Aminoquinazoline derivatives as P2X3 inhibitors

Abstract

The present invention relates to compounds that inhibit P2X purinoceptor 3; in particular, the present invention relates to compounds that are aminoquinazoline derivatives, methods for preparing such compounds, pharmaceutical compositions containing them, and their therapeutic uses.The compounds of the present invention can be useful in treating many disorders related to P2X3 receptor mechanisms, for example, respiratory diseases including cough, asthma, idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD).

Description

[Technical field]

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

[0002] The compounds of the invention may be useful in the treatment of a number of disorders related to P2X3 receptor mechanisms, such as respiratory diseases including cough, asthma, idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). [Background technology]

[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 that includes an intracellular end, two transmembrane helices that form an ion channel, and a large extracellular domain that contains the ATP binding site. Homomeric P2X1, P2X2, P2X3, P2X4, P2X5 and P2X7 channels and heteromeric P2X 2 / 3 and P2X 1 / 5The channels have been thoroughly characterized after heterologous expression. P2X receptors are abundantly distributed and functional responses are found 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 ejection). 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 sensing tissue injury and inflammatory stimuli. A paracrine role for ATP signaling through P2X receptors may be in the neurohypophysis, ductal 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 involved in the initiation of Na + and Ca + They are nonselective cation channels that are permeable to ions and are activated by ATP; however, the pharmacology of receptor subtypes varies with 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 in the heart and spinal cord at the mRNA level, and in the DRG, gut (intramural plexus neurons), bladder (urothelium and urothelium) and dental pulp at the protein level (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 P2X3 receptors in airway sensory nerve function is similar to their 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 the hypothesis of their involvement 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). P2X3 subunits are also co-localized in many neurons, particularly in 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 diabetic neuropathic pain (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 / 3The channel plays an important role in the development of articular hyperalgesia in arthritis (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 therapeutic treatment of bladder pain. They have also been proposed as analgesic targets for treating ureteral colic and for 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 associated with poor recurrence-free survival in hepatocellular carcinoma patients, 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] It has been suggested that P2X3 antagonists may improve erectile function recovery (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 citrate- and histamine-induced cough in preclinical models, but 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 afferents and mediates the hypersensitivity of the cough reflex, 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 P2X 2 / 3 It is a key neurotransmitter in the taste system that acts primarily through heteromultimeric receptors. Consequently, disruption of taste function may be an unintended consequence of the treatment of pain, chronic cough, and other conditions with purinergic P2X3 antagonists (Vandenbeuch A et al: Role of the ectonucleotidase NTPDase2 in taste bud function, Proc Natl Acad Sci USA, 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 A wide variety of compounds have been described in the literature as inhibitors.

[0015] WO 2017058645 (Afferent Pharmaceuticals INC) discloses a diaminopyrimidine P2X3 / P2X4 inhibitor for the treatment of disorders involving cough, chronic cough and urge to cough, including cough associated with a respiratory disease or disorder, by administering an effective amount of the disclosed compound. 2 / 3 The use of antagonists is disclosed, however, aminoquinazoline derivatives are not disclosed.

[0016] WO 2017011729 (Patara Pharma LLC) describes a combination of cromolyn or a pharma- ceutical acceptable salt thereof and P2X3 and / or P2X4 for the treatment of pulmonary diseases and conditions. 2 / 3 The use of receptor antagonists as cough suppressants has been disclosed.

[0017] WO2016091776 (Evotec AG) discloses 1,3-thiazol-2-yl substituted benzamide compounds that inhibit the P2X3 receptor and 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.) describes novel P2X3 and / or P2X 2 / 3 Purine derivative compounds having receptor antagonistic activity have been disclosed.

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

[0020] WO2008123963 (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, and autoimmune disorders, by administering the disclosed compounds are also provided.

[0021] WO2008130481 (Renovis) discloses 2-cyanophenyl fused heterocyclic compounds of the tetrahydropyrido[4,3-d]pyrimidine class and pharmaceutical compositions containing such compounds.

[0022] WO 2010033168 (Renovis) describes a series of phenyl or pyridyl substituted benzamides believed to be useful in the treatment of diseases associated with the P2X purinergic receptor, and more specifically, P2X3 receptors and / or P2X 2 / 3 Receptor antagonists are disclosed, however, pyridopyrimidine derivatives are not disclosed.

[0023] WO2009110985 (Renovis) relates to phenyl and pyridyl substituted benzamide compounds and pharmaceutical compositions containing such compounds, but excludes thiazole substituted benzamides, which are different compounds from the compounds of the present invention.

[0024] WO 2008000645 (Roche) describes compounds that are useful for treating urogenital, pain, gastrointestinal and respiratory diseases, conditions and disorders, including P2X3 and / or P2X4. 2 / 3 Receptor tetrazole-substituted aryl amide compound antagonists are disclosed.

[0025] Notwithstanding the above cited prior art, there remains a need for novel aminoquinazoline compounds, preferably with selective action on the P2X3 receptor, for the treatment of diseases associated with the P2X3 receptor in many therapeutic areas, e.g., in particular respiratory diseases.

[0026] Notably, the prior art does not describe or suggest the aminoquinazoline derivative compounds of the present invention of general formula (I) which provide a solution to the above-mentioned needs. Summary of the Invention

[0027] The present invention relates to a compound represented by formula (I) [ka] [During the ceremony, Z is (C3-C8)heterocycloalkyl, (R A R B ) selected from the group consisting of N-, heteroaryl, and aryl; wherein any of said alkyl, heteroaryl, heterocycloalkyl and aryl are optionally selected from (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-; R1 is H or (C1-C4)alkyl; R2 is (C1-C6)alkyl-, heteroaryl(C1-C4)alkyl-, (C3-C8)heterocycloalkyl-(C1-C6)alkyl-, heteroaryl-(C1-C6)hydroxyalkyl-, (C3-C8)heterocycloalkyl, (C3-C8)cycloalkyl-(C1-C6)alkyl-, aryl-(C1-C4)alkyl-, (R A R B )N(C1-C6)alkylene-, (R A R B )N(O)C(C1-C4)alkylene-, R A O(C1-C4)alkylene-; wherein any of said alkyl, alkylene, aryl, heteroaryl and heterocycloalkyl are optionally selected from (C1-C3) alkyl, R A O(C1-C4)alkylene-, (C1-C6)haloalkyl, halo, oxo, R A O-, (C3-C8)heterocycloalkyl-(C1-C6)alkyl-, heteroaryl, (R A R B )N-(C(O)R C , -C(O)N(R A R B ), -SO2N(R A R B ), -O(C1-C4)alkylene-N(R A R B ), aryl optionally substituted with halo, -OR C , aryl-(C1-C4)alkyl-, -C(O)R A may be substituted with one or more groups selected from R A and R B is independently, at each occurrence, H or is selected from the group consisting of: (C1-C4)alkyl-, (C3-C8)cycloalkyl, (C1-C6)haloalkyl; R A and R B can be taken together with the nitrogen atom to which they are attached to form a 5- or 6-membered saturated heterocyclic monocyclic ring system which optionally contains a further heteroatom which is nitrogen or oxygen, optionally substituted with one or more groups selected from (C1-C4)alkyl and oxo; R C is, in each occurrence, H or (C-C) alkyl, (R A R B )N-, aryl-(C1-C4)alkyl-; Y is H, -OR D , R C SO2, Halo, -NHSO2R C, heteroaryl, (C3-C8)heterocycloalkyl, wherein any of said heteroaryl and heterocycloalkyl are optionally selected from the group consisting of (C1-C3)alkyl and -C(O)N(R A R B ) may be substituted with one or more groups selected from R D is H, (C1-C6)alkyl, (C3-C8)heterocycloalkyl-(C1-C6)alkyl-, R C OC(O)(C1-C4)alkylene-, (R A R B )N(C1-C6)alkylene-, (C3-C8)heterocycloalkyl, (C3-C8)cycloalkyl-(C1-C6)alkyl-, R C O(C1-C4)alkylene-, (R A R B )N(O)C(C1-C4)alkylene-, wherein any said heterocycloalkyl is optionally substituted with one or more groups selected from (C1-C3)alkyl; J is H or (C1-C6) alkyl, (R A R B )N-, (C1-C6) haloalkyl, -OR C and halo. This refers to a compound of the formula:

[0028] In a second aspect, the present invention refers to a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, alone or in combination with one or more other active ingredients, in admixture with one or more pharma- ceutically 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 embodiment, the invention refers to a compound of formula (I) for use in the prevention and / or treatment of 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.

[0032] In a further aspect, the present invention relates to a compound of formula Ib [ka] [During the ceremony R3 is OH or halo; R4 is H or OH; R5 is halo or -OMe; R6 is halo or Z; Z is as defined above, This refers to a compound of the formula:

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

[0034] Detailed Description of the Invention The present invention relates to a compound represented by formula (I) [ka] [During the ceremony, Z is (C3-C8)heterocycloalkyl, (R A R B )N-, heteroaryl, aryl, wherein any of said alkyl, heteroaryl, heterocycloalkyl, and aryl are optionally selected from the group consisting of (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-, (RA R B )N-; R1 is H or (C1-C4)alkyl; R2 is (C1-C6)alkyl-, heteroaryl(C1-C4)alkyl-, (C3-C8)heterocycloalkyl-(C1-C6)alkyl-, heteroaryl-(C1-C6)hydroxyalkyl-, (C3-C8)heterocycloalkyl, (C3-C8)cycloalkyl-(C1-C6)alkyl-, aryl-(C1-C4)alkyl-, (R A R B )N(C1-C6)alkylene-, (R A R B )N(O)C(C1-C4)alkylene-, R A O(C1-C4)alkylene-, where any of said alkyl, alkylene, aryl, heteroaryl, and heterocycloalkyl are optionally selected from the group consisting of (C1-C3)alkyl, R A O(C1-C4)alkylene-, (C1-C6)haloalkyl, halo, oxo, R A O-, (C3-C8)heterocycloalkyl-(C1-C6)alkyl-, heteroaryl, (R A R B )N-(C(O)R C , -C(O)N(R A R B ), -SO2N(R A R B ), -O(C1-C4)alkylene-N(R A R B ), aryl optionally substituted with halo, -OR C , aryl-(C1-C4)alkyl-, -C(O)R A may be substituted with one or more groups selected from R A and R B is independently, at each occurrence, H or selected from consisting of (C1-C4)alkyl-, (C3-C8)cycloalkyl, (C1-C6)haloalkyl; R A and R Bcan be taken together with the nitrogen atom to which they are attached to form a 5- or 6-membered saturated heterocyclic monocyclic ring system which may optionally contain a further heteroatom which is nitrogen or oxygen, optionally substituted with one or more groups selected from (C1-C4)alkyl and oxo; R C is, in each occurrence, H or (C-C) alkyl, (R A R B )N-, aryl-(C1-C4)alkyl-; Y is H, -OR D , R C SO2, Halo, -NHSO2R C , heteroaryl, (C3-C8)heterocycloalkyl, wherein any of said heteroaryl and heterocycloalkyl are optionally selected from the group consisting of (C1-C3)alkyl and -C(O)N(R A R B ) may be substituted with one or more groups selected from R D is H, (C1-C6)alkyl, (C3-C8)heterocycloalkyl-(C1-C6)alkyl-, R C OC(O)(C1-C4)alkylene-, (R A R B )N(C1-C6)alkylene-, (C3-C8)heterocycloalkyl, (C3-C8)cycloalkyl-(C1-C6)alkyl-, R C O(C1-C4)alkylene-, (R A R B )N(O)C(C1-C4)alkylene-, wherein any said heterocycloalkyl is optionally substituted with one or more groups selected from (C1-C3)alkyl; J is H or (C1-C6) alkyl, (R A R B )N-, (C1-C6) haloalkyl, -OR C and halo. This refers to a compound of the formula:

[0035] definition As used herein, the term "pharmaceutical acceptable salts" refers to derivatives of the compounds of formula (I), where the parent compound is suitably modified by converting any free acid or basic groups, if any, with any base or acid, into the corresponding addition salts that are conventionally intended to be pharmaceutically acceptable.

[0036] Thus, suitable examples of such 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 which may be suitably used to prepare salts include ions of alkali metals or alkaline earth metals, such as potassium, sodium, calcium or magnesium.

[0038] Compounds which can be obtained by reacting the primary compound which functions as a base with an inorganic or organic acid to form a salt 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" refers to a straight or branched chain alkyl group having from x to y carbon atoms. Thus, when x is 1 and y is 6, for example, the term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl.

[0041] As used herein, the term “(C x -C y ) alkylene" refers to a C alkylene radical having a total of two unsatisfied valencies, such as a divalent methylene radical.x -C y This refers to an alkyl group.

[0042] The expression "(C x -C y )Haloalkyl" means "C )haloalkyl" as defined above x -C y "Alkyl" refers to a group in which one or more hydrogen atoms are replaced by one or more halogen atoms, which may be the same or different.

[0043] Therefore, the above "(C x -C y Examples of "haloalkyl" groups may include halogenated, polyhalogenated and fully halogenated alkyl groups in which all hydrogen atoms are replaced with halogen atoms, such as trifluoromethyl or difluoromethyl, trifluoroethyl groups.

[0044] As synonyms, the terms "(C1-C6)hydroxyalkyl" or "(C1-C6)aminoalkyl" refer to a "(C1-C6)alkyl" group as defined above in which one or more hydrogen atoms have been replaced with one or more hydroxy groups (OH) or amino groups, respectively. Examples of these include hydroxymethyl, aminomethyl, dimethylaminopropyl, etc.

[0045] As used herein, unless otherwise indicated, aminoalkyl refers to one or more amino groups (—NR A R B ) (i.e., a "(C1-C6) alkyl" group). Thus, an example of an aminoalkyl is R A R B and monoaminoalkyl groups such as N-(C1-C6) alkyl.

[0046] The substituent R as defined above and below A and R B About R A and R BWhen together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic radical, at least one further ring carbon atom in said 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 said 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 spirodisubstitution and substitution on two adjacent carbon atoms, thus forming in each case a further 5-6 membered heterocyclic ring. Examples of said heterocyclic radicals 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 include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.

[0048] The term "aryl" refers to a monocyclic carbocyclic ring system having 6 atoms, in which 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 or one such monocyclic ring and one monocyclic aryl ring covalently fused together. Examples of suitable 5- and 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" refers to a saturated monocyclic, bicyclic or tricyclic non-aromatic radical 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" refers to a saturated or partially unsaturated monocyclic (C) heterocycloalkyl in which at least one carbon atom is replaced with at least one heteroatom (e.g., N, S, or O) or has an -oxo (=O) substituent. x -C y (C)cycloalkyl groups. Said heterocycloalkyl (i.e., heterocyclic radicals or groups) may be optionally further substituted at available positions on the ring, i.e., on the carbon atoms or on any heteroatom available for substitution. Substitution on a carbon atom includes spirodisubstitution and substitution on two adjacent carbon atoms, thus forming an additional 5-6 membered heterocyclic ring in either case. x -C y ) Examples of 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 radicals, and the like.

[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 linked via an oxygen bridge and an attached aryl-alkoxyl or heteroaryl-alkoxyl group. Examples of such groups are phenyloxy, benzyloxy and pyridinyloxy, respectively.

[0054] The term "aryl(C1-C6)alkyl" refers to an aryl ring attached to a straight or branched alkyl group having from 1 to 6 carbon atoms, such as a phenylmethyl (ie, benzyl), phenylethyl, or phenylpropyl group.

[0055] A term where z and k are integers (C z -C k )Heterocycloalkyl-(C x -C y ) Alkyl refers to a heterocyclic ring attached to a straight or branched alkyl group having from 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 linked to a straight or branched alkyl group having from x to y carbon atoms.

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

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

[0059] A line ("-") that is not present between two letters or symbols is meant to represent a point of attachment for a substituent. When represented diagrammatically, the point of attachment in a cyclic functional group is indicated by a dot ("·") located on one of the available ring atoms where the functional group can be attached to a bond or other fragment of the molecule.

[0060] Oxo moieties are represented by (O) as an alternative to other common designations such as (=O). Thus, for general formulas, carbonyl groups are represented herein as -C(O)-, and generally, bracketed groups are side groups and not included in the chain, and brackets are used when considered useful to avoid ambiguity in linear chemical formulas; for example, a sulfonyl group -SO2- may be represented as -S(O)2- to avoid ambiguity with, for example, a sulfinic group -S(O)O-.

[0061] Whenever a basic amino group or a quaternary ammonium group is present in the compound of formula I, a physiologically acceptable anion may be present, 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 cationic salts also exist, including, for example, alkali metal or alkaline earth metal ions.

[0062] It will be appreciated that when compounds of formula (I) contain one or more stereocenters they may exist as optical stereoisomers.

[0063] When the compounds according to the present invention have at least one stereocenter, they may therefore exist as enantiomers. When the compounds according to the present invention have two or more stereocenters, they may exist as diastereoisomers. All such single enantiomers, diastereoisomers and mixtures thereof in any ratio are included within the scope of the present invention. The absolute configuration (R) or (S) about the carbon bearing the stereocenter is assigned according to the Cahn-Ingold-Prelog naming rules based on group priority.

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

[0065] All preferred groups or embodiments for compounds of formula I described above and hereinafter may be combined with each other and apply mutatis mutandis.

[0066] In a preferred embodiment, the present invention relates to a compound of formula (I) as defined above [ka] [During the ceremony, Z is heteroaryl, aryl, (R A R B )N-, (C3-C8)heterocycloalkyl, wherein any of said heteroaryl, aryl and heterocycloalkyl are optionally selected from the group consisting of (C1-C3)alkyl, halo, CN, (R A R B ) NC(O)—; R1 is H or (C1-C4)alkyl; R2 is heteroaryl(C1-C4)alkyl-, (R A R B )N(O)C(C1-C4)alkylene-, where any said heteroaryl is optionally substituted with one or more groups selected from (C1-C3)alkyl, halo, (C1-C6)haloalkyl; R A and R B is, at each occurrence, independently H, (C-C)alkyl- and (C-C)cycloalkyl-, or R A and R B can form, together with the nitrogen atom to which they are attached, a 5- or 6-membered saturated heterocyclic monocyclic ring system which optionally contains a further heteroatom which is oxygen or nitrogen, optionally substituted with one or more groups selected from oxo, (C1-C4)alkyl; Y is H; J is H or (C1-C4) alkyl, (R A R B )N-, halo, (C1-C6)haloalkyl; This refers to a compound of the formula:

[0067] In another preferred embodiment, the present invention provides Z is selected from the group consisting of heteroaryl and aryl, where any of said heteroaryl and aryl are optionally 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 are optionally substituted with one or more groups selected from (C1-C3)alkyl, (C1-C6)haloalkyl and -OH; Y is H and -OR D Selected from the group consisting of R D But in each case, (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 selected from the group consisting of; J, in each occurrence, is H and -OR C , preferably selected from the group consisting of H or -OH; R C is selected from the group consisting of H and (C1-C6)alkyl, Concerning compounds 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 pharma- ceutically 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 provides a method for the preparation of ... pharmaceutical composition comprising the steps of: 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 a further heteroatom which is oxygen or nitrogen, said heterocyclic radicals in turn being optionally further substituted with one or more of oxo, methyl and fluorine (R A R B any of said heteroaryl and aryl are optionally selected from the group consisting of: Methyl, Fluorine, R C R is selected from the group consisting of fluorine and -OH. C SO2 and RA and R B is H (R A R B )N-, C.N., R A and R B is H (R A R B )NC(O)- may be further substituted with one or more groups selected from the group consisting of R1 is H or methyl; R2 Heteroaryl(C1-C4)alkyl-, preferably (pyridinyl)methyl, (pyridazyl)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 H, cyclopropyl; Any of said heteroaryls may be optionally substituted with one or more groups selected from methyl, fluorine and trifluoromethyl; 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 is, independently at each occurrence, 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 a further heteroatom which is oxygen; (R A R B )N- The present invention refers to a compound of formula (I), which is selected from the group consisting of:

[0070] According to a preferred embodiment, the present invention refers to at least one of the compounds listed in Table 2 below, and pharma- ceutically 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 provides a method for the preparation of ... pharmaceutical composition comprising the steps of: Z is H or is selected from the group consisting of heteroaryl and aryl, where any of said heteroaryl and aryl are optionally 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 is optionally substituted with one or more groups selected from (C1-C3)alkyl and (C1-C6)haloalkyl; Y is H; Regarding compounds of formula (I) wherein J is H or halo.

[0072] According to a preferred embodiment, the present invention refers to at least one compound 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 a compound of formula (I) [ka] [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 (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-; R1 is H or (C1-C4) alkyl; R2 is (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; wherein any of said alkyl, alkylene, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally selected from (C1-C3) alkyl, R A O(C1-C4)alkylene, (C1-C6)haloalkyl, oxo, R A O-, (C3-C8)heterocycloalkyl-(C1-C6)alkyl, heteroaryl, aryl optionally substituted with halo, R C O-, (R A R B )N-, -NHC(O)R C , -C(O)N(RA R B ), halo, -SO2N(R A R B ), -O(R A O(C1-C4)alkylene-N(R A R B ), aryl-(C1-C4)alkyl-, -C(O)R A and optionally substituted with one or more groups selected from R A and R B is independently, at each occurrence, H or is selected from the group consisting of (C1-C4)alkyl-, aryl, (C1-C6)haloalkyl; R A and R B can form together with the nitrogen atom to which they are attached a 6-membered saturated heterocyclic monocyclic ring system which optionally contains a further heteroatom which is nitrogen or oxygen, optionally substituted with (C1-C4)alkyl- and oxo; R C is H or (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; wherein any of said heteroaryl and heterocycloalkyl are optionally selected from (C1-C3)alkyl, -C(O)N(R A R B ) may be substituted with one or more groups selected from J is H or (C1-C6) alkyl, -OR C is selected from the group consisting of R D is H or (C1-C6) alkyl. This refers to a compound of the formula:

[0074] In a further preferred embodiment, the present invention relates to a compound of formula (I) as defined above [ka] [During the ceremony, Z is selected from the group consisting of heteroaryl and aryl, where any of said heteroaryl and aryl are optionally selected from (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-; R1 is H; R2 is (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; wherein any of said alkyl, alkylene, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally selected from (C1-C3) alkyl, R A O(C1-C4)alkylene-, (C1-C6)haloalkyl, oxo, R A O-, (C3-C8)heterocycloalkyl-(C1-C6)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, -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 optionally substituted with one or more groups selected from R A and R B is independently, at each occurrence, H or is selected from the group consisting of (C1-C4)alkyl-, aryl, (C1-C6)haloalkyl; R A and R B can be taken together with the nitrogen atom to which they are attached to form a 6-membered saturated heterocyclic monocyclic ring system which may contain a further heteroatom which is nitrogen or oxygen, optionally substituted with (C1-C4)alkyl- and oxo; R C is H or (C1-C6) alkyl, (R A R B )N-, aryl-(C1-C4)alkyl-; Y is -OR D , R C SO2, Halo, -NHSO2R C , heteroaryl, and (C3-C8)heterocycloalkyl, wherein any of said heteroaryl and heterocycloalkyl are optionally selected from the group consisting of (C1-C3)alkyl, —C(O)N(R A R B ) may be substituted with one or more groups selected from J is H or (C1-C6) alkyl, OR C selected from the group consisting of; R D is H or (C1-C6) alkyl. This refers to a compound of the formula:

[0075] In a further preferred embodiment, the present invention provides a method for the preparation of ... pharmaceutical composition comprising the steps of: Z is H, or (R A R B)N-, Heteroaryl, preferably thiadiazolyl, thiazolyl, pyrazolyl, pyridazyl, oxadiazolyl, pyridinyl, pyrimidinyl, aryl, preferably phenyl; R A R is H A O- is selected from the group consisting of Each of said heteroaryl and aryl is optionally Methyl, halo, preferably fluorine and chlorine; C.N., R A and R B is, in each occurrence, independently H or methyl (R A R B )NC(O)-, C1-C6) haloalkyl, preferably trifluoromethyl and difluoromethyl; R A is H or R is selected from methyl, trifluoromethyl and difluoromethyl A O-, R A and R B is methyl (R A R B )N(C1-C6)alkylene-, Cyclopropyl, R C R is methyl C SO2-, R A and R B are independently H and methyl (R A R B )N- may be substituted with one or more groups selected from R1 is H; R2 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 is selected from the group consisting of Each of said aryl, heteroaryl, cycloalkyl and heterocycloalkyl optionally comprises (C1-C3) alkyl, preferably methyl and ethyl; trifluoromethyl, Oxo, chlorine, R A R is selected from the group consisting of trifluoroethyl, difluoroethyl, methyl and ethyl. A O-, (C3-C8)heterocycloalkyl-(C1-C6)alkyl-, preferably (piperidinyl)methyl; piperazinyl, optionally further substituted with (C3-C8)heterocycloalkyl, preferably methyl; Heteroaryl, preferably pyridinyl; RC -NHC(O)R is methyl C , R A and R B is methyl (R A R B )N-, R C R is methyl C O-, R A is H and R B -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 , and heteroaryl, where any of said heteroaryl is optionally selected from the group consisting of (C1-C3)alkyl, -C(O)N(R A R B ) may be substituted with one or more groups selected from R D is (C1-C6) alkyl, preferably methyl; J (C1-C6) alkyl, preferably methyl; R C is H or (C1-C6) alkyl, preferably methyl C selected from the group consisting of Concerning compounds 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 pharma- ceutically 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

[0077] In a further preferred embodiment, the present invention Z is aryl, where any said aryl is optionally 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-, where any of said alkyl, heteroaryl is optionally selected from (C1-C3)alkyl, (C1-C6)haloalkyl, oxo, R A O-, aryl, (R A R B ) optionally substituted with one or more groups selected from N- and halo; R A and R B is independently, at each occurrence, 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, and heterocycloalkyl, where any of said heteroaryl is optionally selected from the group consisting of (C1-C3)alkyl, -C(O)N(R A R B ) may be substituted with one or more groups selected from J is H or OR C selected from the group consisting of; R C is H or (C1-C6) alkyl, (R A R B )N-; R D is H or (C1-C6)alkyl; Concerning compounds of formula (I):

[0078] According to a preferred embodiment, the present invention refers to at least one compound of Table 5 selected from: 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 Z is heteroaryl, where any said heteroaryl is optionally 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-; wherein any of said alkyl, heteroaryl may be optionally substituted with one or more groups selected from (C1-C3) alkyl, (C1-C6) haloalkyl, and -oxo; Y is -OR D and; J is H; R D is (C1-C6) alkyl; Concerning compounds of formula (I):

[0080] According to a preferred embodiment, the present invention refers to at least one compound of Table 6 selected from: 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 present invention relates to a compound in which Y is -OR D Formula (Ia) [ka] [During the ceremony, Z is selected from the group consisting of aryl, wherein any said aryl is optionally substituted with one or more groups selected from halo; R1 is H; R2 is selected from the group consisting of heteroaryl(C1-C4)alkyl-, where any said heteroaryl is optionally substituted with one or more groups selected from (C1-C3)alkyl, C1-C6)haloalkyl; R A and R B is independently selected from the group consisting of: H or (C1-C4)alkyl-, at each occurrence; R C is selected from the group consisting of: H, at each occurrence, or (C1-C6)alkyl; R D is H, (C1-C6)alkyl, (C3-C8)heterocycloalkyl-(C1-C6)alkyl-, R C OC(O)(C1-C4)alkylene-, (R A R B )N(C1-C6)alkylene-, (C3-C8)heterocycloalkyl, R C O(C1-C4)alkylene-, (R A RB )N(O)C(C1-C4)alkylene-, (C3-C8)cycloalkyl-(C1-C6)alkyl-, wherein any said heterocycloalkyl is optionally substituted with one or more groups selected from (C1-C3)alkyl; J is H. The present invention relates to a compound of formula (I) represented by:

[0082] In a further preferred embodiment, the present invention Z is H, or Aryl, preferably phenyl is selected from the group consisting of Each of said aryl optionally is Halo, preferably fluorine and optionally substituted with one or more groups selected from R1 is H; R2 selected from the group consisting of heteroaryl(C1-C4)alkyl-, (pyrimidinyl)ethyl, (pyridazinyl)methyl; Each of said heteroaryls is optionally (C1-C3) alkyl, preferably methyl Trifluoromethyl may be 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 is 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 is selected from the group consisting of Each of said heterocycloalkyls is optionally substituted with one or more groups selected from methyl, ethyl, and propyl; J is H, Concerning compounds of formula (Ia):

[0083] According to certain embodiments, the present invention provides at least one of the compounds listed in Table 7 below and at least one of their pharma- ceutically 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] The compounds of formula (I), including any of the compounds listed above or at least one of these compounds, may be prepared using commonly known methods and according to the methods detailed in the schemes set forth below.

[0085] Scheme 1 [ka] In one embodiment of the present invention, compound (IA) can be prepared from compound (II) according to Scheme 1. Compound (II) was prepared according to the method described in J.Med Chem., 2015, 58 (8), 3548-3571.

[0086] Compound (III) can be prepared from compound (II) with an appropriate amine (Reagent 1) by a deoxyamination reaction mediated by a coupling agent such as PyBOP.

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

[0091] Compound (IA) may be prepared from compound (V) with the appropriate amine (Reagent 1) by a deoxyamination reaction mediated by a reagent such as PyBOP or a similar reagent.

[0092] Some of the compounds (IA) may contain protected hydroxyl or amino groups which are subsequently deprotected by known methods.

[0093] Scheme 2 [ka] In another embodiment of the present invention, compound (IB) may be prepared from compound (VI) according to Scheme 2.

[0094] Compound (VII) may be prepared from compound (VI) by means of a 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 the Stille, Suzuki coupling or 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 deoxyamination 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 are subsequently removed by known methods.

[0098] Scheme 3 [ka] In another embodiment of the present invention, compound (IC) may be prepared from compound (IX) according to Scheme 3.

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

[0100] Compound (XI) may be prepared from compound (X) by halogenation using a suitable reagent such as bromine, NBS, NIS, iodine, iodonium salts or similar reagents.

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

[0102] Compound (XIII) may be prepared from compound (XII) by a quinazoline ring construction reaction using an appropriate reagent such as formamide or a similar reagent.

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

[0104] Compounds (IC) can be prepared from compounds (XIV) by a metal-catalyzed cross-coupling reaction such as the Stille, Suzuki coupling or 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 subsequently removed by known methods.

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

[0106] Scheme 4 [ka] In another embodiment of the present invention, compound (ID) may be prepared from compound (IA) according to Scheme 4.

[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 with a suitable alkylating agent (reagent 4), such as an alkyl chloride, bromide, iodide, mesylate, tosylate or similar reagent.

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

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

[0111] Scheme 5 [ka] In another embodiment of the present invention, compound (IE) may be prepared from compound (XVI) according to Scheme 5.

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

[0113] Compound (IE) may 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, for example, an organoboron compound.

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

[0115] Scheme 6 [ka] In another embodiment of the present invention, compounds (IF) and (IG) may be prepared from compound (XIII) according to Scheme 6.

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

[0117] Compounds (IF) can be prepared from compounds (XVIII) by deoxyamination 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 subsequently removed by known methods.

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

[0119] Compounds (IG) can be prepared from compounds (XIX) by a deoxyamination 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 are subsequently removed by known methods.

[0121] Scheme 7 [ka] In another embodiment of the present invention, compounds (IH) and (IJ) can be prepared from compound (VI) according to Scheme 7.

[0122] Compound (XX) may 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) may be prepared from compound (XX) by, for example, a metal catalyzed cross-coupling reaction such as the Stille, Suzuki coupling or similar reaction using an organoboron compound or a suitable organometallic reagent (reagent 2).

[0124] Compound (XXII) can be prepared from compound (XXI) by a chlorination reaction with 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) may be prepared from compound (XXIII) by hydrolysis with a suitable reagent such as, for example, acetic acid.

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

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

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

[0130] In a particular embodiment, the present invention provides a compound of formula (Ib) [ka] [During the ceremony, R3 is OH or halo; R4 is H or OH; R5 is halo or -OMe; R6 is halo or Z; Z is as defined above. The present invention relates to a compound of the formula:

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

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

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

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

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

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

[0137] The present invention also provides pharmaceutical compositions comprising a compound of formula (I) 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.

[0138] In one embodiment, 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 the present invention of formula (I) or a pharma- ceutically 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 respiratory diseases, preferably 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.

[0141] More preferably, the present invention refers to compounds of formula (I) for use in the prevention and / or treatment of chronic cough and cough associated with respiratory diseases such as COPD, asthma and bronchospasm.

[0142] The present invention also provides a method for the prevention and / or treatment of disorders associated with P2X3 receptor mechanisms, which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of the present invention.

[0143] In particular, the present invention refers to a method for the prevention and / or treatment of 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, 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 pharma- ceutically acceptable salt thereof. As used herein, a "safe and effective amount" in reference to a compound of formula (I) or a pharma- ceutically acceptable salt thereof or other pharma- ceutical active substance means an amount sufficient to treat the patient's condition but low enough to avoid serious side effects, however the amount is routinely determined by one skilled in the art. The compound of formula (I) or a pharma- ceutical acceptable salt thereof may be administered once or according to a dosing regimen in which various doses are administered at different time intervals during a given period of time. Typical daily dosages may vary depending on the particular route of administration selected.

[0146] The present invention provides pharmaceutical compositions of a compound of formula (I) in admixture with one or more pharma- ceutically acceptable carriers or excipients, e.g., as described in Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., NY, USA.

[0147] Administration of the compounds of the present invention and pharmaceutical compositions thereof can be accomplished, for example, orally, nasally, parenterally (subcutaneous, intravenous, intramuscular, intrasternal and infusion) and by inhalation, depending on the needs of the patient.

[0148] Preferably, the compounds of the present invention may 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, including solid forms such as tablets, gel capsules, capsules, caplets, granules, lozenges and bulk powders.The compounds of the present invention can be administered alone or in combination with a variety of pharma- ceutically acceptable carriers, diluents (e.g., sucrose, mannitol, lactose, starch) and known excipients, including suspending agents, solubilizing agents, buffering agents, binders, disintegrating agents, preservatives, coloring agents, flavoring agents, lubricants, etc.Time-release capsules, tablets and gels are also advantageous for administering 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, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups and elixirs.Such dosage forms also contain suitable known inert diluents such as water and suitable known excipients such as preservatives, wetting agents, sweeteners, flavoring agents, and substances for emulsifying and / or suspending the compounds of the present invention.The compounds of the present invention can be administered in the form of isotonic sterile solution, for example, intravenously.

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

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

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

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

[0156] Inhalation aerosols containing a propellant gas such as hydrofluoroalkanes contain the compounds of the invention in solution or in dispersed form. Propellant-driven formulations may also contain other ingredients such as cosolvents, stabilizers and optionally other excipients.

[0157] Propellant-free inhalable formulations containing the compounds of the invention may be in the form of solutions or suspensions in aqueous, alcoholic or hydroalcoholic vehicles, which may be delivered by jet or ultrasonic nebulizers or soft mist nebulizers known in the art.

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

[0159] The compounds of the invention may be administered as the sole active substance or in combination with other pharma- ceutical active ingredients.

[0160] Preferably, the compounds of the present invention may be combined with therapeutic agents or active ingredients useful in the treatment of diseases associated with or mediated by the P2X3 receptor.

[0161] The dosage of the compounds of the present invention will depend on a variety of factors, including, inter alia, the particular disease being treated, the severity of the condition, the route of administration, and the like.

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

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

[0164] The examples of experimental implementations described herein serve to illustrate the invention, and the invention is not limited to the examples shown. EXAMPLES

[0165] Preparation of intermediates and example compounds Chemical names were assigned using Dotmatics software. In some cases, commonly used names of commercially available reagents were used in place of the names assigned by the Dotmatics software.

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

[0167] (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine HCl, (R)-1-(6-methylpyridazin-3-yl)ethan-1-amine HCl were prepared according to the method described in WO 2016 / 091776.

[0168] Abbreviation-Meaning 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 pressure liquid chromatography; SFC: supercritical fluid chromatography; dppf: 1,1'-bis(diphenylphosphino)ferrocene; DIEA or DIPEA: N,N-diisopropylethylamine; MeCN: acetonitrile; MTBE: tert-butyl methyl ether; TBDMSCl: tert-butyl(chloro)dimethylsilane; DMSO: dimethyl sulfoxide; Boc2O: di-tert-butyl dicarbonate; UPLC: Ultra-high performance liquid chromatography

[0169] General Experimental Details and Methods Analysis method 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) with an initial hold of 1.2 min at 5% acetonitrile / water (each mobile phase contained 0.1% formic acid), followed by a linear gradient from 5 to 100% within 3.5 min, followed by a hold at 100% for 1.5 min (F = 0.5 mL / min).

[0170] Method 2 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 BEH Shield RP18 column (1.7 μm, 100 × 2.1 mm) with an initial hold of 1.2 min at 5% acetonitrile / water (each mobile phase containing 10 mM ammonium bicarbonate), followed by a linear gradient of 5 to 100% within 3.5 min, followed by a hold of 100% for 1.5 min (F = 0.5 mL / min).

[0171] Method 3 UPLC-MS was performed on a Waters DAD + Waters SQD2, single quadrupole UPLC-MS spectrometer using an Acquity UPLC BEH Shield RP18 1.7 μm 100 × 2.1 mm (Plus guard cartridge) and the column temperature was maintained at 5% acetonitrile / water (each mobile phase containing 10 mM ammonium bicarbonate) for 0.4 min, followed by a linear gradient from 5 to 95% within 6.4 min, followed by a hold at 95% for 1.2 min (F = 0.4 mL / min).

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

[0173] Method 5 Acquity UPLC-QDa mass spectrometer using a C18-reversed phase column (50 x 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] Detection – MS, UV PDA MS Ionization Method - Electrospray (positive / negative ion)

[0174] Method 6 Acquity UPLC-QDa mass spectrometer equipped with a C18 reversed phase column (50 x 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] Detection – MS, UV PDA MS Ionization Method - Electrospray (positive / negative ion)

[0175] Method 7 Dionex UHPLC Ultimate 3000 equipped with a Kinetex® 2.6 μm XB-C18 (4.6 × 50 mm), 110A DAD detector / Thermo Scientific MSQ Pluse maintained at 25 °C, elution with A: 0.1% v / v formic acid in water, B: 0.1% v / v formic acid in acetonitrile. gradient: [Table 10] Detection – MS, UV PDA MS Ionization Method - Electrospray (positive / negative ion)

[0176] NMR 1 H nuclear magnetic resonance (NMR) spectroscopy was performed at near room temperature using Bruker or Varian instruments operating at 300 or 400 MHz with the solvents indicated unless otherwise noted. In all cases, the NMR data were consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts per million using conventional abbreviations for the designation of major peaks, e.g., s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; m, multiplet; br, broad.

[0177] Preparative reversed-phase HPLC conditions Preparative HPLC purification was performed by reversed-phase HPLC using a Waters Fractionlynx preparative HPLC system (2525 pump, 2996 / 2998 UV / VIS detector, 2767 liquid handler) or an equivalent HPLC system, such as a Gilson Trilution UV directed system. The Waters 2767 liquid handler acted as both an autosampler and a fraction collector. The columns used for the preparative purification of the compounds were Waters Sunfire OBD Phenomenex Luna Phenyl Hexyl, 10 μm 19×150 mm or Waters Xbridge Phenyl, 19×150, 5 μm columns. Appropriate predefined gradients were selected based on the acidic or basic conditions, acetonitrile and methanol solvent systems. 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 from 210-400 nm, triggering a threshold collection value at 260 nm, and triggering the presence of the target molecular ion as observed under API conditions when using Fractionlynx. Collected fractions were analyzed by LCMS (Waters Acquity system equipped with a Waters SQD).

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

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

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

[0181] Method 10 SFC-MS was performed isocratically using a Lux Cellulose-4 column on a Waters / Thar SFC system equipped with a Waters SQD, with 55% ethyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and a column temperature of 40 °C.

[0182] Method 11 SFC-MS was performed isocratically using a Lux Cellulose-4 column on a Waters / Thar SFC system equipped with a Waters SQD, with 20% isopropyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and a column temperature of 40 °C.

[0183] Method 12 SFC-MS was performed isocratically using a Lux Cellulose-4 column on a Waters / Thar SFC system equipped with a Waters SQD, 30% isopropyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and a column temperature of 40 °C.

[0184] Method 13 SFC-MS was performed isocratically using a Lux Cellulose-4 column on a Waters / Thar SFC system equipped with a Waters SQD, with 50% isopropyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and a column temperature of 40 °C.

[0185] Method 14 SFC-MS was performed isocratically using a Lux Cellulose-4 column on a Waters / Thar SFC system equipped with a Waters SQD, with 25% methyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and a column temperature of 40 °C.

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

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

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

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

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

[0191] Method 20 SFC-MS was performed isocratically on a Waters / Thar SFC system equipped with a Waters SQD using a YMC Amylose-C column, with 20% methyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and a column temperature of 40 °C.

[0192] Method 21 SFC-MS was performed isocratically on a Waters / Thar SFC system equipped with a Waters SQD using a YMC cellulose-C column, with 15% isopropyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and a column temperature of 40 °C.

[0193] Method 22 SFC-MS was performed isocratically on a Waters / Thar SFC system equipped with a Waters SQD using a YMC cellulose-C column, with 15% methyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and a column temperature of 40 °C.

[0194] Method 23 SFC-MS was performed isocratically on a Waters / Thar SFC system equipped with a Waters SQD using a YMC cellulose-C column, with 25% methyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and a column temperature of 40 °C.

[0195] Method 24 SFC-MS was performed isocratically on a Waters / Thar SFC system equipped with a Waters SQD using a YMC Cellulose-SC column, with 55% isopropyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and a column temperature of 40 °C.

[0196] Method 25 SFC-MS was performed isocratically using a Lux Cellulose-3 column on a Waters / Thar SFC system equipped with a Waters SQD, with 10% methyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and a column temperature of 40 °C.

[0197] Method 26 SFC-MS was performed isocratically using a Lux Cellulose-3 column on a Waters / Thar SFC system equipped with an SQD, with 25% methyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and a column temperature of 40 °C.

[0198] Method 27 SFC-MS was performed isocratically using a Lux Cellulose-3 column on a Waters / Thar SFC system equipped with a Waters SQD, with 30% methyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and a column temperature of 40 °C.

[0199] Method 28 SFC-MS was performed isocratically using a Lux Cellulose-4 column on a Waters / Thar SFC system equipped with a Waters SQD, with 40% isopropyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and a column temperature of 40 °C.

[0200] Method 29 SFC-MS was performed isocratically using a Lux Cellulose-4 column on a Waters / Thar SFC system equipped with a Waters SQD, with 40% methyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and a column temperature of 40 °C.

[0201] method 30 SFC-MS was performed isocratically using a Lux Cellulose-4 column on a Waters / Thar SFC system equipped with a Waters SQD, with 50% methyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and a column temperature of 40 °C.

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

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

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

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

[0206] Method 35 SFC-MS was performed isocratically on a Waters / Thar SFC system equipped with a Waters SQD using a YMC Amylose-C column, with 30% methyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and a column temperature of 40 °C.

[0207] method 36 SFC-MS was performed isocratically on a Waters / Thar SFC system equipped with a Waters SQD using a YMC Amylose-C column, with 40% methyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and a column temperature of 40 °C.

[0208] Method 37 SFC-MS was performed isocratically on a Waters / Thar SFC system equipped with a Waters SQD using a YMC Amylose-C column, with 55% methyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and a column temperature of 40 °C.

[0209] Method 38 SFC-MS was performed isocratically on a Waters / Thar SFC system equipped with a Waters SQD using a YMC cellulose-C column, with 20% methyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and a column temperature of 40 °C.

[0210] Method 39 SFC-MS was performed isocratically on a Waters / Thar SFC system equipped with a Waters SQD using a YMC Cellulose-SC column, with 35% isopropyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and a column temperature of 40 °C.

[0211] method 40 SFC-MS was performed isocratically on a Waters / Thar SFC system equipped with a Waters SQD using a YMC Cellulose-SC column, with 45% isopropyl alcohol / CO2 (containing 0.1% diethylamine) at 5 mL / min, 120 bar back pressure, and a column temperature of 40 °C.

[0212] Preparation 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 Preparation of intermediate 1,2-amino-5-bromo-3-methoxybenzoic acid hydrobromide [ka] At 0° C., a solution of bromine (6.0 g, 1.9 mL, 37.70 mmol) in chloroform (15 mL) was added dropwise over 1 h to a suspension of 2-amino-3-methoxybenzoic acid (6.0 g, 35.90 mmol) in chloroform (180 mL). The reaction was stirred for a further 5 h and allowed to warm slowly to room temperature. The solvent was removed in vacuo and the residue triturated with diethyl ether. The reaction was filtered to give the title compound as a beige solid (11.3 g, 96%). LCMS (Method 4): [MH + ]=247(4.07 minutes).

[0213] Preparation of intermediate 2,6-bromo-8-methoxyquinazolin-4-ol [ka] 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 h. After returning to room temperature, the reaction 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 give the title compound as a light brown solid (5.9 g, 76%). LCMS (Method 4): [MH + ]=255(3.07) minutes.

[0214] Preparation of intermediate 3,6-(4-fluorophenyl)-8-methoxyquinazolin-4-ol [ka] Nitrogen was bubbled through a mixture of 6-bromo-8-methoxyquinazolin-4-ol (Intermediate 2) (1.18 g, 4.63 mmol), 4-fluorophenylboronic acid (710 mg, 5.09 mmol) and cesium carbonate (5.73 g, 17.58 mmol) in 1,4-dioxane (30 mL) and water (7.5 mL) for 5 min, after which [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (190 mg, 0.23 mmol) was added and the reaction heated at 110° C. for 5 h. After returning to room temperature, the reaction was diluted with water (20 mL), filtered and the solid washed with 10% methanol-diethyl ether followed by diethyl ether to give the title compound as a beige solid (1.0 g, 80%). LCMS (Method 5): [MH + ]=271.1(0.81) minutes.

[0215] 6-(4-Fluorophenyl)-8-methoxy-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)quinazolin-4-amine [ka] To a solution of 6-(4-fluorophenyl)-8-methoxyquinazolin-4-ol (intermediate 3) (100 mg, 0.37 mmol) in N,N-dimethylformamide (2 mL) was added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (212 mg, 0.41 mmol) and diisopropylethylamine (0.32 mL, 1.85 mmol). The resulting mixture was heated to 40° C. and stirred for 20 min, after which 1-(3-methyl-1,2,4-oxadiazol-5-yl)ethan-1-amine (67 mg, 0.41 mmol) was added and heating was maintained at 40° C. for 18 h. After returning to room temperature, the mixture was diluted with ethyl acetate (50 mL) and water (20 mL). The organic phase was washed with brine (2×20 mL), passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by preparative HPLC to give the title compound as a white solid (43 mg, 31%). 1 H NMR (400MHz, DMSO):δ 8.85(d, J=6.8Hz, 1H), 8.49(s, 1H), 8.24(s, 1H), 7.99(dd, J=5.6, 8.6Hz, 2H), 7.61(s, 1H), 7. 44(dd, J=8.8, 8.8Hz, 2H), 5.88-5.82(m, 1H), 4.08(s, 3H), 2.37(s, 3H), 1.78(d, J=7.1Hz, 3H). LCMS (Method 4): [MH + ]=375(3.29) minutes.

[0216] Following a similar method 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, the compounds shown in the table below were synthesized. [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

[0217] Example 114 N-(((1r,4r)-4-aminocyclohexyl)methyl)-6-(4-fluorophenyl)-8-methoxyquinazolin-4-amine [ka] Step 1: Preparation of benzyl ((1r,4r)-4-(((6-(4-fluorophenyl)-8-methoxyquinazolin-4-yl)amino)methyl)cyclohexyl)carbamate [ka] To a solution of 6-(4-fluorophenyl)-8-methoxyquinazolin-4-ol (intermediate 3) (80 mg, 0.30 mmol) in N,N-dimethylformamide (2 mL) was added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (169 mg, 0.32 mmol) and diisopropylethylamine (0.32 mL, 1.85 mmol) successively. The resulting mixture was heated to 40° C. and stirred for 20 min, after which benzyl ((1r,4r)-4-(aminomethyl)cyclohexyl)carbamate (93 mg, 0.36 mmol) was added and heating was maintained at 40° C. for 18 h. After returning to room temperature, the mixture was diluted with ethyl acetate (50 mL) and water (20 mL). The organic phase was washed with brine (2×20 mL), passed through a hydrophobic frit and the solvent removed in vacuo. The residue was used directly in the next step without further purification.

[0218] Step 2: Preparation of N-(((1r,4r)-4-aminocyclohexyl)methyl)-6-(4-fluorophenyl)-8-methoxyquinazolin-4-amine [ka] Nitrogen was bubbled through a solution of benzyl ((1r,4r)-4-(((6-(4-fluorophenyl)-8-methoxyquinazolin-4-yl)amino)methyl)cyclohexyl)carbamate (152 mg, 0.30 mmol) in MeOH (3.0 mL) for 5 min, then Pd / C (10%) (31 mg, 0.03 mmol) was added and sodium borohydride (88 mg, 2.36 mmol) was added in portions. The resulting mixture was stirred at room temperature for 2 h. The reaction was filtered through Celite® and then loaded onto an SCX cartridge. The cartridge was washed with methanol and the filtrate was collected when eluting with 7M ammonia-methanol solution. The solvent was removed in vacuo and the residue was purified by preparative HPLC to give the title compound as a brown solid (2.0 mg, 1.8%). 1H NMR((400MHz, MeOD)δ 8.45(s, 1H), 8.31(s, 1H), 7.80(d, J=1.6Hz, 1H), 7.72-7.68(m, 2H), 7.38(d, J=1.6Hz, 1H), 7.13(dd, J=8.8, 8.8Hz, 2H), 3.9 8(s, 3H), 3.41(d, J=7.0Hz, 2H), 2.95-2.86(m, 1H), 1.97-1.87(m, 4H), 1.80-1.70(m, 1H), 1.32-1.03(m, 4H): LCMS (Method 4): [MH. + ]=381(2.43 minutes).

[0219] Intermediate 4 (R)-6-Bromo-8-methoxy-N-(1-(6-methylpyridazin-3-yl)ethyl)quinazolin-4-amine [ka] To a solution of 6-bromo-8-methoxyquinazolin-4-ol (intermediate 2) (65 mg, 0.27 mmol) in N,N-dimethylformamide (1.5 mL) was added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (139 mg, 0.27 mmol) and diisopropylethylamine (0.2 mL, 0.81 mmol) successively. The resulting mixture was heated at 60° C. for 1 h, after which (R)-1-(6-methylpyridazin-3-yl)ethan-1-amine (65 mg, 0.27 mmol) was added and heating was maintained at 60° C. for 18 h. After returning to room temperature, the reaction mixture was concentrated directly onto silica gel and purified by silica gel chromatography eluting with 0-100% in ethyl acetate (10% MeOH in ethyl acetate) to give the title compound as a beige solid (100 mg, quantitative yield). LCMS (Method 4): [MH + ]=374(2.42 minutes).

[0220] Following a similar method as described for the preparation of (R)-6-bromo-8-methoxy-N-(1-(6-methylpyridazin-3-yl)ethyl)quinazolin-4-amine (Intermediate 4), the following intermediates shown in the table below were synthesized. [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 [ka] Step 1: Preparation of 8-methoxy-N-((6-methylpyridazin-3-yl)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-amine [ka] Nitrogen was bubbled through a mixture of 6-bromo-8-methoxy-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine (Intermediate 6) (250 mg, 0.69 mmol), bis-(pinacolato)diboron (194 mg, 0.76 mmol), [1,1'-bis-(diphenylphosphino)-ferrocene]dichloropalladium(II) (25 mg, 0.03 mmol) and potassium acetate (204 mg, 2.08 mmol) in 1,4-dioxane (15.0 mL) for 5 min. The mixture was stirred at 90° C. for 18 h. After returning to room temperature, the reaction 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: Preparation of 8-methoxy-6-(5-methyl-1,3,4-thiadiazol-2-yl)-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine [ka] Nitrogen was bubbled through a mixture of 2-bromo-5-methyl-1,3,4-thiadiazole (34 mg, 0.19 mmol), 8-methoxy-N-((6-methylpyridazin-3-yl)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-amine (70 mg, 0.17 mmol), potassium carbonate (36 mg, 0.26 mmol) and water (0.5 mL) in 1,4-dioxane (4.0 mL) for 5 minutes before adding tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.02 mmol). The resulting mixture was heated at 95° C. for 16 hours. After cooling to room temperature, the reaction was filtered through Celite® and washed with ethyl acetate (20 mL). The organic phases were combined, passed through a hydrophobic frit and the solvent 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 (400MHz, DMSO):δ 9.31(dd, J=5.8, 5.8Hz, 1H), 8.47(s, 1H), 8.44(d, J=1.7Hz, 1H), 7.80(d, J=1.4Hz, 1H), 7.58(d, J =8.7Hz, 1H), 7.51(d, J=8.7Hz, 1H), 5.03(d, J=5.8Hz, 2H), 4.03(s, 3H), 2.84(s, 3H), 2.60(s, 3H). LCMS (Method 3): [MH + ]=380(2.13 minutes).

[0223] Following a similar method as 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, the compounds were prepared in the following steps as shown in the table below. [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 [ka] Step 1: Preparation of 6-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-8-methoxy-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine [ka] Nitrogen was bubbled through a mixture of 6-bromo-8-methoxy-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine (Intermediate 6) (100 mg, 0.28 mmol), bis(neopentylglycolato)diboron (66 mg, 0.29 mmol), [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane complex (10 mg, 0.02 mmol) and potassium acetate (54 mg, 0.55 mmol) in 1,4-dioxane (3.0 mL) for 5 min. The mixture was heated at 100 °C for 3 h. After returning to room temperature, the mixture was used in the next step as a 1,4-dioxane solution without further purification.

[0225] Step 2: Preparation of 8-methoxy-N-((6-methylpyridazin-3-yl)methyl)-6-(5-methylthiazol-2-yl)quinazolin-4-amine [ka] To the above solution of 6-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-8-methoxy-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine (100 mg, 0.28 mmol) was added aqueous cesium carbonate (181 mg, 0.56 mmol, 0.4 mL), 2-bromo-5-methylthiazole (64 mg, 0.28 mmol) and tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.02 mmol). The resulting mixture was heated at 95° C. for 16 h. After returning to room temperature, the mixture was filtered through Celite® and the filter cake was washed with ethyl acetate (2×10 mL). The organic phase was washed with saturated aqueous ammonium chloride (10 mL), passed through a hydrophobic frit and the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound as an off-white solid (25 mg, 24%). 1 H NMR (400MHz, DMSO):δ 9.24(dd, J=5.7, 5.7Hz, 1H), 8.43(s, 1H), 8.37(d, J=1.5Hz, 1H), 7.75(d, J=1.5Hz, 1H), 7.68(d, J=1.1Hz, 1H) , 7.57(d, J=8.7Hz, 1H), 7.50(d, J=8.7Hz, 1H), 5.02(d, J=5.8Hz, 2H), 4.00(s, 3H), 2.60(s, 3H), 2.50(s, 3H). LCMS (Method 3): [MH + ]=379(3.20 minutes).

[0226] Following a similar method as described for the preparation of 8-methoxy-N-((6-methylpyridazin-3-yl)methyl)-6-(5-methylthiazol-2-yl)quinazolin-4-amine, the compounds were prepared in the following steps as shown in the table below. [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 [ka] To a solution of 6-bromo-8-methoxy-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine (Intermediate 6) (100 mg, 0.28 mmol) in 1,4-dioxane (2.0 mL) was added 1-methyl-4-(tributylstannyl)-1H-pyrazole (124 mg, 0.33 mmol) and tetrakis(triphenylphosphine)palladium(0) (32 mg, 0.03 mmol). The resulting mixture was heated at 80° C. for 18 h. After returning to room temperature, the reaction was filtered through Celite®. The Celite® cake was washed with ethyl acetate (2×20 mL). The combined organic phases were washed with 1N aqueous potassium fluoride (10 mL), filtered through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by preparative HPLC to give the title compound as an off-white solid (6.7 mg, 7%). 1 H NMR (400MHz, DMSO):δ 8.83(dd, J=5.8, 5.8Hz, 1H), 8.36(s, 1H), 8.27(s, 1H), 8.09(d, J=1.5Hz, 1H), 8.02(s, 1H), 7.55( d, J=8.7Hz, 1H), 7.52-7.46(m, 2H), 5.03(d, J=5.8Hz, 2H), 3.98(s, 3H), 3.92(s, 3H), 2.60(s, 3H). LCMS (Method 3): [MH + ]=362(2.64 minutes).

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

[0229] Example 164 6-(4-Fluoro-3-methylphenyl)-8-methoxy-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine [ka] To a solution of 6-bromo-8-methoxy-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine (Intermediate 6) (70 mg, 0.19 mmol) in 1,4-dioxane (4.0 mL) was added 4-fluoro-3-methylphenylboronic acid (33 mg, 0.21 mmol), tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.02 mmol), potassium carbonate (36 mg, 0.26 mmol) and water (0.5 mL). The resulting mixture was heated at 95° C. for 18 hours. After cooling to room temperature, the reaction 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 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 (400MHz, DMSO)d 9.03(dd, J=5.8, 5.8Hz, 1H), 8.41(s, 1H), 8.15(d, J=1.8Hz, 1H), 7.82(dd, J=2.0, 7.4Hz, 1H), 7.77-7.72(m, 1H), 7.5 7-7.49(m, 3H), 7.31(dd, J=9.1, 9.1Hz, 1H), 5.03(d, J=5.8Hz, 2H), 4.03(s, 3H), 2.60(s, 3H), 2.37(d, J=1.8Hz, 3H). LCMS (Method 4): [MH + ]=390(3.12 minutes).

[0230] Following a similar method as described for the preparation of 6-(4-fluoro-3-methylphenyl)-8-methoxy-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine, the compounds were prepared in the following steps as shown in the table below. [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 [ka] To a solution of 6-bromo-8-methoxy-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine (Intermediate 6) (70 mg, 0.19 mmol) in 1,2-dimethoxyethane (3.0 mL) was added (4-fluoro-2-methoxyphenyl)boronic acid (41 mg, 0.24 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (8.2 mg, 0.01 mmol), cesium carbonate (130 mg, 0.40 mmol) and water (0.3 mL). The resulting mixture was heated at 95° C. for 18 hours. After cooling to room temperature, the reaction 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 removed in vacuo. The residue was purified by preparative HPLC to give the title compound as an off-white solid (35 mg, 45%). 1 H NMR (400MHz, DMSO):δ 8.92(dd, J=5.8, 5.8Hz, 1H), 8.41(s, 1H), 7.91(d, J=1.5Hz, 1H), 7.54-7.46(m, 3H), 7.37(d, J=1.4Hz, 1H), 7. 10(dd, J=2.4, 11.5Hz, 1H), 6.97-6.91(m, 1H), 4.99(d, J=5.6Hz, 2H), 3.93(s, 3H), 3.84(s, 3H), 2.59(s, 3H). LCMS (Method 3): [MH + ]=406(3.97 minutes).

[0232] Starting from the appropriate intermediates shown in the table and applying the methods described above, 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 [ka] Step 1: Preparation of 6-bromo-8-methoxy-2-methylquinazolin-4-ol [ka] To a solution of 2-amino-5-bromo-3-methoxybenzoic acid hydrobromide (0.5 g, 1.53 mmol) (Intermediate 1) in N,N-dimethylformamide (5 mL) was added 1-hydroxybenzotriazole hydrate (0.23 g, 1.68 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.32 g, 1.68 mmol) and N,N-diisopropylethylamine (0.29 mL, 1.68 mmol) in succession. The resulting mixture was stirred at room temperature for 2 hours. The reaction was then cooled to 0°C and 28% aqueous ammonium hydroxide solution (1.5 mL) was added dropwise and the reaction was allowed to warm to room temperature overnight. The reaction was concentrated in vacuo and the residue was dissolved in triethyl orthoacetate (3.4 mL, 18.36 mmol), acetic acid (0.84 mL, 14.69 mmol) was added and the reaction was heated at 120° C. for 2 h. The reaction was then cooled and concentrated. The crude residue was triturated with isopropanol and filtered to give the title compound as an off-white solid (0.10 g, 30%). LCMS (Method 3): [MH + ]=268 / 270(3.28 minutes).

[0234] Step 2: Preparation of 6-(4-fluorophenyl)-8-methoxy-2-methylquinazolin-4-ol [ka] A mixture of 6-bromo-8-methoxy-2-methylquinazolin-4-ol (0.10 g, 0.37 mmol), 4-fluorophenylboronic acid (57 mg, 0.409 mmol), cesium carbonate (0.46 g, 1.41 mmol), and water (0.5 mL) in 1,4-dioxane (2 mL) was bubbled with nitrogen for 5 minutes, after which [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (15 mg, 0.0186 mmol) was added. The reaction was heated at 120° C. for 4 hours. After returning to room temperature, the reaction was diluted with water (10 mL) and ethyl acetate (10 mL), after which the reaction was filtered and the collected solid was washed with water (10 mL) and diethyl ether (10 mL). The title compound was obtained as a grey solid (0.10 g, 94%). LCMS (Method 3): [MH + ]=285(3.59 minutes).

[0235] Step 3: Preparation of (R)-6-(4-fluorophenyl)-8-methoxy-2-methyl-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine [ka] To a solution of 6-(4-fluorophenyl)-8-methoxy-2-methylquinazolin-4-ol (100 mg, 0.35 mmol) in N,N-dimethylformamide (2 mL) was added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (201 mg, 0.39 mmol) and diisopropylethylamine (0.31 mL, 1.76 mmol) in succession. The resulting mixture was heated at 40° C. and stirred for 20 minutes, after which (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethan-1-amine (88 mg, 0.387 mmol) was added and heating was maintained at 40° C. for 4 hours. After returning to room temperature, the reaction was purified by preparative HPLC to give the title compound (15.1 mg, 9%). 1 H NMR (400MHz, DMSO):δ 9.22(s, 2H), 8.55(d, J=6.8Hz, 1H), 8.18(s, 1H), 7.95(dd, J=5.6, 8.6Hz, 2H), 7.51(s, 1H), 7. 42(dd, J=8.7, 8.7Hz, 2H), 5.73-5.66(m, 1H), 4.03(s, 3H), 2.46(s, 3H), 1.78(d, J=7.1Hz, 3H). LCMS (Method 4): [MH + ]=458(4.97 minutes).

[0236] Example 184 (R)-6-(4-fluorophenyl)-8-methoxy-4-((1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-amino)-quinazolin-2-ol [ka] Step 1: Preparation of 6-bromo-8-methoxyquinazoline-2,4-diol [ka] A mixture of 2-amino-5-bromo-3-methoxybenzoic acid hydrobromide (Intermediate 1) (1.0 g, 3.06 mmol) and urea (1.84 g, 30.58 mmol) was heated at 170° C. for 18 h. After returning to room temperature, the reaction was diluted with water (50 mL) and filtered. The collected solid was washed with water (20 mL) and diethyl ether (20 mL) to give the title compound as a light brown solid (0.7 g, 84%), which was used in the next step without further purification. LCMS (Method 4): [MH + ]=271(3.17 minutes).

[0237] Step 2: Preparation of 2,4-dichloro-6-(4-fluorophenyl)-8-methoxyquinazoline [ka] Nitrogen was bubbled through a mixture of 6-bromo-8-methoxyquinazoline-2,4-diol (0.5 g, 1.84 mmol), 4-fluorophenylboronic acid (284 mg, 2.03 mmol), cesium carbonate (2.28 g, 7.01 mmol) and water (2.5 mL) in 1,4-dioxane (10.0 mL) for 5 min, after which [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (75 mg, 0.09 mmol) was added. The resulting mixture was heated at 120° C. for 4 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was dry loaded onto silica gel and purified by silica gel chromatography eluting with 0-5% methanol in dichloromethane to give 160 mg of crude product. This product (68 mg) was suspended in phosphorus oxychloride (1 mL, 10.73 mmol) and N,N-diisopropylethylamine (0.026 mL, 0.147 mmol) was added dropwise followed by N,N-dimethylformamide. The solution was then heated at 130 °C for 18 h. After returning to room temperature the solvent was removed in vacuo. The residue was taken up in H2O (10 mL) and stirred at room temperature for 1 h. The reaction was filtered to give the title compound as an off-white solid (44 mg, 65%). LCMS (Method 4): [MH + ]=323(5.76 minutes).

[0238] Step 3: Preparation of (R)-6-(4-fluorophenyl)-8-methoxy-4-((1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-amino)-quinazolin-2-ol [ka] A mixture of 2,4-dichloro-6-(4-fluorophenyl)-8-methoxyquinazoline (44 mg, 0.13 mmol), (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethan-1-amine (35 mg, 0.13 mmol) and N,N-diisopropylethylamine (0.046 mL, 0.27 mmol) in dichloromethane (2 mL) was stirred at room temperature for 2 h. The reaction was diluted with HO (10 mL) and extracted with dichloromethane (3×30 mL). The combined organic phase was passed through a hydrophobic frit and concentrated in vacuo. The residue was dissolved in acetic acid (2 mL) and heated at 70° C. for 2 h. After returning to room temperature the reaction was concentrated in vacuo and the residue purified by preparative HPLC to give the title compound as an off-white solid (6.1 mg, 10%). 1 H NMR (400MHz, DMSO):δ 10.04(s, 1H), 9.15(s, 2H), 8.68(d, J=7.2Hz, 1H), 8.04(s, 1H), 7.87-7.82(m, 2H), 7.48(d, J=1 .4Hz, 1H), 7.36(dd, J=8.9, 8.9Hz, 2H), 5.66-5.60(m, 1H), 3.97(s, 3H), 1.71(d, J=7.2Hz, 3H). LCMS (Method 4): [MH + ]=460(4.5 minutes).

[0239] Example 185 (R)-6-(4-fluorophenyl)-2,8-dimethoxy-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine [ka] A mixture of 2,4-dichloro-6-(4-fluorophenyl)-8-methoxyquinazoline (143 mg, 0.44 mmol), (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethan-1-amine (117 mg, 0.44 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.89 mmol) in dichloromethane (5 mL) was stirred at room temperature for 2 h. The reaction was then diluted with HO (10 mL) and extracted with dichloromethane (3×30 mL). The combined organic phases were passed through a hydrophobic frit and concentrated in vacuo. The residue was dissolved in methanol (2 mL) and sodium methoxide (25% in methanol) (0.13 mL, 0.58 mmol) was added. The mixture was heated at 80° C. for 2 h. After returning to room temperature, the reaction was concentrated in vacuo and the residue purified by preparative HPLC to give the title compound as a brown solid (3.5 mg, 3.2%). 1 H NMR (400MHz, DMSO):δ 9.17(s, 2H), 8.68(d, J=6.9Hz, 1H), 8.15(d, J=1.8Hz, 1H), 7.93-7.88(m, 2H), 7.47(d, J=1.5Hz, 1H), 7. 38(dd, J=8.9, 8.9Hz, 2H), 5.61(dd, J=6.8, 6.8Hz, 1H), 3.99(s, 3H), 3.83(s, 3H), 1.73(d, J=7.2Hz, 3H). LCMS (Method 4): [MH + ]=474(3.87 minutes).

[0240] Example 186 (R)-6-(4-fluorophenyl)-8-iodo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine [ka] Step 1: Preparation of methyl 4-amino-4'-fluoro-[1,1'-biphenyl]-3-carboxylate [ka] A mixture of methyl 2-amino-5-bromobenzoate (2.00 g, 8.69 mmol), 4-fluorophenylboronic acid, pinacol ester (2.90 g, 12.04 mmol), tripotassium phosphate (3.69 g, 17.39 mmol), and water (3.5 mL) in N,N-dimethylformamide (10.5 mL) was bubbled with nitrogen for 5 min, after which [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (710 mg, 0.87 mmol) was added. The resulting mixture was heated at 100 °C for 1.25 h. After returning to room temperature, the reaction was diluted with water (100 mL) and diethyl ether (100 mL) and the organic phase was separated. The aqueous layer was further extracted with diethyl ether (100 mL) followed by ethyl acetate (100 mL). The organic phases were combined, washed with water (100 mL), dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel chromatography eluting with 5-35% ethyl acetate in cyclohexane to give the title compound as an off-white solid (2.08 g, 97%). 1 H NMR (400MHz, CDCl3): δ 8.06 (d, J=2.3Hz, 1H), 7.50-7.44 (m, 3H), 7.08 (dd, J=8.7, 8.7Hz, 2H), 6.74 (d, J=8.6Hz, 1H), 5.78 (s, 2H), 3.90 (s, 3H).

[0241] Step 2: Preparation of methyl 4-amino-4'-fluoro-5-iodo-[1,1'-biphenyl]-3-carboxylate [ka] A solution of methyl 4-amino-4'-fluoro-[1,1'-biphenyl]-3-carboxylate (2.08 g, 8.48 mmol) in dichloromethane (25 mL) was treated with bis(pyridine)iodonium tetrafluoroborate (4.73 g, 12.72 mmol) and TFA (2.1 mL, 27.42 mmol). The resulting mixture was stirred at room temperature for 2 days. HPLC analysis showed 70% conversion, and additional bis(pyridine)iodonium tetrafluoroborate (1.25 g, 3.36 mmol) was added and stirring was maintained for an additional 2.5 h. The reaction was diluted with dichloromethane (25 mL) and carefully treated with a solution of NaHCO3 (7 g, 83 mmol) in water (100 mL). The aqueous layer was collected and further extracted with dichloromethane (2 x 25 mL). The organic phases were combined, washed with 8% aqueous sodium thiosulfate (100 mL), filtered through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by silica gel chromatography eluting with 0-25% ethyl acetate in cyclohexane to give the title compound as an off-white solid (2.71 g, 86%). 1 H NMR (400MHz, CDCl3): δ 8.10-8.07(m, 1H), 8.04-8.00(m, 1H), 7.46-7.41(m, 2H), 7.09(dd, J=8.6, 8.6Hz, 2H), 6.48-6.37(m, 2H), 3.91(s, 3H).

[0242] Step 3: Preparation of 4-amino-4'-fluoro-5-iodo-[1,1'-biphenyl]-3-carboxylic acid [ka] To a solution of methyl 4-amino-4'-fluoro-5-iodo-[1,1'-biphenyl]-3-carboxylate (2.59 g, 6.98 mmol) in 1,4-dioxane (25 mL) and water (5 mL) was added lithium hydroxide monohydrate (1.75 g, 41.87 mmol). The mixture was stirred at room temperature for 18 h. The reaction was diluted with water (100 mL) and diethyl ether (100 mL) and separated. The aqueous layer was acidified to pH=1 with 1N HCl (45 mL) and extracted with dichloromethane (3×50 mL). The organic phases were combined, filtered through a hydrophobic frit and the solvent removed in vacuo to give the title compound as an off-white solid (2.39 g, 96%). 1 H NMR (400MHz, DMSO):δ 13.17(s, 1H), 8.18(d, J=2.0Hz, 1H), 8.09(d, J=2.3Hz, 1H), 7.65(dd, J=5.4, 8.5Hz, 2H), 7.27(dd, J=8.8, 8.8Hz, 2H), 6.84(s, 2H).

[0243] Step 4: Preparation of 6-(4-fluorophenyl)-8-iodoquinazolin-4(3H)-one [ka] A solution of 4-amino-4'-fluoro-5-iodo-[1,1'-biphenyl]-3-carboxylic acid (2.39 g, 6.69 mmol) in formamide (4 mL) was heated at 130°C for 16 h. After returning to room temperature, the reaction was diluted with water (20 mL), stirred for 20 min, and then filtered. The solid was washed with water (3 x 5 mL) followed by 10% MeOH-diethyl ether solution (3 x 5 mL) to give the title compound as an off-white solid (2.14 g, 87%). 1 H NMR (400MHz, DMSO): δ 12.57(s, 1H), 8.66(s, 1H), 8.36(s, 1H), 8.28(s, 1H), 7.89(dd, J=5.6, 7.8Hz, 2H), 7.38(dd, J=8.6, 8.6Hz, 2H).

[0244] Step 5: Preparation of (R)-6-(4-fluorophenyl)-8-iodo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine [ka] To a solution of 6-(4-fluorophenyl)-8-iodoquinazolin-4-(3H)-one (1.14 g, 3.11 mmol) in N,N-dimethylformamide (10 mL) was added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (2.03 g, 1.25 mmol) and diisopropylethylamine (2.7 mL, 15.57 mmol) in succession. The resulting mixture was heated at 45° C. for 1 h, after which (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethan-1-amine hydrochloride (0.96 g, 4.2 mmol) was added and heating was maintained at 45° C. for 2 h. After returning to room temperature, the mixture was diluted with ethyl acetate (75 mL) and water (175 mL). The organic phase was washed with brine (2×20 mL), passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by silica gel chromatography eluting with 0-15% ethyl acetate in dichloromethane to give the title compound as an off-white solid (1.27 g, 75%). 1 H NMR (400MHz, DMSO):δ 9.18(s, 2H), 8.88(d, J=6.9Hz, 1H), 8.71(d, J=1.8Hz, 1H), 8.67(d, J=1.8Hz, 1H), 8.51(s, 1H) ), 7.95-7.90(m, 2H), 7.40(dd, J=8.9, 8.9Hz, 2H), 5.73-5.67(m, 1H), 1.75(d, J=7.2Hz, 3H).

[0245] Applying the above procedure, using the appropriate amine, the following compounds shown in the table below were prepared. [Table 18]

[0246] Example 188 (R)-6-(4-fluorophenyl)-8-(methylsulfonyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine [ka] Step 1: Preparation of 6-(4-fluorophenyl)-8-(methylsulfonyl)quinazolin-4(3H)-one [ka] To a solution of 6-(4-fluorophenyl)-8-iodoquinazolin-4-(3H)-one (200 mg, 0.546 mmol) in dry DMSO (1.5 mL) was added sodium methanesulfonate (67 mg, 0.655 mmol), copper(I) iodide (10.40 mg, 0.055 mmol) and L-proline (13 mg, 0.109 mmol). The reaction was heated at 110° C. and stirred for 18 hours. All reagents were added once more to ensure complete consumption of starting material. The reaction mixture was cooled to room temperature and loaded onto a column. Purification by RP flash chromatography (Biotage Isolera, C8 40 g cartridge, gradient elution 0-80% B in A; A: water / MeCN 95:5+0.1% HCOOH, B: MeCN / water 95:5+0.1% HCOOH) afforded the title compound as a white powder (52 mg, 0.163 mmol, 30%). LCMS (method 5): 0.81 min, 319[M+H] + .

[0247] Step 2: Preparation of (R)-6-(4-fluorophenyl)-8-(methylsulfonyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine [ka] To a suspension of 6-(4-fluorophenyl)-8-(methylsulfonyl)quinazolin-4(3H)-one (52 mg, 0.163 mmol) in DMF (1 mL) was added (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (94 mg, 0.180 mmol) and diisopropylethylamine (0.086 mL, 0.490 mmol), followed 10 min later by the addition of (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethan-1-amine HCl (56 mg, 0.245 mmol). The resulting mixture was stirred at room temperature for 16 h. Purification by RP flash chromatography (Biotage Isolera, Ultra SNAP 30 g cartridge, gradient elution 0-90% B in A; A: water / MeCN 95:5+0.1% HCOOH, B: MeCN / water 95:5+0.1% HCOOH) afforded the title compound contaminated with impurities. A second purification by flash chromatography (Biotage Isolera, KP-NH 28 g cartridge, gradient elution 5%-100% EtOAc in heptane) afforded the title compound as a pale yellow powder (20 mg, 0.041 mmol, 25% yield). LCMS (Method 5): 1.14 min, 492[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ ppm 9.16(s, 2H), 9.04(brd, J=6.61Hz, 1H), 8.97(s, 1H), 8.58(s, 1H), 8.53(d, J=1.76Hz, 1H), 7.89(dd, J =8.60, 5.29Hz, 2H), 7.41(t, J=8.82Hz, 2H), 5.60-5.70(m, 1H), 3.53(s, 3H), 1.72(d, J=7.28Hz, 3H).

[0248] Applying the above procedure, using the appropriate amine, the following compounds shown in the table below were prepared. [Table 19]

[0249] Example 190 (R)-N-(6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)amino)quinazolin-8-yl)methanesulfonamide [ka] To a solution of (R)-6-(4-fluorophenyl)-8-iodo-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine (60 mg, 0.111 mmol) in 1,4-dioxane (1.5 mL) was added methanesulfonamide (14 mg, 0.145 mmol), copper(I) iodide (2.119 mg, 0.011 mmol), L-proline (2.56 mg, 0.022 mmol) and potassium carbonate (46 mg, 0.334 mmol). The resulting mixture was heated at 150° C. for 6 h. The reaction was diluted with DCM and water was added. The two phases were separated, the aqueous layer was extracted with DCM (2×10 mL) and the combined organic phases were filtered through a PhaseSeparator tube. The volatiles were removed in vacuo. Purification by RP flash chromatography (Biotage Isolera, Ultra SNAP 30 g cartridge, gradient elution 5% to 100% B in A; A: water / MeCN 95:5 + 0.1% HCOOH, B: MeCN / water 95:5 + 0.1% HCOOH) afforded the title compound as a pale beige powder (9 mg, 0.018 mmol, 16% yield). LCMS (Method 5): 1.17 min, 507[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ ppm 9.14(s, 3H), 8.71-8.86(m, 1H), 8.47(s, 1H), 8.36(brs, 1H), 7.95(s, 1H), 7.81(brdd, J=8.16, 5.73Hz, 2H), 7.37(brt, J=8.71Hz, 2H), 5.66(brs, 1H), 3.12(s, 3H), 1.71(brd, J=7.06Hz, 3H).

[0250] Applying the above method, the following compounds shown in the table below were prepared. [Table 20]

[0251] Example 192 (R)-6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)amino)quinazoline-8-sulfonamide [ka] Step 1: Preparation of 6-(4-fluorophenyl)-4-oxo-3,4-dihydroquinazoline-8-sulfonamide [ka] To a suspension of 6-(4-fluorophenyl)-8-(methylsulfonyl)quinazolin-4(3H)-one (167 mg, 0.525 mmol) in dry THF (2 mL) cooled to 0° C. was added lithium diisopropylamide 2.0 M in THF heptane ethylbenzene (1.049 mL, 2.099 mmol). The reaction was allowed to warm to room temperature and stirred for 30 minutes until complete dissolution. To the resulting orange solution was added tributylborane 1.0 M in THF (2.62 mL, 2.62 mmol) and the reaction was heated to 64° C. and stirred for 12 hours. A solution of (aminooxy)sulfonic acid (208 mg, 1.836 mmol) and potassium acetate (232 mg, 2.361 mmol) in water (2 mL) was added and the resulting mixture was stirred at 65° C. for 6 hours. The volatiles were removed in vacuo. The crude was taken up in DMF and purified by RP flash chromatography (Biotage Isolera, Ultra SNAP C18 60 g cartridge, gradient elution 0-80% B in A; A: water / MeCN 95:5+0.1% HCOOH, B: MeCN / water 95:5+0.1% HCOOH). An inseparable mixture of the title compound and starting material was isolated and used as such in the next step.

[0252] Step 2: Preparation of (R)-6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)amino)quinazoline-8-sulfonamide [ka] To a suspension of crude 6-(4-fluorophenyl)-4-hydroxyquinazoline-8-sulfonamide (40 mg, 0.125 mmol) in DMF (1.5 mL) was added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (78 mg, 0.150 mmol) and diisopropylethylamine (0.066 mL, 0.376 mmol), followed 5 min later by (R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethan-1-amine (36 mg, 0.188 mmol). The resulting mixture was stirred at room temperature for 12 h. The reaction was diluted with DCM and quenched with water. The two phases were separated and the aqueous layer was extracted once with DCM. The combined organic phase was filtered through a PhaseSeparator tube and the volatiles were removed in vacuo. Purification by flash chromatography (Biotage Isolera, Ultra SNAP 25 g cartridge, gradient elution 5% to 100% EtOAc in heptane) gave the title compound contaminated with impurity. A second purification by flash chromatography (Biotage Isolera, SNAP NH 28 g cartridge, gradient elution 5% to 100% EtOAc in heptane) gave the title compound as a white powder (4 mg, 8.12 μmol, 6.48% yield). LCMS (method 5): 1.08 min, 493[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ ppm 9.15(s, 2H), 9.01(brs, 1H), 8.88(brd, J=1.98Hz, 1H), 8.54(s, 1H), 8.42-8.49(m, 1H), 7.81-7.96( m, 2H), 7.40(brt, J=8.82Hz, 2H), 7.21(brs, 2H), 5.67(brd, J=6.84Hz, 1H), 1.72(d, J=7.06Hz, 3H).

[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 [ka] Nitrogen was bubbled through a solution of (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), caesium fluoride (85 mg, 0.56 mmol) and water (0.5 mL) in N,N-dimethylformamide (2.0 mL) for 5 minutes before the addition of tetrakis(triphenylphosphine)palladium(0) (21 mg, 0.02 mmol). 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 phase was filtered through a hydrophobic frit and the solvent 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 (400MHz, DMSO):δ 9.24(s, 2H), 8.76(d, J=6.8Hz, 1H), 8.71(s, 1H), 8.59-8.54(m, 2H), 8.39(d, J=1.5Hz, 1H), 8.35(s, 1H), 8.0 3(dd, J=5.4, 8.7Hz, 2H), 7.45(dd, J=8.8, 8.8Hz, 2H), 5.80-5.71(m, 1H), 3.97(s, 3H), 1.80(d, J=7.1Hz, 3H). LCMS (Method 3): [MH + ]=494(5.1 minutes).

[0254] Following a similar procedure to that described for the preparation of (R)-6-(4-fluorophenyl)-8-(1-methyl-1H-pyrazol-4-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine, the following compounds shown in the table below were prepared. [Table 21-1] [Table 20-2]

[0255] Example 198 (R)-6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)amino)-quinazolin-8-ol [ka] To a solution of 6-(4-fluorophenyl)-8-methoxy-N-[(1R)-1-[2-(trifluoromethyl)-pyrimidin-5-yl]ethyl]quinazolin-4-amine (490 mg, 1.11 mmol) in chloroform (8 mL) was added boron tribromide (0.32 mL, 3.32 mmol) dropwise at 0° C. The reaction was then allowed to warm to room temperature and heated at 65° C. for 18 hours. After returning to room temperature the reaction was cooled in an ice bath and quenched with methanol (2 mL). The solvent was removed in vacuo. The residue was diluted with ethyl acetate (50 mL) and washed with saturated aqueous NaHCO3 solution (50 mL). The aqueous layer was then extracted with ethyl acetate (2×20 mL). The organic phases were combined, passed through a hydrophobic frit and the solvent removed in vacuo to give the title compound as a grey solid (416 mg, 88%). 1H NMR (400MHz, DMSO):δ 9.18(s, 2H), 8.65(d, J=7.0Hz, 1H), 8.46(s, 1H), 8.09(s, 1H), 7.86(dd, J=5.5, 8.7Hz, 2H), 7 .45(d, J=1.3Hz, 1H), 7.37(dd, J=8.8, 8.8Hz, 2H), 5.71-5.67(m, 1H), 1.75(d, J=7.0Hz, 3H). OH Not observed.

[0256] Applying the above method, starting from the substrates indicated in the table, the following compounds were prepared: [Table 22]

[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 [ka] Nitrogen was bubbled through a mixture of (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 in toluene, 0.14 mL, 0.14 mmol) in toluene (3.0 mL) for 5 min. The mixture was heated at 100° C. for 72 h. 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%). 1H NMR (400MHz, DMSO): δ 9.18 (s, 2H), 8.64 (d, J=7.0Hz, 1H), 8.44 (s, 1H), 8.23 ​​(d, J=1.6Hz, 1H), 7.94-7.89 (m, 2H), 7.65 (d, J=1.6Hz, 1H), 7.39 (dd, J=8.8, 8.8H z, 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, 9.7Hz, 2H), 2.07-2.00 (m, 2H), 1.74 (d, J=7.0Hz, 5H). LCMS (Method 3): [MH + ]=514(3.79 points).

[0258] Implementation Example 201 6-(4-Fluorophenyl)-8-(((R)-tetrahydrofuran-3-yl)oxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine

change

[0259] Applying the above method, starting from the substrates indicated in the table, the following compounds were prepared: [Table 23-1] [Table 23-2] [Table 23-3] [Table 23-4] [Table 23-5]

[0260] Example 214 2-[6-(4-fluorophenyl)-4-[(6-methylpyridazin-3-yl)methylamino]quinazolin-8-yl]oxyacetic acid, sodium salt [ka] 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 and filtered to give 2-[6-(4-fluorophenyl)-4-[(6-methylpyridazin-3-yl)methylamino]quinazolin-8-yl]oxyacetic acid sodium salt as a white powder (87 mg, 75% yield).

[0261] Example 215 8-(azetidin-3-ylmethoxy)-6-(4-fluorophenyl)-N-[(6-methylpyridazin-3-yl)methyl]quinazolin-4-amine [ka] To a mixture of Example 186A (200 mg, 0.55 mmol) and N-Boc-3-(iodomethyl)azetidine (247 mg, 0.72 mmol) in DMF (volume: 3 ml) was added cesium carbonate (360 mg, 1.1 mmol). The mixture was stirred at 25° C. for 48 hours. The crude material was By chromatography Purification: The intermediate Boc-protected amine (150 mg, 0.28 mmol) was treated with 8 N HCl in MeOH at room temperature for 3 days to give 8-(azetidin-3-ylmethoxy)-6-(4-fluorophenyl)-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine as a white powder (122 mg, 87% yield). LCMS (Method 7)::2.24 min, [M+H] + 431.1 Se1 6 min 1 H NMR (300MHz, methanol-d4) δ ppm 8.80(s, 1H), 8.49(d, J=8.80Hz, 1H), 8.37(d, J=1.28Hz, 1H), 8.31(brd, J=8.44Hz, 1H), 7.90-7.97(m, 3H) , 7.33(t, J=8.71Hz, 2H), 5.43(s, 2H), 4.60(d, J=4.95Hz, 2H), 4.34(dd, J=8.44, 3.48Hz, 4H), 2.89(s, 3H) LCMS (Method 5): Method 5 0.74 min, 500.0[M+H] + , CSH method 2 minutes). 1 H NMR (400MHz, DMSO-d6) δ ppm 9.16(s, 2H), 8.61(d, J=6.6Hz, 1H), 8.42(s, 1H), 8.21(d, J=1.3Hz, 1H), 7.84-8.01(m, 2H), 7.51(d, J=1.3Hz, 1H), 7.38(t, J=8.8Hz, 2H), 5.6 7(t, J=7.0Hz, 1H), 5.35-5.50(m, 1H), 3.85-4.04(m, 3H), 3.79(d, J=4.4Hz, 1H), 2.19-2.37(m, 1H), 2.03-2.17(m, 1H), 1.72(d, J=7.0Hz, 3H).

[0262] Applying the above method, starting from the substrates indicated in the table, the following compounds were prepared: [Table 24-1] [Table 24-2]

[0263] Example 220 6-(4-Fluorophenyl)-8-[(1-methylazetidin-3-yl)methoxy]-N-[(6-methylpyridazin-3-yl)methyl]quinazolin-4-amine [ka] 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), dimethyl sulfate (247 mg, 0.72 mmol) in DMF (1.65 mL). Stirred at 25° C. for 18 hours. 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, 4% yield). LCMS (Method 7): LCMS (Method 7): 2.09 min, [M+H] + 445.1 1 H NMR (300MHz, DMSO-d6) 1H NMR (300MHz, chloroform-d) δ ppm 8.71(s, 1H), 7.73(brs, 1H), 7.54-7.63(m, 3H), 7.51(d, J=8.80Hz, 1H), 7.35-7.41(m, 1H), 7.33(s, 1H), 7.11-7.22(m, 2H), 5.0 9(d, J=3.85Hz, 2H), 4.42(d, J=6.24Hz, 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] Applying the above method, starting from the substrates indicated in the table, the following compounds were prepared: [Table 25]

[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) [ka] Nitrogen was bubbled through a mixture of (R)-6-bromo-8-methoxy-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine (107 mg, 0.25 mmol), copper(I) iodide (2.4 mg, 0.01 mmol) and potassium carbonate (73 mg, 0.53 mmol) for 5 min. A solution of a mixture of 5-methyl-1H-pyrazole (20 mg, 0.25 mmol) and (rac)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (3.6 mg, 0.03 mmol) in toluene (0.5 mL) was added and the reaction mixture was heated at 115° C. for 72 h. After cooling to room temperature, the reaction was filtered through Celite® and the filter cake was washed with toluene (2×5 mL). The organic phase was filtered through a hydrophobic frit and the solvent was removed in vacuo. The residue was purified by preparative HPLC to obtain the title compound. The structures of each regioisomer (Example 223 and Example 224) are shown below. 1 This was confirmed by 1 H NMR measurement. Example 223: 33 mg, 30%, off-white solid 1 H NMR (400MHz, DMSO):δ 9.18(s, 2H), 8.59(d, J=7.0Hz, 1H), 8.52(d, J=2.4Hz, 1H), 8.39(s, 1H), 8.23(d, J=2.1Hz, 1H), 7.69(d, J =2.0Hz, 1H), 6.46(d, J=2.3Hz, 1H), 5.69-5.63(m, 1H), 4.01(s, 3H), 2.35(s, 3H), 1.74(d, J=7.1Hz, 3H). LCMS (Method 3): [MH + ]=430(3.30 minutes). Example 224: 6 mg, 6%, off-white solid 1 H NMR (400MHz, DMSO):δ 9.16(s, 2H), 8.64(d, J=7.0Hz, 1H), 8.08(d, J=2.0Hz, 1H), 7.65(d, J=1.6Hz, 1H), 7.39(d, J=2.0Hz, 1H), 6.77(s, 1H), 6.37(s, 1H), 5.69-5.64(m, 1H), 3.97(s, 3H), 2.43(s, 3H), 1.70(d, J=7.1Hz, 3H). LCMS (Method 3): [MH +]=430(3.18 minutes).

[0266] Example 225 and Example 226 (R)-8-Methoxy-6-(4-methyl-1H-imidazol-1-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine (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) [ka] Nitrogen was bubbled through a mixture of (R)-6-bromo-8-methoxy-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine (214 mg, 0.50 mmol), copper(I) iodide (5.0 mg, 0.02 mmol) and cesium carbonate (145 mg, 1.05 mmol) for 5 min. 5-Methyl-1H-imidazole (50 mg, 0.60 mmol) and (rac)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (3.6 mg, 0.03 mmol) in N,N-dimethylformamide (0.3 mL) were added and the reaction mixture was heated at 115° C. for 72 h. After cooling to room temperature, the reaction was filtered through Celite® and the filter cake was washed with N,N-dimethylformamide (2×3 mL). The organic phase was filtered through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by preparative HPLC to give the title compounds. The structures of each regioisomer, Example 225 and Example 226, are shown in Table 1. 1 This was confirmed by 1 H NMR measurement. Example 225: 18 mg, 8%, off-white solid 1H NMR (400MHz, DMSO):δ 9.17(s, 2H), 8.50(d, J=6.7Hz, 1H), 8.41(s, 1H), 8.32(s, 1H), 8.09(d, J=1.9Hz, 1H), 7.62(s, 1 H), 7.53(d, J=2.1Hz, 1H), 5.69-5.63(m, 1H), 4.01(s, 3H), 2.23(s, 3H), 1.74(d, J=7.2Hz, 3H). LCMS (Method 4): [MH + ]=430(4.01 minutes). Example 226: 14 mg, 7%, off-white solid 1 H NMR (400MHz, DMSO):δ 9.40(s, 1H), 9.33(s, 1H), 9.18(s, 2H), 8.70(s, 1H), 8.26(s, 1H), 7.74(d, J=1.5Hz, 1 H), 7.65(s, 1H), 5.77(q, J=7.0Hz, 1H), 4.04(s, 3H), 2.31(s, 3H), 1.77-1.72(m, 3H). LCMS (Method 3): [MH + ]=430(2.23 minutes).

[0267] Example 227 (R)-8-Methoxy-6-(4-methyl-1H-pyrazol-1-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine [ka] Nitrogen was bubbled through a mixture of (R)-6-bromo-8-methoxy-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine (107 mg, 0.25 mmol), copper(I) iodide (2.4 mg, 0.01 mmol), 4-methyl-1H-pyrazole (25 mg, 0.30 mmol) and potassium carbonate (73 mg, 0.53 mmol) for 5 min. A solution of (rac)-(+)-N,N′-dimethyl-1,2-cyclohexanediamine (3.6 mg, 0.03 mmol) in toluene (0.5 mL) was added and the reaction mixture was heated at 115° C. for 72 h. After cooling to room temperature, the reaction was filtered through Celite® and the filter cake was washed with toluene (2×5 mL). The organic phase was filtered through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by preparative HPLC to give the title compound (4 mg, 6%) as an off-white solid. 1 H NMR (400MHz, DMSO):δ 9.20(s, 2H), 8.67(s, 1H), 8.49(s, 1H), 8.45(s, 1H), 7.94(d, J=1.5Hz, 1H), 7.74 (s, 1H), 5.83(q, J=6.9Hz, 1H), 4.13(s, 3H), 2.17(s, 3H), 1.80(d, J=7.2Hz, 3H). LCMS (Method 3): [MH + ]=430(4.42 minutes).

[0268] Intermediate 8 6-Bromo-N-((6-methylpyridin-3-yl)methyl)quinazolin-4-amine [ka] A mixture of 6-bromo-4-chloroquinazoline (1 g, 4.11 mmol), (6-methylpyridin-3-yl)methanamine (0.500 g, 4.09 mmol) and triethylamine (3 ml, 21.52 mmol) in 1,4-dioxane / DMF 5:1 (volume: 12 ml) was stirred at 100 °C for 16 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (Biotage Isolere, 55 g NH cartridge, gradient elution 0-50% acetone in heptane) afforded 6-bromo-N-((6-methylpyridin-3-yl)methyl)quinazolin-4-amine as a pale yellow powder (1.35 g, 4.10 mmol, 100% yield). LCMS (method 6): 0.82 min, m / z 328.8[M] + and 330.8[M+2] + ,

[0269] Applying a similar methodology, the following intermediates were synthesized by reacting the appropriate amine with the substrates shown in the table. [Table 26-1] [Table 26-2]

[0270] Example 228 6-(5-methylpyridin-2-yl)-N-((6-methylpyridin-3-yl)methyl)quinazolin-4-amine [ka] To a mixture of 6-bromo-N-((6-methylpyridin-3-yl)methyl)quinazolin-4-amine (intermediate 8) (100 mg, 0.304 mmol) and 5-methyl-2-(tributylstannyl)pyridine (0.315 ml, 0.911 mmol) in DMF (volume: 2 ml) was added tetrakis(triphenylphosphine)palladium(0) (70.2 mg, 0.061 mmol). Stirred at 80 °C for 16 h. Purification by DP chromatography (Biotage Isolera, 28 g NH cartridge, gradient elution 0-100% EtOAC in dichloromethane with 20 CV) afforded 6-(5-methylpyridin-2-yl)-N-((6-methylpyridin-3-yl)methyl)quinazolin-4-amine as a white powder (69.8 mg, 0.204 mmol, 67.3% yield). LCMS: 0.33 min, 341.9 m / z [M+H] + , CSH 2 minutes). 1 H NMR (400MHz, DMSO-d6) ppm 9.02(t, J=5.7Hz, 1H), 8.93-8.96(m, 1H), 8.55-8.58(m, 1H), 8.49-8.54(m, 2H), 8.48(s, 1H), 8.00-8.09(m, 1H), 7.73-7.82(m, 2H), 7.66-7.72(m, 1H), 7.16-7.22(m, 1H), 4.76-4.82(m, 2H), 2.43(s, 3H), 2.37(s, 3H).

[0271] Applying the above methodology, starting from the substrates shown in the table using the appropriate stannane reagent, the following compounds were synthesized: [Table 27-1] [Table 27-2]

[0272] Example 234 6-(4-Fluorophenyl)-N2,N2-dimethyl-N4-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)quinazoline-2,4-diamine [ka] A solution of 2-chloro-6-(4-fluorophenyl)-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)quinazolin-4-amine (Example 223) (80 mg, 0.208 mmol) and dimethylamine 2.0 M in THF (0.625 ml, 1.251 mmol) in 1,4-dioxane (volume: 3 ml) was stirred at 100° C. for 16 hours. The reaction mixture was partitioned between saturated aqueous ammonium chloride and dichloromethane. The organic layer was concentrated in vacuo. Purification by DP chromatography (Biotage Isolera, 10 g KP-Sil cartridge, gradient elution 15 CV 0–70% in dichloromethane [dichloromethane / MeOH 9:1]) afforded 6-(4-fluorophenyl)-N2,N2-dimethyl-N4-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)quinazoline-2,4-diamine as a pale yellow powder (73.5 mg, 0.187 mmol, 90% yield). LCMS: 0.71 min, m / z 393.0 [M+H] + , Method 5 Acid method. 1 H NMR (400MHz, DMSO-d6) δ ppm 8.51-8.84(m, 1H), 8.45(d, J=1.8Hz, 1H), 7.81(dd, J=8.8, 5.7Hz, 3H), 7.32(t, J =8.8Hz, 3H), 5.45-5.55(m, 1H), 3.02(s, 6H), 2.30(s, 3H), 1.72(d, J=7.0Hz, 3H).

[0273] By applying the above method, the following compounds were synthesized: Compound 237 was obtained using the same conditions as in Example 235, and Compound 238 was obtained using the same reaction conditions as in Example 236. [Table 28-1] [Table 28-2]

[0274] Example 239 6-(4-Fluorophenyl)-2-methyl-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine [ka] To a mixture of 6-bromo-2-methyl-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine (Intermediate 9) (50 mg, 0.145 mmol), (4-fluorophenyl)boronic acid (30.5 mg, 0.218 mmol) and potassium phosphate (61.7 mg, 0.291 mmol) in DMF / water 2:1 (volume: 3 ml) was added Pd(dppf)Cl2·CH2Cl2 (11.86 mg, 0.015 mmol). The mixture was stirred at 80° for 16 h. Purification by RP chromatography (Biotage Isolera, 30 g C18 cartridge, gradient elution 0-65% B in A over 20 CV, A: water / acetonitrile 95:5 + 0.1% concentrated ammonia, B: acetonitrile:water 95:5 + 0.1% concentrated ammonia) followed by RP chromatography (Biotage Isolera, 30 g C18 cartridge, gradient elution 0-50% B in A over 15 CV, A: water / acetonitrile 95:5 + 0.1% HCOOH, B: acetonitrile:water 95:5 + 0.1% HCOOH) gave 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, 68.8% yield). LCMS (method 5): 0.53 min, m / z 360[M+H] + . 1H NMR (400MHz, DMSO-d6) δ ppm 12.17-13.22(bs, 1H), 9.00(brs, 1H), 8.60(d, J=1.8Hz, 1H), 8.07(dd, J=8.8, 1.8Hz, 1H), 7.87(dd, J=8.8, 5.7Hz, 2H ), 7.69(d, J=8.3Hz, 1H), 7.46-7.61(m, 2H), 7.35(t, J=8.8Hz, 2H), 5.03(d, J=5.3Hz, 2H), 2.59(s, 3H), 2.43(s, 3H).

[0275] Applying similar methods, starting from the appropriate intermediates indicated in the table, the following intermediates were synthesized: Using conditions similar to those used in Example 245, the compound of Example 246 was obtained. [Table 29-1] [Table 29-2] [Table 29-3]

[0276] Example 249 N-((3,5-difluoropyridin-2-yl)methyl)-6-(4-fluorophenyl)quinazolin-4-amine hydrochloride [ka] To a mixture of 6-bromo-4-chloroquinazoline (100 mg, 0.411 mmol) and (3,5-difluoropyridin-2-yl)methanamine hydrochloride (74.2 mg, 0.411 mmol) in DMF (volume: 2 ml) was added DIPEA (0.15 mL, 0.861 mmol). Stirred at 80 °C for 6 h. 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, followed by 4-fluorophenylboronic acid (86 mg, 0.614 mmol), potassium phosphate (174 mg, 0.818 mmol) and Pd(dppf)Cl2·CHCl2 (33.5 mg, 0.041 mmol). Stirred at 80 °C for 16 h. The mixture was cooled to room temperature, after which formic acid (150 μL, 3.98 mmol) was added and purified by RP chromatography (Biotage Isolera, 30 g C18 cartridge, gradient elution 100:0 to 65:35 A / B in 15 CV, A: water / acetonitrile 95:5 + 0.1% HCOOH, B: acetonitrile:water 95:5 + 0.1% HCOOH) to give 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 (400MHz, 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=8.88Hz, 2H), 5.13(brd, J=5.26Hz, 2H).

[0277] Example 250 6-(4-Fluorophenyl)-N-methyl-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)quinazolin-4-amine [ka] To a solution of 6-(4-fluorophenyl)-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)quinazolin-4-amine (30 g, 0.086 mmol) in DMF (1 mL) cooled to 0 °C was added NaH (6.07 mg, 0.240 mmol) and the reaction was stirred for 30 min, after which MeI (10.74 μL, 0.172 mmol) was added. After 20 h, the crude mixture was loaded directly 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 give the title compound as a pale beige powder (16 mg, 0.044 mmol, 51.3%). LCMS (method 5): 0.57 min, 364.0[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ ppm 8.33(d, J=2.2Hz, 1H), 8.08(s, 1H), 7.98(dd, J=8.4, 2.2Hz, 1H), 7.69-7.77(m, 2H), 7.51(d, J=8.8Hz , 1H), 7.32(t, J=8.8Hz, 2H), 5.72(d, J=6.6Hz, 1H), 3.63(s, 3H), 2.31(s, 3H), 1.53(d, J=7.1Hz, 3H).

[0278] Example 251 (R)-6-(3,3-difluoropyrrolidin-1-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine [ka] To 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 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). The resulting mixture was heated to 100° C. and stirred for 7 h. The mixture was cooled to room temperature and filtered. The volatiles 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 the impure product. 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 (400MHz, DMSO-d6)δ 9.13(s, 2H), 8.31(d, J=7.06Hz, 1H), 8.27(s, 1H), 7.55-7.62(m, 3H), 5.66(quin, J=6.89Hz, 1H) ), 3.76(t, J=13.89Hz, 2H), 3.51(t, J=7.06Hz, 2H), 2.39-2.49(m, 2H), 1.72(d, J=7.06Hz, 3H).

[0279] By applying the above method, the following example compounds were synthesized. [Table 30]

[0280] Chiral preparative SFC purification of the appropriate racemic mixture above afforded the following compounds as single isomers as shown in the table below. [Table 31-1] [Table 31-2] [Table 31-3] [Table 31-4] [Table 31-5] [Table 31-6] [Table 31-7] [Table 31-8] [Table 31-9] [Table 31-10]

[0281] Intermediate 15 6-Bromo-8-methoxy-4-((2-(trimethylsilyl)ethoxy)methoxy)quinazoline [ka] 6-Bromo-8-methoxyquinazolin-4-ol (200 mg, 0.78 mmol) (Intermediate 2) was dissolved in N,N-dimethylformamide (10 mL) and the reaction mixture was cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 38 mg, 0.94 mmol) was added portionwise and the reaction mixture was stirred for 30 minutes. (2-Chloromethoxyethyl)trimethylsilane (0.21 ml, 1.18 mmol) was then added dropwise. The reaction was then stirred at 0° C. for 1 hour before being allowed to warm to room temperature. The reaction mixture was quenched with water (5 mL) and partitioned with ethyl acetate (15 mL). The phases were separated and the aqueous layer was washed with ethyl acetate (2×10 mL). The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by column silica gel chromatography eluting with 0-40% ethyl acetate in cyclohexane to give the title compound as a colorless solid (181 mg, 60%). 1 H NMR (400MHz, CDCl3):δ 8.17(s, 1H), 8.04(d, J=2.0Hz, 1H), 7.3(d, J=2.0Hz, 1H), 5.43(s, 2H), 4.02(s. 3H), 3.66(m, J=4.1Hz, 2H), 0.95(m, J=4.1Hz, 2H)), 0.02(s, 9H). LCMS (Method 3): [MH + ]=385(5.24 minutes).

[0282] Intermediate 16 8-Methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-((2-(trimethylsilyl)ethoxy)methoxy)quinazoline [ka] Nitrogen was bubbled through a solution of 6-bromo-8-methoxy-4-((2-(trimethylsilyl)ethoxy)methoxy)quinazoline (190 mg, 0.49 mmol), bis(pinacolato)diboron (150 mg, 0.59 mmol) and potassium acetate (97 mg, 0.99 mmol) in 1,4-dioxane (5 mL) for 5 minutes before adding [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36 mg, 0.05 mmol). The reaction mixture was then heated at 95° C. for 2 hours. The reaction was then cooled to room temperature and filtered through Celite®. The title compound was used directly as a solution in 1,4-dioxane, assuming quantitative yield.

[0283] Intermediate 17 6-(5-fluoropyridin-2-yl)-8-methoxy-4-((2-(trimethylsilyl)ethoxy)-methoxy)-quinazoline [ka] To 8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-((2-(trimethylsilyl)ethoxy)methoxy)quinazoline (330 mg, 0.78 mmol) was added 2-bromo-5-fluoropyridine (137 mg, 0.78 mmol), cesium carbonate (508 mg, 1.56 mmol), 1,4-dioxane (8 mL) and water (1 mL). Nitrogen was bubbled through the reaction mixture for 10 minutes before tetrakis(triphenylphosphine)palladium(0) (90 mg, 0.078 mmol) was added. The reaction was then heated at 90° C. for 16 hours. The reaction mixture was then cooled to room temperature, filtered through Celite® and concentrated in vacuo. The residue was purified by column silica gel chromatography eluting with 0-60% ethyl acetate in cyclohexane to give the title compound as a pale yellow solid. 1H NMR (400MHz, DMSO):δ 8.76(d, J=2.4Hz, 1H), 8.46(s, 1H), 8.42(d, J=1.7Hz, 1H), 8.30(dd, J=9.1Hz, 4.4Hz, 1H), 8.06(d, J=1.7Hz, 1H), 7.91(dt, J=2.4, 9.1Hz, 1H), 5.44(s, 2H), 4.06(s, 3H), 3.64(t, J=8.1Hz, 2H), 0.97(t, J=8.1Hz, 2H), 0.01(s, 9H). LCMS (Method 3): [MH + ]=402(5.43 minutes).

[0284] Following a similar method to that described for the preparation of 6-(5-fluoropyridin-2-yl)-8-methoxy-4-((2-(trimethylsilyl)ethoxy)-methoxy)-quinazoline (Intermediate 17), the following intermediates shown in the table below were synthesized. [Table 32]

[0285] Intermediate 23 6-(5-fluoropyridin-2-yl)-8-methoxyquinazolin-4-ol [ka] 6-(5-Fluoropyridin-2-yl)-8-methoxy-4-((2-(trimethylsilyl)ethoxy)methoxy)quinazoline (225 mg, 0.56 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (0.21 mL, 2.81 mmol). The reaction mixture was stirred for 16 hours. The reaction mixture was concentrated in vacuo to give the title compound as an orange solid (142 mg, 93%). 1H NMR (400MHz, DMSO): δ8,76(d, J=2.4Hz, 1H), 8.39(d, J=1.7Hz, 1H), 8.29(dd, J=9.0Hz, 4.6Hz, 1H ), 8.13(s, 1H), 8.05(d, J=1.7Hz, 1H), 7.92(dt, J=2.4, 9.1Hz, 1H), 5.69(brs, 1H), 4.06(s, 3H). LCMS (Method 3): [MH + ]=272(3.08 minutes).

[0286] Following a similar method to that described for the preparation of 6-(5-fluoropyridin-2-yl)-8-methoxyquinazolin-4-ol (Intermediate 23), the following intermediates shown in the table below were synthesized. [Table 33]

[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 [ka] Example 325 (S)-6-(5-fluoropyridin-2-yl)-8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl)quinazolin-4-amine [ka] Step 1: Preparation of 4-chloro-6-(5-fluoropyridin-2-yl)-8-methoxyquinazoline [ka] 8-Methoxy-6-(5-fluoropyridin-2-yl)quinazolin-4-ol (750 mg, 2.81 mmol) was suspended in thionyl chloride (4.1 mL, 56.12 mmol) and DMF (0.0005 mL, 0.006 mmol) was added. The reaction mixture was stirred at 95° C. for 4 h. The reaction was cooled to room temperature and the solvent was removed in vacuo to give 4-chloro-6-(5-fluoropyridin-2-yl)-8-methoxyquinazoline (800 mg, 98%). The crude residue was used directly in the next step without further purification.

[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 [ka] and (S)-6-(5-fluoropyridin-2-yl)-8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl)quinazolin-4-amine [ka] Manufacturing To a mixture of 4-chloro-6-(5-fluoropyridin-2-yl)-8-methoxyquinazoline (100 mg, 0.367 mmol) and N,N-diisopropylethylamine (0.32 mL, 1.84 mmol) in 1,4-dioxane (5 mL) was added (R)-1-(5-methyl-1,2,4-oxadiazol-3-yl)ethan-1-amine (93 mg, 0.735 mmol). The resulting mixture was stirred at 50° C. for 5 days. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound as an off-white solid (25 mg, 19%). Example 315 (R)-6-(5-fluoropyridin-2-yl)-8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl)quinazolin-4-amine: 1H NMR (400MHz, CDCl3)δ 8.57(s, 1H), 8.54(d, J=3.8Hz, 1H), 7.88(s, 2H), 7.69(s, 1H), 7.54(ddd, J=8.6, 8.6, 2.9 Hz, 1H), 6.82(s, 1H), 5.92-5.84(m, 1H), 4.13(s, 3H), 2.65(s, 3H), 1.77(d, J=6.1Hz, 3H). LCMS (Method 3): [MH + ]=381 (2.90 min). Chiral Analysis (Method 31) (2.24 min). Example 325 (S)-6-(5-fluoropyridin-2-yl)-8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl)quinazolin-4-amine Chiral Analysis (Method 31) (0.58 min).

[0289] Following a similar method as described for (R)-6-(5-fluoropyridin-2-yl)-8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl)quinazolin-4-amine, the following compounds shown in the table below were prepared. Some compounds were purified by preparative chiral SFC to give pure enantiomers. [Table 34-1] [Table 34-2] [Table 34-3]

[0290] Pharmacological Activity of the Compounds of the Invention. In vitro electrophysiology assay of P2X3 Cells expressing P2X3 receptors were grown according to standard methods and maintained at 37°C in a humidified 5% CO2 atmosphere. Two days prior to the day of assay, cells were seeded into T175 flasks and, when grown to 80-90% confluence, detached from the flasks using TrypLE. Dissociated cells were cultured in serum-free medium at a cell density of 3 × 10 6 Cells were resuspended at 1000 cells / ml and loaded into a Sophion Qube automated patch-clamp system. The extracellular assay buffer contained 145 mM NaCl, 4 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, and 10 mM glucose at pH 7.4. The intracellular assay solution contained 140 mM CsF, 10 mM NaCl, 10 mM EGTA, 10 mM HEPES at pH 7.2. Agonist stock solutions were prepared in H2O and diluted with bath solution before use. All antagonists were prepared as 10 mM stock solutions in DMSO and diluted with bath solution before use. All experiments were performed in a whole-cell patch clamp configuration at room temperature, with 384 individual cells 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, which were washed with extracellular assay buffer containing 0.5 U / ml apyrase. After the second agonist application, antagonist was incubated for 10 min in the absence of α,β-MeATP. After antagonist preincubation, 800 nM α,β-MeATP and antagonist were co-administered to determine the inhibitory effect of the antagonist. A concentration of antagonist was evaluated on a single cell, and different concentrations of antagonist were applied to other cells on 384 recorded substrates. Control P2X3 current amplitudes were obtained from the peak current amplitudes from the second agonist response, before preincubation with antagonist. Peak P2X3 current amplitudes in the presence of antagonist were used to calculate the inhibitory effect at each concentration of antagonist according to the following formula: Percent inhibition of P2X3=(P2X3 control peak amplitude-P2X3 antagonist peak amplitude / P2X3 control peak amplitude)*100.

[0291] Concentration-response curves were generated from 10 different concentrations with each concentration of antagonist tested in at least two individual cells. The concentration of antagonist that inhibited P2X3 currents by 50% (IC 50 ) was calculated. Y=a+[(ba) / (1+10^((logc-x)d)] where "a" is the minimum response, "b" is the maximum response, and "c" is the IC 50 and "d" is the hill slope.

[0292] The results for individual compounds are provided below in Table 8 and are presented as ranges of activity. [Table 35-1] [Table 35-2] [Table 35-3] [Table 35-4] [Table 35-5] [Table 35-6] [Table 35-7] [Table 35-8]

[0293] P2X 2 / 3 In vitro electrophysiology assay Representative compounds of the present invention are P2X 2 / 3 The receptor was tested. Two modifications were made: 1) 10 μM ATP was used as the agonist; and 2) P2X3 assay was used in which the post-average current amplitude was measured 7 s after agonist application. 2 / 3 A similar assay protocol was used for the assay.

[0294] The results in Table 9 indicate that the compounds of the present invention are selective P2X3 antagonists. [Table 36-1] [Table 36-2]

[0295] Comparative Example A 6-(4-fluorophenyl)-4-[(6-methyl-3-pyridyl)methoxy]pyrido[2,3-d]pyrimidine [ka] Step 1: Synthesis of 6-bromo-4-((6-methylpyridin-3-yl)methoxy)pyrido[2,3-d]pyrimidine [ka] 6-Bromopyrido[2,3-d]pyrimidin-4(3H)-one (202 mg, 0.89 mmol) (Intermediate 1), 5-hydroxymethyl-2-methylpyridine (110 mg, 0.89 mmol) and triphenylphosphine (328 mg, 1.25 mmol) were stirred in dry THF (7 mL) and a solution of diisopropyl azodicarboxylate (229 μL, 1.16 mmol) in THF (3 mL) was added dropwise and stirred at room temperature for 6 h. The reaction was filtered and the precipitate washed with (2:1) DCM / MeOH (20 mL). The filtrates were combined and the solvent removed in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc in DCM to give 6-bromo-4-((6-methylpyridin-3-yl)methoxy)pyrido[2,3-d]pyrimidine (164 mg, 55%). 1 H NMR (400MHz, DMSO):δ 9.08(d, J=2.6Hz, 1H), 8.89(s, 1H), 8.67(d, J=2.6Hz, 1H), 8.55(d, J=2.1Hz, 1H ), 7.72(dd, J=2.4, 8.0Hz, 1H), 7.24(d, J=8.0Hz, 1H), 5.20(s, 2H), 2.44(s, 3H).

[0296] Step 2: Synthesis of 6-(4-fluorophenyl)-4-[(6-methyl-3-pyridyl)methoxy]pyrido[2,3-d]pyrimidine [ka] Nitrogen gas was bubbled through a solution of 6-bromo-4-((6-methylpyridin-3-yl)methoxy)pyrido[2,3-d]pyrimidine (84 mg, 0.254 mmol), 4-fluorophenylboronic acid, pinacol ester (76 mg, 0.342 mmol) and cesium fluoride (116 mg, 0.761 mmol) in DMF (1 mL) and water (0.3 mL). After 5 min, tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol) was added and the resulting mixture was stirred at 95 °C for 16 h. The reaction was diluted with water (6 mL) and EtOAc (3 mL). The aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic phases were passed through a hydrophobic frit, combined and the solvent removed in vacuo. Purification by reverse phase preparative HPLC afforded 6-(4-fluorophenyl)-4-[(6-methyl-3-pyridyl)methoxy]pyrido[2,3-d]pyrimidine (52 mg, 59%) as 0.5 equivalents of the formate salt. 1 H NMR (400MHz, DMSO):δ 9.35(d, J=2.8Hz, 1H), 8.92(s, 1H), 8.73(d, J=2.5Hz, 1H), 8.61(d, J=1.5Hz, 1H), 8.32(s, 0.5H), 7.97(dd, J=5.3, 8. 6Hz, 2H), 7.77(dd, J=2.1, 8.0Hz, 1H), 7.42(dd, J=8.8, 8.8Hz, 2H), 7.29(d, J=8.1Hz, 1H), 5.27(s, 2H), 2.49(s, 3H). LCMS (Method 4): [MH + ]=347(2.82 minutes).

[0297] Following a similar procedure to that described for the preparation of 6-(4-fluorophenyl)-4-[(6-methyl-3-pyridyl)methoxy]pyrido[2,3-d]pyrimidine, the following compounds shown in the table below were prepared. [Table 37]

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

[0299] The results for individual compounds are provided in Table 10 below and are presented as ranges of activity. [Table 38]

Claims

1. Formula (I) 【Chemistry 1】 [During the ceremony, Z is (C ３ -C ８ ) heterocycloalkyl, heteroaryl, aryl, wherein any of said 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 -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(C １ -C ４ ) 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, 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. The compound of formula (I) according to claim 1 【Chemistry 2】 [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.

4. The compound of 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-, 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.

5. The compound according to claim 3 or 4, 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.

6. Y is -OR Ｄ Formula (Ia) 【Chemistry 4】 [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:

7. The compound of claim 1 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, 6-(4-fluorophenyl)-8-(((R)-tetrahydrofuran-3-yl)oxy)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine, 6-(4-fluorophenyl)-8-isopropoxy-N-[(6-methylpyridazin-3-yl)methyl]quinazolin-4-amine, 8-(cyclopropylmethoxy)-6-(4-fluorophenyl)-N-[(6-methylpyridazin-3-yl)methyl]quinazolin-4-amine, 2-[6-(4-fluorophenyl)-4-[(6-methylpyridazin-3-yl)methylamino]quinazolin-8-yl]oxyethanol, 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.

8. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 7, 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.

9. A pharmaceutical composition according to claim 8 for oral administration.

10. A pharmaceutical composition according to claim 8 or 9 for use as a medicament.

11. P2X ３ 10. A pharmaceutical composition according to claim 8 or 9 for use in the treatment of any disease in which the receptor is involved.

12. 10. A pharmaceutical composition according to claim 8 or 9 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.

13. 13. A pharmaceutical composition according to claim 12 for use in the treatment of chronic cough.

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