Table 32-8

Table 32-9

Table 32-10

[0281] Intermediate 15 6-Bromo-8-methoxy-4-((2-(trimethylsilyl)ethoxy)methoxy)quinazoline

Chemical formula

[0282] Intermediate 16 8-Methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-((2-(trimethylsilyl)ethoxy)methoxy)quinazoline

Chemical Structure

[0283] Intermediate 17 6-(5-Fluoropyridin-2-yl)-8-methoxy-4-((2-(trimethylsilyl)ethoxy)methoxy)quinazoline

Chemical formula

[0284] The following intermediates shown in the table below were synthesized according to a method similar to that described for the production of 6-(5-fluoropyridin-2-yl)-8-methoxy-4-((2-(trimethylsilyl)ethoxy)-methoxy)-quinazoline (Intermediate 17).

Table 33

[0285] Intermediate 23 6-(5-Fluoropyridin-2-yl)-8-methoxyquinazolin-4-ol

Chemical formula

[0286] The following intermediates shown in the table below were synthesized according to the same method as described for the production of 6-(5-fluoropyridin-2-yl)-8-methoxyquinazolin-4-ol (Intermediate 23).

Table 34

[0287] Example 315 (R)-6-(5-Fluoropyridin-2-yl)-8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl)quinazolin-4-amine

Chemical formula

Chemical formula

Chemical formula

[0288] Step 2: (R)-6-(5-Fluoropyridin-2-yl)-8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl)quinazolin-4-amine

Chem.

Chem.

[0289] (R)-6-(5-Fluoropyridin-2-yl)-8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl)quinazolin-4-amine was prepared in the same manner as described for, and the following compounds shown in the table below were prepared. Some compounds were purified by preparative chiral SFC to obtain pure enantiomers.

Table 35 - 1

Table 35 - 2

Table 35 - 3

[0290] The pharmacological activity of the compounds of the present invention. In vitro electrophysiology assay of P2X3 Cells expressing P2X3 receptors were grown according to standard methods and maintained at 37 °C in a 5% humidified CO2 atmosphere. Two days before the assay day, the cells were seeded into a T175 flask and detached from the flask using TrypLE when they had grown to 80 - 90% confluence. The detached cells were resuspended in serum-free medium at a cell density of 3×10 6 cells / ml and loaded into a Sophion Qube automated patch-clamp system. The extracellular assay buffer had a pH of 7.4 and contained 145 mM NaCl, 4 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, and 10 mM glucose. The intracellular assay solution had a pH of 7.2 and contained 140 mM CsF, 10 mM NaCl, 10 mM EGTA, and 10 mM HEPES. The agonist stock solution was prepared in H2O and diluted with the bath solution before use. All antagonists were prepared as 10 mM stock solutions in DMSO and diluted with the bath solution before use. All experiments were performed at room temperature under whole-cell patch-clamp configuration, and 384 individual cells were simultaneously voltage-clamped at -60 mV on a Sophion Qube instrument. α,β-MeATP (800 nM) was applied, followed by agonist application to establish two baseline responses, and then washed with extracellular assay buffer containing 0.5 U / ml apyrase. After the second agonist application, the antagonist was incubated for 10 min in the absence of α,β-MeATP. After pre-incubation with the antagonist, 800 nM α,β-MeATP and the antagonist were co-administered to determine the inhibitory effect of the antagonist. A certain concentration of the antagonist was evaluated on a single cell, and different concentrations of the antagonist were applied to other cells on 384 recorded substrates. The control P2X3 current amplitude was obtained from the peak current amplitude from the second agonist response before pre-incubation with the antagonist. The peak P2X3 current amplitude in the presence of the antagonist was used to calculate the inhibitory effect at each concentration of the antagonist according to the following formula: Inhibition rate of P2X3 = ((P2X3 control peak amplitude - P2X3 antagonist peak amplitude) / P2X3 control peak amplitude) * 100.

[0291] Concentration-response curves were created from 10 different concentrations for each concentration of the antagonist tested in at least 2 different individual cells. By fitting the following equation to the data, the concentration of the antagonist that inhibits the P2X3 current by 50% (IC 50 ) was calculated. Y = a + [(b - a) / (1 + 10^((logc - x)d)] where "a" is the minimum response, "b" is the maximum response, "c" is the IC 50 , and "d" is the Hill slope.

[0292] The results for the individual compounds are provided in Table 8 below and are shown as the range of activities.

Table 36-1

Table 36-2

Table 36-3

Table 36-4

Table 36-5

Table 36-6

Table 36-7

Table 36-8

[0293] P2X 2 / 3 in vitro electrophysiology assay Representative compounds of the present invention were tested on P2X 2 / 3 receptors. Two points were changed: 1) 10 μm ATP was used as the agonist; and 2) the post-mean current amplitude was measured 7 seconds after agonist application. As the P2X3 assay, the same assay protocol was used for the P2X 2 / 3 assay.

[0294] The results in Table 9 show that the compounds of the present invention are selective P2X3 antagonists.

Table 37-1

Table 37-2

[0295] Comparative Example A 6-(4-Fluorophenyl)-4-[(6-methyl-3-pyridyl)methoxy]pyrido[2,3-d]pyrimidine

Chemical formula

Chemical formula

[0296] Step 2: Synthesis of 6-(4-fluorophenyl)-4-[(6-methyl-3-pyridyl)methoxy]pyrido[2,3-d]pyrimidine

Chemical Structure

[0297] The following compounds shown in the table below were prepared according to a method similar to that described for the preparation of 6-(4-fluorophenyl)-4-[(6-methyl-3-pyridyl)methoxy]pyrido[2,3-d]pyrimidine.

Table 38

[0298] The activities of the compounds of Comparative Examples A and B were tested in the above in vitro electrophysiology assay for P2X3.

[0299] The results for the individual compounds are provided in Table 10 below and are shown as the range of activities.

Table 39

Claims

1. Formula (I) 【Chemistry 1】 [During the ceremony, Z is (C ３ -C ８ ) heterocycloalkyl, (R Ａ R Ｂ )N-, heteroaryl, aryl, wherein any of said alkyl, heteroaryl, heterocycloalkyl, and aryl are optionally 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 (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- and R Ａ O(C １ -C ４ ) alkylene-; wherein any of said alkyl, alkylene, aryl, heteroaryl and heterocycloalkyl are optionally selected from the group consisting of: １ -C ３ ) alkyl, R Ａ O(C １ -C ４ ) alkylene-, (C １ -C ６ ) haloalkyl, halo, oxo, R Ａ O-, (C ３ -C ８ ) Heterocycloalkyl-(C １ -C ６ ) alkyl-, heteroaryl, (R Ａ R Ｂ )N-(C(O)R Ｃ , -C(O)N(R Ａ R Ｂ ), -SO ２ N(R Ａ R Ｂ ), -O(C １ -C ４ ) alkylene-N(R Ａ R Ｂ ), aryl optionally substituted with halo, —OR Ｃ , aryl-(C １ -C ４ ) alkyl-, -C(O)R Ａ may be substituted with one or more groups selected from R Ａ and R Ｂ is, in each occurrence, independently H, or (C １ -C ４ ) alkyl-, (C ３ -C ８ ) cycloalkyl-, (C １ -C ６ ) haloalkyl; or R Ａ and R Ｂ together with the nitrogen atom to which they are attached, (C １ -C ４ ) can form a 5- or 6-membered saturated heterocyclic monocyclic ring system that may contain an additional heteroatom, which is nitrogen or oxygen, optionally substituted with one or more groups selected from alkyl and oxo; R Ｃ is, in each case, H or (C １ -C ６ ) alkyl, (R Ａ R Ｂ )N-, aryl-(C １ -C ４ ) alkyl-; Y is H, -OR Ｄ , R Ｃ SO ２ , halo, -NHSO ２ R Ｃ , heteroaryl, (C ３ -C ８ ) heterocycloalkyl; wherein any of said heteroaryl and heterocycloalkyl are optionally selected from the group consisting of: １ -C ３ ) alkyl, —C(O)N(R Ａ R Ｂ ) may be substituted with one or more groups selected from R Ｄ is H, (C １ -C ６ ) alkyl, (C ３ -C ８ ) Heterocycloalkyl-(C １ -C ６ ) alkyl-, R Ｃ O.C. (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(C1-C4)alkylene-, (R Ａ R Ｂ )N(O)C(C １ -C ４ ) alkylene-; wherein any of said heterocycloalkyl is optionally selected from the group consisting of: １ -C ３ ) alkyl-, optionally substituted with one or more groups selected from; J is H or (C １ -C ６ ) alkyl, (R Ａ R Ｂ )N-, (C １ -C ６ ) haloalkyl, -OR Ｃ and halo. Compound.

2. A compound of formula I according to claim 1 selected from the group consisting of: (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, 6-(4-fluorophenyl)-8-methoxy-N-(2-(6-methylpyridin-3-yl)ethyl)quinazolin-4-amine, 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, 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-5-yl)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, 6-(5-methylpyridin-2-yl)-N-((6-methylpyridin-3-yl)methyl)quinazolin-4-amine, N-((6-methylpyridazin-3-yl)methyl)-6-(5-methylpyridin-2-yl)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, (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, 6-(4-fluorophenyl)-N-((6-methylpyridin-3-yl)methyl)quinazolin-4-amine formate, Single enantiomer 1 of 6-(4-fluorophenyl)-8-methoxy-N-(1-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)ethyl)quinazolin-4-amine 2, a single enantiomer 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, 2, a single enantiomer 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, 2, a single enantiomer 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, 2, a single enantiomer 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, (R)-8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl)-6-(5-methylpyridin-2-yl)quinazolin-4-amine, 8-methoxy-N-[1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]-6-(5-methyl-2-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, 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, and 8-Methoxy-N-[(1S)-1-(6-methylpyridazin-3-yl)ethyl]-6-(5-methylpyrimidin-2-yl)quinazolin-4-amine.

3. Formula I according to claim 1 【Chemistry 2】 [During the ceremony, Z is heteroaryl, aryl, (R Ａ R Ｂ )N-, (C ３ -C ８ )heterocycloalkyl, wherein any of the above heteroaryl, aryl and heterocycloalkyl are optionally selected from the group consisting of (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 heteroaryl(C1-C4)alkyl-, (R Ａ R Ｂ )N(O)C(C １ -C ４ ) alkylene-; wherein any of said heteroaryls is optionally selected from the group consisting of: １ -C ３ ) alkyl, halo, (C １ -C ６ ) haloalkyl; R Ａ and R Ｂ are, in each occurrence, independently: H, (C １ -C ４ ) alkyl- and (C ３ -C ８ ) cycloalkyl- or R Ａ and R Ｂ together with the nitrogen atom to which they are attached, contain a further heteroatom which is oxygen or nitrogen; oxo, (C １ -C ４ ) alkyl; Y is H; J is H or (C １ -C ４ ) alkyl, (R Ａ R Ｂ )N-, halo, (C １ -C ６ ) haloalkyl; Compound.

4. The compound of claim 2 selected from the group consisting of: 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, N-((6-methylpyridazin-3-yl)methyl)-6-(5-methylpyridin-2-yl)-2-(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, 2-chloro-6-(4-fluorophenyl)-N-(1-(3-methyl-1,2,4-oxadiazol-5-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, 6-(4-fluorophenyl)-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)-2-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, 6-(4-fluorophenyl)-2-methyl-N-((6-methylpyridazin-3-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, (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, 2, a single enantiomer 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, 2, a single enantiomer of 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]-2-morpholino-quinazolin-4-amine; 6-(4-fluorophenyl)-N2,N2-dimethyl-N4-[1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]quinazoline-2,4-diamine, and 6-(4-fluorophenyl)-N2,N2-dimethyl-N4-[1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]quinazoline-2,4-diamine.

5. Formula I according to claim 1 【Chemistry 3】 [During the ceremony, Z is selected from the group consisting of heteroaryl and aryl; wherein any of said heteroaryl and aryl are optionally selected from the group consisting of: 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 (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; wherein any of said alkyl, alkylene, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally selected from the group consisting of: 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 with 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 Ａ and optionally substituted with one or more groups selected from R Ａ and R Ｂ is, in each occurrence, independently H, or (C １ -C ４ ) alkyl-, aryl, (C １ -C ６ ) haloalkyl; or R Ａ and R Ｂ together with the nitrogen atom to which they are attached, (C １ -C ４ ) can form a 6-membered saturated heterocyclic monocyclic ring system that may optionally contain a further heteroatom, which is nitrogen or oxygen, optionally substituted with alkyl- and oxo; R Ｃ is H or (C １ -C ６ ) alkyl, (R Ａ R Ｂ )N-, aryl-(C １ -C ４ ) alkyl-; Y is -OR Ｄ , R Ｃ SO ２ -, halo, -NHSO ２ R Ｃ , heteroaryl, (C ３ -C ８ ) heterocycloalkyl; wherein any of said heteroaryl and heterocycloalkyl are optionally selected from the group consisting of: １ -C ３ ) alkyl, —C(O)N(R Ａ R Ｂ ) may be substituted with one or more groups selected from J is H or (C １ -C ６ ) alkyl, -OR Ｃ Selected from the group consisting of R Ｄ is H or (C １ -C ６ ) alkyl Compound.

6. Formula I according to claim 1 【Chemistry 4】 [During the ceremony, Z is selected from the group consisting of heteroaryl and aryl; wherein any of said heteroaryl and aryl are optionally selected from the group consisting of: 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-, optionally substituted with one or more groups selected from the group consisting of: R １ is H, R ２ (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; wherein any of said alkyl, alkylene, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally selected from the group consisting of: 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 with 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 Ａ and optionally substituted with one or more groups selected from R Ａ and R Ｂ is, in each occurrence, independently H, or (C １ -C ４ ) alkyl-, aryl, (C １ -C ６ ) haloalkyl; or R Ａ and R Ｂ together with the nitrogen atom to which they are attached, (C １ -C ４ ) can form a 6-membered saturated heterocyclic monocyclic ring system that optionally contains a further heteroatom which is nitrogen or oxygen, optionally substituted with alkyl- and oxo; R Ｃ is H or (C １ -C ６ ) alkyl, (R Ａ R Ｂ )N-, aryl-(C １ -C ４ ) alkyl-; Y is -OR Ｄ , R Ｃ SO ２ -, halo, -NHSO ２ R Ｃ , heteroaryl, (C ３ -C ８ ) heterocycloalkyl; wherein any of said heteroaryl and heterocycloalkyl are optionally selected from the group consisting of: １ -C ３ ) alkyl, —C(O)N(R Ａ R Ｂ ) may be substituted with one or more groups selected from J is H or (C １ -C ６ ) alkyl, -OR Ｃ is selected from the group consisting of R Ｄ is H or (C １ -C ６ ) alkyl Compound.

7. The compound according to claim 5 or 6, selected from the group consisting of: (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, (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, 6-(4-fluorophenyl)-8-methoxy-N-((5-methylpyridin-2-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, 6-(4-fluorophenyl)-8-methoxy-N-((6-methylpyridin-3-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, 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, A single enantiomer of 3-((6-(4-fluorophenyl)-8-methoxyquinazolin-4-yl)amino)tetrahydrothiophene 1,1-dioxide 1, 2, a single enantiomer 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, 6-(4-fluorophenyl)-8-methoxy-N-((6-methoxypyridin-3-yl)methyl)quinazolin-4-amine, N-(4-ethoxybenzyl)-6-(4-fluorophenyl)-8-methoxyquinazolin-4-amine, 6-(4-fluorophenyl)-8-methoxy-N-(2-methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)propyl)quinazolin-4-amine, 6-(4-fluorophenyl)-8-methoxy-N-[[2-(trifluoromethyl)-4-pyridyl]methyl]quinazolin-4-amine, 6-(4-fluorophenyl)-8-methoxy-N-((1-methyl-1H-tetrazol-5-yl)methyl)quinazolin-4-amine, 6-(4-fluorophenyl)-8-methoxy-N-((1-methyl-1H-pyrazol-4-yl)methyl)quinazolin-4-amine, 4-(2-((6-(4-fluorophenyl)-8-methoxyquinazolin-4-yl)amino)ethyl)morpholin-3-one, 6-(4-fluorophenyl)-8-methoxy-N-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)quinazolin-4-amine, 6-(4-fluorophenyl)-8-methoxy-N-((2-methyl-2H-tetrazol-5-yl)methyl)quinazolin-4-amine, 6-(4-fluorophenyl)-8-methoxy-N-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)quinazolin-4-amine, 6-(4-fluorophenyl)-N-(imidazo[1,2-a]pyrimidin-6-ylmethyl)-8-methoxyquinazolin-4-amine, 6-(4-fluorophenyl)-8-methoxy-N-((6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)quinazolin-4-amine, N-((4-ethyl-4H-1,2,4-triazol-3-yl)methyl)-6-(4-fluorophenyl)-8-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, N-[(3S,4R)-4-ethoxytetrahydrofuran-3-yl]-6-(4-fluorophenyl)-8-methoxy-quinazolin-4-amine, N-[(1,1-dioxothi-n-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, 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, 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, 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, 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, 6-(5-fluoro-2-pyridyl)-8-methoxy-N-[(6-methylpyridazin-3-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, 8-methoxy-N-((6-methylpyridazin-3-yl)methyl)-6-(5-(trifluoromethyl)pyridin-2-yl)quinazolin-4-amine, 8-methoxy-6-(5-methoxypyridin-2-yl)-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine, 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, 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, 6-(5-fluoro-2-pyridyl)-8-methoxy-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]quinazolin-4-amine, 8-methoxy-6-(3-methylisothiazol-5-yl)-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine, (R)-8-methoxy-6-(5-methylpyridin-2-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine, (R)-8-methoxy-6-(5-methylthiazol-2-yl)-N-(1-(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, 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-methylpyridazin-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, 6-(4-fluorophenyl)-8-methoxy-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)quinazolin-4-amine, single enantiomer 2 of 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, 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 9, 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-methoxy-6-(3-methyl-1H-pyrazol-1-yl)-N-(1-(2-(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, 2, a single enantiomer of 6-(4-fluorophenyl)-8-methoxy-N-(1-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)ethyl)quinazolin-4-amine; Single enantiomer 1 of 6-(4-fluorophenyl)-8-methoxy-N-(1-(6-methylpyridin-3-yl)ethyl)quinazolin-4-amine, 2, a single enantiomer of 6-(4-fluorophenyl)-8-methoxy-N-(1-(6-methylpyridin-3-yl)ethyl)quinazolin-4-amine; Single enantiomer 1 of 6-(4-fluorophenyl)-8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl)quinazolin-4-amine, 2, a single enantiomer of 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, 2, a single enantiomer 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, 2, a single enantiomer 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, 2, a single enantiomer 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, 2, a single enantiomer of N-(1-(3-ethyl-1,2,4-oxadiazol-5-yl)ethyl)-6-(4-fluorophenyl)-8-methoxyquinazolin-4-amine; Single enantiomer 1 of N-(1-cyclopropylethyl)-6-(4-fluorophenyl)-8-methoxyquinazolin-4-amine, 2, a single enantiomer of N-(1-cyclopropylethyl)-6-(4-fluorophenyl)-8-methoxyquinazolin-4-amine; Single enantiomers of N3-(6-(4-fluorophenyl)-8-methoxyquinazolin-4-yl)-N1,N1-dimethylbutane-1,3-diamine, 2, a single enantiomer 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, 2, a single enantiomer 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, 2, a single enantiomer 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, 2, a single enantiomer 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, (rac)-N-(1-(4H-1,2,4-triazol-3-yl)ethyl)-6-(4-fluorophenyl)-8-methoxyquinazolin-4-amine, (S)-6-(4-fluorophenyl)-8-methoxy-N-(1-(5-methyl-4H-1,2,4-triazol-3-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, (R)-8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl)-6-(5-methylpyridin-2-yl)quinazolin-4-amine, 8-methoxy-N-[1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]-6-(5-methyl-2-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, 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, and 8-Methoxy-N-[(1S)-1-(6-methylpyridazin-3-yl)ethyl]-6-(5-methylpyrimidin-2-yl)quinazolin-4-amine.

8. Y is -OR Ｄ Formula (Ia) 【Chemistry 5】 [During the ceremony, Z is selected from the group consisting of aryl; wherein any said aryl may be optionally substituted with one or more groups selected from halo; R １ is H, R ２ is heteroaryl (C １ -C ４ ) alkyl-, wherein any of said heteroaryls is optionally selected from the group consisting of: １ -C ３ ) alkyl, (C １ -C ６ ) haloalkyl; R Ａ and R Ｂ is, in each occurrence, independently H, or (C １ -C ４ ) alkyl-; R Ｃ is, in each case, 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 O.C. (O) (C １ -C ４ ) alkylene-, (R Ａ R Ｂ )N(C １ -C ６ ) alkylene-, (C ３ -C ８ ) heterocycloalkyl, R Ｃ O(C1-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 said heterocycloalkyl is optionally selected from the group consisting of: １ -C ３ ) alkyl; J is H. The compound of claim 1 , represented by:

9. The compound of claim 4 selected from the group consisting of: (R)-6-(4-fluorophenyl)-8-((tetrahydro-2H-pyran-4-yl)oxy)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine, (R)-4-(2-(1,1-dioxidothiomorpholino)ethyl)-8-(4-fluorophenyl)-3-oxo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide, 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, 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, 6-(4-fluorophenyl)-N-[(6-methylpyridazin-3-yl)methyl]-8-(2-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 2-[6-(4-fluorophenyl)-4-[(6-methylpyridazin-3-yl)methylamino]quinazolin-8-yl]oxyacetate, 8-ethoxy-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]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)-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, and 6-(4-Fluorophenyl)-N-[(6-methylpyridazin-3-yl)methyl]-8-[(3R)-pyrrolidin-3-yl]oxy-quinazolin-4-amine.

10. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, alone or in combination with one or more further active ingredients, in admixture with one or more pharma- ceutically acceptable carriers or excipients.

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

12. A compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 or 11 for use as a medicament.

13. P2X ３ A compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 or 11 for use in the treatment of any disease in which the receptor is involved.

14. A compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 or 11 for use in the prevention and / or treatment of respiratory diseases including cough, subacute or chronic cough, refractory cough, idiopathic chronic cough, cough after viral infection, iatrogenic cough, asthma, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and cough associated with respiratory diseases such as COPD, asthma and bronchospasm.

15. 15. A compound or pharmaceutical composition according to claim 14 for use in the treatment of chronic cough.

16. Formula Ib 【Chemistry 6】 [During the ceremony, R ３ is OH or halo, R ４ is H or OH, R ５ is halo or -OMe; R ６ is halo or Z; Z is as defined above. Compound.

17. 17. Use of a compound of formula (Ib) as defined in claim 16 as an intermediate in the preparation of a compound of formula (I) as defined in claim 1.

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